Impact of cachexia on outcomes in aggressive lymphomas.

PubMed

Karmali, Reem; Alrifai, Taha; Fughhi, Ibtihaj A M; Ng, Ronald; Chukkapalli, Vineela; Shah, Palmi; Basu, Sanjib; Nathan, Sunita; Szymanski-Grant, Kelly; Gordon, Leo I; Venugopal, Parameswaran; Penedo, Frank J; Borgia, Jeffrey A

2017-06-01

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87-93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into "non-cachectic" (CXI ≥49.8, n = 41) and "cachectic" (CXI <49.8, n = 40) groups. Cachectic patients had significantly worse PFS (HR 2.18, p = 0.044) and OS (HR = 4.05, p = 0.004) than non-cachectic patients. Cachexia as defined by the CXI is prognostic in aggressive lymphomas and implies that novel therapeutic strategies directed at reversing cachexia may improve survival in this population.

Cachexia among US cancer patients.

PubMed

Arthur, Susan T; Van Doren, Bryce A; Roy, Debosree; Noone, Joshua M; Zacherle, Emily; Blanchette, Christopher M

2016-09-01

Cancer cachexia is a debilitating condition and results in poor prognosis. The purpose of this study was to assess hospitalization incidence, patient characteristics, and medical cost and burden of cancer cachexia in the US. This study used a cross-sectional analysis of the Nationwide Inpatient Sample (NIS) for 2009. Five cancers reported to have the highest cachexia incidence were assessed. The hospitalization incidence related to cachexia was estimated by cancer type, cost and length of stay were compared, and descriptive statistics were reported for each cancer type, as well as differences being compared between patients with and without cachexia. Risk of inpatient death was higher for patients with cachexia in lung cancer (OR = 1.32; CI = 1.20-1.46) and in all cancers combined (OR = 1.76; CI = 1.67-1.85). The presence of cachexia increased length of stay in lung (IRR = 1.05; CI = 1.03-1.08), Kaposi's sarcoma (IRR = 1.47; CI = 1.14-1.89) and all cancers combined (IRR = 1.09; CI = 1.08-1.10). Additionally, cachectic patients in the composite category had a longer hospitalization stay compared to non-cachectic patients (3-9 days for those with cachexia and 2-7 days for those without cachexia). The cost of inpatient stay was significantly higher in cachexic than non-cachexic lung cancer patients ($13,560 vs $13 190; p < 0.0001), as well as cachexic vs non-cachexic cancer patients in general (14 751 vs 13 928; p < 0.0001). Cachexia increases hospitalization costs and length of stay in several cancer types. Identifying the medical burden associated with cancer cachexia will assist in developing an international consensus for recognition and coding by the medical community and ultimately an effective treatment plans for cancer cachexia.

The rationale for preventing cancer cachexia: targeting excessive fatty acid oxidation.

PubMed

Qian, Chao-Nan

2016-07-21

Cachexia commonly occurs at the terminal stage of cancer and has largely unclear molecular mechanisms. A recent study published in Nature Medicine, entitled "Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia," reveals that cachectic cancer cells can secrete multiple cytokines that induce excessive fatty acid oxidation, which is responsible for muscle loss in cancer cachexia. Inhibition of fatty acid oxidation using etomoxir can increase muscle mass and body weight in cancer cachexia animal models. The usage of stable cachexia animal models is also discussed in this research highlight.

The influence of different muscle mass measurements on the diagnosis of cancer cachexia

PubMed Central

Blauwhoff‐Buskermolen, Susanne; Langius, Jacqueline A.E.; Becker, Annemarie; Verheul, Henk M.W.

2017-01-01

Abstract Background Progressive loss of muscle mass is a major characteristic of cancer cachexia. Consensus definitions for cachexia provide different options to measure muscle mass. This study describes the effect of different methods to determine muscle mass on the diagnosis of cancer cachexia. In addition, the association of cachexia with other features of cachexia, quality of life, and survival was explored. Methods Prior to chemotherapy, cachexia was assessed by weight loss, body mass index, and muscle mass measurements, the latter by mid‐upper arm muscle area (MUAMA), computed tomography (CT) scans, and bio‐electrical impedance analysis (BIA). In addition, appetite, inflammation, muscle strength, fatigue, quality of life, and survival were measured, and associations with cachexia were explored. Results Included were 241 patients with advanced cancer of the lung (36%), colon/rectum (31%), prostate (18%), or breast (15%). Mean age was 64 ± 10 years; 54% was male. Prevalence of low muscle mass was as follows: 13% with MUAMA, 59% with CT, and 93% with BIA. In turn, the prevalence of cachexia was 37, 43, and 48%, whereby weight loss >5% was the most prominent component of being defined cachectic. Irrespective of type of muscle measurement, patients with cachexia presented more often with anorexia, inflammation, low muscle strength, and fatigue and had lower quality of life. Patients with cachexia had worse overall survival compared with patients without cachexia: HRs 2.00 (1.42–2.83) with MUAMA, 1.64 (1.15–2.34) with CT, and 1.50 (1.05–2.14) with BIA. Conclusions Although the prevalence of low muscle mass in patients with cancer depended largely on the type of muscle measurement, this had little influence on the diagnosis of cancer cachexia (as the majority of patients was already defined cachectic based on weight loss). New studies are warranted to further elucidate the additional role of muscle measurements in the diagnosis of cachexia and the association with clinical outcomes. PMID:28447434

[Prevention and treatment of cachexia : Exercise and nutritional therapy].

PubMed

Wilms, B; Schmid, S M; Luley, K; Wiskemann, J; Lehnert, H

2016-10-01

Cachexia is a multifactorial and complex syndrome characterized by progressive functional impairment and ongoing loss in quality of life, which lead to a deterioration of the prognosis for affected patients. The prevalence of cachexia can be very high and is up to 80 % in patients with malignant tumors. The aim of the study was to assess the relevance of exercise and nutrition in the prevention and therapy of cachexia. An evaluation of the current literature on exercise and nutritional therapy in patients with cachexia or with advanced stage diseases where a high prevalence of cachexia is probable, was carried out. There is a lack of scientific evidence for the benefits of exercise in cachexia. A major problem of relevant studies was that cachexia was frequently not defined according to valid criteria; however, data indicate a benefit of exercise training in patients with advanced diseases associated with a high prevalence of cachexia. A solely nutritional intervention and dietary counselling seem to be of minimal benefit. The administration of omega 3 fatty acids is controversially discussed. Although there is a lack of data on the effects of exercise and nutritional therapy in cachexia, there is evidence for the benefits. The present data indicate the necessity for the use of a multimodal treatment including exercise, nutritional and pharmacological therapy in cachexia. There is a great necessity for prospective studies.

Biomarkers of cancer cachexia.

PubMed

Loumaye, Audrey; Thissen, Jean-Paul

2017-12-01

Cachexia is a complex multifactorial syndrome, characterized by loss of skeletal muscle and fat mass, which affects the majority of advanced cancer patients and is associated with poor prognosis. Interestingly, reversing muscle loss in animal models of cancer cachexia leads to prolong survival. Therefore, detecting cachexia and maintaining muscle mass represent a major goal in the care of cancer patients. However, early diagnosis of cancer cachexia is currently limited for several reasons. Indeed, cachexia development is variable according to tumor and host characteristics. In addition, safe, accessible and non-invasive tools to detect skeletal muscle atrophy are desperately lacking in clinical practice. Finally, the precise molecular mechanisms and the key players involved in cancer cachexia remain poorly characterized. The need for an early diagnosis of cancer cachexia supports therefore the quest for a biomarker that might reflect skeletal muscle atrophy process. Current research offers different promising ways to identify such a biomarker. Initially, the quest for a biomarker of cancer cachexia has mostly focused on mediators of muscle atrophy, produced by both tumor and host, in an attempt to define new therapeutic approaches. In another hand, molecules released by the muscle into the circulation during the atrophy process have been also considered as potential biomarkers. More recently, several "omics" studies are emerging to identify new muscular or circulating markers of cancer cachexia. Some genetic markers could also contribute to identify patients more susceptible to develop cachexia. This article reviews our current knowledge regarding potential biomarkers of cancer cachexia. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Research priorities in cancer cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program Research Base Symposium on Cancer Cachexia and Sarcopenia.

PubMed

Dunne, Richard F; Mustian, Karen M; Garcia, Jose M; Dale, William; Hayward, Reid; Roussel, Breton; Buschmann, Mary M; Caan, Bette J; Cole, Calvin L; Fleming, Fergal J; Chakkalakal, Joe V; Linehan, David C; Hezel, Aram F; Mohile, Supriya G

2017-12-01

Cancer cachexia remains understudied and there are no standard treatments available despite the publication of an international consensus definition and the completion of several large phase III intervention trials in the past 6 years. In September 2015, The University of Rochester Cancer Center NCORP Research Base led a Symposium on Cancer Cachexia and Sarcopenia with goals of reviewing the state of the science, identifying knowledge gaps, and formulating research priorities in cancer cachexia through active discussion and consensus. Research priorities that emerged from the discussion included the implementation of morphometrics into clinical decision making, establishing specific diagnostic criteria for the stages of cachexia, expanding patient selection in intervention trials, identifying clinically meaningful trial endpoints, and the investigation of exercise as an intervention for cancer cachexia. Standardizing how we define and measure cancer cachexia, targeting its complex biologic mechanisms, enrolling patients early in their disease course, and evaluating exercise, either alone or in combination, were proposed as initiatives that may ultimately result in the improved design of cancer cachexia therapeutic trials.

Establishing a clinical phenotype for cachexia in end stage kidney disease - study protocol.

PubMed

Reid, Joanne; Noble, Helen R; Adamson, Gary; Davenport, Andrew; Farrington, Ken; Fouque, Denis; Kalantar-Zadeh, Kamyar; Mallett, John; McKeaveney, C; Porter, S; Seres, David S; Shields, Joanne; Slee, Adrian; Witham, Miles D; Maxwell, Alexander P

2018-02-13

Surveys using traditional measures of nutritional status indicate that muscle wasting is common among persons with end-stage kidney disease (ESKD). Up to 75% of adults undergoing maintenance dialysis show some evidence of muscle wasting. ESKD is associated with an increase in inflammatory cytokines and can result in cachexia, with the loss of muscle and fat stores. At present, only limited data are available on the classification of wasting experienced by persons with ESKD. Individuals with ESKD often exhibit symptoms of anorexia, loss of lean muscle mass and altered energy expenditure. These symptoms are consistent with the syndrome of cachexia observed in other chronic diseases, such as cancer, heart failure, and acquired immune deficiency syndrome. While definitions of cachexia have been developed for some diseases, such as cardiac failure and cancer, no specific cachexia definition has been established for chronic kidney disease. The importance of developing a definition of cachexia in a population with ESKD is underscored by the negative impact that symptoms of cachexia have on quality of life and the association of cachexia with a substantially increased risk of premature mortality. The aim of this study is to determine the clinical phenotype of cachexia specific to individuals with ESKD. A longitudinal study which will recruit adult patients with ESKD receiving haemodialysis attending a Regional Nephrology Unit within the United Kingdom. Patients will be followed 2 monthly over 12 months and measurements of weight; lean muscle mass (bioelectrical impedance, mid upper arm muscle circumference and tricep skin fold thickness); muscle strength (hand held dynamometer), fatigue, anorexia and quality of life collected. We will determine if they experience (and to what degree) the known characteristics associated with cachexia. Cachexia is a debilitating condition associated with an extremely poor outcome. Definitions of cachexia in chronic illnesses are required to reflect specific nuances associated with each disease. These discrete cachexia definitions help with the precision of research and the subsequent clinical interventions to improve outcomes for patients suffering from cachexia. The absence of a definition for cachexia in an ESKD population makes it particularly difficult to study the incidence of cachexia or potential treatments, as there are no standardised inclusion criteria for patients with ESKD who have cachexia. Outcomes from this study will provide much needed data to inform development and testing of potential treatment modalities, aimed at enhancing current clinical practice, policy and education.

Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics".

PubMed

Muscaritoli, M; Anker, S D; Argilés, J; Aversa, Z; Bauer, J M; Biolo, G; Boirie, Y; Bosaeus, I; Cederholm, T; Costelli, P; Fearon, K C; Laviano, A; Maggio, M; Rossi Fanelli, F; Schneider, S M; Schols, A; Sieber, C C

2010-04-01

Chronic diseases as well as aging are frequently associated with deterioration of nutritional status, loss muscle mass and function (i.e. sarcopenia), impaired quality of life and increased risk for morbidity and mortality. Although simple and effective tools for the accurate screening, diagnosis and treatment of malnutrition have been developed during the recent years, its prevalence still remains disappointingly high and its impact on morbidity, mortality and quality of life clinically significant. Based on these premises, the Special Interest Group (SIG) on cachexia-anorexia in chronic wasting diseases was created within ESPEN with the aim of developing and spreading the knowledge on the basic and clinical aspects of cachexia and anorexia as well as of increasing the awareness of cachexia among health professionals and care givers. The definition, the assessment and the staging of cachexia, were identified as a priority by the SIG. This consensus paper reports the definition of cachexia, pre-cachexia and sarcopenia as well as the criteria for the differentiation between cachexia and other conditions associated with sarcopenia, which have been developed in cooperation with the ESPEN SIG on nutrition in geriatrics. Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Is there a genetic cause for cancer cachexia? – a clinical validation study in 1797 patients

PubMed Central

Solheim, T S; Fayers, P M; Fladvad, T; Tan, B; Skorpen, F; Fearon, K; Baracos, V E; Klepstad, P; Strasser, F; Kaasa, S

2011-01-01

Background: Cachexia has major impact on cancer patients' morbidity and mortality. Future development of cachexia treatment needs methods for early identification of patients at risk. The aim of the study was to validate nine single-nucleotide polymorphisms (SNPs) previously associated with cachexia, and to explore 182 other candidate SNPs with the potential to be involved in the pathophysiology. Method: A total of 1797 cancer patients, classified as either having severe cachexia, mild cachexia or no cachexia, were genotyped. Results: After allowing for multiple testing, there was no statistically significant association between any of the SNPs analysed and the cachexia groups. However, consistent with prior reports, two SNPs from the acylpeptide hydrolase (APEH) gene showed suggestive statistical significance (P=0.02; OR, 0.78). Conclusion: This study failed to detect any significant association between any of the SNPs analysed and cachexia; although two SNPs from the APEH gene had a trend towards significance. The APEH gene encodes the enzyme APEH, postulated to be important in the endpoint of the ubiquitin system and thus the breakdown of proteins into free amino acids. In cachexia, there is an extensive breakdown of muscle proteins and an increase in the production of acute phase proteins in the liver. PMID:21934689

Post-translationally modified muscle-specific ubiquitin ligases as circulating biomarkers in experimental cancer cachexia

PubMed Central

Mota, Roberto; Rodríguez, Jessica E; Bonetto, Andrea; O’Connell, Thomas M; Asher, Scott A; Parry, Traci L; Lockyer, Pamela; McCudden, Christopher R; Couch, Marion E; Willis, Monte S

2017-01-01

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Up to 80% of cancer patients experience cachexia, with 20-30% of cancer-related deaths directly linked to cachexia. Despite efforts to identify early cachexia and cancer relapse, clinically useful markers are lacking. Recently, we identified the role of muscle-specific ubiquitin ligases Atrogin-1 (MAFbx, FBXO32) and Muscle Ring Finger-1 in the pathogenesis of cardiac atrophy and hypertrophy. We hypothesized that during cachexia, the Atrogin-1 and MuRF1 ubiquitin ligases are released from muscle and migrate to the circulation where they could be detected and serve as a cachexia biomarker. To test this, we induced cachexia in mice using the C26 adenocarcinoma cells or vehicle (control). Body weight, tumor volume, and food consumption were measured from inoculation until ~day 14 to document cachexia. Western blot analysis of serum identified the presence of Atrogin-1 and MuRF1 with unique post-translational modifications consistent with mono- and poly- ubiquitination of Atrogin-1 and MuRF1 found only in cachectic serum. These findings suggest that both increased Atrogin-1 and the presence of unique post-translational modifications may serve as a surrogate marker specific for cachexia. PMID:28979816

Cancer Cachexia: Beyond Weight Loss.

PubMed

Bruggeman, Andrew R; Kamal, Arif H; LeBlanc, Thomas W; Ma, Joseph D; Baracos, Vickie E; Roeland, Eric J

2016-11-01

Cancer cachexia is a multifactorial syndrome characterized by skeletal muscle loss leading to progressive functional impairment. Despite the ubiquity of cachexia in clinical practice, prevention, early identification, and intervention remain challenging. The impact of cancer cachexia on quality of life, treatment-related toxicity, physical function, and mortality are well established; however, establishing a clinically meaningful definition has proven challenging because of the focus on weight loss alone. Attempts to more comprehensively define cachexia through body composition, physical functioning, and molecular biomarkers, while promising, are yet to be routinely incorporated into clinical practice. Pharmacologic agents that have not been approved by the US Food and Drug Administration but that are currently used in cancer cachexia (ie, megestrol, dronabinol) may improve weight but not outcomes of interest such as muscle mass, physical activity, or mortality. Their routine use is limited by adverse effects. For the practicing oncologist, early identification and management of cachexia is critical. Oncologists must recognize cachexia beyond weight loss alone, focusing instead on body composition and physical functioning. In fact, becoming emaciated is a late sign of cachexia that characterizes its refractory stage. Given that cachexia is a multifactorial syndrome, it requires early identification and polymodal intervention, including optimal cancer therapy, symptom management, nutrition, exercise, and psychosocial support. Consequently, oncologists have a role in ensuring that these resources are available to their patients. In addition, in light of the promising investigational agents, it remains imperative to refer patients with cachexia to clinical trials so that available options can be expanded to effectively treat this pervasive problem.

Perception of need for nutritional support in advanced cancer patients with cachexia: a survey in palliative care settings.

PubMed

Amano, Koji; Morita, Tatsuya; Miyamoto, Jiro; Uno, Teruaki; Katayama, Hirofumi; Tatara, Ryohei

2018-03-05

Few studies have investigated the need for nutritional support in advanced cancer patients in palliative care settings. Therefore, we conducted a questionnaire to examine the relationship between the perception of need for nutritional support and cancer cachexia and the prevalence of specific needs, perceptions, and beliefs in nutritional support. We conducted a questionnaire in palliative care settings. Patients were classified into two groups: (1) non-cachexia/pre-cachexia and (2) cachexia/refractory cachexia. A total of 117 out of 121 patients responded (96.7%). A significant difference was observed in the need for nutritional support between the groups: non-cachexia/pre-cachexia (32.7%) and cachexia/refractory cachexia (53.6%) (p = 0.031). The specific needs of patients requiring nutritional support were nutritional counseling (93.8%), ideas to improve food intake (87.5%), oral nutritional supplements (83.0%), parenteral nutrition and hydration (77.1%), and tube feeding (22.9%). The top perceptions regarding the best time to receive nutritional support and the best medical staff to provide nutritional support were "when anorexia, weight loss, and muscle weakness become apparent" (48.6%) and "nutritional support team" (67.3%), respectively. The top three beliefs of nutritional treatments were "I do not wish to receive tube feeding" (78.6%), "parenteral nutrition and hydration are essential" (60.7%), and "parenteral hydration is essential" (59.6%). Patients with cancer cachexia expressed a greater need for nutritional support. They wished to receive nutritional support from medical staff when they become unable to take sufficient nourishment orally and the negative impact of cachexia becomes apparent. Most patients wished to receive parenteral nutrition and hydration.

Healthcare professionals' response to cachexia in advanced cancer: a qualitative study.

PubMed

Millar, Claire; Reid, Joanne; Porter, Sam

2013-11-01

To explore healthcare professionals' experience, understanding, and perception of the needs of patients with cachexia in advanced cancer. A qualitative approach based on symbolic interactionism. A regional cancer center in a large teaching hospital in the United Kingdom. 34 healthcare professionals who had experience providing care to patients with cachexia in advanced cancer. Data collection consisted of two phases: focus group and semistructured interviews. Interviews were digitally recorded and transcribed verbatim for analysis. This article reports on findings from the second phase of data collection. Analysis revealed that professional approaches to cachexia were influenced by three overarching and interthinking themes: knowledge, culture, and resources. Healthcare professionals commonly recognized the impact of the syndrome; however, for nonpalliative healthcare professionals, a culture of avoidance and an overreliance on the biomedical model of care had considerable influence on the management of cachexia in patients with advanced cancer. Cachexia management in patients with advanced cancer can be difficult and is directed by a variable combination of the influence of knowledge, culture of the clinical area, and available resources. Distinct differences exist in the management of cachexia among palliative and nonpalliative care professionals. This study presented a multiprofessional perspective on the management of cachexia in patients with advanced cancer and revealed that cachexia is a complex and challenging syndrome that needs to be addressed from a holistic model of care. Cachexia management in patients with advanced cancer is complex and challenging and is directed by a combination of variables. An overreliance on the biomedical model of health and illness occurs in the management of cachexia in patients with advanced cancer. Cachexia needs to be addressed from a holistic model of care to reflect the multidimensional needs of patients and their families.

The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the ApcMin/+ Mouse

PubMed Central

White, James P.; Baynes, John W.; Welle, Stephen L.; Kostek, Matthew C.; Matesic, Lydia E.; Sato, Shuichi; Carson, James A.

2011-01-01

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The ApcMin/+ mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the ApcMin/+ mouse is not known. Cachexia progression was studied in ApcMin/+ mice that were either weight stable (WS) or had initial (≤5%), intermediate (6–19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process. PMID:21949739

Cardiac Cachexia: Perspectives for Prevention and Treatment.

PubMed

Okoshi, Marina Politi; Capalbo, Rafael Verardino; Romeiro, Fernando G; Okoshi, Katashi

2017-01-01

Cachexia is a prevalent pathological condition associated with chronic heart failure. Its occurrence predicts increased morbidity and mortality independent of important clinical variables such as age, ventricular function, or heart failure functional class. The clinical consequences of cachexia are dependent on both weight loss and systemic inflammation, which accompany cachexia development. Skeletal muscle wasting is an important component of cachexia; it often precedes cachexia development and predicts poor outcome in heart failure. Cachexia clinically affects several organs and systems. It is a multifactorial condition where underlying pathophysiological mechanisms are not completely understood making it difficult to develop specific prevention and treatment therapies. Preventive strategies have largely focused on muscle mass preservation. Different treatment options have been described, mostly in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reducing intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimens. Currently, nonpharmacological therapy such as nutritional support and physical exercise are considered central to cachexia prevention and treatment.

Does Skeletal Muscle Mass Influence Breast Cancer? Evaluating Mammary Tumorigenesis and Progression in Genetically Hyper-Muscular Mice

DTIC Science & Technology

2007-07-01

preserve muscle in the end-stages of cancer, cancer cachexia . Up to 25% of breast cancer deaths may be attributed to muscle wasting from the complex... cachexia . 15. SUBJECT TERMS Breast cancer, skeletal muscle, myostatin, MPA, DMBA, Activin receptor, cachexia . 16. SECURITY CLASSIFICATION OF: 17...progress, we turned to another question relating skeletal muscle and cancer—pathological muscle wasting in cancer cachexia . (6) (7) (8) Cancer cachexia

Sex Differences in the Relationship of IL-6 Signaling to Cancer Cachexia Progression

PubMed Central

Hetzler, Kimbell L.; Hardee, Justin P.; Puppa, Melissa J.; Narsale, Aditi A.; Sato, Shuichi; Davis, J. Mark; Carson, James A.

2015-01-01

A devastating aspect of cancer cachexia is severe loss of muscle and fat mass. Though cachexia occurs in both sexes, it is not well-defined in the female. The Apc Min/+ mouse is genetically predisposed to develop intestinal tumors; circulating IL-6 is a critical regulator of cancer cachexia in the male Apc Min/+ mouse. The purpose of this study was to examine the relationship between IL-6 signaling and cachexia progression in the female Apc Min/+ mouse. Male and female Apc Min/+ mice were examined during the initiation and progression of cachexia. Another group of females had IL-6 overexpressed between 12-14 weeks or 15-18 weeks of age to determine whether IL-6 could induce cachexia. Cachectic female Apc Min/+ mice lost body weight, muscle mass, and fat mass; increased muscle IL-6 mRNA expression was associated with these changes, but circulating IL-6 levels were not. Circulating IL-6 levels did not correlate with downstream signaling in muscle in the female. Muscle IL-6r mRNA expression and SOCS3 mRNA expression as well as muscle IL-6r protein and STAT3 phosphorylation increased with severe cachexia in both sexes. Muscle SOCS3 protein increased in cachectic females but decreased in cachectic males. IL-6 overexpression did not affect cachexia progression in female Apc Min/+ mice. Our results indicate that female Apc Min/+ mice undergo cachexia progression that is at least initially IL-6-independent. Future studies in the female will need to determine mechanisms underlying regulation of IL-6 response and cachexia induction. PMID:25555992

Distinguishing starvation from cachexia.

PubMed

Thomas, David R

2002-11-01

The poor response to hypercaloric feeding in ill adults may be caused by failure to distinguish cachexia from starvation (Table 1). The chief difference between starvation and cachexia is that refeeding reverses starvation but is less effective for cachexia. The ineffectiveness of refeeding in treating cachexia may explain some of the poor results from direct nutritional interventions in clinical trials. Simple starvation should respond to voluntary or involuntary hypercaloric feedings. The failure to demonstrate a more positive response may be caused by underlying cachexic states.

Serial Echocardiographic Characteristics, Novel Biomarkers and Cachexia Development in Patients with Stable Chronic Heart Failure.

PubMed

Gaggin, Hanna K; Belcher, Arianna M; Gandhi, Parul U; Ibrahim, Nasrien E; Januzzi, James L

2016-12-01

Little is known regarding objective predictors of cachexia affecting patients with heart failure (HF). We studied 108 stable chronic systolic HF patients with serial echocardiography and biomarker measurements over 10 months. Cachexia was defined as weight loss ≥5 % from baseline or final BMI <20 kg/m 2 ; 18.5 % developed cachexia. While there were no significant differences in baseline or serial echocardiographic measures in those developing cachexia, we found significant differences in baseline amino-terminal pro-B type natriuretic peptide (NT-proBNP), highly sensitive troponin I, sST2, and endothelin-1. Baseline log NT-proBNP (hazard ratio (HR) = 2.57, p = 0.004) and edema (HR = 3.36, p = 0.04) were predictive of cachexia in an adjusted analysis. When serial measurement of biomarkers was considered, only percent time with NT-proBNP ≥1000 pg/mL was predictive of cachexia. Thus, a close association exists between baseline and serial measurement of NT-proBNP and HF cachexia.

Identification of neutrophil-derived proteases and angiotensin II as biomarkers of cancer cachexia

PubMed Central

Penafuerte, Claudia A; Gagnon, Bruno; Sirois, Jacinthe; Murphy, Jessica; MacDonald, Neil; Tremblay, Michel L

2016-01-01

Background: Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre-cachexia (no cachexia but high CRP levels: ⩾5 mg l−1) and no cachexia (no cachexia and CRP: <5 mg l−1). Methods: A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software. Results: In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (⩾1.5-folds) in mRNA expression of neutrophil-derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (P=0.005 and P=0.02, respectively), TGFβ1 (P=0.042 and P<0.0001, respectively) and CRP (both P<0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (P=0.005), IL-8 (P=0.001) and absolute neutrophil counts (P=0.007). Conclusions: Ang II, TGFβ1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia. PMID:26954714

Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies.

PubMed

Johns, N; Tan, B H; MacMillan, M; Solheim, T S; Ross, J A; Baracos, V E; Damaraju, S; Fearon, K C H

2014-12-01

Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986-2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia.

Cachexia.

PubMed

Graul, A I; Stringer, M; Sorbera, L

2016-09-01

Cachexia is a multiorgan, multifactorial and often irreversible wasting syndrome associated with cancer and other serious, chronic illnesses including AIDS, chronic heart failure, chronic kidney disease and chronic obstructive pulmonary disease. Treatment of the patient with cachexia is currently targeted to correcting the two underlying features of the condition: anorexia and metabolic disturbances. Greater understanding of the mechanisms behind cachexia and muscle wasting have led to new therapeutic possibilities, however. Several classes of drugs are under active development for cachexia including drugs acting on hormone receptors or cytokine receptors, myostatin/activin pathway antagonists, beta-adrenoceptor agonists and cannabinoids. This review will cover the pathophysiology, epidemiology, diagnosis, treatment, drug candidates under active development and targets for therapeutic intervention of cachexia. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

Identification of possible genetic polymorphisms involved in cancer cachexia: a systematic review.

PubMed

Tan, Benjamin H L; Ross, James A; Kaasa, Stein; Skorpen, Frank; Fearon, Kenneth C H

2011-04-01

Cancer cachexia is a polygenic and complex syndrome. Genetic variations in regulation of the inflammatory response, muscle and fat metabolic pathways, and pathways in appetite regulation are likely to contribute to the susceptibility or resistance to developing cancer cachexia. A systematic search of Medline and EmBase databases, covering 1986-2008 was performed for potential candidate genes/genetic polymorphisms relating to cancer cachexia. Related genes were then identified using pathway functional analysis software. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Genes with variants which had functional or clinical associations with cachexia and replicated in at least one study were entered into pathway analysis software to reveal possible network associations between genes. A total of 184 polymorphisms with functional or clinical relevance to cancer cachexia were identified in 92 candidate genes. Of these, 42 polymorphisms (in 33 genes) were replicated in more than one study with 13 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Thirty-three genes were found to be significantly interconnected in two major networks with four genes (ADIPOQ, IL6, NFKB1 and TLR4) interlinking both networks. Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides an initial framework to select genes/polymorphisms for further study in cancer cachexia, and to develop their potential as susceptibility biomarkers of developing cachexia.

Effect of Sipjeondaebo-Tang on Cancer-Induced Anorexia and Cachexia in CT-26 Tumor-Bearing Mice

PubMed Central

Jung, Ki Yong; Woo, Sang-Mi; Jun, Chan-Yong; Park, Jong Hyeong; Shin, Yong Cheol; Ko, Seong-Gyu

2014-01-01

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia. PMID:24963216

Effect of Sipjeondaebo-tang on cancer-induced anorexia and cachexia in CT-26 tumor-bearing mice.

PubMed

Choi, Youn Kyung; Jung, Ki Yong; Woo, Sang-Mi; Yun, Yee Jin; Jun, Chan-Yong; Park, Jong Hyeong; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

2014-01-01

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

Prevalence and clinical significance of cancer cachexia based on time from treatment in advanced-stage head and neck squamous cell carcinoma.

PubMed

Kwon, Minsu; Kim, Rock Bum; Roh, Jong-Lyel; Lee, Sang-Wook; Kim, Sung-Bae; Choi, Seung-Ho; Nam, Soon Yuhl; Kim, Sang Yoon

2017-04-01

The purpose of this study was to identify the prevalence of cancer cachexia and its prognostic impact in patients with advanced head and neck squamous cell carcinoma (HNSCC). The prevalence of cancer cachexia was analyzed according to the follow-up periods during the first year after curative initial treatment. Recurrences, noncancer health events (NCHEs), and cause-specific survival outcomes were also analyzed according to the incidence of cancer cachexia during follow-up. Cancer cachexia was identified in 22 (6.1%), 148 (41%), 66 (18.4%), and 65 (18.7%) of 361 enrolled patients at pretreatment, immediately after treatment, 6-months after treatment, and 12-months after treatment, respectively. Sustained or newly developed cachexia at 6 and 12 months showed a significant association with recurrence and NCHE occurrence (p < .05). In cause-specific survival analysis, patients with cachexia had a higher probability of cancer-specific death, noncancerous death, and overall death (p < .05). Cachexia prevalence at 6 and 12 months after treatment for HNSCC indicates a higher chance of recurrence, NCHE, and death. © 2016 Wiley Periodicals, Inc. Head Neck 39: 716-723, 2017. © 2016 Wiley Periodicals, Inc.

Cachexia and pancreatic cancer: Are there treatment options?

PubMed Central

Mueller, Tara C; Burmeister, Marc A; Bachmann, Jeannine; Martignoni, Marc E

2014-01-01

Cachexia is frequently described in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with reduced survival and quality of life. Unfortunately, the therapeutic options of this multi-factorial and complex syndrome are limited. This is due to the fact that, despite extensive preclinical and clinical research, the underlying pathological mechanisms leading to PDAC-associated cachexia are still not fully understood. Furthermore, there is still a lack of consensus on the definition of cachexia, which complicates the standardization of diagnosis and treatment as well as the analysis of the current literature. In order to provide an efficient therapy for cachexia, an early and reliable diagnosis and consistent monitoring is required, which can be challenging especially in obese patients. Although many substances have been tested in clinical and preclinical settings, so far none of them have been proven to have a long-term effect in ameliorating cancer-associated cachexia. However, recent studies have demonstrated that multidimensional therapeutic modalities are able to alleviate pancreatic cancer-associated cachexia and ultimately improve patients’ outcome. In this current review, we propose a stepwise and pragmatic approach to facilitate and standardize the treatment of cachexia in pancreatic cancer patients. This strategy consists of nutritional, dietary, pharmacological, physical and psychological methods. PMID:25071331

Ovarian function's role during cancer cachexia progression in the female mouse.

PubMed

Hetzler, Kimbell L; Hardee, Justin P; LaVoie, Holly A; Murphy, E Angela; Carson, James A

2017-05-01

Cachexia is a debilitating condition that occurs with chronic disease, including cancer; our research has shown that some regulation of cancer cachexia progression is affected by sex differences. The Apc Min/+ mouse is genetically predisposed to develop intestinal tumors; IL-6 signaling and hypogonadism are associated with cachexia severity in the male. This relationship in the female warrants further investigation, as we have shown that the ability of IL-6 to induce cachexia differs between the sexes. Since ovarian reproductive function relies on a complex system of endocrine signaling to affect whole body homeostasis, we examined the relationship between ovarian reproductive function and progression of cancer cachexia in the female Apc Min/+ mouse. Our study of ovarian reproductive function in female Apc Min/+ mice showed disease-related cessation of estrous cycling (acyclicity) in 38% of mice. Acyclicity, including morphological and functional losses and enhanced muscle inflammatory gene expression, was associated with severe cachexia. Interestingly, ovariectomy rescued body weight and muscle mass and function but increased muscle sensitivity to systemic IL-6 overexpression. In conclusion, our results provide evidence for a relationship between ovarian reproductive function and cachexia progression in female Apc Min/+ mice. Copyright © 2017 the American Physiological Society.

The pathogenesis and treatment of cardiac atrophy in cancer cachexia.

PubMed

Murphy, Kate T

2016-02-15

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia. Copyright © 2016 the American Physiological Society.

Sarcopenia, cachexia, and muscle performance in heart failure: Review update 2016.

PubMed

Saitoh, Masakazu; Ishida, Junichi; Doehner, Wolfram; von Haehling, Stephan; Anker, Markus S; Coats, Andrew J S; Anker, Stefan D; Springer, Jochen

2017-07-01

Cachexia in the context of heart failure (HF) has been termed cardiac cachexia, and represents a progressive involuntary weight loss. Cachexia is mainly the result of an imbalance in the homeostasis of muscle protein synthesis and degradation due to a lower activity of protein synthesis pathways and an over-activation of protein degradation. In addition, muscle wasting leads to of impaired functional capacity, even after adjusting for clinical relevant variables in patients with HF. However, there is no sufficient therapeutic strategy in muscle wasting in HF patients and very few studies in animal models. Exercise training represents a promising intervention that can prevent or even reverse the process of muscle wasting, and worsening the muscle function and performance in HF with muscle wasting and cachexia. The pathological mechanisms and effective therapeutic approach of cardiac cachexia remain uncertain, because of the difficulty to establish animal cardiac cachexia models, thus novel animal models are warranted. Furthermore, the use of improved animal models will lead to a better understanding of the pathways that modulate muscle wasting and therapeutics of muscle wasting of cardiac cachexia. Copyright © 2017 Elsevier B.V. All rights reserved.

Ovarian function’s role during cancer cachexia progression in the female mouse

PubMed Central

Hetzler, Kimbell L.; Hardee, Justin P.; LaVoie, Holly A.; Murphy, E. Angela

2017-01-01

Cachexia is a debilitating condition that occurs with chronic disease, including cancer; our research has shown that some regulation of cancer cachexia progression is affected by sex differences. The ApcMin/+ mouse is genetically predisposed to develop intestinal tumors; IL-6 signaling and hypogonadism are associated with cachexia severity in the male. This relationship in the female warrants further investigation, as we have shown that the ability of IL-6 to induce cachexia differs between the sexes. Since ovarian reproductive function relies on a complex system of endocrine signaling to affect whole body homeostasis, we examined the relationship between ovarian reproductive function and progression of cancer cachexia in the female ApcMin/+ mouse. Our study of ovarian reproductive function in female ApcMin/+ mice showed disease-related cessation of estrous cycling (acyclicity) in 38% of mice. Acyclicity, including morphological and functional losses and enhanced muscle inflammatory gene expression, was associated with severe cachexia. Interestingly, ovariectomy rescued body weight and muscle mass and function but increased muscle sensitivity to systemic IL-6 overexpression. In conclusion, our results provide evidence for a relationship between ovarian reproductive function and cachexia progression in female ApcMin/+ mice. PMID:28292759

Cachexia: a new definition.

PubMed

Evans, William J; Morley, John E; Argilés, Josep; Bales, Connie; Baracos, Vickie; Guttridge, Denis; Jatoi, Aminah; Kalantar-Zadeh, Kamyar; Lochs, Herbert; Mantovani, Giovanni; Marks, Daniel; Mitch, William E; Muscaritoli, Maurizio; Najand, Armine; Ponikowski, Piotr; Rossi Fanelli, Filippo; Schambelan, Morrie; Schols, Annemie; Schuster, Michael; Thomas, David; Wolfe, Robert; Anker, Stefan D

2008-12-01

On December 13th and 14th a group of scientists and clinicians met in Washington, DC, for the cachexia consensus conference. At the present time, there is no widely agreed upon operational definition of cachexia. The lack of a definition accepted by clinician and researchers has limited identification and treatment of cachectic patient as well as the development and approval of potential therapeutic agents. The definition that emerged is: "cachexia, is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. While this definition has not been tested in epidemiological or intervention studies, a consensus operational definition provides an opportunity for increased research.

Cancer cachexia decreases specific force and accelerates fatigue in limb muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roberts, B.M.; Frye, G.S.; Ahn, B.

Highlights: •C-26 cancer cachexia causes a significant decrease in limb muscle absolute force. •C-26 cancer cachexia causes a significant decrease in limb muscle specific force. •C-26 cancer cachexia decreases fatigue resistance in the soleus muscle. •C-26 cancer cachexia prolongs time to peak twitch tension in limb muscle. •C-26 cancer cachexia prolongs one half twitch relaxation time in limb muscle. -- Abstract: Cancer cachexia is a complex metabolic syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia havemore » recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. However, more recently, we provided evidence that during severe cancer cachexia muscle weakness in the diaphragm muscle cannot be entirely accounted for by the muscle atrophy. This indicates that muscle weakness is not just a consequence of muscle atrophy but that there is also significant contractile dysfunction. The current study aimed to determine whether contractile dysfunction is also present in limb muscles during severe Colon-26 (C26) carcinoma cachexia by studying the glycolytic extensor digitorum longus (EDL) muscle and the oxidative soleus muscle, which has an activity pattern that more closely resembles the diaphragm. Severe C-26 cancer cachexia caused significant muscle fiber atrophy and a reduction in maximum absolute force in both the EDL and soleus muscles. However, normalization to muscle cross sectional area further demonstrated a 13% decrease in maximum isometric specific force in the EDL and an even greater decrease (17%) in maximum isometric specific force in the soleus. Time to peak tension and half relaxation time were also significantly slowed in both the EDL and the solei from C-26 mice compared to controls. Since, in addition to postural control, the oxidative soleus is also important for normal locomotion, we further performed a fatigue trial in the soleus and found that the decrease in relative force was greater and more rapid in solei from C-26 mice compared to controls. These data demonstrate that severe cancer cachexia causes profound muscle weakness that is not entirely explained by the muscle atrophy. In addition, cancer cachexia decreases the fatigue resistance of the soleus muscle, a postural muscle typically resistant to fatigue. Thus, specifically targeting contractile dysfunction represents an additional means to counter muscle weakness in cancer cachexia, in addition to targeting the prevention of muscle atrophy.« less

Circulating monocyte chemoattractant protein‐1 (MCP‐1) is associated with cachexia in treatment‐naïve pancreatic cancer patients

PubMed Central

Talbert, Erin E.; Lewis, Heather L.; Farren, Matthew R.; Ramsey, Mitchell L.; Chakedis, Jeffery M.; Rajasekera, Priyani; Haverick, Ericka; Sarna, Angela; Bloomston, Mark; Pawlik, Timothy M.; Zimmers, Teresa A.; Lesinski, Gregory B.; Hart, Phil A.; Dillhoff, Mary E.; Schmidt, Carl R.

2018-01-01

Abstract Background Cancer‐associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer‐induced cachexia in patients with earlier stages of disease. Methods A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high‐sensitivity multiplex was used for increased sensitivity for nine cytokines. Results Resectable pancreatic cancer patients with cachexia had low levels of canonical pro‐inflammatory cytokines including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), interferon‐γ (IFN‐γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein‐1 (MCP‐1) was increased in treatment‐naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were found to be decreased in the same cohort of treatment‐naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. Conclusions Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment‐naïve patients have higher levels of MCP‐1, suggesting that MCP‐1 may be useful as a biomarker of cancer cachexia. PMID:29316343

Cachexia research in Japan: facts and numbers on prevalence, incidence and clinical impact.

PubMed

Konishi, Masaaki; Ishida, Junichi; Springer, Jochen; Anker, Stefan D; von Haehling, Stephan

2016-12-01

Even though most clinical data on cachexia have been reported from Western countries, cachexia may be a growing problem in Asia as well, as the population in this area of the world is considerably larger. Considering the current definitions of obesity and sarcopenia in Japan, which are different from the ones in Western countries, the lack of a distinct cachexia definition in Japan is strinking. Only one epidemiological study has reported the prevalence of cachexia using weight loss as part of the definition in patients with stage III or IV non-small cell lung cancer. Although the reported prevalence of 45.6% is within the range of that in Western countries (28-57% in advanced cancer), we cannot compare the prevalence of cachexia in other types of cancer, heart failure, chronic obstructive pulmonary disease (COPD), and kidney disease (CKD) between Japan and Western countries. In patients with heart failure, one third of Japanese patients has a body mass index <20.3 kg/m 2 whereas the prevalence of underweight is 13.6% in reports from Western countries. These results may suggest that there are more cachectic heart failure patients in Japan, or that using the same definition like Western countries leads to gross overestimation of the prevalence of cachexia in Japan. The rate of underweight patients in COPD has been reported as 31-41% in COPD and seems to be high in comparison to the prevalence of cachexia in Western countries (27-35%). The reported lowest quartile value of BMI (19.6 kg/m 2 ) in CKD may match with the prevalence of cachexia in Western countries (30-60%). The number of clinical trials targeting cachexia is very limited in Japan so far.

MAP3K11/GDF15 axis is a critical driver of cancer cachexia

PubMed Central

Tao, Julie; Liu, Qing; Nicoletti, Richard; Feng, Bin; Krieger, Brian; Mazsa, Elizabeth; Siddiquee, Zakir; Wang, Ruoji; Huang, Lucia; Shen, Luhua; Lin, Jie; Vigano, Antonio; Chiu, M. Isabel; Weng, Zhigang; Winston, William; Weiler, Solly

2015-01-01

Abstract Background Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro‐inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. Methods Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non‐cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. Results Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour‐produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. Conclusions The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome. PMID:27239403

Early suppression of adipocyte lipid turnover induces immunometabolic modulation in cancer cachexia syndrome.

PubMed

Henriques, Felipe Santos; Sertié, Rogério Antônio Laurato; Franco, Felipe Oliveira; Knobl, Pamela; Neves, Rodrigo Xavier; Andreotti, Sandra; Lima, Fabio Bessa; Guilherme, Adilson; Seelaender, Marilia; Batista, Miguel Luiz

2017-05-01

Cancer cachexia is a multifactorial syndrome characterized by body weight loss, atrophy of adipose tissue (AT) and systemic inflammation. However, there is limited information regarding the mechanisms of immunometabolic response in AT from cancer cachexia. Male Wistar rats were inoculated with 2 × 10 7 of Walker 256 tumor cells [tumor bearing (TB) rats]. The mesenteric AT (MeAT) was collected on d 0, 4, 7 (early stage), and 14 (cachexia stage) after tumor cell injection. Surgical biopsies for MeAT were obtained from patients who had gastrointestinal cancer with cachexia. Lipolysis showed an early decrease in glycerol release in TB d 4 (TB4) rats in relation to the control, followed by a 6-fold increase in TB14 rats, whereas de novo lipogenesis was markedly lower in the incorporation of glucose into fatty acids in TB14 rats during the development of cachexia. CD11b and CD68 were positive in TB7 and TB14 rats, respectively. In addition, we found cachexia stage results similar to those of animals in MeAT from patients: an increased presence of CD68 + , iNOS2 + , TNFα + , and HSL + cells. In summary, translational analysis of MeAT from patients and an animal model of cancer cachexia enabled us to identify early disruption in Adl turnover and subsequent inflammatory response during the development of cancer cachexia.-Henriques, F. S., Sertié, R. A. L., Franco, F. O., Knobl, P., Neves, R. X., Andreotti, S., Lima, F. B., Guilherme, A., Seelaender, M., Batista, M. L., Jr. Early suppression of adipocyte lipid turnover induces immunometabolic modulation in cancer cachexia syndrome. © FASEB.

Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016.

PubMed

von Haehling, Stephan; Anker, Markus S; Anker, Stefan D

2016-12-01

Cachexia is a serious clinical consequence of almost all chronic diseases when reaching advanced stages. Its prevalence ranges from 5-15% in end-stage chronic heart failure to 50-80% in advanced malignant cancer. Cachexia is also frequently occurring in patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) or neurological diseases, and rheumatoid arthritis. Mortality rates of patients with cachexia range from 15-25% per year in severe COPD through 20-40% per year in patients with chronic heart failure or chronic kidney disease to 20-80% in cancer cachexia. In the industrialized world (North America, Europe, and Japan) where epidemiological data are to some degree available, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing with the growth of the chronic illness prevalence, and it currently affects around 0.5-1.0% of the population, i.e. around 6-12 million people. From this, one can estimate that 1.5-2 million deaths are occurring in patients with cachexia per year. It is also a very significant health problem in other parts of the globe, but epidemiological data are scarce. The multifactorial nature of cachexia is now much better understood, and particularly, the role of inflammatory mediators and the imbalance of anabolism and catabolism are considered important therapeutic targets. Several approaches to develop cachexia and muscle wasting treatments have failed to be successful in phase III clinical trials, but new approaches are in development. Given the high prevalence and very high mortality associated with cachexia, advances are urgently needed for patients worldwide.

Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016

PubMed Central

von Haehling, Stephan; Anker, Markus S.

2016-01-01

Abstract Cachexia is a serious clinical consequence of almost all chronic diseases when reaching advanced stages. Its prevalence ranges from 5–15% in end‐stage chronic heart failure to 50–80% in advanced malignant cancer. Cachexia is also frequently occurring in patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) or neurological diseases, and rheumatoid arthritis. Mortality rates of patients with cachexia range from 15–25% per year in severe COPD through 20–40% per year in patients with chronic heart failure or chronic kidney disease to 20–80% in cancer cachexia. In the industrialized world (North America, Europe, and Japan) where epidemiological data are to some degree available, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing with the growth of the chronic illness prevalence, and it currently affects around 0.5–1.0% of the population, i.e. around 6–12 million people. From this, one can estimate that 1.5–2 million deaths are occurring in patients with cachexia per year. It is also a very significant health problem in other parts of the globe, but epidemiological data are scarce. The multifactorial nature of cachexia is now much better understood, and particularly, the role of inflammatory mediators and the imbalance of anabolism and catabolism are considered important therapeutic targets. Several approaches to develop cachexia and muscle wasting treatments have failed to be successful in phase III clinical trials, but new approaches are in development. Given the high prevalence and very high mortality associated with cachexia, advances are urgently needed for patients worldwide. PMID:27891294

Health care professionals' experience, understanding and perception of need of advanced cancer patients with cachexia and their families: The benefits of a dedicated clinic.

PubMed

Scott, David; Reid, Joanne; Hudson, Peter; Martin, Peter; Porter, Sam

2016-12-30

Cachexia is defined as the on-going loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support. It is found in up to 80% of patients with advanced cancer and has profound psycho-social consequences for patients and their families. Previous studies demonstrate that many healthcare professionals receive little formal education in cachexia management leading them to feel that they have limited understanding of the syndrome and cannot intervene effectively. This study aims to examine the value of a dedicated cachexia clinic and its influence on staff understanding and practice. An exploratory qualitative study was conducted. The study employed semi-structured interviews with a range of healthcare professionals responsible for designing and delivering cancer care in a large teaching hospital in Australia. This hospital had a dedicated cachexia clinic. In-depth interviews were conducted with 8 healthcare professionals and senior managers. Four themes were identified: formal and informal education; knowledge and understanding; truth telling in cachexia and palliative care; and, a multi-disciplinary approach. Findings show that improved knowledge and understanding across a staff body can lead to enhanced staff confidence and a willingness to address cancer cachexia and its consequences with patients and their families. Comparisons with similar previous research demonstrate the advantages of providing a structure for staff to gain knowledge about cachexia and how this can contribute to feelings of improved understanding and confidence necessary to respond to the challenge of cachexia.

Phase II drugs that are currently in development for the treatment of cachexia.

PubMed

Dingemans, Anne-Marie C; de Vos-Geelen, Judith; Langen, Ramon; Schols, Annemie M W

2014-12-01

Cachexia is a syndrome presenting with progressive unintentional weight loss and wasting and weakness of skeletal muscle. Cachexia is prevalent in cancer and in chronic diseases including chronic obstructive pulmonary disease (COPD). The authors searched trial registers for current Phase II clinical trials on cachexia. Twelve studies were found with 11 compounds, including the anti-inflammatory drugs thalidomide, OHR/AVR118, celecoxib, VT-122, omega-3 supplements, and anabolic agents such as ghrelin analogues, MT-102, BYM338 and ruxolotinib. The authors note that one of the studies related to COPD while the others were related to different cancers. Herein, the authors describe the mechanisms of action and their Phase II study design. The compounds under study affect several pathways involved in cachexia by modulating inflammatory activity, anabolic potential, digestion and direct interaction with the muscle. Due to the multifactorial aspects of cachexia syndrome, combinations of these new drugs with nutritional intervention is probably the most promising approach. Furthermore, future studies should include interventions in pre-cachetic patients, as this stage might be more responsive to treatment. Future studies will benefit from well-defined end points and improved measures of cachexia, providing new insight into the disease. This insight, in combination with the elucidation of cachexia's underlying mechanism, will yield new treatment strategies in the near future.

Ghrelin and cachexia: will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes?

PubMed

DeBoer, Mark D

2011-06-20

Cachexia is a syndrome of wasting and anorexia that worsens the prognosis of many chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease. Properties of the orexigenic hormone ghrelin-including appetite-stimulation, weight-gain production and increased cardiac output make it a logical treatment for cachexia. While endogenous ghrelin levels are increased in the setting of cachexia, treatment with ghrelin and other GHSR-1a agonists in animal models of cachexia and in humans with cachexia has demonstrated consistent effects of increased appetite and improved weight gain. These positive effects occur in multiple underlying diseases associated with cachexia and appear to be sustained over treatment duration of up to 12 weeks. The mechanism of action in producing these effects is likely related to stimulation of central appetite centers such as the central melanocortin system and to increased growth hormone release, though ghrelin's effects may also relate to decreased systemic inflammation and other direct and indirect actions. Questions regarding the long-term safety of ghrelin treatment are still unanswered, as is the important question of whether successful treatment of cachexia will improve the prognosis of the underlying disease itself. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Ghrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes?

PubMed Central

DeBoer, Mark D.

2011-01-01

Cachexia is a syndrome of wasting and anorexia that worsens the prognosis of many chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease. Properties of the orexigenic hormone ghrelin—including appetite-stimulation, weight-gain production and increased cardiac output—make it a logical treatment for cachexia. While endogenous ghrelin levels are increased in the setting of cachexia, treatment with ghrelin and other GHSR-1a agonists in animal models of cachexia and in humans with cachexia have demonstrated consistent effects of increased appetite and improved weight gain. These positive effects occur in multiple underlying diseases associated with cachexia and appear to be sustained over treatment duration of up to 12 weeks. The mechanism of action in producing these effects is likely related to stimulation of central appetite centers such as the central melanocortin system and to increased growth hormone release, though ghrelin’s effects may also relate to decreased systemic inflammation and other direct and indirect actions. Questions regarding the long-term safety of ghrelin treatment are still unanswered, as is the important question of whether successful treatment of cachexia will improve the prognosis of the underlying disease itself. PMID:21354462

Possible Involvement of Insulin Resistance in the Progression of Cancer Cachexia in Mice.

PubMed

Ohsawa, Masahiro; Murakami, Tomoyasu; Kume, Kazuhiko

2016-01-01

Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia.

Fn14: a new player in cancer-induced cachexia.

PubMed

Johnston, Amelia J; Hoogenraad, Nicholas J

2016-07-01

Although cancer cachexia is a very significant condition that is present in up to 80% of cancer cases, the cause of the condition has remained a puzzle. Cancer cachexia is a condition which is mainly characterised by muscle wasting, mobilization of fat reserves, and overall metabolic disturbance. This review aims to highlight some of the recent findings in cancer cachexia research. It has been recently demonstrated that the expression of a single receptor, fibroblast growth factor-inducible 14, on a tumour can initiate cachexia and that this can be completely ablated by treatment with an antibody against this receptor. Also recently described was the role of parathyroid hormone receptor-binding proteins in causing cachexia through a mechanism where white adipose tissue is replaced with brown adipose tissue. In parallel, work done in drosophila suggests that the impaired insulin signalling is a direct cause of cancer cachexia through the release of an insulin growth factor binding protein that inhibits insulin and insulin-like growth factor 1 signalling. Successful therapies are urgently needed to combat cancer cachexia in the clinic. Recent research is making progress toward discovering the underlying molecular causes of the condition, which could lead to new therapeutic approaches and in the future contribute to more positive clinical outcomes for cancer sufferers.

Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia.

PubMed

Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E; Nosacka, Rachel L; Rocha, Fernanda G; DiVita, Bayli B; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Wallet, Shannon M; Judge, Andrew R; Trevino, Jose G

2017-01-03

Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

Optimal management of cancer anorexia–cachexia syndrome

PubMed Central

Argilés, Josep M; Olivan, Mireia; Busquets, Sílvia; López-Soriano, Francisco Javier

2010-01-01

According to a recent consensus, cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss. Cachexia occurs in the majority of cancer patients before death and it is responsible for the deaths of 22% of cancer patients. Although bodyweight is the most important endpoint of any cachexia treatment, body composition, physical performance and quality of life should be monitored. From the results presented here, one can speculate that a single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. The objectives of any therapeutic combination are two-fold: an anticatabolic aim directed towards both fat and muscle catabolism and an anabolic objective leading to the synthesis of macromolecules such as contractile proteins. PMID:21188094

Molecular Pathways: Cachexia Signaling-A Targeted Approach to Cancer Treatment.

PubMed

Miyamoto, Yuji; Hanna, Diana L; Zhang, Wu; Baba, Hideo; Lenz, Heinz-Josef

2016-08-15

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin-SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999-4004. ©2016 AACR. ©2016 American Association for Cancer Research.

Rikkunshito, a ghrelin potentiator, ameliorates anorexia–cachexia syndrome

PubMed Central

Fujitsuka, Naoki; Uezono, Yasuhito

2014-01-01

Anorexia–cachexia syndrome develops during the advanced stages of various chronic diseases in which patients exhibit a decreased food intake, weight loss, and muscle tissue wasting. For these patients, this syndrome is a critical problem leading to an increased rate of morbidity and mortality. The present pharmacological therapies for treating anorexia–cachexia have limited effectiveness. The Japanese herbal medicine rikkunshito is often prescribed for the treatment of anorexia and upper gastrointestinal (GI) disorders. Thus, rikkunshito is expected to be beneficial for the treatment of patients with anorexia–cachexia syndrome. In this review, we summarize the effects of rikkunshito and its mechanisms of action on anorexia–cachexia. Persistent loss of appetite leads to a progressive depletion of body energy stores, which is frequently associated with cachexia. Consequently, regulating appetite and energy homeostasis is critically important for treating cachexia. Ghrelin is mainly secreted from the stomach, and it plays an important role in initiating feeding, controlling GI motility, and regulating energy expenditure. Recent clinical and basic science studies have demonstrated that the critical mechanism of rikkunshito underlies endogenous ghrelin activity. Interestingly, several components of rikkunshito target multiple gastric and central sites, and regulate the secretion, receptor sensitization, and degradation of ghrelin. Rikkunshito is effective for the treatment of anorexia, body weight loss, muscle wasting, and anxiety-related behavior. Furthermore, treatment with rikkunshito was observed to prolong survival in an animal model of cachexia. The use of a potentiator of ghrelin signaling, such as rikkunshito, may represent a novel approach for the treatment of anorexia–cachexia syndrome. PMID:25540621

Nutrition in cachexia: from bench to bedside.

PubMed

Konishi, Masaaki; Ishida, Junichi; von Haehling, Stephan; Anker, Stefan D; Springer, Jochen

2016-05-01

As malnutrition is often present in cachexia, nutritional intervention has been one of the widely accepted strategies. A literature review of cachexia models with dietary interventions in the present issue of this journal pointed out that the majority of nutrient intervention studies were of n-3 fatty acid, mainly eicosapentaenoic acid and docosahexaenoic acid. Effect on protein catabolism and anti-inflammation are most pronounced benefits of n-3 fatty acid. The effectiveness of n-3 fatty acid may depend on control diet or even be attributed to the polyunsaturated fatty acid deficiency inadvertently produced in control group. However, there is not enough clinical evidence to support a benefit of n-3 fatty acid substitution in patients with cachexia. The second important result from this review is that the majority of studies did not provide information about dietary design or did not standardize design, content, source, and overall composition. To guide dietary design for researchers in preclinical studies, a model has been proposed in this review, which may be useful to predict the efficacy of new dietary intervention in cachexia science. From a clinical point of view, the limited effectiveness of nutritional support in cachexia may partly be explained by the multifactorial nature of this condition. Cachexia differs from malnutrition inasmuch as malnutrition can be reversed by adequate nutrition and/or by overcoming problems of absorption or utilization of nutrients, but cachexia cannot be successfully treated by nutrition alone. Multidisciplinary approach including the assessment and intervention in feeding, appetite, swallowing, exercise, psychosocial, and psychological issue may be needed to improve nutrition in patients with cachexia.

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia.

PubMed

Asp, Michelle L; Tian, Min; Kliewer, Kara L; Belury, Martha A

2011-12-01

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia.

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia

PubMed Central

Asp, Michelle L.; Tian, Min; Kliewer, Kara L.

2011-01-01

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia. PMID:22104958

A comparison of research into cachexia, wasting and related skeletal muscle syndromes in three chronic disease areas.

PubMed

Stewart Coats, Andrew J; Shewan, Louise G

2017-05-15

We compared the frequency of cancer, heart and lung related cachexia and cachexia-related research articles in the specialist journal, Journal of Cachexia, Sarcopenia and Muscle (JCSM) to those seen in a leading European journal in each specialist area during 2015 and 2016 to assess whether work on cachexia and related fields is relatively over or under represented in each specialist area. In the dedicated journal, Journal of Cachexia, Sarcopenia and Muscle, there were 44 references related to cancer, 5 related to respiratory disease, 5 related to heart failure, and 21 related to more than one of these chronic diseases. Despite this cancer preponderance, in the European Journal of Cancer in the two publication years, there were only 5 relevant publications (0.67% of the journal output), compared to 16 (1.41%) in the European Respiratory Journal and 10 (2.19%) in the European Journal of Heart Failure. There is considerable under-representation of cancer cachexia-related papers in the major European Cancer journal despite a high proportion in the dedicated cachexia journal. The under-representation is even more marked when expressed as a percentage, 0.67%, compared to 1.41% and 2.19% of the lung and heart journals respectively. These results are consistent with a worrying lack of interest in, or publication of, cachexia and related syndromes research in the cancer literature in Europe compared to its importance as a clinical syndrome. Greater interest is shown in lung and cardiology journals. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis.

PubMed

Vagnildhaug, Ola Magne; Blum, David; Wilcock, Andrew; Fayers, Peter; Strasser, Florian; Baracos, Vickie E; Hjermstad, Marianne J; Kaasa, Stein; Laird, Barry; Solheim, Tora S

2017-10-01

A body mass index (BMI) adjusted weight loss grading system (WLGS) is related to survival in patients with cancer. The aim of this study was to examine the applicability of the WLGS by confirming its prognostic validity, evaluating its relationship to cachexia domains, and exploring its ability to predict cachexia progression. An international, prospective observational study of patients with incurable cancer was conducted. For each patient, weight loss grade was scored 0-4. Weight loss grade 0 represents a high BMI with limited weight loss, progressing through to weight loss grade 4 representing low BMI and a high degree of weight loss. Survival analyses were used to confirm prognostic validity. Analyses of variance were used to evaluate the relationship between the WLGS and cachexia domains [anorexia, dietary intake, Karnofsky performance status (KPS), and physical and emotional functioning]. Cox regression was used to evaluate if the addition of cachexia domains to the WLGS improved prognostic accuracy. Predictive ability of cachexia progression was assessed by estimating proportion of patients progressing to a more advanced weight loss grade. One thousand four hundred six patients were analysed (median age 66 years; 50% female, 63% KPS ≤ 70). The overall effect of the WLGS on survival was significant as expressed by change in -2 log likelihood (P < 0.001) and persisted after adjustment for age, sex, and cancer type and stage (P < 0.001). Median survival decreased across the weight loss grades ranging from 407 days (95% CI 312-502)-weight loss grade 0 to 119 days (95% CI 93-145)-weight loss grade 4. All cachexia domains significantly deteriorated with increasing weight loss grade, and deterioration was greatest for dietary intake, with a difference corresponding to 0.87 standard deviations between weight loss grades 0 and 4. The addition of KPS, anorexia, and physical and emotional functioning improved the prognostic accuracy of the WLGS. Likelihood of cachexia progression was greater in patients with weight loss grade 2 (39%) than that with weight loss grade 0 (19%) or 1 (22%). The WLGS is related to survival, cachexia domains, and the likelihood of progression. Adding certain cachexia domains to the WLGS improves prognostic accuracy. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Cancer cachexia: understanding the molecular basis.

PubMed

Argilés, Josep M; Busquets, Sílvia; Stemmler, Britta; López-Soriano, Francisco J

2014-11-01

Cancer cachexia is a devastating, multifactorial and often irreversible syndrome that affects around 50-80% of cancer patients, depending on the tumour type, and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. Since cachexia may account for up to 20% of cancer deaths, understanding the underlying molecular mechanisms is essential. The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria. Interestingly, crosstalk between different cell types ultimately seems to result in muscle wasting. Some of the recent progress in understanding the molecular mechanisms of cachexia may lead to new therapeutic approaches.

Nonmuscle Tissues Contribution to Cancer Cachexia

PubMed Central

Stemmler, Britta

2015-01-01

Cachexia is a syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting, and inflammation, being often associated with anorexia. In spite of the fact that muscle tissue represents more than 40% of body weight and seems to be the main tissue involved in the wasting that occurs during cachexia, recent developments suggest that tissues/organs such as adipose (both brown and white), brain, liver, gut, and heart are directly involved in the cachectic process and may be responsible for muscle wasting. This suggests that cachexia is indeed a multiorgan syndrome. Bearing all this in mind, the aim of the present review is to examine the impact of nonmuscle tissues in cancer cachexia. PMID:26523094

Molecular characterization of skin microbiota between cancer cachexia patients and healthy volunteers.

PubMed

Li, Wei; Han, Lei; Yu, Pengbo; Ma, Chaofeng; Wu, Xiaokang; Moore, John E; Xu, Jiru

2014-04-01

Systemic inflammation contributes to both the development of cancer and of cachexia. The microenvironment of bacterial habitats might be changed during the progression of cancer cachexia. The aim of this study was to quantitatively and qualitatively compare the composition of the skin microbiota between cancer cachexia patients and healthy volunteers. Cutaneous bacteria were swabbed at the axillary fossa of 70 cancer cachexia patients and 34 healthy individuals from China. Nested-PCR-denaturing gradient gel electrophoresis (PCR-DGGE) with primers specifically targeting V3 region and quantitative PCR (qPCR) for total bacteria, Corynebacterium spp., Staphylococcus spp., and Staphylococcus epidermidis were performed on all samples. Barcoded 454 pyrosequencing of the V3-V4 regions was performed on 30 randomly selected samples. By comparing diversity and richness indices, we found that the skin microbiome of cachectic cancer patients is less diverse than that of healthy participants, though these differences were not significant. The main microbes that reside on human skin were divided into four phyla: Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes. Staphylococcus spp. and Corynebacterium spp. were the dominant bacteria at the genus level. Significantly fewer Corynebacterium spp. had been observed in cachexia patients compared to healthy subjects. These results suggest that the presence of cancer and cachexia alters human skin bacterial communities. Understanding the changes in microbiota during cancer cachexia may lead to new insights into the syndrome.

Nutritional Interventions for Cancer-induced Cachexia

PubMed Central

Gullett, Norleena P.; Mazurak, Vera; Hebbar, Gautam; Ziegler, Thomas R.

2011-01-01

Cancer-induced cachexia remains a significant cause of morbidity and mortality in cancer treatment. Cancer research and development continues at an aggressive pace and yet a degree of cancer-induced cachexia is experienced by up to 80% of advanced stage cancer patients. Unfortunately, there are no established treatment regimens for this condition. Weight loss and fatigue consistently appear in patient oncologic histories and progress notes. However, few oncologists fully understand the pathologic mechanisms causing cachexia resulting in well-meaning advice to increase caloric intake with minimal results. Our goal is to describe the pathologic basis of cancer-induced cachexia and to detail accompanying metabolic derangements. Understanding the causes of cachexia sheds light on the subsequent need for multi-modality therapy including clinical intervention with specialized nutrition support, drug therapy, lifestyle and diet changes. In addition to nutrition support modalities, practicing oncologists may prescribe medical therapies designed to increase body weight and lean body mass, including megestrol acetate, tetrahydrocannibinol, oxandrolone, and non-steroidal anti-inflammatory drugs. A variety of experimental therapies are also being investigated for cancer-induced cachexia including tumor necrosis factor-alpha inhibitors and ghrelin infusions. We review the available data to support nutrition-oriented interventions in cancer-induced cachexia, including omega-3 fatty acids, amino-acid loading/protein supplementation, parenteral and enteral nutrition support, and food-derived compounds such as curcumin, reservatrol, and pomegranate. PMID:21420558

Preoperative cancer cachexia and short-term outcomes following surgery.

PubMed

Mason, Meredith C; Garcia, Jose M; Sansgiry, Shubhada; Walder, Annette; Berger, David H; Anaya, Daniel A

2016-10-01

Cancer cachexia is an important measure of physiologic reserve associated with worse survival and represents an actionable factor for the cancer population. However, the incidence of cachexia in surgical cancer patients and its impact on postoperative outcomes are currently unknown. A prospective cohort study enrolling patients having elective cancer surgery (2012-2014) at a Veterans Affairs tertiary referral center. Preoperative cancer cachexia (weight loss ≥5% over 6-mo period before surgery) was the predictor of interest. The primary outcome was 60-d postoperative complications (VA Surgical Quality Improvement Program). Patients were grouped by body mass index (BMI) category (<25, 25-29.9, ≥30), and interaction between cachexia and BMI was tested for the primary outcome. Multivariate logistic regression was used to examine the association between preoperative cachexia and postoperative complications. Of 253 patients, 16.6% had preoperative cachexia, and 51.8% developed ≥ 1 postoperative complications. Complications were more common in cachectic patients (64.3% versus 49.3%, P = 0.07). This association varied by BMI category, and interaction analysis was significant for those with normal or underweight BMI (BMI < 25, P = 0.03). After multivariate modeling, in patients with normal or underweight BMI, preoperative cachexia was associated with higher odds of postoperative complications (odds ratios, 5.08 [95% confidence intervals, 1.18-21.88]; P = 0.029). Additional predictors of complications included major surgery (3.19 [1.24-8.21], P = 0.01), ostomy (4.43 [1.68-11.72], P = 0.003), and poor baseline performance status (2.31 [1.05-5.08], P = 0.03). Cancer cachexia is common in surgical patients, and is an important predictor of postoperative complications, though its effect varies by BMI. As a modifiable predictor of worse outcomes, future studies should examine the role of cachexia treatment before cancer surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia.

PubMed

Michaelis, Katherine A; Zhu, Xinxia; Burfeind, Kevin G; Krasnow, Stephanie M; Levasseur, Peter R; Morgan, Terry K; Marks, Daniel L

2017-10-01

Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRAS G12D P53 R172H Pdx-Cre +/+ (KPC) mouse. Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone. Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study.

PubMed

Ebhardt, H Alexander; Degen, Simone; Tadini, Valentina; Schilb, Alain; Johns, Neil; Greig, Carolyn A; Fearon, Kenneth C H; Aebersold, Ruedi; Jacobi, Carsten

2017-08-01

Cancer cachexia (cancer-induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age-related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early. We used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH-MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy. We quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age-related muscle loss (aka age-related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration. The work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia.

PubMed

Greco, Stephanie H; Tomkötter, Lena; Vahle, Anne-Kristin; Rokosh, Rae; Avanzi, Antonina; Mahmood, Syed Kashif; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Ochi, Atsuo; Zambirinis, Constantinos; Mohaimin, Tasnima; Rendon, Mauricio; Levie, Elliot; Pansari, Mridul; Torres-Hernandez, Alejandro; Daley, Donnele; Barilla, Rocky; Pachter, H Leon; Tippens, Daniel; Malik, Hassan; Boutajangout, Allal; Wisniewski, Thomas; Miller, George

2015-01-01

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

[The Nutritional Care Experience of a Post-Operative Periampullary Cancer Patient With Cachexia].

PubMed

Liou, Yan-Ting; Chiang, Pin-Yi; Shun, Shiow-Ching

2016-04-01

Cachexia is one of the most widely overlooked of the syndromes that are experienced by cancer patients. This syndrome is especially prevalent among patients with gastroenterology tract cancer. Although the National Comprehensive Cancer Network (NCCN) issued palliative-care practice guidelines for cachexia in 2015, guidelines have yet to be issued for the clinical setting. The authors reviewed the literature and applied their clinical experience to create an approach for identifying the degree of cachexia in a post-operative patient with periampullary cancer. This approach assesses the nutritional status, physical status, laboratory results, and gastrointestinal system functions of the patient using the Cachexia Assessment Scale (CAS) and NCCN Practice Guidelines for Cachexia. The patient improved under nursing care with an increase in nutritional intake and physical activity facilitating their process of post-surgical physical recovery. The authors hope that this experience using the combined CAS-NCCN Practice Guidelines will help clinical caregivers better understand how to apply the relevant guidelines in clinical settings. The developed approach may help nurses assess the comprehensive nutrition status of patients and related factors in order to provide interventions that will decrease the progression of cachexia effectively and promote quality of life.

Omics/systems biology and cancer cachexia.

PubMed

Gallagher, Iain J; Jacobi, Carsten; Tardif, Nicolas; Rooyackers, Olav; Fearon, Kenneth

2016-06-01

Cancer cachexia is a complex syndrome generated by interaction between the host and tumour cells with a background of treatment effects and toxicity. The complexity of the physiological pathways likely involved in cancer cachexia necessitates a holistic view of the relevant biology. Emergent properties are characteristic of complex systems with the result that the end result is more than the sum of its parts. Recognition of the importance of emergent properties in biology led to the concept of systems biology wherein a holistic approach is taken to the biology at hand. Systems biology approaches will therefore play an important role in work to uncover key mechanisms with therapeutic potential in cancer cachexia. The 'omics' technologies provide a global view of biological systems. Genomics, transcriptomics, proteomics, lipidomics and metabolomics approaches all have application in the study of cancer cachexia to generate systems level models of the behaviour of this syndrome. The current work reviews recent applications of these technologies to muscle atrophy in general and cancer cachexia in particular with a view to progress towards integration of these approaches to better understand the pathology and potential treatment pathways in cancer cachexia. Copyright © 2016. Published by Elsevier Ltd.

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

PubMed Central

Rokosh, Rae; Avanzi, Antonina; Mahmood, Syed Kashif; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Ochi, Atsuo; Zambirinis, Constantinos; Mohaimin, Tasnima; Rendon, Mauricio; Levie, Elliot; Pansari, Mridul; Torres-Hernandez, Alejandro; Daley, Donnele; Barilla, Rocky; Pachter, H. Leon; Tippens, Daniel; Malik, Hassan; Boutajangout, Allal; Wisniewski, Thomas; Miller, George

2015-01-01

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival. PMID:26172047

Cachexia in children with chronic kidney disease: challenges in diagnosis and treatment.

PubMed

Mak, Robert H

2016-12-01

Although cachexia is highly prevalent in adult patients with chronic kidney disease (CKD), it is understudied and less well characterized in children. Recent evidence suggests that cachexia is also prevalent in children with CKD but presents challenges in diagnosis and treatment. A study from the CKD in children cohort showed that CKD cachexia or protein-energy wasting, using modified pediatric diagnostic criteria, such as lack of expected weight gain instead of weight loss and BMI for height age, had a prevalence of 7-20%. When growth indices such as height SD score (SDS)/height velocity SDS was included in the criteria, cachexia or PEW correlated with the morbidity outcome of increased hospitalization risk in children with CKD. Conversely, aggressive nutritional supplementation in children with advanced CKD, with nasogastric or gastric tube feeding, led to prevalence of obesity over that of cachexia. Body habitus of underweight and obesity have been shown to be associated with the worst clinical outcomes in both adults and children with CKD. Optimal nutritional therapy remains the mainstay of treatment of cachexia in CKD children with therapeutic goals of maintaining BMI as well as linear growth within the normal range.

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice.

PubMed

Narsale, Aditi A; Puppa, Melissa J; Hardee, Justin P; VanderVeen, Brandon N; Enos, Reilly T; Murphy, E Angela; Carson, James A

2016-09-13

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

PubMed Central

VanderVeen, Brandon N.; Enos, Reilly T.; Murphy, E. Angela; Carson, James A.

2016-01-01

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6. PMID:27449092

Omics and cachexia.

PubMed

Twelkmeyer, Brigitte; Tardif, Nicolas; Rooyackers, Olav

2017-05-01

The purpose of this review is to recapture recent advances in cachexia-related diseases, mainly cancer cachexia, and treatment using genomic, transcriptomics, proteomic, and metabolomics-related techniques. From recent studies in the cancer cachexia field it is clear that the tumor has a direct effect on distant organs via its secretome. The affected pathways on the other hand were largely known from earlier studies with changes in energy-related pathways (mainly lipid metabolism) and the protein degradation pathways. Treatment-oriented studies use mostly rodent models and in-vivo cultures and it is too early for human studies. Omics tools are powerful if used in the right way. Omics research has identified the tumor as an important player in cancer cachexia and some interesting novel treatments have been found in experimental models.

Highlights from the 9th Cachexia Conference.

PubMed

Ebner, Nicole; von Haehling, Stephan

2017-06-01

This article highlights updates of pathways as well as pre-clinical and clinical studies into the field of wasting disorders that were presented at the 9th Cachexia Conference held in Berlin, Germany, December 2016. This year, some interesting results from clinical trials and different new therapeutic targets were shown. This article presents the biological and clinical significance of different markers and new diagnostic tools and cut-offs of detecting skeletal muscle wasting. Effective treatments of cachexia and wasting disorders are urgently needed in order to improve the patients' quality of life and their survival. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Mechanisms and treatment of cancer cachexia.

PubMed

Argilés, J M; López-Soriano, F J; Busquets, S

2013-12-01

According to a recent consensus, cachexia is a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss. Cachexia occurs in the majority of terminal cancer patients and it is responsible for the deaths of 22% of cancer patients. Although body weight is, indeed, an important factor to be taken into consideration in any cachexia treatment, body composition, physical performance and quality of life should be monitored. From the results presented here, one can speculate that a single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. The objectives of any therapeutical combination are two: an anticatabolic aim directed towards both fat and muscle catabolism and an anabolic objective leading to the synthesis of macromolecules such as contractile proteins. Copyright © 2012 Elsevier B.V. All rights reserved.

PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer.

PubMed

Kir, Serkan; Komaba, Hirotaka; Garcia, Ana P; Economopoulos, Konstantinos P; Liu, Wei; Lanske, Beate; Hodin, Richard A; Spiegelman, Bruce M

2016-02-09

Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia. Copyright © 2016 Elsevier Inc. All rights reserved.

Definition and classification of cancer cachexia: an international consensus.

PubMed

Fearon, Kenneth; Strasser, Florian; Anker, Stefan D; Bosaeus, Ingvar; Bruera, Eduardo; Fainsinger, Robin L; Jatoi, Aminah; Loprinzi, Charles; MacDonald, Neil; Mantovani, Giovanni; Davis, Mellar; Muscaritoli, Maurizio; Ottery, Faith; Radbruch, Lukas; Ravasco, Paula; Walsh, Declan; Wilcock, Andrew; Kaasa, Stein; Baracos, Vickie E

2011-05-01

To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] <20 kg/m(2)) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages--precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective

PubMed Central

Sanders, Karin J. C.; Kneppers, Anita E. M.; van de Bool, Coby; Langen, Ramon C. J.

2015-01-01

Abstract Cachexia and muscle wasting are well recognized as common and partly reversible features of chronic obstructive pulmonary disease (COPD), adversely affecting disease progression and prognosis. This argues for integration of weight and muscle maintenance in patient care. In this review, recent insights are presented in the diagnosis of muscle wasting in COPD, the pathophysiology of muscle wasting, and putative mechanisms involved in a disturbed energy balance as cachexia driver. We discuss the therapeutic implications of these new insights for optimizing and personalizing management of COPD‐induced cachexia. PMID:27066314

The wasting continuum in heart failure: from sarcopenia to cachexia.

PubMed

von Haehling, Stephan

2015-11-01

Sarcopenia (muscle wasting) and cachexia share some pathophysiological aspects. Sarcopenia affects approximately 20 %, cachexia <10 % of ambulatory patients with heart failure (HF). Whilst sarcopenia means loss of skeletal muscle mass and strength that predominantly affects postural rather than non-postural muscles, cachexia means loss of muscle and fat tissue that leads to weight loss. The wasting continuum in HF implies that skeletal muscle is lost earlier than fat tissue and may lead from sarcopenia to cachexia. Both tissues require conservation, and therapies that stop the wasting process have tremendous therapeutic appeal. The present paper reviews the pathophysiology of muscle and fat wasting in HF and discusses potential treatments, including exercise training, appetite stimulants, essential amino acids, growth hormone, testosterone, electrical muscle stimulation, ghrelin and its analogues, ghrelin receptor agonists and myostatin antibodies.

The nursing contribution to nutritional care in cancer cachexia.

PubMed

Hopkinson, Jane B

2015-11-01

Cancer cachexia is a complex syndrome. Its defining feature is involuntary weight loss, which arises, in part, because of muscle atrophy and is accompanied by functional decline. International expert consensus recommends that nutritional support and counselling is a component of multimodal therapy for cancer cachexia, as poor nutritional intake can contribute to progression of the syndrome. The present paper focuses on what is presently known about the nursing contribution to nutritional care in cancer cachexia. There is potential for nurses to play an important role. However, obstacles to this include lack of a robust evidence base to support their nutritional care practices and unmet need for education about nutrition in cancer. The nursing role's boundaries and the outcomes of nurse-delivered nutritional care in cancer cachexia are both uncertain and should be investigated.

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

PubMed

Fukawa, Tomoya; Yan-Jiang, Benjamin Chua; Min-Wen, Jason Chua; Jun-Hao, Elwin Tan; Huang, Dan; Qian, Chao-Nan; Ong, Pauline; Li, Zhimei; Chen, Shuwen; Mak, Shi Ya; Lim, Wan Jun; Kanayama, Hiro-Omi; Mohan, Rosmin Elsa; Wang, Ruiqi Rachel; Lai, Jiunn Herng; Chua, Clarinda; Ong, Hock Soo; Tan, Ker-Kan; Ho, Ying Swan; Tan, Iain Beehuat; Teh, Bin Tean; Shyh-Chang, Ng

2016-06-01

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.

White adipose tissue IFN-γ expression and signalling along the progression of rodent cancer cachexia.

PubMed

Yamashita, Alex Shimura; das Neves, Rodrigo Xavier; Rosa-Neto, José Cesar; Lira, Fábio Dos Santos; Batista, Miguel Luís; Alcantara, Paulo Sérgio; Otoch, José Pinhata; Seelaender, Marília

2017-01-01

Cachexia is associated with increased morbidity and mortality in cancer. The White adipose tissue (WAT) synthesizes and releases several pro-inflammatory cytokines that play a role in cancer cachexia-related systemic inflammation. IFN-γ is a pleiotropic cytokine that regulates several immune and metabolic functions. To assess whether IFN-γ signalling in different WAT pads is modified along cancer-cachexia progression, we evaluated IFN-γ receptors expression (IFNGR1 and IFNGR2) and IFN-γ protein expression in a rodent model of cachexia (7, 10, and 14days after tumour implantation). IFN-γ protein expression was heterogeneously modulated in WAT, with increases in the mesenteric pad and decreased levels in the retroperitoneal depot along cachexia progression. Ifngr1 was up-regulated 7days after tumour cell injection in mesenteric and epididymal WAT, but the retroperitoneal depot showed reduced Ifngr1 gene expression. Ifngr2 gene expression was increased 7 and 14days after tumour inoculation in mesenteric WAT. The results provide evidence that changes in IFN-γ expression and signalling may be perceived at stages preceding refractory cachexia, and therefore, might be employed as a means to assess the early stage of the syndrome. Copyright © 2016 Elsevier Ltd. All rights reserved.

TNF-α and cancer cachexia: Molecular insights and clinical implications.

PubMed

Patel, Hetal J; Patel, Bhoomika M

2017-02-01

Cancer cachexia characterized by a chronic wasting syndrome, involves skeletal muscle loss and adipose tissue loss and resistance to conventional nutritional support. Cachexia is responsible for the reduction in quality and length of life of cancer patients. It also decreases the muscle strength of the patients. The pro-inflammatory and pro-cachectic factors produced by the tumor cells have important role in genesis of cachexia. A number of pro-inflammatory cytokines, like interleukin-1 (IL-1), IL-6, tumor necrosis factor- alpha (TNF-α) may have important role in the pathological mechanisms of cachexia in cancer. Particularly, TNF-α has a direct catabolic effect on skeletal muscle and causes wasting of muscle by the induction of the ubiquitin-proteasome system (UPS). In cancer cachexia condition, there is alteration in carbohydrate, protein and fat metabolism. TNF-α is responsible for the increase in gluconeogenesis, loss of adipose tissue and proteolysis, while causing decrease in protein, lipid and glycogen synthesis. It has been associated with the formation of IL-1 and increases the uncoupling protein-2 (UCP2) and UCP3 expression in skeletal muscle in cachectic state. The main aim of the present review is to evaluate and discuss the role of TNF-α in different metabolic alterations and muscle wasting in cancer cachexia. Copyright © 2016 Elsevier Inc. All rights reserved.

Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia

PubMed Central

Yang, Quan‐Jun; Zhao, Jiang‐Rong; Hao, Juan; Li, Bin; Huo, Yan; Han, Yong‐Long; Wan, Li‐Li; Li, Jie; Huang, Jinlu; Lu, Jin

2017-01-01

Abstract Background Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance‐based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model. Methods Eighty‐four cancer cachexia patients, 33 pre‐cachectic patients, 105 weight‐stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model. Results Forty‐six cancer cachexia patients, 22 pre‐cachectic patients, 68 weight‐stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre‐cachectic patients, 37 weight‐stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age‐matched and sex‐matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = −400.53 – 481.88 × log(Carnosine) −239.02 × log(Leucine) + 383.92 × log(Phenyl acetate), and the result showed 94.64% accuracy in the validation set. Conclusions This metabolomics study revealed a distinct metabolic profile of cancer cachexia and established and validated a diagnostic model. This research provided a feasible diagnostic tool for identifying at‐risk populations through the detection of serum metabolites. PMID:29152916

Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benny Klimek, Margaret E.; Aydogdu, Tufan; Link, Majik J.

2010-01-15

Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely.more » The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.« less

Aliskiren targets multiple systems to alleviate cancer cachexia.

PubMed

Wang, Chaoyi; Guo, Dunwei; Wang, Qiang; You, Song; Qiao, Zhongpeng; Liu, Yong; Dai, Hang; Tang, Hua

2016-11-01

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia.

PubMed

Benny Klimek, Margaret E; Aydogdu, Tufan; Link, Majik J; Pons, Marianne; Koniaris, Leonidas G; Zimmers, Teresa A

2010-01-15

Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia. Copyright 2009 Elsevier Inc. All rights reserved.

Biomarkers for cardiac cachexia: reality or utopia.

PubMed

Martins, Telma; Vitorino, Rui; Amado, Francisco; Duarte, José Alberto; Ferreira, Rita

2014-09-25

Cardiac cachexia is a serious complication of chronic heart failure, characterized by significant weight loss and body wasting. Chronic heart failure-related muscle wasting results from a chronic imbalance in the activation of anabolic or catabolic pathways, caused by a series of immunological, metabolic, and neurohormonal processes. In spite of the high morbidity and mortality associated to this condition, there is no universally accepted definition or specific biomarkers for cardiac cachexia, which makes its diagnosis and treatment difficult. Several hormonal, inflammatory and oxidative stress molecules have been proposed as serological markers of prognosis in cardiac cachexia but with doubtful success. As individual biomarkers may have limited sensitivity and specificity, multimarker strategies involving mediators of the biological processes modulated by cardiac cachexia will strongly contribute for the diagnosis and management of the disease, as well as for the establishment of new therapeutic targets. An integrated analysis of the biomarkers proposed so far for cardiac cachexia is made in the present review, highlighting the biological processes to which they are related. Copyright © 2014 Elsevier B.V. All rights reserved.

Mitochondrial plasticity in cancer-related muscle wasting: potential approaches for its management.

PubMed

Vitorino, Rui; Moreira-Gonçalves, Daniel; Ferreira, Rita

2015-05-01

Cancer cachexia represents a critical problem in clinical oncology due to its negative impact on patients' quality of life, therapeutic tolerance and survival. This paraneoplasic condition is characterized by significant weight loss mainly from skeletal muscle wasting. Understanding the molecular mechanisms underlying cancer cachexia is urgent in order to develop and apply efficient therapeutic strategies. Mitochondrial dysfunction is an early event in cancer-induced muscle wasting. Decreased ability for ATP synthesis, impaired mitochondrial biogenesis, increased oxidative stress, impairment of protein quality control systems, increased susceptibility to mitophagy and to apoptosis were all shown to mediate contractile dysfunction and wasting in cancer cachexia. Anti-inflammatory therapies as well as exercise training seem to counteract muscle mass loss in part by improving mitochondrial functionality. Given its central role in muscle wasting, mitochondrial plasticity should be viewed as a key therapeutic target for the preservation of muscle mass in cancer cachexia. Few studies have addressed the mitochondrial events modulated by cancer cachexia and contradictory data were reported. Scarcer studies have focused on the mitochondrial adaptation to anticancer cachexia strategies.

Practical multimodal care for cancer cachexia.

PubMed

Maddocks, Matthew; Hopkinson, Jane; Conibear, John; Reeves, Annie; Shaw, Clare; Fearon, Ken C H

2016-12-01

Cancer cachexia is common and reduces function, treatment tolerability and quality of life. Given its multifaceted pathophysiology a multimodal approach to cachexia management is advocated for, but can be difficult to realise in practice. We use a case-based approach to highlight practical approaches to the multimodal management of cachexia for patients across the cancer trajectory. Four cases with lung cancer spanning surgical resection, radical chemoradiotherapy, palliative chemotherapy and no anticancer treatment are presented. We propose multimodal care approaches that incorporate nutritional support, exercise, and anti-inflammatory agents, on a background of personalized oncology care and family-centred education. Collectively, the cases reveal that multimodal care is part of everyone's remit, often focuses on supported self-management, and demands buy-in from the patient and their family. Once operationalized, multimodal care approaches can be tested pragmatically, including alongside emerging pharmacological cachexia treatments. We demonstrate that multimodal care for cancer cachexia can be achieved using simple treatments and without a dedicated team of specialists. The sharing of advice between health professionals can help build collective confidence and expertise, moving towards a position in which every team member feels they can contribute towards multimodal care.

Disrupted Skeletal Muscle Mitochondrial Dynamics, Mitophagy, and Biogenesis during Cancer Cachexia: A Role for Inflammation

PubMed Central

VanderVeen, Brandon N.; Fix, Dennis K.

2017-01-01

Chronic inflammation is a hallmark of cancer cachexia in both patients and preclinical models. Cachexia is prevalent in roughly 80% of cancer patients and accounts for up to 20% of all cancer-related deaths. Proinflammatory cytokines IL-6, TNF-α, and TGF-β have been widely examined for their regulation of cancer cachexia. An established characteristic of cachectic skeletal muscle is a disrupted capacity for oxidative metabolism, which is thought to contribute to cancer patient fatigue, diminished metabolic function, and muscle mass loss. This review's primary objective is to highlight emerging evidence linking cancer-induced inflammation to the dysfunctional regulation of mitochondrial dynamics, mitophagy, and biogenesis in cachectic muscle. The potential for either muscle inactivity or exercise to alter mitochondrial dysfunction during cancer cachexia will also be discussed. PMID:28785374

Update on Management of Cancer-Related Cachexia.

PubMed

Anderson, Lindsey J; Albrecht, Eliette D; Garcia, Jose M

2017-01-01

Cachexia is a metabolic syndrome driven by inflammation and characterized by loss of muscle with or without loss of fat mass. In cancer cachexia, the tumor burden and host response induce increased inflammation, decreased anabolic tone, and suppressed appetite leading to the clinical presentation of reduced body weight and quality of life (QOL). There is no approved treatment for cancer cachexia, and commonly used nutritional and anti-inflammatory strategies alone have proven ineffective for management of symptoms. Several other pharmacological agents are currently in development and have shown promise as a clinical strategy in early-phase trials. Recently, it has been proposed that multimodal strategies, with an anabolic focus, initiated early in the disease/treatment progression may provide the most therapeutic potential for symptom management. Here we review the data from recent clinical trials in cancer cachexia including pharmacological, exercise, and nutritional interventions.

The complex liaison between cachexia and tumor burden (Review).

PubMed

De Lerma Barbaro, Andrea

2015-10-01

Cachexia is a wasting syndrome that afflicts end-stage cancer patients. Whereas a consensus statement for a definition of cachexia recently has been accomplished, a useful measurement for this condition at present is lacking. The aim of the present review is to discuss the advantage of introducing the measurement of tumor burden for a better overall evaluation of cachexia. Our suggestion ensues from a somewhat novel perspective in the field of infectious disease research where a careful measurement of the pathogen load, between i.e. different host genotypes, leads to the definition of the concept of tolerance to the infectious insult. Indeed tolerance concurs, together the more classical resistance, in maintaining the host reproductive fitness or health state. Noticeably a similar reasoning may apply to tumor biology as well. Whereas the extent of cachexia increases with tumor burden, the relationship between these two correlates of tumor progression fluctuates in a broad range. We have selected from the literature studies in the rodent model where significant variation in the course of the wasting illness during cancer was observed and quantitatively assessed comparing experimental groups marked by different genotype, drug treatment, diet or gender. These studies may be further classified in two categories: the former where the experimental condition associated to milder cachexia is accompanied to a lesser tumor burden, the latter where the inhibition of cachexia results disentangled from the tumor burden, that is the whole number of cancer cells results unchanged or even, paradoxically, is increased. In addition we survey, even in the context of human malignancy, the significance and feasibility of plotting quantitative estimates of cachexia against the whole tumor burden. Ultimately, the principal endeavor of introducing the measurement of tumor burden, in both experimental and clinical oncology, may be to achieve a better assessment of the inter-individual variation in the host vulnerability to cancer cachexia.

New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss.

PubMed

Johns, Neil; Stretch, Cynthia; Tan, Benjamin H L; Solheim, Tora S; Sørhaug, Sveinung; Stephens, Nathan A; Gioulbasanis, Ioannis; Skipworth, Richard J E; Deans, D A Christopher; Vigano, Antonio; Ross, James A; Bathe, Oliver F; Tremblay, Michel L; Kaasa, Stein; Strasser, Florian; Gagnon, Bruno; Baracos, Vickie E; Damaraju, Sambasivarao; Fearon, Kenneth C H

2017-02-01

Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/- computerized tomography-defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype METHODS: A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform. Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle-specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05). The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro-inflammatory cytokines and the renin-angiotensin system as biomarkers/mediators of muscle wasting in cachexia. © 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Animal models of cachexia and sarcopenia in chronic illness: Cardiac function, body composition changes and therapeutic results.

PubMed

Ishida, Junichi; Saitoh, Masakazu; Doehner, Wolfram; von Haehling, Stephan; Anker, Markus; Anker, Stefan D; Springer, Jochen

2017-07-01

Cachexia is defined as a complex metabolic syndrome associated with underlying illness that is characterized by the loss of body weight consisting of muscle and fat mass wasting. Sarcopenia is defined as the ageing related loss of muscle mass in health and disease that may not have an effect on body weight. As millions of patients are in cachectic or sarcopenic states, both conditions contribute to high numbers to death worldwide. A number of treatments have been proposed for cachexia and sarcopenia, but these are either in the preclinical stage or in clinical trials and hence not available to the general population. Particularly in cachexia there is a massive problem of recruiting patients for trials and also with the follow-up, due to the seriousness of the disease. This underlines the importance of well-characterized animal models. Obviously, most of the widely used cachexia and sarcopenia animal models have limitations in reproducibility of the condition and novel models are warranted in this context. The key findings of developing models in the field of cachexia and sarcopenia are that more types of the conditions have been taken into the researchers' interest. In cardiac cachexia, technical issues, which limit the preciseness and reproducibility in surgical heart failure models, have been overcome by a combination of surgery and the use of transgenic mouse models or salt sensitive rat models. Fatigue is the most pronounced symptom of cachexia and may be caused by reduced cardiac function independent of the underlying disease. Sarcopenia models often suffer from the use of young animals, due to the limited availability and very high costs of using aged animals. This review will focus on rodent models designed to mimic cachexia and sarcopenia including co-morbidities such as cancer, heart failure, as well as other diseases and conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

Liver Inflammation and Metabolic Signaling in ApcMin/+ Mice: The Role of Cachexia Progression

PubMed Central

Narsale, Aditi A.; Enos, Reilly T.; Puppa, Melissa J.; Chatterjee, Saurabh; Murphy, E. Angela; Fayad, Raja; Pena, Majorette O’; Durstine, J. Larry; Carson, James A.

2015-01-01

The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-κB (Nuclear factor—κB) signaling. PMID:25789991

New strategies to overcome cancer cachexia: from molecular mechanisms to the 'Parallel Pathway'.

PubMed

Muscaritoli, Maurizio; Costelli, Paola; Aversa, Zaira; Bonetto, Andrea; Baccino, Francesco Maria; Rossi Fanelli, Filippo

2008-01-01

Cancer has always a negative impact on nutritional status, weight loss being a common feature in patients with neoplastic diseases. If left untreated, weight loss may evolve into cancer cachexia, a complex syndrome characterized by marked depletion of body weight, associated with profound alterations of both nutritional status and metabolic homeostasis. Progressive wasting of skeletal muscle mass and adipose tissue is a typical feature of cancer cachexia. Cachexia has a large impact on morbidity and mortality, and significantly affects patients' response and tolerance to treatments and quality of life. On this line, understanding the pathogenic mechanisms of cachexia is of crucial importance to define targeted therapeutic strategies. Well structured, systematic and timely appropriate nutritional intervention in cancer patients is of pivotal importance. Indeed, it has been shown that malnutrition in cancer patients can be delayed when nutritional supplementation is adopted early in the course of the disease. The preservation of a good nutritional status, in particular when it is achieved concurrently with specific antineoplastic treatments, will prevent or at least delay the onset of overt cachexia, allowing the use of more aggressive therapeutic regimens. The inclusion of specific, metabolically active nutritional substrates, such as branched chain amino acids or eicosapentaenoic acid may be helpful in interfering with the mechanisms responsible for the metabolic alterations and the perturbations of molecular pathways ultimately leading to the clinical picture of cancer cachexia.

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

PubMed Central

Miao, Chunxiao; Lv, Yuanyuan; Zhang, Wanli; Chai, Xiaoping; Feng, Lixing; Fang, Yanfen; Liu, Xuan; Zhang, Xiongwen

2017-01-01

Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC) was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia. PMID:29311924

Cancer cachexia: global awareness and guideline implementation on the web.

PubMed

Mauri, Davide; Tsiara, Anna; Valachis, Antonis; Kalopita, Konstantina; Tsali, Lampriani; Tolis, Panagiotis; Polyzos, Nikolaos P

2013-06-01

Cancer cachexia is a common associate of cancer and has a negative impact on patients' survival. Nonetheless, cancer cachexia assessment and management are frequently less than satisfactory in daily practice. To scrutinise global cancer cachexia awareness and relative web guideline implementation among oncology societies. Systematical identification of scientific and policymaker oncology societies and their guideline implementation on cancer cachexia. Assessment of the general level of awareness on cancer cachexia and evaluation of intercontinental and national variations on guideline implementation. 144,000 web pages were scrutinised, and 275 oncology societies identified covering a large array of oncology setting (educational/clinical/research/policymaker); 71 were international (African, American, Asian, European, Oceania and Intercontinental), 110 belonged to the top 10 countries with the highest development index and 94 pertained to 10 countries with a long lasting tradition in medical oncology (not included in the top 10 high developed countries). Overall, only 10/275 web sites provided guidelines; six of them (2.2%) provided guidelines for physicians and four (0.7%) for patients. Half of the guidelines (4/10) were outdated. All guidelines for physicians reported references, while only one of the recommendations for patients reported references to support its sentences. Cancer cachexia global awareness appears extremely low; guideline implementation on the web was inconsistent for any category analysed (nation vs continent vs international vs society type vs physician vs patient oriented) and for updating.

Validation of the Chinese version of functional assessment of anorexia-cachexia therapy (FAACT) scale for measuring quality of life in cancer patients with cachexia.

PubMed

Zhou, Ting; Yang, Kaixiang; Thapa, Sudip; Fu, Qiang; Jiang, Yongsheng; Yu, Shiying

2017-04-01

The assessment of quality of life (QOL) is an important part of cachexia management for cancer patients. Functional assessment of anorexia-cachexia therapy (FAACT), a specific QOL instrument for cachexia patients, has not been validated in Chinese population. The aim of this study was to validate the FAACT scale in Chinese cancer patients for its future use. Eligible cancer patients were included in our study. Patients' demographic and clinical characteristics were collected from the electronic medical records. Patients were asked to complete the Chinese version of FAACT scale and the MD Anderson symptom inventory (MDASI), and then the reliability and validity were analyzed. A total of 285 patients were enrolled in our study, data of 241 patients were evaluated. Coefficients of Cronbach's alpha, test-retest and split-half analyses were all greater than 0.8, which indicated an excellent reliability for FAACT scale. In item-subscale correlation analysis and factor analysis, good construct validity for FAACT scale was found. The correlation between FAACT and MDASI interference subscale showed reasonable criterion-related validity, and for further clinical validation, the FAACT scale showed excellent discriminative validity for distinguishing patients in different cachexia status and in different performance status. The Chinese version of FAACT scale has good reliability and validity and is suitable for measuring QOL of cachexia patients in Chinese population.

Bioelectrical impedance analysis for diagnosing sarcopenia and cachexia: what are we really estimating?

PubMed

Gonzalez, Maria Cristina; Heymsfield, Steven B

2017-04-01

As reference methods are not available for identifying low skeletal muscle mass in clinical practice, the European Group on Sarcopenia in Older People the Asian Working Group for Sarcopenia and the International Consensus for Cancer Cachexia guidelines accept bioelectrical impedance analysis (BIA) as an option for sarcopenia and cachexia assessment. Using different BIA equations, several components that represent 'muscularity' can be assessed. Total skeletal muscle mass or appendicular skeletal muscle mass normalized in relation to height (skeletal muscle mass index or appendicular skeletal muscle index, respectively) is the most common term used in the consensus. These terms are similar, but they should not be used as synonymous. Both terms can be used to define sarcopenia, but adequate equations and cut-off values should be used according to the studied population. However, there is a disagreement between the sarcopenia definition assessed by using BIA from the European Group on Sarcopenia in Older People and Cachexia Consensus, and this can lead to an overestimation of sarcopenia and, consequently, cachexia. An effort should be made to standardize the terminology employed by the Societies to define low muscularity and sarcopenia by using BIA. Future validation studies may show the need for specific cut-off values for each population using this method. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Advanced Cancer Detection Center

DTIC Science & Technology

2009-01-01

Hydrochloride (Periactin®), With and Without a Nutritional Supplement, PediaSure, on Weight in Children with Cancer/Treatment Related Cachexia (HLMCC 0702...Prevention of Cancer/Treatment-Related Cachexia in Children Receiving Moderate to Highly Emetic Chemotherapy (HLMCC 0703) • Modafinil to Improve...hydrochloride (periactin) and megestrol acetate (megace) on weight in children with cancer/treatment-related cachexia . J Pediatr Hematol Oncol. 30(11

Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2‐independent mechanisms, unlike muscular dystrophy

PubMed Central

Suzuki, Nobuyuki; Ohtake, Hitomi; Kamauchi, Shinya; Hashimoto, Naohiro; Kiyono, Tohru; Wakabayashi, Shigeo

2015-01-01

Abstract Background Muscle wasting during cancer cachexia contributes to patient morbidity. Cachexia‐induced muscle damage may be understood by comparing its symptoms with those of other skeletal muscle diseases, but currently available data are limited. Methods We modelled cancer cachexia in mice bearing Lewis lung carcinoma/colon adenocarcinoma and compared the associated muscle damage with that in a murine muscular dystrophy model (mdx mice). We measured biochemical and immunochemical parameters: amounts/localization of cytoskeletal proteins and/or Ca2+ signalling proteins related to muscle function and abnormality. We analysed intracellular Ca2+ mobilization and compared results between the two models. Involvement of Ca2+‐permeable channel transient receptor potential vanilloid 2 (TRPV2) was examined by inoculating Lewis lung carcinoma cells into transgenic mice expressing dominant‐negative TRPV2. Results Tumourigenesis caused loss of body and skeletal muscle weight and reduced muscle force and locomotor activity. Similar to mdx mice, cachexia muscles exhibited myolysis, reduced sarcolemmal sialic acid content, and enhanced lysosomal exocytosis and sarcolemmal localization of phosphorylated Ca2+/CaMKII. Abnormal autophagy and degradation of dystrophin also occurred. Unlike mdx muscles, cachexia muscles did not exhibit regeneration markers (centrally nucleated fibres), and levels of autophagic proteolytic pathway markers increased. While a slight accumulation of TRPV2 was observed in cachexia muscles, Ca2+ influx via TRPV2 was not elevated in cachexia‐associated myotubes, and the course of cachexia pathology was not ameliorated by dominant‐negative inhibition of TRPV2. Conclusions Thus, cancer cachexia may induce muscle damage through TRPV2‐independent mechanisms distinct from those in muscular dystrophy; this may help treat patients with tumour‐induced muscle wasting. PMID:27239414

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

PubMed Central

Bonetto, Andrea; Kays, Joshua K.; Parker, Valorie A.; Matthews, Ryan R.; Barreto, Rafael; Puppa, Melissa J.; Kang, Kyung S.; Carson, James A.; Guise, Theresa A.; Mohammad, Khalid S.; Robling, Alexander G.; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.

2017-01-01

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia. PMID:28123369

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

PubMed Central

Ebhardt, H. Alexander; Degen, Simone; Tadini, Valentina; Schilb, Alain; Johns, Neil; Greig, Carolyn A.; Fearon, Kenneth C.H.; Aebersold, Ruedi

2017-01-01

Abstract Background Cancer cachexia (cancer‐induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age‐related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early. Methods We used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH‐MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy. Results We quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age‐related muscle loss (aka age‐related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration. Conclusions The work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature. PMID:28296247

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia.

PubMed

Bonetto, Andrea; Kays, Joshua K; Parker, Valorie A; Matthews, Ryan R; Barreto, Rafael; Puppa, Melissa J; Kang, Kyung S; Carson, James A; Guise, Theresa A; Mohammad, Khalid S; Robling, Alexander G; Couch, Marion E; Koniaris, Leonidas G; Zimmers, Teresa A

2016-01-01

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and Apc Min/+ . The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the Apc Min/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

Cachexia in cancer: what is in the definition?

PubMed Central

Vanhoutte, Greetje; van de Wiel, Mick; Wouters, Kristin; Sels, Michaël; Bartolomeeussen, Linda; De Keersmaecker, Sven; Verschueren, Caroline; De Vroey, Veronique; De Wilde, Annemieke; Smits, Elke; Cheung, Kin Jip; De Clerck, Liesbeth; Aerts, Petra; Baert, Didier; Vandoninck, Caroline; Kindt, Sofie; Schelfhaut, Sofie; Vankerkhoven, Marc; Troch, Annelies; Ceulemans, Lore; Vandenbergh, Hanne; Leys, Sven; Rondou, Tim; Dewitte, Elke; Maes, Kristel; Pauwels, Patrick; De Winter, Benedicte; Van Gaal, Luc; Ysebaert, Dirk; Peeters, Marc

2016-01-01

Objective This study aimed to provide evidence-based results on differences in overall survival (OS) rate to guide the diagnosis of cancer cachexia. Design Data collection and clinical assessment was performed every 3 months (5 visits): baseline data, muscle strength, nutritional and psychosocial status. 2 definitions on cachexia using different diagnostic criteria were applied for the same patient population. Fearon et al's definition is based on weight loss, body mass index (BMI) and sarcopenia. Evans et al nuances the contribution of sarcopenia and attaches additional attention to abnormal biochemistry parameters, fatigue and anorexia. The mean OS rates were compared between patients with and without cachexia for both definitions. Results Based on the population of 167 patients who enrolled, 70% developed cachexia according to Fearon et al's definition and 40% according to Evans et al's definition. The OS in the cachectic population is 0.97 and 0.55 years, respectively. The difference in OS between patients with and without cachexia is more significant using the diagnostic criteria of Evans et al. The focus of Fearon et al on weight loss and sarcopenia over-rates the assignment of patients to the cachectic group and OS rates have less prognostic value. Conclusion This study presents a correlation with prognosis in favour of Evans et al’ definition as a tool for cachexia diagnosis. This means that weight loss and BMI decline are both key factors in patients with cancer leading to cachexia but less decisive as stated by Fearon et al. Instead, extra factors gain importance in order to predict survival, such as chronic inflammation, anaemia, protein depletion, reduced food intake, fatigue, decreased muscle strength and lean tissue depletion. Trial registration number B300201112334. PMID:27843571

Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation.

PubMed

Quan-Jun, Yang; Yan, Huo; Yong-Long, Han; Li-Li, Wan; Jie, Li; Jin-Lu, Huang; Jin, Lu; Peng-Guo, Chen; Run, Gan; Cheng, Guo

2017-02-01

Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases, and MEK/ERK-related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases, MuRF1 and Fbx32, was inhibited following selumetinib treatment of the gastrocnemius muscle. Furthermore, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake, and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed analysis of the mechanism revealed AKT and mTOR were activated, while ERK, FoxO3a, and GSK3β were inhibited in the selumetinib -treated cachexia group. These indicated that selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in gastrocnemius muscle via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia. Mol Cancer Ther; 16(2); 334-43. ©2016 AACR. ©2016 American Association for Cancer Research.

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer.

PubMed

Solheim, Tora S; Laird, Barry J A; Balstad, Trude Rakel; Stene, Guro B; Bye, Asta; Johns, Neil; Pettersen, Caroline H; Fallon, Marie; Fayers, Peter; Fearon, Kenneth; Kaasa, Stein

2017-10-01

Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n-3 polyunsaturated fatty acid nutritional supplements, exercise, and anti-inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy. Patients receiving two cycles of standard chemotherapy were randomized to either the multimodal cachexia intervention or standard care. Primary outcome measures were feasibility assessed by recruitment, attrition, and compliance with intervention (>50% of components in >50% of patients). Key secondary outcomes were change in weight, muscle mass, physical activity, safety, and survival. Three hundred and ninety-nine were screened resulting in 46 patients recruited (11.5%). Twenty five patients were randomized to the treatment and 21 as controls. Forty-one completed the study (attrition rate 11%). Compliance to the individual components of the intervention was 76% for celecoxib, 60% for exercise, and 48% for nutritional supplements. As expected from the sample size, there was no statistically significant effect on physical activity or muscle mass. There were no intervention-related Serious Adverse Events and survival was similar between the groups. A multimodal cachexia intervention is feasible and safe in patients with incurable lung or pancreatic cancer; however, compliance to nutritional supplements was suboptimal. A phase III study is now underway to assess fully the effect of the intervention. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

A systematic review and thematic synthesis of quality of life in the informal carers of cancer patients with cachexia.

PubMed

Wheelwright, Sally; Darlington, Anne-Sophie; Hopkinson, Jane B; Fitzsimmons, Deborah; Johnson, Colin

2016-02-01

Informal carers of cancer patients with cachexia face additional challenges to those encountered by informal carers in general because of the central role food and eating play in everyday life. Patient weight loss and anorexia, core features of cancer cachexia, are frequent causes of distress in caregivers. Identification of quality of life issues can inform the development of interventions for both caregivers and patients and facilitate communication with healthcare professionals. To identify quality of life issues that are relevant to carers of cancer patients with cachexia. A systematic review and thematic synthesis of the qualitative literature were conducted. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, ISI Web of Knowledge, EMBASE, MEDLINE, CINAHL, PsycINFO and PsycARTICLES were searched for publications dated from January 1980 to February 2015 using search terms relating to cancer, cachexia, quality of life and carers. Papers written in the English language, featuring direct quotes from the carers of adult patients with any cancer diagnosis and cachexia or problems with weight loss or anorexia, were included. Five themes were extracted from the 16 identified studies. These highlighted the impact on everyday life, the attempts of some carers to take charge, the need for healthcare professional's input, conflict with the patient and negative emotions. The complexity of caring for a cancer patient with cachexia translates into a range of problems and experiences for informal carers. By addressing the impact of caring for a patient with cancer cachexia on carers, both caregiver and patient quality of life may improve. © The Author(s) 2015.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

PubMed Central

Michaelis, Katherine A.; Zhu, Xinxia; Burfeind, Kevin G.; Krasnow, Stephanie M.; Levasseur, Peter R.; Morgan, Terry K.

2017-01-01

Abstract Background Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC‐associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx‐Cre+/+ (KPC) mouse. Methods Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. Results All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil‐dominant leukocytosis and anaemia, and decreased serum testosterone. Conclusions Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies. PMID:28730707

Malnutrition and cachexia in patients with head and neck cancer treated with (chemo)radiotherapy

PubMed Central

Gorenc, Mojca; Kozjek, Nada Rotovnik; Strojan, Primož

2015-01-01

Aim To highlight the problems associated with nutrition that occur in patients with squamous cell carcinoma of the head and neck (SCCHN). Background SCCHN is associated with weight loss before, during and after radiotherapy or concurrent chemoradiotherapy. Because of serious consequences of malnutrition and cachexia on treatment outcome, mortality, morbidity, and quality of life, it is important to identify SCCHN patients with increased risk for the development of malnutrition and cachexia. Materials and methods Critical review of the literature. Results This review describes pathogenesis, diagnosis and treatment of malnutrition and cancer cachexia. Treatment of malnutrition and cancer cachexia includes nutritional interventions and pharmacological therapy. Advantages and disadvantages of different nutritional interventions and their effect on the nutritional status, quality of life and specific oncological treatment are presented. Conclusions Nutritional management is an essential part of care of these patients, including early screening, assessment of nutritional status and appropriate intervention. PMID:26109912

Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies.

PubMed

Dodson, Shontelle; Baracos, Vickie E; Jatoi, Aminah; Evans, William J; Cella, David; Dalton, James T; Steiner, Mitchell S

2011-01-01

Cancer cachexia is a complex metabolic condition characterized by loss of skeletal muscle. Common clinical manifestations include muscle wasting, anemia, reduced caloric intake, and altered immune function, which contribute to increased disability, fatigue, diminished quality of life, and reduced survival. The prevalence of cachexia and the impact of this disorder on the patient and family underscore the need for effective management strategies. Dietary supplementation and appetite stimulation alone are inadequate to reverse the underlying metabolic abnormalities of cancer cachexia and have limited long-term impact on patient quality of life and survival. Therapies that can increase muscle mass and physical performance may be a promising option; however, there are currently no drugs approved for the prevention or treatment of cancer cachexia. Several agents are in clinical development, including anabolic agents, such as selective androgen receptor modulators and drugs targeting inflammatory cytokines that promote skeletal muscle catabolism.

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

PubMed

Ábrigo, Johanna; Elorza, Alvaro A; Riedel, Claudia A; Vilos, Cristian; Simon, Felipe; Cabrera, Daniel; Estrada, Lisbell; Cabello-Verrugio, Claudio

2018-01-01

Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

Molecular mechanism of sarcopenia and cachexia: recent research advances.

PubMed

Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

2017-06-01

Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Muscle loss occurs as a consequence of several chronic diseases (cachexia) and normal aging (sarcopenia). Although many negative regulators (atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.) have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of these mediators markedly differs within both conditions. Sarcopenia and cachectic muscles have been demonstrated to be abundant in myostatin-linked molecules. The ubiquitin-proteasome system (UPS) is activated during rapid atrophy model (cancer cachexia), but few mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Recent studies have indicated the age-related defect of autophagy signaling in skeletal muscle, whereas autophagic activation occurs in cachectic muscle. This review provides recent research advances dealing with molecular mediators modulating muscle mass in both sarcopenia and cachexia.

Malnutrition and Cachexia in Heart Failure.

PubMed

Rahman, Adam; Jafry, Syed; Jeejeebhoy, Khursheed; Nagpal, A Dave; Pisani, Barbara; Agarwala, Ravi

2016-05-01

Heart failure is a growing public health concern. Advanced heart failure is frequently associated with severe muscle wasting, termed cardiac cachexia This process is driven by systemic inflammation and tumor necrosis factor in a manner common to other forms of disease-related wasting seen with cancer or human immunodeficiency virus. A variable degree of malnutrition is often superimposed from poor nutrient intake. Cardiac cachexia significantly decreases quality of life and survival in patients with heart failure. This review outlines the evaluation of nutrition status in heart failure, explores the pathophysiology of cardiac cachexia, and discusses therapeutic interventions targeting wasting in these patients. © 2015 American Society for Parenteral and Enteral Nutrition.

Metabolic and nutritional aspects of cancer.

PubMed

Krawczyk, Joanna; Kraj, Leszek; Ziarkiewicz, Mateusz; Wiktor-Jędrzejczak, Wiesław

2014-08-22

Cancer, being in fact a generalized disease involving the whole organism, is most frequently associated with metabolic deregulation, a latent inflammatory state and anorexia of various degrees. The pathogenesis of this disorder is complex, with multiple dilemmas remaining unsolved. The clinical consequences of the above-mentioned disturbances include cancer-related cachexia and anorexia-cachexia syndrome. These complex clinical entities worsen the prognosis, and lead to deterioration of the quality of life and performance status, and thus require multimodal treatment. Optimal therapy should include nutritional support coupled with pharmacotherapy targeted at underlying pathomechanisms of cachexia. Nevertheless, many issues still need explanation, and efficacious and comprehensive therapy of cancer-related cachexia remains a future objective.

Experimental cancer cachexia: Evolving strategies for getting closer to the human scenario.

PubMed

Penna, Fabio; Busquets, Sílvia; Argilés, Josep M

2016-06-01

Cancer cachexia is a frequent syndrome that dramatically affects patient quality of life, anti-cancer treatment effectiveness, and overall survival. To date, no effective treatment is available and most of the studies are performed in experimental models in order to uncover the underlying mechanisms and to design prospective therapeutic strategies. This review summarizes the most relevant information regarding the use of animal models for studying cancer cachexia. Technical limitations and degree of recapitulation of the features of human cachexia are highlighted, in order to help investigators choose the most suitable model according to study-specific endpoints. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exercise training as treatment in cancer cachexia.

PubMed

Lira, Fábio Santos; Neto, José Cesar Rosa; Seelaender, Marília

2014-06-01

Cachexia is a wasting syndrome that may accompany a plethora of diseases, including cancer, chronic obstructive pulmonary disease, aids, and rheumatoid arthritis. It is associated with central and systemic increases of pro-inflammatory factors, and with decreased quality of life, response to pharmacological treatment, and survival. At the moment, there is no single therapy able to reverse cachexia many symptoms, which include disruption of intermediary metabolism, endocrine dysfunction, compromised hypothalamic appetite control, and impaired immune function, among other. Growing evidence, nevertheless, shows that chronic exercise, employed as a tool to counteract systemic inflammation, may represent a low-cost, safe alternative for the prevention/attenuation of cancer cachexia. Despite the well-documented capacity of chronic exercise to counteract sustained disease-related inflammation, few studies address the effect of exercise training in cancer cachexia. The aim of the present review was hence to discuss the results of cachexia treatment with endurance training. As opposed to resistance exercise, endurance exercise may be performed devoid of equipment, is well tolerated by patients, and an anti-inflammatory effect may be observed even at low-intensity. The decrease in inflammatory status induced by endurance protocols is paralleled by recovery of various metabolic pathways. The mechanisms underlying the response to the treatment are considered.

Coming back: autophagy in cachexia.

PubMed

Penna, Fabio; Baccino, Francesco M; Costelli, Paola

2014-05-01

Cachexia is a complex syndrome characterized by body weight loss, tissue wasting, systemic inflammation, metabolic abnormalities, and altered nutritional status. One of the most prominent features of cachexia is the loss of muscle mass, mainly because of increased protein degradation rates. This review is aimed at discussing the involvement of autophagy in the pathogenesis of muscle wasting in cachexia. Modulations of muscle mass in the adult reflect an imbalance between protein synthesis and degradation rates. Muscle depletion in cachexia is associated with increased protein breakdown, mainly involving the pathways dependent on ubiquitin-proteasome and autophagy-lysosomes. This latter, in particular, was considered not relevant for a long time. Just in the last years, autophagy was shown to contribute to the pathogenesis of muscle wasting not only in myopathies because of intrinsic muscle defects, but also in muscle depletion associated with conditions such as sepsis, chronic obstructive pulmonary disease, glucocorticoid treatment, cancer cachexia, and aging. The present review highlights that both excess and defective autophagy are relevant to the onset of muscle depletion, and draws some considerations about possible therapeutic intervention aimed at modulating autophagy in order to improve muscle trophism. http://links.lww.com/COCN/A5.

The use of herbal medicine in cancer-related anorexia/ cachexia treatment around the world.

PubMed

Cheng, Kai-Chun; Li, Ying-Xiao; Cheng, Juei-Tang

2012-01-01

Cancer-related cachexia, a condition in which the body is consumed by deranged carbohydrate, lipid and protein metabolism that is induced by inflammatory cytokines. Cachexia is associated with poor treatment outcome, fatigue and poor quality of life. Pharmacological intervention in the treatment and/or prevention of cachexia has been mainly aimed at the use of appetite enhancers to increase oral nutritional intake so far. Herbal remedies are part of traditional and folk healing methods with long histories of use. In this report, we have assessed which herbal approaches have had associated cancer cachexia case reports. Commonly used herbal medicines in western countries include essiac, iscador, pau d'arco tea, cannabinoids and so on. Some Kampo herbs and formulations are commonly used by cancer patients reduce the side effects and complications during the antitumor therapy. The relevant herbal medicines include ginseng, C. rhizome and radix astragali, and the related herbal remedies, such as TJ-48, TJ-41, PHY906 and Rikkunshito. However, there still have some adverse effects caused or amplified by herb and drug interactions that are difficult to separate. However, randomized effectiveness of herbal medicines shall be further identified in controlled clinical trials involving cancer patients with cachexia.

Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia

PubMed Central

Schäfer, Michaela; Oeing, Christian U.; Rohm, Maria; Baysal-Temel, Ezgi; Lehmann, Lorenz H.; Bauer, Ralf; Volz, H. Christian; Boutros, Michael; Sohn, Daniela; Sticht, Carsten; Gretz, Norbert; Eichelbaum, Katrin; Werner, Tessa; Hirt, Marc N.; Eschenhagen, Thomas; Müller-Decker, Karin; Strobel, Oliver; Hackert, Thilo; Krijgsveld, Jeroen; Katus, Hugo A.; Berriel Diaz, Mauricio; Backs, Johannes; Herzig, Stephan

2015-01-01

Objectives Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown. Methods and results By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven “cachexokines”, including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models. Conclusions As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia. PMID:26909315

A non-human primate model of radiation-induced cachexia.

PubMed

Cui, Wanchang; Bennett, Alexander W; Zhang, Pei; Barrow, Kory R; Kearney, Sean R; Hankey, Kim G; Taylor-Howell, Cheryl; Gibbs, Allison M; Smith, Cassandra P; MacVittie, Thomas J

2016-03-31

Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

F-BOX proteins in cancer cachexia and muscle wasting: emerging regulators and therapeutic opportunities

PubMed Central

Sukari, Ammar; Muqbil, Irfana; Mohammad, Ramzi M.; Philip, Philip A.; Azmi, Asfar S.

2016-01-01

Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder. PMID:26804424

Control of food intake and muscle wasting in cachexia.

PubMed

Amitani, Marie; Asakawa, Akihiro; Amitani, Haruka; Inui, Akio

2013-10-01

Cachexia is characterized by anorexia, weakness, weight loss, and muscle wasting. Anorexia and muscle wasting are the key features of cachexia and they affect mortality, morbidity, and quality of life. Consistent studies have found that feeding-regulating peptides such as melanocortin, ghrelin, and leptin are related to muscle metabolism, and the balance of catabolism and anabolism in muscle is regulated in the hypothalamus, which also regulates appetite and energy expenditure. In cachexia, proinflammatory cytokines, such as TNF-α, IL-1, IL-6 and Angiotensin II induce muscle atrophy. The mechanism is suggested via upregulation of MuRF1 and MAFbx. In contrast, the orexigenic peptide, AgRP and ghrelin have the effect to decrease proinflammatory cytokines and increase body weight, food intake, and muscle mass. The understandings of the pathological mechanism of anorexia and muscle metabolism in view of the crosstalk between brain and muscle will open the new way for the management of cachexia. In this review, we describe recent experimental and clinical studies that have examined the regulation of food intake and muscle wasting in cachexia. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. Copyright © 2013 Elsevier Ltd. All rights reserved.

Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-α ratio in skeletal muscle of 4T1 breast cancer mice with cachexia.

PubMed

Molanouri Shamsi, M; Chekachak, S; Soudi, S; Quinn, L S; Ranjbar, K; Chenari, J; Yazdi, M H; Mahdavi, M

2017-02-01

Cancer cachexia is characterized by inflammation, loss of skeletal muscle and adipose tissue mass, and functional impairment. Oxidative stress and inflammation are believed to regulate pathways controlling skeletal muscle wasting. The aim of this study was to determine the effects of aerobic interval training and the purported antioxidant treatment, selenium nanoparticle supplementation, on expression of IL-15 and inflammatory cytokines in 4T1 breast cancer-bearing mice with cachexia. Selenium nanoparticle supplementation accelerated cachexia symptoms in tumor-bearing mice, while exercise training prevented muscle wasting in tumor-bearing mice. Also, aerobic interval training enhanced the anti-inflammatory indices IL-10/TNF-α ratio and IL-15 expression in skeletal muscle in tumor-bearing mice. However, combining exercise training and antioxidant supplementation prevented cachexia and muscle wasting and additionally decreased tumor volume in 4T1 breast cancer mice. These finding suggested that combining exercise training and antioxidant supplementation could be a strategy for managing tumor volume and preventing cachexia in breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Physiological characterization of a mouse model of cachexia in colorectal liver metastases.

PubMed

Murphy, Kate T; Struk, Adam; Malcontenti-Wilson, Cathy; Christophi, Christopher; Lynch, Gordon S

2013-05-15

Loss of skeletal muscle mass and function (cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20-29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls (P < 0.03). MoCR mice exhibited impaired rotarod performance and grip strength (P < 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity (P < 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue (P < 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases.

Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy

PubMed Central

Reed, Sarah A.; Sandesara, Pooja B.; Senf, Sarah M.; Judge, Andrew R.

2012-01-01

Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.—Reed, S. A., Sandesara, P. B., Senf, S. F., Judge, A. R. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. PMID:22102632

Casting the net broader to confirm our imaginations: the long road to treating wasting disorders

PubMed Central

2017-01-01

Abstract Wasting embraces muscle and tissue wasting in sarcopenia and cachexia. This article describes recent advances in the field published in the Journal of Cachexia, Sarcopenia and Muscle concerning diagnostic tools, biomarker development, pathophysiology, and treatment. Studies discussed herein embrace those on sarcopenia and cachexia in heart failure, chronic obstructive pulmonary disease, and cancer including also animal models. PMID:29168628

Cachexia and protein-energy wasting in children with chronic kidney disease.

PubMed

Mak, Robert H; Cheung, Wai W; Zhan, Jian-Ying; Shen, Qian; Foster, Bethany J

2012-02-01

Children with chronic kidney disease (CKD) are at risk for "cachexia" or "protein-energy wasting" (PEW). These terms describe a pathophysiologic process resulting in the loss of muscle, with or without loss of fat, and involving maladaptive responses, including anorexia and elevated metabolic rate. PEW has been defined specifically in relation to CKD. We review the diagnostic criteria for cachexia and PEW in CKD and consider the limitations and applicability of these criteria to children with CKD. In addition, we present an overview of the manifestations and mechanisms of cachexia and PEW. A host of pathogenetic factors are considered, including systemic inflammation, endocrine perturbations, and abnormal neuropeptide signaling, as well as poor nutritional intake. Mortality risk, which is 100- to 200-fold higher in patients with end-stage renal disease than in the general population, is strongly correlated with the components of cachexia/PEW. Further research into the causes and consequences of wasting and growth retardation is needed in order to improve the survival and quality of life for children with CKD.

Novel investigational drugs mimicking exercise for the treatment of cachexia.

PubMed

Penna, F; Pin, F; Ballarò, R; Baccino, F M; Costelli, P

2016-01-01

Cachexia is a syndrome characterized by body weight loss, muscle wasting and metabolic abnormalities, that frequently complicates the management of people affected by chronic diseases. No effective therapy is actually available, although several drugs are under clinical evaluation. Altered energy metabolism markedly contributes to the pathogenesis of cachexia; it can be improved by exercise, which is able to both induce anabolism and inhibit catabolism. This review focuses on exercise mimetics and their potential inclusion in combined protocols to treat cachexia. The authors pay with particular reference to the cancer-associated cachexia. Even though exercise improves muscle phenotype, most patients retain sedentary habits which are quite difficult to disrupt. Moreover, they frequently present with chronic fatigue and comorbidities that reduce exercise tolerance. For these reasons, drugs mimicking exercise could be beneficial to those who are unable to comply with the practice of physical activity. Since some exercise mimetics may exert serious side effects, further investigations should focus on treatments which maintain their effectiveness on muscle phenotype while remaining tolerable at the same time.

Increased gut permeability in cancer cachexia: mechanisms and clinical relevance.

PubMed

Bindels, Laure B; Neyrinck, Audrey M; Loumaye, Audrey; Catry, Emilie; Walgrave, Hannah; Cherbuy, Claire; Leclercq, Sophie; Van Hul, Matthias; Plovier, Hubert; Pachikian, Barbara; Bermúdez-Humarán, Luis G; Langella, Philippe; Cani, Patrice D; Thissen, Jean-Paul; Delzenne, Nathalie M

2018-04-06

Intestinal disorders often occur in cancer patients, in association with body weight loss, and this alteration is commonly attributed to the chemotherapy. Here, using a mouse model of cancer cachexia induced by ectopic transplantation of C26 cancer cells, we discovered a profound alteration in the gut functions (gut permeability, epithelial turnover, gut immunity, microbial dysbiosis) independently of any chemotherapy. These alterations occurred independently of anorexia and were driven by interleukin 6. Gut dysfunction was found to be resistant to treatments with an anti-inflammatory bacterium ( Faecalibacterium prausnitzii ) or with gut peptides involved in intestinal cell renewal (teduglutide, a glucagon-like peptide 2 analogue). The translational value of our findings was evaluated in 152 colorectal and lung cancer patients with or without cachexia. The serum level of the lipopolysaccharide-binding protein, often presented as a reflection of the bacterial antigen load, was not only increased in cachectic mice and cancer patients, but also strongly correlated with the serum IL-6 level and predictive of death and cachexia occurrence in these patients. Altogether, our data highlight profound alterations of the intestinal homeostasis in cancer cachexia occurring independently of any chemotherapy and food intake reduction, with potential relevance in humans. In addition, we point out the lipopolysaccharide-binding protein as a new biomarker of cancer cachexia related to gut dysbiosis.

Increased gut permeability in cancer cachexia: mechanisms and clinical relevance

PubMed Central

Bindels, Laure B.; Neyrinck, Audrey M.; Loumaye, Audrey; Catry, Emilie; Walgrave, Hannah; Cherbuy, Claire; Leclercq, Sophie; Van Hul, Matthias; Plovier, Hubert; Pachikian, Barbara; Bermúdez-Humarán, Luis G.; Langella, Philippe; Cani, Patrice D.; Thissen, Jean-Paul; Delzenne, Nathalie M.

2018-01-01

Intestinal disorders often occur in cancer patients, in association with body weight loss, and this alteration is commonly attributed to the chemotherapy. Here, using a mouse model of cancer cachexia induced by ectopic transplantation of C26 cancer cells, we discovered a profound alteration in the gut functions (gut permeability, epithelial turnover, gut immunity, microbial dysbiosis) independently of any chemotherapy. These alterations occurred independently of anorexia and were driven by interleukin 6. Gut dysfunction was found to be resistant to treatments with an anti-inflammatory bacterium (Faecalibacterium prausnitzii) or with gut peptides involved in intestinal cell renewal (teduglutide, a glucagon-like peptide 2 analogue). The translational value of our findings was evaluated in 152 colorectal and lung cancer patients with or without cachexia. The serum level of the lipopolysaccharide-binding protein, often presented as a reflection of the bacterial antigen load, was not only increased in cachectic mice and cancer patients, but also strongly correlated with the serum IL-6 level and predictive of death and cachexia occurrence in these patients. Altogether, our data highlight profound alterations of the intestinal homeostasis in cancer cachexia occurring independently of any chemotherapy and food intake reduction, with potential relevance in humans. In addition, we point out the lipopolysaccharide-binding protein as a new biomarker of cancer cachexia related to gut dysbiosis. PMID:29719601

F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities.

PubMed

Sukari, Ammar; Muqbil, Irfana; Mohammad, Ramzi M; Philip, Philip A; Azmi, Asfar S

2016-02-01

Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist.

PubMed

Esposito, Angela; Criscitiello, Carmen; Gelao, Lucia; Pravettoni, Gabriella; Locatelli, Marzia; Minchella, Ida; Di Leo, Maria; Liuzzi, Rita; Milani, Alessandra; Massaro, Mariangela; Curigliano, Giuseppe

2015-11-01

Cancer cachexia is a multi-organ, multifactorial and often irreversible syndrome affecting many patients with cancer. Cancer cachexia is invariably associated with weight loss, mainly from loss of skeletal muscle and body fat, conditioning a reduced quality of life due to asthenia, anorexia, anaemia and fatigue. Treatment options for treating cancer cachexia are limited. The approach is multimodal and may include: treatment of secondary gastrointestinal symptoms, nutritional treatments, drug, and non-drug treatments. Nutritional counselling and physical training may be beneficial in delaying or preventing the development of anorexia-cachexia. However, these interventions are limited in their effect, and no definitive pharmacological treatment is available to address the relevant components of the syndrome. Anamorelin is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. It represents a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. In this review we examine the mechanisms of anamorelin by which it contrasts catabolic states, its role in regulation of metabolism and energy homeostasis, the data of recent trials in the setting of cancer cachexia and its safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review.

PubMed

Solheim, Tora S; Fearon, Kenneth C H; Blum, David; Kaasa, Stein

2013-01-01

There are no established treatments for cachexia. Recently it has been suggested that the evidence for non-steroidal anti-inflammatory (NSAID) treatment is sufficient to support its regular clinical use. Primary objective in this systematic review was to assess efficacy and safety of NSAID treatment in improving body weight and muscle mass in patients with cancer cachexia. Secondary objectives were to assess whether this treatment could improve other cachexia domains such as anorexia and food intake, catabolic drive and function. A systematic literature review of PubMed, EMBASE and Cochrane Central register of controlled trials database was carried out using both text words and MeSH/EMTREE terms. Thirteen studies were included; all but two trials showed either improvement or stabilization in weight or lean body mass. Seven studies were without a comparator. Studies are generally small and a few are methodologically flawed, often due to multiple outcomes with excess risk of false positives. NSAIDs may improve weight in cancer patients with cachexia, and there is some evidence on effect on physical performance, self-reported quality of life and inflammatory parameters. Evidence is too frail to recommend NSAID for cachexia outside clinical trials. This is supported by the known side effects of NSAIDs, even though the reviewed literature report almost negligible toxicity.

JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia.

PubMed

Bonetto, Andrea; Aydogdu, Tufan; Jin, Xiaoling; Zhang, Zongxiu; Zhan, Rui; Puzis, Leopold; Koniaris, Leonidas G; Zimmers, Teresa A

2012-08-01

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C(2)C(12) myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia.

JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia

PubMed Central

Bonetto, Andrea; Aydogdu, Tufan; Jin, Xiaoling; Zhang, Zongxiu; Zhan, Rui; Puzis, Leopold; Koniaris, Leonidas G.

2012-01-01

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C2C12 myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia. PMID:22669242

Treatment of Cachexia in Oncology

PubMed Central

Tazi, EM; Errihani, H

2010-01-01

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. PMID:21218002

Comparative molecular analysis of early and late cancer cachexia-induced muscle wasting in mouse models.

PubMed

Sun, Rulin; Zhang, Santao; Lu, Xing; Hu, Wenjun; Lou, Ning; Zhao, Yan; Zhou, Jia; Zhang, Xiaoping; Yang, Hongmei

2016-12-01

Cancer-induced muscle wasting, which commonly occurs in cancer cachexia, is characterized by impaired quality of life and poor patient survival. To identify an appropriate treatment, research on the mechanism underlying muscle wasting is essential. Thus far, studies on muscle wasting using cancer cachectic models have generally focused on early cancer cachexia (ECC), before severe body weight loss occurs. In the present study, we established models of ECC and late cancer cachexia (LCC) and compared different stages of cancer cachexia using two cancer cachectic mouse models induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC). In each model, tumor-bearing (TB) and control (CN) mice were injected with cancer cells and PBS, respectively. The TB and CN mice, which were euthanized on the 24th day or the 36th day after injection, were defined as the ECC and ECC-CN mice or the LCC and LCC-CN mice. In addition, the tissues were harvested and analyzed. We found that both the ECC and LCC mice developed cancer cachexia. The amounts of muscle loss differed between the ECC and LCC mice. Moreover, the expression of some molecules was altered in the muscles from the LCC mice but not in those from the ECC mice compared with their CN mice. In conclusion, the molecules with altered expression in the muscles from the ECC and LCC mice were not exactly the same. These findings may provide some clues for therapy which could prevent the muscle wasting in cancer cachexia from progression to the late stage.

Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF-1/Akt and autophagy signal in cancer cachexia.

PubMed

Zhuang, Pengwei; Zhang, Jinbao; Wang, Yan; Zhang, Mixia; Song, Lili; Lu, Zhiqiang; Zhang, Lu; Zhang, Fengqi; Wang, Jing; Zhang, Yanjun; Wei, Hongjun; Li, Hongyan

2016-03-01

Muscle atrophy is the prominent clinical feature of cancer-induced cachexia. Zhimu and Huangbai herb pair (ZBHP) has been used since ancient China times and have been phytochemically investigated for constituents that might cause anti-cancer, diabetes, and their complication. In this study, the effects and mechanisms of ZBHP on reversal of muscle atrophy were explored. C57BL/6 mice implanted with colon-26 adenocarcinoma were chosen to develop cancer cachexia for evaluating the effects of ZBHP on reversal of muscle atrophy. The body weight, survival time, inflammatory cytokines, and pathological changes of muscle were monitored. In addition, IGF-1/Akt and autophagy pathway members were analyzed to interpret the mechanism of drug response. The function and morphology of skeletal muscle in cachexia model were significantly disturbed, and the survival time was shortened. Consistently, inflammatory cytokines and muscle atrophy-related atrogin-1, MuRF1, and FOXO3 were significantly increased, and IGF-1/Akt and autophagy signal pathways were depressed. Treatment with ZBHP significantly alleviated tumor-free body weight reduction and cachexia-induced changes in cytokines and prolonged survival. ZBHP treatment not only inhibited the muscle atrophy-related genes but also activated the IGF-1/Akt and autophagy signal pathways to facilitate the protein synthesis. The results revealed that ZBHP treatment could inhibit the muscle atrophy induced by cancer cachexia and prolong the survival time, and ZBHP may be of value as a pharmacological alternative in treatment of cancer cachexia.

The prevalence of deranged C-reactive protein and albumin in patients with incurable cancer approaching death.

PubMed

Gray, Sarah; Axelsson, Bertil

2018-01-01

Amongst patients with incurable cancer approaching death, cachexia is common and associated with adverse outcomes. The term cachexia lacks a universally accepted definition and there is no consensus regarding which variables are to be measured. Furthermore, an elevated C-reactive protein is a common clinical challenge in this patient group. This study aims to add to the ongoing discussion regarding the definition of cancer cachexia and to study the role of C-reactive protein and s-albumin in this context. A 1-year cohort, consisting of 155 cancer patients enrolled in a specialized palliative home care team in the city of Östersund, Sweden, that were deceased during the year of 2015 was studied. Laboratory measures were studied within 0-30 and 31-60 days prior to death. C-reactive protein >10 mg/L and coinciding s-albumin <30 g/L was referred to as "laboratory cachexia". Also, the number of days from the first found "laboratory cachexia" until death was noted. The prevalence of "laboratory cachexia" was 85% 0-30 days prior to death compared to 66% 31-60 days prior to death (p<0.01). The majority of patients (75%) had an onset of "laboratory cachexia" within 0-120 days prior to death, with a median of 47 days. The median values for C-reactive protein and s-albumin within 0-30 days prior to death were 84mg/L and 23g/L respectively. Could markedly deranged values of C-reactive protein and s-albumin, such as found in this study, signal a relatively short remaining survival time in patients with incurable cancer and no clinical signs of ongoing infection? The role of "laboratory cachexia" in this context as well as the cut off values for the laboratory measures included may be further discussed.

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia.

PubMed

Au, Ernie D; Desai, Aditya P; Koniaris, Leonidas G; Zimmers, Teresa A

2016-01-01

Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo . The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro , Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific.

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

PubMed Central

Au, Ernie D.; Desai, Aditya P.; Koniaris, Leonidas G.; Zimmers, Teresa A.

2017-01-01

Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific. PMID:28149280

An analysis of the relationship between metastases and cachexia in lung cancer patients.

PubMed

Shiono, Masatoshi; Huang, Kan; Downey, Robert J; Consul, Nikita; Villanueva, Nicolas; Beck, Kristen; Fenn, Kathleen; Dietz, Donald; Yamaguchi, Takuhiro; Kato, Shunsuke; Divgi, Chaitanya; Kalinsky, Kevin; Wei, Ying; Zhang, Yuan; Borczuk, Alain C; Inoue, Akira; Halmos, Balazs; Acharyya, Swarnali

2016-09-01

Weight loss and hematogenous metastases are poor prognosis factors in lung cancer patients that can but do not necessarily co-occur. We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. The medical records of 394 lung cancer patients from two institutions (Columbia University, USA and Tohoku University, Japan) were reviewed. Information collected included the presence of cachexia, histologic subtype, tumor stage, number of metastases, mutation status, treatment, and survival. Descriptive statistics were performed. Only stage IV patients exhibited >5% weight loss (0.8%, 2.2%, 3.6%, and 5.1%, for stages I to IV; P = 0.0001). Patients with metastases developed cachexia more often than patients without metastases independent of treatment (6.0% and 7.1% weight loss in patients with metastases vs. 2.5% and 2.0% in patients without metastases, before [P = 0.0001] and after [P < 0.0001] treatment, respectively). The change in number of metastatic sites over time correlated with increasing weight loss (5.2%, 10.6%, 13.4%, and 13.4%, for an increase of 0, 1, 2, and ≥3 metastatic sites, from initial diagnosis to the endpoint; P < 0.0001). Patients with cachexia had worse survival than patients without cachexia (hazard ratio, 2.94; 95% confidence interval, 2.08-4.16; P < 0.0001). Tumors with mutated KRAS were associated with an increased risk of weight loss (11.4% weight loss in patients with mutated KRAS vs. 6.0% in patients with wild-type KRAS; P = 0.0011). Our findings suggest that the capabilities of lung cancer to metastasize and cause cachexia might be linked intrinsically and are independent of treatments administered. KRAS-mutated tumors were more commonly associated with cachexia. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Impaired Regeneration: A Role for the Muscle Microenvironment in Cancer Cachexia

PubMed Central

Talbert, Erin E.; Guttridge, Denis C.

2016-01-01

While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia. PMID:26385617

[Obesity and cardiac cachexia in chronic heart failure].

PubMed

Clauser, M; Altenberger, J

2013-09-01

Obesity as well as cardiac cachexia in heart failure patients are not fully understood and therefore of high scientific interest. Obesity as a common risk factor for cardiovascular disease is associated with a high mortality. In contrast obesity in patients suffering from chronic heart failure seems to be accompanied with a favorable outcome in contrast to people with normal weight, known as the obesity paradox. In the last decade there has been growing interest in cachexia, which is common in advanced stages of chronic diseases, such as heart failure, chronic obstructive pulmonary disease (COPD), cancer and renal failure and is associated with a poor prognosis. Until now cachexia has been underdiagnosed and undertreated. This review discusses the complex underlying pathomechanisms as well as potential therapeutic approaches.

[Tumour anorexia--tumour cachexia in case of gastrointestinal tumours: standards and visions].

PubMed

Ockenga, J; Pirlich, M; Gastell, S; Lochs, H

2002-11-01

The development of progressive malnutrition or cachexia is frequent in patients with gastrointestinal cancer - especially in patients with a carcinoma of the pancreas. The cachexia syndrome which is characterised by loss of body weight, negative nitrogen balance and fatigue significantly affects patients' quality of life, morbidity and survival. Because the currently established therapeutical strategies are often disappointing many physicians tended to develop a therapeutical nihilism. Cancer anorexia and cachexia are two distinct syndromes which may have synergistic effects in a patient. This review highlights the growing understanding of the multidimensional pathophysiological background. An algorithm of the current treatment strategies is given. In addition, we discuss new anabolic and anticatabolic agents (e.g. eicosapentanoic acid) and the results from first clinical trials.

Rheumatoid Cachexia Revisited: A Metabolic Co-Morbidity in Rheumatoid Arthritis

PubMed Central

Masuko, Kayo

2014-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, play a crucial role. The chronic inflammation, combined with reduced physical activity, leads to muscle wasting whereas fat mass would be maintained; the resulting abnormal metabolic state is described as rheumatoid cachexia. Since the loss of muscle volume would be compensated by the increased fat mass, body mass index (BMI) is reported not to reflect the nutritional status in RA patients. The implication of rheumatoid cachexia for cardiovascular risk and clinical prognosis is not clearly understood, however, adequate control of disease activity in combination with appropriate physical exercise could be the most important strategy to control rheumatoid cachexia and related metabolic problems. PMID:25988122

Diet composition as a source of variation in experimental animal models of cancer cachexia.

PubMed

Giles, Kaitlin; Guan, Chen; Jagoe, Thomas R; Mazurak, Vera

2016-05-01

A variety of experimental animal models are used extensively to study mechanisms underlying cancer cachexia, and to identify potential treatments. The important potential confounding effect of dietary composition and intake used in many preclinical studies of cancer cachexia is frequently overlooked. Dietary designs applied in experimental studies should maximize the applicability to human cancer cachexia, meeting the essential requirements of the species used in the study, matched between treatment and control groups as well as also being generally similar to human consumption. A literature review of scientific studies using animal models of cancer and cancer cachexia with dietary interventions was performed. Studies that investigated interventions using lipid sources were selected as the focus of discussion. The search revealed a number of nutrient intervention studies (n = 44), with the majority including n-3 fatty acids (n = 16), mainly eicosapentaenoic acid and/or docosahexaenoic acid. A review of the literature revealed that the majority of studies do not provide information about dietary design; food intake or pair-feeding is rarely reported. Further, there is a lack of standardization in dietary design, content, source, and overall composition in animal models of cancer cachexia. A model is proposed with the intent of guiding dietary design in preclinical studies to enable comparisons of dietary treatments within the same study, translation across different study designs, as well as application to human nutrient intakes. The potential for experimental endpoints to be affected by variations in food intake, macronutrient content, and diet composition is likely. Diet content and composition should be reported, and food intake assessed. Minimum standards for diet definition in cachexia studies would improve reproducibility of pre-clinical studies and aid the interpretation and translation of results to humans with cancer.

Role of Activin A and myostatin in human cancer cachexia.

PubMed

Loumaye, Audrey; de Barsy, Marie; Nachit, Maxime; Lause, Pascale; Frateur, Lena; van Maanen, Aline; Trefois, Pierre; Gruson, Damien; Thissen, Jean-Paul

2015-05-01

Cachexia is a multifactorial syndrome, characterized by the loss of skeletal muscle mass and not fully reversible by nutritional support. Recent animal observations suggest that production of Activin A (ActA) and Myostatin (Mstn) by some tumors might contribute to cancer cachexia. Our goal was to investigate the role of ActA and Mstn in the development of the human cancer cachexia. The ACTICA study is a cross-sectional study, which prospectively enrolled patients from a tertiary-care center between January 2012 and March 2014. Subjects/Outcome Measures: One hundred fifty two patients with colorectal or lung cancer had clinical, nutritional and functional assessment. Body composition was measured by CT-scan, anthropometry, and bioimpedance. Plasma concentrations of ActA, Mstn, and Follistatin were determined. Cachexia was associated with reduced lean and fat mass (p < .01 and p < .001), reduced physical function, lower quality of life, and increased symptoms (QLQC30; p < .001). Anorexia (SNAQ score < 14) was more common in cachectic patients (CC) than in noncachectic patients (CNC) (p < .001). ActA concentrations in CC patients were higher than in CNC patients (+40%; p < .001) and were correlated positively with weight loss (R = 0.323; p < .001) and negatively with the SNAQ score (R = -0.225; p < .01). In contrast, Mstn concentrations were decreased in CC patients compared to CNC patients (-35%; p < .001). These results demonstrate an association between circulating concentrations of ActA and the presence of the anorexia/cachexia syndrome in cancer patients. Given the known muscle atrophic effects of ActA, our study suggests that increased circulating concentrations of ActA may contribute to the development of cachexia in cancer patients.

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

PubMed

Bohnert, Kyle R; Gallot, Yann S; Sato, Shuichi; Xiong, Guangyan; Hindi, Sajedah M; Kumar, Ashok

2016-09-01

Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia. © FASEB.

Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response

PubMed Central

Guo, Dunwei; Wang, Chaoyi; Wang, Qiang; Qiao, Zhongpeng; Tang, Hua

2017-01-01

Objective Cancer cachexia is often present in patients with advanced malignant tumors, and the subsequent body weight reduction results in poor quality of life. However, there has been no progress in developing effective clinical therapeutic strategies for skeletal muscle wasting in cancer cachexia. Herein, we explored the functions of pantoprazole on cancer cachexia skeletal muscle wasting. Methods The mouse colon adenocarcinoma cell line C26 was inoculated in the right forelimb of male BALB/C mice to establish a cancer cachexia model. The animals were treated with or without different concentrations of pantoprazole orally, and the body weight, tumor growth, spontaneous activity, and muscle functions were determined at various time points. Two weeks later, the levels of serum IL-6 and TNF-α, the mRNA levels of gastrocnemius JAK2 and STAT3, and the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 were examined with ELISA assay, qRT-PCR assay, and Western blotting, respectively. Further studies were performed to assess the levels of Fbx32 and MuRF1 expression and morphological changes. Results Pantoprazole can alleviate cancer cachexia-induced body weight reduction and inhibit skeletal muscle wasting in a dose-dependent manner. Our results indicated that pantoprazole treatment can decrease the levels of serum IL-6 and TNF-α (56.3% and 67.6%, respectively), and inhibit the activation of the JAK2/STAT3 signaling pathway. Moreover, the expression levels of MuRF1 and Fbx32 were also suppressed after pantoprazole treatment. Conclusion Our findings suggested that pantoprazole can alleviate cancer cachexia skeletal muscle wasting by inhibiting the inflammatory response and blocking the JAK2/STAT3 or ubiquitin proteasome pathway. PMID:28489606

Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia.

PubMed

Murphy, Kate T; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S

2013-09-01

Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin-angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p < 0.05). In severely cachectic mice, perindopril reduced tumor growth, improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ (p < 0.05), which was associated with increased oxidative enzyme capacity (succinate deyhydrogenase, p < 0.05). Perindopril attenuated the increase in MuRF-1 and IL-6 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased. These findings support the therapeutic potential of ACE inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia. Copyright © 2013 UICC.

Validation of the CAchexia SCOre (CASCO). Staging Cancer Patients: The Use of miniCASCO as a Simplified Tool

PubMed Central

Argilés, Josep M.; Betancourt, Angelica; Guàrdia-Olmos, Joan; Peró-Cebollero, Maribel; López-Soriano, Francisco J.; Madeddu, Clelia; Serpe, Roberto; Busquets, Sílvia

2017-01-01

The CAchexia SCOre (CASCO) was described as a tool for the staging of cachectic cancer patients. The aim of this study is to show the metric properties of CASCO in order to classify cachectic cancer patients into three different groups, which are associated with a numerical scoring. The final aim was to clinically validate CASCO for its use in the classification of cachectic cancer patients in clinical practice. We carried out a case -control study that enrolled prospectively 186 cancer patients and 95 age-matched controls. The score includes five components: (1) body weight loss and composition, (2) inflammation/metabolic disturbances/immunosuppression, (3) physical performance, (4) anorexia, and (5) quality of life. The present study provides clinical validation for the use of the score. In order to show the metric properties of CASCO, three different groups of cachectic cancer patients were established according to the results obtained with the statistical approach used: mild cachexia (15 ≤ × ≤ 28), moderate cachexia (29 ≤ × ≤ 46), and severe cachexia (47 ≤ × ≤ 100). In addition, a simplified version of CASCO, MiniCASCO (MCASCO), was also presented and it contributes as a valid and easy-to-use tool for cachexia staging. Significant statistically correlations were found between CASCO and other validated indexes such as Eastern Cooperative Oncology Group (ECOG) and the subjective diagnosis of cachexia by specialized oncologists. A very significant estimated correlation between CASCO and MCASCO was found that suggests that MCASCO might constitute an easy and valid tool for the staging of the cachectic cancer patients. CASCO and MCASCO provide a new tool for the quantitative staging of cachectic cancer patients with a clear advantage over previous classifications. PMID:28261113

Validation of the CAchexia SCOre (CASCO). Staging Cancer Patients: The Use of miniCASCO as a Simplified Tool.

PubMed

Argilés, Josep M; Betancourt, Angelica; Guàrdia-Olmos, Joan; Peró-Cebollero, Maribel; López-Soriano, Francisco J; Madeddu, Clelia; Serpe, Roberto; Busquets, Sílvia

2017-01-01

The CAchexia SCOre (CASCO) was described as a tool for the staging of cachectic cancer patients. The aim of this study is to show the metric properties of CASCO in order to classify cachectic cancer patients into three different groups, which are associated with a numerical scoring. The final aim was to clinically validate CASCO for its use in the classification of cachectic cancer patients in clinical practice. We carried out a case -control study that enrolled prospectively 186 cancer patients and 95 age-matched controls. The score includes five components: (1) body weight loss and composition, (2) inflammation/metabolic disturbances/immunosuppression, (3) physical performance, (4) anorexia, and (5) quality of life. The present study provides clinical validation for the use of the score. In order to show the metric properties of CASCO, three different groups of cachectic cancer patients were established according to the results obtained with the statistical approach used: mild cachexia (15 ≤ × ≤ 28), moderate cachexia (29 ≤ × ≤ 46), and severe cachexia (47 ≤ × ≤ 100). In addition, a simplified version of CASCO, MiniCASCO (MCASCO), was also presented and it contributes as a valid and easy-to-use tool for cachexia staging. Significant statistically correlations were found between CASCO and other validated indexes such as Eastern Cooperative Oncology Group (ECOG) and the subjective diagnosis of cachexia by specialized oncologists. A very significant estimated correlation between CASCO and MCASCO was found that suggests that MCASCO might constitute an easy and valid tool for the staging of the cachectic cancer patients. CASCO and MCASCO provide a new tool for the quantitative staging of cachectic cancer patients with a clear advantage over previous classifications.

New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss

PubMed Central

Johns, Neil; Stretch, Cynthia; Tan, Benjamin H.L.; Solheim, Tora S.; Sørhaug, Sveinung; Stephens, Nathan A.; Gioulbasanis, Ioannis; Skipworth, Richard J.E.; Deans, D.A. Christopher; Vigano, Antonio; Ross, James A.; Bathe, Oliver F.; Tremblay, Michel L.; Kaasa, Stein; Strasser, Florian; Gagnon, Bruno; Baracos, Vickie E.; Damaraju, Sambasivarao

2016-01-01

Background Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/− computerized tomography‐defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype Methods A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform. Results Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle‐specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05). Conclusions The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro‐inflammatory cytokines and the renin–angiotensin system as biomarkers/mediators of muscle wasting in cachexia. PMID:27897403

Diet composition as a source of variation in experimental animal models of cancer cachexia

PubMed Central

Giles, Kaitlin; Guan, Chen; Jagoe, Thomas R.

2015-01-01

Abstract Background A variety of experimental animal models are used extensively to study mechanisms underlying cancer cachexia, and to identify potential treatments. The important potential confounding effect of dietary composition and intake used in many preclinical studies of cancer cachexia is frequently overlooked. Dietary designs applied in experimental studies should maximize the applicability to human cancer cachexia, meeting the essential requirements of the species used in the study, matched between treatment and control groups as well as also being generally similar to human consumption. Methods A literature review of scientific studies using animal models of cancer and cancer cachexia with dietary interventions was performed. Studies that investigated interventions using lipid sources were selected as the focus of discussion. Results The search revealed a number of nutrient intervention studies (n = 44), with the majority including n‐3 fatty acids (n = 16), mainly eicosapentaenoic acid and/or docosahexaenoic acid. A review of the literature revealed that the majority of studies do not provide information about dietary design; food intake or pair‐feeding is rarely reported. Further, there is a lack of standardization in dietary design, content, source, and overall composition in animal models of cancer cachexia. A model is proposed with the intent of guiding dietary design in preclinical studies to enable comparisons of dietary treatments within the same study, translation across different study designs, as well as application to human nutrient intakes. Conclusion The potential for experimental endpoints to be affected by variations in food intake, macronutrient content, and diet composition is likely. Diet content and composition should be reported, and food intake assessed. Minimum standards for diet definition in cachexia studies would improve reproducibility of pre‐clinical studies and aid the interpretation and translation of results to humans with cancer. PMID:27493865

Management of Cancer Cachexia and Guidelines Implementation in a Comprehensive Cancer Center: A Physician-Led Cancer Nutrition Program Adapted to the Practices of a Country.

PubMed

Senesse, Pierre; Isambert, Agnès; Janiszewski, Chloé; Fiore, Stéphanie; Flori, Nicolas; Poujol, Sylvain; Arroyo, Eric; Courraud, Julie; Guillaumon, Vanessa; Mathieu-Daudé, Hélène; Colasse, Sophie; Baracos, Vickie; de Forges, Hélène; Thezenas, Simon

2017-09-01

Cancer-associated cachexia is correlated with survival, side-effects, and alteration of the patients' well-being. We implemented an institution-wide multidisciplinary supportive care team, a Cancer Nutrition Program (CNP), to screen and manage cachexia in accordance with the guidelines and evaluated the impact of this new organization on nutritional care and funding. We estimated the workload associated with nutrition assessment and cachexia-related interventions and audited our clinical practice. We then planned, implemented, and evaluated the CNP, focusing on cachexia. The audit showed a 70% prevalence of unscreened cachexia. Parenteral nutrition was prescribed to patients who did not meet the guideline criteria in 65% cases. From January 2009 to December 2011, the CNP team screened 3078 inpatients. The screened/total inpatient visits ratio was 87%, 80%, and 77% in 2009, 2010, and 2011, respectively. Cachexia was reported in 74.5% (n = 2253) patients, of which 94.4% (n = 1891) required dietary counseling. Over three years, the number of patients with artificial nutrition significantly decreased by 57.3% (P < 0.001), and the qualitative inpatients enteral/parenteral ratio significantly increased: 0.41 in 2009, 0.74 in 2010, and 1.52 in 2011. Between 2009 and 2011, the CNP costs decreased significantly for inpatients nutritional care from 528,895€ to 242,272€, thus financing the nutritional team (182,520€ per year). Our results highlight the great benefits of implementing nutritional guidelines through a physician-led multidisciplinary team in charge of nutritional care in a comprehensive cancer center. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Z-505 hydrochloride, an orally active ghrelin agonist, attenuates the progression of cancer cachexia via anabolic hormones in Colon 26 tumor-bearing mice.

PubMed

Yoshimura, Makoto; Shiomi, Yoshihiro; Ohira, Yuta; Takei, Mineo; Tanaka, Takao

2017-09-15

Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC 50 ) value of 0.45nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a. Copyright © 2017 Elsevier B.V. All rights reserved.

Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response.

PubMed

Guo, Dunwei; Wang, Chaoyi; Wang, Qiang; Qiao, Zhongpeng; Tang, Hua

2017-06-13

Cancer cachexia is often present in patients with advanced malignant tumors, and the subsequent body weight reduction results in poor quality of life. However, there has been no progress in developing effective clinical therapeutic strategies for skeletal muscle wasting in cancer cachexia. Herein, we explored the functions of pantoprazole on cancer cachexia skeletal muscle wasting. The mouse colon adenocarcinoma cell line C26 was inoculated in the right forelimb of male BALB/C mice to establish a cancer cachexia model. The animals were treated with or without different concentrations of pantoprazole orally, and the body weight, tumor growth, spontaneous activity, and muscle functions were determined at various time points. Two weeks later, the levels of serum IL-6 and TNF-α, the mRNA levels of gastrocnemius JAK2 and STAT3, and the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 were examined with ELISA assay, qRT-PCR assay, and Western blotting, respectively. Further studies were performed to assess the levels of Fbx32 and MuRF1 expression and morphological changes. Pantoprazole can alleviate cancer cachexia-induced body weight reduction and inhibit skeletal muscle wasting in a dose-dependent manner. Our results indicated that pantoprazole treatment can decrease the levels of serum IL-6 and TNF-α (56.3% and 67.6%, respectively), and inhibit the activation of the JAK2/STAT3 signaling pathway. Moreover, the expression levels of MuRF1 and Fbx32 were also suppressed after pantoprazole treatment. Our findings suggested that pantoprazole can alleviate cancer cachexia skeletal muscle wasting by inhibiting the inflammatory response and blocking the JAK2/STAT3 or ubiquitin proteasome pathway.

Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size.

PubMed

Lee, David E; Brown, Jacob L; Rosa-Caldwell, Megan E; Blackwell, Thomas A; Perry, Richard A; Brown, Lemuel A; Khatri, Bhuwan; Seo, Dongwon; Bottje, Walter G; Washington, Tyrone A; Wiggs, Michael P; Kong, Byung-Whi; Greene, Nicholas P

2017-05-01

Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia. Copyright © 2017 the American Physiological Society.

High prevalence of cachexia in newly diagnosed head and neck cancer patients: An exploratory study.

PubMed

Jager-Wittenaar, Harriët; Dijkstra, Pieter U; Dijkstra, Gerard; Bijzet, Johan; Langendijk, Johannes A; van der Laan, Bernard F A M; Roodenburg, Jan L N

2017-03-01

In patients with cancer, weight loss can be related to simple starvation, disturbed metabolism, or both. In patients with head and neck cancer (HNC), weight loss often is attributed to simple starvation because the obvious oral symptoms are known to hinder dietary intake. In this population, cachexia remains a relatively unexplored phenomenon. The aim of this study was to explore the prevalence of cachexia and precachexia in patients with newly diagnosed HNC. Fifty-nine patients with newly diagnosed HNC were asked to participate in the prospective cohort study, from which only baseline data were used in the analyses. Measurements were performed 1 wk before cancer treatment, that is, cachexia status by Fearon's cancer-specific framework, dietary intake, muscle mass, muscle strength, and biochemical markers (C-reactive protein, albumin, hemoglobin, interleukin-1β, interleukin-6, and tumor necrosis factor-α) were assessed. Data of 26 patients were included in the analyses (59% participation rate). Forty-two percent of the patients (n = 12) were classified as cachectic and 15% (n = 4) as precachectic. Muscle mass depletion was significantly more frequent in cachectic patients (67%) than in noncachectic patients (14%; P = 0.014). No differences in inflammatory markers were observed between cachectic and noncachectic patients. This exploratory study suggested a high prevalence of cachexia (42%) in patients with newly diagnosed HNC. Although a large study is needed to further elucidate the role of cachexia in patients with HNC, the data presented here suggest that cachexia is a common problem in this patient population, which has therapeutic and prognostic implications. Copyright © 2016 Elsevier Inc. All rights reserved.

Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure.

PubMed

Valentova, Miroslava; von Haehling, Stephan; Bauditz, Juergen; Doehner, Wolfram; Ebner, Nicole; Bekfani, Tarek; Elsner, Sebastian; Sliziuk, Veronika; Scherbakov, Nadja; Murín, Ján; Anker, Stefan D; Sandek, Anja

2016-06-01

Mechanisms leading to cachexia in heart failure (HF) are not fully understood. We evaluated signs of intestinal congestion in patients with chronic HF and their relationship with cachexia. Of the 165 prospectively enrolled outpatients with left ventricular ejection fraction ≤40%, 29 (18%) were cachectic. Among echocardiographic parameters, the combination of right ventricular dysfunction and elevated right atrial pressure (RAP) provided the best discrimination between cachectic and non-cachectic patients [area under the curve 0.892, 95% confidence interval (CI): 0.832-0.936]. Cachectic patients, compared with non-cachectic, had higher prevalence of postprandial fullness, appetite loss, and abdominal discomfort. Abdominal ultrasound showed a larger bowel wall thickness (BWT) in the entire colon and terminal ileum in cachectic than in non-cachectic patients. Bowel wall thickness correlated positively with gastrointestinal symptoms, high-sensitivity C-reactive protein, RAP, and truncal fat-free mass, the latter serving as a marker of the fluid content. Logistic regression analysis showed that BWT was associated with cachexia, even after adjusting for cardiac function, inflammation, and stages of HF (odds ratio 1.4, 95% CI: 1.0-1.8; P-value = 0.03). Among the cardiac parameters, only RAP remained significantly associated with cachexia after multivariable adjustment. Cardiac cachexia was associated with intestinal congestion irrespective of HF stage and cardiac function. Gastrointestinal discomfort, appetite loss, and pro-inflammatory activation provide probable mechanisms, by which intestinal congestion may trigger cardiac cachexia. However, our results are preliminary and larger studies are needed to clarify the intrinsic nature of this relationship. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment.

PubMed

Chevalier, Stéphanie; Farsijani, Samaneh

2014-06-01

Cancer cachexia is a metabolic syndrome featuring many alterations typical of type 2 diabetes (T2D). While muscle wasting is a hallmark of cachexia, epidemiological evidence also supports an accelerated age-related muscle loss in T2D. Insulin resistance manifests in both conditions and impairs glucose disposal and protein anabolism by tissues. A greater contribution of gluconeogenesis to glucose production may limit amino acid availability for muscle protein synthesis, further aggravating muscle loss. In the context of inter-dependence between glucose and protein metabolism, the present review summarizes the current state of knowledge on alterations that may lead to muscle wasting in human cancer. By highlighting the similarities with T2D, a disease that has been more extensively studied, the objective of this review is to provide a better understanding of the pathophysiology of cancer cachexia and to consider potential treatments usually targeted for T2D. Nutritional approaches aimed at stimulating protein anabolism might include specially formulated food with optimal protein and amino acid composition. Because the gradual muscle loss in T2D may be attenuated by diabetes treatment, anti-diabetic drugs might be considered in cachexia treatment. Metformin emerges as a choice candidate as it acts both on reducing gluconeogenesis and improving insulin sensitivity, and has demonstrated tumour suppressor properties in multiple cancer types. Such a multimodal approach to slow or reverse muscle wasting in cachexia warrants further investigation.

A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart.

PubMed

Sala, Valentina; Gatti, Stefano; Gallo, Simona; Medico, Enzo; Cantarella, Daniela; Cimino, James; Ponzetto, Antonio; Crepaldi, Tiziana

2016-01-01

Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia.

PubMed

Torres-Fuentes, Cristina; Pastor-Cavada, Elena; Cano, Rafael; Kandil, Dalia; Shanahan, Rachel; Juan, Rocio; Shaban, Hamdy; McGlacken, Gerard P; Schellekens, Harriët

2018-05-30

Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.

Cachexia at diagnosis is associated with poor survival in head and neck cancer patients.

PubMed

Orell-Kotikangas, Helena; Österlund, Pia; Mäkitie, Outi; Saarilahti, Kauko; Ravasco, Paula; Schwab, Ursula; Mäkitie, Antti A

2017-07-01

One third of the patients had cachexia with an association of significantly shorter survival. These results suggest that combining HGS and MAMA seems to be a practical method to screen cachexia in patients with head and neck cancer and may also be used when assessing their prognosis. The aim of this study was to analyze the hypothesis that cachexia defined as both low mid-arm muscle area (MAMA) and handgrip strength (HGS) is associated with decreased survival in patients with head and neck squamous cell carcinoma (HNSCC). Sixty-five consecutive patients with primary HNSCC were enrolled prior to cancer therapy. Cachexia was defined as low handgrip strength (HGS) and low mid-arm muscle area (MAMA). Nutritional status was assessed by patient-generated subjective global assessment (PG-SGA) and sarcopenia by low MAMA. Biochemical parameters reflecting nutritional status and S-25-OHD were measured. Cachexia was seen in 31% and sarcopenia in 46% of patients. Altogether, 34% of patients were malnourished. Disease-free survival was 13 months (3-62) in cachectic patients, compared with 66 months (31-78) in non-cachectic patients (p = 0.009). S-25-OHD was 28 nmol/l in cachectic patients, compared with 46 nmol/l in non-cachectic patients (p = 0.009) and prealbumin 187 mg/l and 269 mg/l, respectively (p < 0.001).

Impact of a multidisciplinary rehabilitation nutrition team on evaluating sarcopenia, cachexia and practice of rehabilitation nutrition.

PubMed

Kokura, Yoji; Wakabayashi, Hidetaka; Maeda, Keisuke; Nishioka, Shinta; Nakahara, Saori

2017-01-01

To determine whether the presence of a multidisciplinary rehabilitation nutrition team affects sarcopenia and cachexia evaluation and practice of rehabilitation nutrition. A cross-sectional study using online questionnaire among members of the Japanese Association of Rehabilitation Nutrition (JARN) was conducted. Questions were related to sarcopenia and cachexia evaluation and practice of rehabilitation nutrition. 677 (14.7%) questionnaires were analysed. 44.5% reported that their institution employed a rehabilitation nutrition team, 20.2% conducted rehabilitation nutrition rounds and 26.1% conducted rehabilitation nutrition meetings. A total of 51.7%, 69.7%, 69.0% and 17.8% measured muscle mass, muscle strength, physical function and cachexia, respectively. For those with a rehabilitation nutrition team, 63.5%, 80.7%, 82.4% and 22.9% measured muscle mass, muscle strength, physical function and cachexia, respectively, whereas 46.7%, 78.0% and 78.1% of the respondents reported implementation of nutrition planning strategies in consideration of energy accumulation, rehabilitation training in consideration of nutritional status and use of dietary supplements, respectively. Multivariate logistic regression analysis showed that the use of a rehabilitation nutrition team independently affected sarcopenia evaluation and practice of rehabilitation nutrition but not cachexia evaluation. The presence of a multidisciplinary rehabilitation nutrition team increased the frequency of sarcopenia evaluation and practice of rehabilitation nutrition. J. Med. Invest. 64: 140-145, February, 2017.

The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome.

PubMed

van Norren, Klaske; Dwarkasing, Jvalini T; Witkamp, Renger F

2017-09-01

In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1β-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.

Cancer cachexia, mechanism and treatment

PubMed Central

Aoyagi, Tomoyoshi; Terracina, Krista P; Raza, Ali; Matsubara, Hisahiro; Takabe, Kazuaki

2015-01-01

It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials. PMID:25897346

Animal models of the cancer anorexia-cachexia syndrome.

PubMed

Bennani-Baiti, Nabila; Walsh, Declan

2011-09-01

Cancer cachexia, a complex wasting syndrome, is common in palliative medicine. Animal models expand our understanding of its mechanisms. A review of cancer cachexia and anorexia animal models will help investigators make an informed choice of the study model. Cancer-anorexia cachexia animal models are numerous. No one is ideal. The choice should depend on the research question. To investigate cancer-anorexia cachexia independent of pro-inflammatory cytokine effects, the MAC16 ADK and XK1 are useful. MAC16 ADK helps study the host's tumor metabolic effects, independent of any anorexia or inflammation. XK1 is both anorectic and cachectic, but data about it is limited. All other models induce a host inflammatory response. The Walker 256 ADK and MCG 101 are best avoided due to excessive tumor growth. Since individual models do not address all aspects of the syndrome, use of a combination seems wise. Suggested combinations: MAC16-ADK (non-inflammatory and non-anorectic) with YAH-130 (inflammatory, anorectic, and cachectic), Lewis lung carcinoma (slow onset anorexia) or prostate adenocarcinoma (inflammatory, anorectic but not cachectic) with YAH-130.

Systemic inflammation in chronic obstructive pulmonary disease and lung cancer: common driver of pulmonary cachexia?

PubMed

Ceelen, Judith J M; Langen, Ramon C J; Schols, Annemie M W J

2014-12-01

In this article, a putative role of systemic inflammation as a driver of pulmonary cachexia induced by either chronic obstructive pulmonary disease or nonsmall cell lung cancer is reviewed. Gaps in current translational research approaches are discussed and alternative strategies are proposed to provide new insights. Activation of the ubiquitin proteasome system has generally been considered a cause of pulmonary cachexia, but current animal models lack specificity and evidence is lacking in nonsmall cell lung cancer and conflicting in chronic obstructive pulmonary disease patients. Recent studies have shown activation of the autophagy-lysosome pathway in both nonsmall cell lung cancer and chronic obstructive pulmonary disease. Myonuclear loss, as a consequence of increased apoptotic events in myofibers, has been suggested in cancer-cachexia-associated muscle atrophy. Plasma transfer on myotube cultures can be used to detect early inflammatory signals in patients and presence of atrophy-inducing activity within the circulation. Comparative clinical research between nonsmall cell lung cancer and chronic obstructive pulmonary disease in different disease stages is useful to unravel disease-specific versus common denominators of pulmonary cachexia.

The therapeutic potential of exercise to treat cachexia.

PubMed

Lira, Fábio S; Antunes, Barbara de M M; Seelaender, Marília; Rosa Neto, José C

2015-12-01

To discuss the role of physical exercise in the attenuation of cancer cachexia-associated symptoms, and upon the outcome of chemotherapy, with special focus on the anti-inflammatory role of chronic exercise. The review addresses the recent findings regarding the positive effects of endurance and strength exercise training upon metabolic dysfunction, systemic inflammation and body composition alterations in the syndrome of cachexia. The employment of different exercise protocol strategies, in respect to intensity, duration, work load and in concomitance with pharmacological treatment is considered. Cachexia is a multifactorial wasting syndrome afflicting patients with cancer, chronic obstructive pulmonary disease, chronic heart failure, trauma, among other diseases. This condition markedly compromises the quality of life, treatment outcome and survival. Recent literature indicates an unequivocal role of chronic exercise in modulating cachexia and other cancer-associated dysfunctions. Exercise is proposed as a complementary treatment in cancer, and represents a function-preserving, anti-inflammatory and metabolism-modulating strategy with low cost, and high versatility and availability. Furthermore, exercise decreases cancer recurrence and presents a positive impact on public health management, reducing hospitalization and medication costs.

Cachexia: common, deadly, with an urgent need for precise definition and new therapies.

PubMed

Lainscak, Mitja; Filippatos, Gerasimos S; Gheorghiade, Mihai; Fonarow, Gregg C; Anker, Stefan D

2008-06-02

Cachexia--sometimes also referred to as wasting disease, malnutrition, or hypercatabolism--has been described for centuries and has always raised ominous thoughts that "the end is near." The disease is encountered in many malignant and nonmalignant chronic, ultimately fatal, illnesses. Yet, although cachexia is a deadly syndrome, little is known about its pathophysiology, and the debate regarding its definition is ongoing. Thus, the data on epidemiology can be contested, but a few things are certain: Cachexia is associated with exceedingly high mortality once the syndrome has fully developed, irrespective of the definition we apply, and it is associated with weakness, weight loss, muscle wasting, and inflammation. It is not simply an ancillary event, and it may contribute to the death of the patient either through effects on neuroendocrine and immune defense mechanisms or through protein calorie malnutrition. The therapeutic standard of care for cachexia remains undefined to date, with a few exceptions. Among the recognized approaches, exogenous oral amino acid supplementation appears very promising. Further research efforts are needed and they are ongoing.

Cachexia and sarcopenia: mechanisms and potential targets for intervention.

PubMed

Argilés, Josep M; Busquets, Silvia; Stemmler, Britta; López-Soriano, Francisco J

2015-06-01

Cachexia is a multi-organ syndrome associated with cancer and other chronic diseases, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. Skeletal muscle tissue represents more than 40% of body weight and seems to be one of the main tissues involved in the wasting that occurs during cachexia. Sarcopenia is a degenerative loss of skeletal muscle mass, quality, and strength associated with healthy ageing. The molecular mechanisms behind cachexia and sarcopenia share some common trends. Muscle wasting is the result of a combination of an imbalance between synthetic and degradative protein pathways together with increased myocyte apoptosis and decreased regenerative capacity. Oxidative pathways are also altered in skeletal muscle during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. The aim of the present review is to analyse common molecular pathways between cachexia and sarcopenia in order to put forward potential targets for intervention. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impaired regeneration: A role for the muscle microenvironment in cancer cachexia.

PubMed

Talbert, Erin E; Guttridge, Denis C

2016-06-01

While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anorexia of ageing: a key component in the pathogenesis of both sarcopenia and cachexia.

PubMed

Morley, John E

2017-08-01

The anorexia of aging was first recognized as a physiological syndrome 30 years ago. Its major causes are an alteration in fundal compliance with an increase in antral stretch and enhanced cholecystokinin activity leading to increased satiation.This anorexia leads to weight loss in aging persons and is one of the component causes of the aging related sarcopenia. This physiological anorexia also increases the risk of more severe anorexia when an older person has an increase in inflammatory cytokines such as occurs when they have an illness. This results in an increase in the anorexia due to cachexia in older persons. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia.

PubMed

Conte, Elena; Camerino, Giulia Maria; Mele, Antonietta; De Bellis, Michela; Pierno, Sabata; Rana, Francesco; Fonzino, Adriano; Caloiero, Roberta; Rizzi, Laura; Bresciani, Elena; Ben Haj Salah, Khoubaib; Fehrentz, Jean-Alain; Martinez, Jean; Giustino, Arcangela; Mariggiò, Maria Addolorata; Coluccia, Mauro; Tricarico, Domenico; Lograno, Marcello Diego; De Luca, Annamaria; Torsello, Antonio; Conte, Diana; Liantonio, Antonella

2017-06-01

Cachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose-limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium-dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS-R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood. By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast-twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin-induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention. Cisplatin-treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up-regulation of atrogin1/Murf-1 genes and a down-regulation of Pgc1-a gene, all indexes of muscle atrophy, and by a two-fold increase in resting intracellular calcium, [Ca 2+ ] i , compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store-operated calcium entry were ~50% significantly reduced in cisplatin-treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin-induced alteration of calcium homeostasis by both common as well as drug-specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis. Our findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin-induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin-induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy-associated cachexia. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Tumor Secreted Autocrine Motility Factor (AMF): Causal Role in an Animal Model of Cachexia

DTIC Science & Technology

2005-08-01

AD Award Number: DAMD17-02-1-0586 TITLE: Tumor Secreted Autocrine Motility Factor ( AMF ): Causal Role in an Animal Model of Cachexia PRINCIPAL...5a. CONTRACT NUMBER Tumor Secreted Autocrine Motility Factor ( AMF ): Causal Role in an Animal Model of Cachexia 5b. GRANT NUMBER DAM D1 7-02-1-0586 5c...quality of life and postpone mortality. We proposed that autocrine motility factor ( AMF ) is released into the bloodstream from cancer sites and

[Anorexia-cachexia frequency and its gastrointestinal symptoms association in paliative patients at the Instituto Nacional de Cancerología, México].

PubMed

Pérez Camargo, Dana Aline; Allende Pérez, Silvia R; Meneses García, Abelardo; De Nicola Delfin, Luigina; Copca Mendoza, Erika Thalía; Sánchez López, Miriam S; Flores García, Martha Karen; Verástegui Avilés, Emma

2014-10-01

Anorexia-cachexia is a frequent syndrome among cancer patients, specially in late stages: the global prevalence of para-neoplastic anorexia-cachexia ranges between 20-40% in the diagnostic stage and between 70-80% in the late stage of the disease. The co-existence of functional or structural digestive abnormalities is frequently observed among cancer patients; this is a consequence of the tumor growth and of those systemic phenomena related to metabolism, which are affected by the relationship tumor-host specific to anorexia- cachexia. This study aimed at establishing the frequency of anorexia-cachexia, as well as its relationship to GI symptoms in the context of palliative care patients at the Instituto Nacional de Cancerología, México City. Analytic cross-sectional study including 100 patients diagnosed with late-stage cancer, age range 18-80, and a Karnofsky score > 50, as well as an ECOG <2; patients with a bad general health status were not allowed in the study. After reviewing inclusion and exclusion criteria, participants fulfilled the FAACT questionnaire, as well as the EGS. Patients recruitment was carried out by the Instituto Nacional de Cancerología. Results and discussion: Results show that 61% (n=61)of the patients had anorexia-cachexia, and 39% (n=39)did not. 56% of the sample participants (n=34) were women, and 44% (n=27) were men. GI symptoms associated with anorexia-cachexia were: nausea (p= 0.0001), vomiting (p=0.004), early satiety (p=0.0005), dysgeusia(p=0.0005) and dysphagia (p=0.001). Anorexia and cachexia are among the most devastating and frequent symptoms in late-stage cancer patients and they are also associated with GI symptoms affecting the physical, psychosocial and existential aspects of the patient's life. Data from this research validate the importance of an early nutrition support in palliative patients so that they can achieve a better quality of life. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

PubMed

Miller, A; McLeod, L; Alhayyani, S; Szczepny, A; Watkins, D N; Chen, W; Enriori, P; Ferlin, W; Ruwanpura, S; Jenkins, B J

2017-05-25

Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130 F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130 F/F :Kras G12D model, but not parental Kras G12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130 F/F :Kras G12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with Kras G12D muscle tissue. These cachectic features of gp130 F/F :Kras G12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130 F/F :Kras G12D :Stat3 -/+ or gp130 F/F :Kras G12D :Il6 -/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130 F/F :Kras G12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130 F/F :Kras G12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.

β-Hydroxy-β-methylbutyrate as a countermeasure for cancer cachexia: a cellular and molecular rationale.

PubMed

Kim, Jeong-Su; Khamoui, Andy V; Jo, Edward; Park, Bong-Sup; Lee, Won Jun

2013-10-01

Cancer cachexia is a life-threatening condition characterized by involuntary body weight loss and skeletal muscle wasting. In addition to being associated with poor prognosis and reduced survival, patients with cachexia exhibit a critical loss of physical function that impinges upon their ability to perform basic activities of daily living. Consequently, there is a loss of independence and a drastically reduced quality of life. Despite being a major unmet medical need of patients, very few treatment options exist. Maintaining muscle mass represents an important objective in the cancer patient trajectory not only because it relates to one's capacity to perform activities of daily living, but also because muscle preservation may be a critical determinant of survival while in a tumor-bearing state. In this regard, research has been directed towards identifying countermeasures effective in preserving muscle. With respect to nutritional approaches, administration of the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) could be a viable component in multi-modal therapies targeting cancer cachexia. Evidence suggests that HMB treatment promotes regenerative events (i.e. myogenic program), suppresses protein degradation, and activates signaling pathways preceding protein synthesis and skeletal muscle growth. HMB therefore, could conceivably act on key regulatory events driving cancer cachexia, thereby favoring muscle growth/preservation. In this review, we take a mechanistic approach in making a case for the use of HMB provision as a possible therapeutic strategy for cancer cachexia by highlighting the cellular and molecular aspects of HMB function.

Cachexia in patients with oesophageal cancer.

PubMed

Anandavadivelan, Poorna; Lagergren, Pernilla

2016-03-01

Oesophageal cancer is a debilitating disease with a poor prognosis, and weight loss owing to malnutrition prevails in the majority of patients. Cachexia, a multifactorial syndrome characterized by the loss of fat and skeletal muscle mass and systemic inflammation arising from complex host-tumour interactions is a major contributor to malnutrition, which is a determinant of tolerance to treatment and survival. In patients with oesophageal cancer, cachexia is further compounded by eating difficulties owing to the stage and location of the tumour, and the effects of neoadjuvant therapy. Treatment with curative intent involves exceptionally extensive and invasive surgery, and the subsequent anatomical changes often lead to eating difficulties and severe postoperative malnutrition. Thus, screening for cachexia by means of percentage weight loss and BMI during the cancer trajectory and survivorship periods is imperative. Additionally, markers of inflammation (such as C-reactive protein), dysphagia and appetite loss should be assessed at diagnosis. Routine assessments of body composition are also necessary in patients with oesophageal cancer to enable assessment of skeletal muscle loss, which might be masked by sarcopenic obesity in these patients. A need exists for clinical trials examining the effectiveness of therapeutic and physical-activity-based interventions in mitigating muscle loss and counteracting cachexia in these patients.

Clinical results in cachexia therapeutics.

PubMed

Crawford, Jeffrey

2016-05-01

This article highlights recent developments in the area of cancer cachexia and therapeutic interventions. Therapeutic interventions in cancer cachexia have been guided by clinical studies focused on the central role of muscle and the increased use of CT imaging to measure the impact of skeletal muscle loss on clinical outcomes. At the translational level, a number of different model systems have emphasized the importance of blockade of tumor-induced inflammation and its potential impact on reversing the cachexia phenotype, including FN14, a receptor in the TNF pathway, as well as the parathyroid hormone-related protein. Clinical studies continue to demonstrate the importance of nutrition and exercise as part of a multimodality approach. Although a number of promising agents are being evaluated, both enobosarm, a selected androgen receptor modulator, and anamorelin, a ghrelin agonist have completed phase III trials. Both agents have shown significant impact on reversal of skeletal muscle loss, but inconsistent effect on physical function improvement. Anamorelin also has a positive effect on appetite and weight gain. Further analysis of these studies, along with regulatory guidance, will be critical in the further development of these and other promising agents in the clinical management of patients with cancer cachexia.

Advances in pharmacologic strategies for cancer cachexia.

PubMed

Madeddu, Clelia; Mantovani, Giovanni; Gramignano, Giulia; Macciò, Antonio

2015-01-01

Cancer cachexia is a severe inflammatory metabolic syndrome accounting for fatigue, an impairment of normal activities and, eventually, death. The loss of muscle mass associated with body weight loss is the main feature of this syndrome. The present review aims to describe the advances in the pharmacological approaches for cancer cachexia, highlighting the impact on weight loss, muscle wasting and related outcomes. Among the pharmacological agents, attention should yet be given to the currently most widely studied drugs, such as progestogens and NSAIDs. Emerging drugs, such as ghrelin and selective androgen receptor modulators, have obtained promising results in recent randomized clinical trials. Larger sample sizes and more robust data on the effectiveness of anti-cytokine agents are needed. Any pharmacological approach to counteract cancer cachexia should always be associated with an adequate caloric intake, obtained by diet or through enteral or parenteral supplementation, if indicated. Finally, we can currently state that a combined approach that simultaneously targets the fundamental pathways involved in the pathogenesis of cancer cachexia is likely to be the most effective in terms of improvements in body weight as well as muscle wasting, function, physical performance and quality of life.

PARP-1 and PARP-2 activity in cancer-induced cachexia: potential therapeutic implications.

PubMed

Barreiro, Esther; Gea, Joaquim

2018-01-26

Skeletal muscle dysfunction and mass loss is a characteristic feature in patients with chronic diseases including cancer and acute conditions such as critical illness. Maintenance of an adequate muscle mass is crucial for the patients' prognosis irrespective of the underlying condition. Moreover, aging-related sarcopenia may further aggravate the muscle wasting process associated with chronic diseases and cancer. Poly(adenosine diphosphate-ribose) polymerase (PARP) activation has been demonstrated to contribute to the pathophysiology of muscle mass loss and dysfunction in animal models of cancer-induced cachexia. Genetic inhibition of PARP activity attenuated the deleterious effects seen on depleted muscles in mouse models of oncologic cachexia. In the present minireview the mechanisms whereby PARP activity inhibition may improve muscle mass and performance in models of cancer-induced cachexia are discussed. Specifically, the beneficial effects of inhibition of PARP activity on attenuation of increased oxidative stress, protein catabolism, poor muscle anabolism and mitochondrial content and epigenetic modulation of muscle phenotype are reviewed in this article. Finally, the potential therapeutic strategies of pharmacological PARP activity inhibition for the treatment of cancer-induced cachexia are also being described in this review.

Anorexia/cachexia-related quality of life for children with cancer.

PubMed

Lai, Jin-Shei; Cella, David; Peterman, Amy; Barocas, Joshua; Goldman, Stewart

2005-10-01

Anorexia is a common symptom in patients with cancer, which can lead to poor tolerance of treatment and can contribute to cachexia in extreme cases. Children with advanced-stage cancer are especially vulnerable to malnutrition resulting from anorexia and cachexia. Currently, there are no instruments that measure common concerns specifically associated with anorexia and cachexia in children with cancer. The purpose of the current article was to test the psychometric properties of a newly developed pediatric Functional Assessment of Anorexia and Cachexia Therapy (peds-FAACT) for children with cancer. Ninety-six patients (ages 7-17 yrs) receiving cancer treatment and their parents were asked to complete the 12-item peds-FAACT. The authors implemented both classical test theory and item response theory to evaluate the agreement between parents and patients, internal consistency and unidimensionality of the scale, and stability of items across subgroups. As a result, a patient-reported six-item scale was recommended as the core measure for all pediatric patients with cancer and four additional peripheral items were recommended for adolescent patients. The peds-FAACT demonstrated good psychometric properties, differentiated patients with different functional performance status, and was determined to be a useful tool for future clinical trials.

Tumor-Secreted Autocrine Motility Factor (AMF): Casual Role in a Animal Model of Cachexia

DTIC Science & Technology

2004-08-01

83:526-531 Crown AL, Cottle K, Lightman SL, Falk S, Mohamed-Ali V, Armstrong L, Millar AB, Holly JM (2002). What is the role of the insulin-like growth...Falk S, Mohamed-Ali V, Armstrong L, Millar AB, Holly JM (2002). What is the role of the insulin-like growth factor system in the pathophysiology of...Regulation of lipolysis: natriuretic peptides and the development of cachexia. Int J Cardiol 85:125-132 Kotler DP (2000). Cachexia. Ann Intern Med 133:622-634

Mechanisms of metabolic dysfunction in cancer-associated cachexia

PubMed Central

Petruzzelli, Michele; Wagner, Erwin F.

2016-01-01

Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding. PMID:26944676

Progesterone therapy for the treatment of non-cancer cachexia: a systematic review.

PubMed

Taylor, Joanne K; Pendleton, Neil

2016-09-01

Cachexia describes a complex pathological syndrome of muscle wasting, anorexia and weight loss. Progesterone therapies have been shown to improve appetite and promote weight gain in patients with cachexia; however, research has focused heavily on patients with cancer, and its effectiveness in other diseases remains unclear. This systematic review aimed to present the evidence available for progesterone therapy as a treatment for non-cancer cachexia. Surrogate outcome measures used were weight change, lean body mass (LBM), muscle strength, appetite, health-related quality of life (HRQOL) and serum albumin. Both randomised and non-randomised trials were included. A literature search of clinical trials using the medical subject heading (MeSH) terms 'cachexia' OR 'anorexia' OR 'weight' OR 'frail (truncated)' OR 'appetite' OR 'wasting syndrome' PLUS 'megestrol acetate' OR 'medroxyprogesterone acetate' was performed. Eighteen studies were included in this review; 12 randomised control trials and 6 non-randomised trials. This collated results from 916 patients with HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD) and geriatric cachexia. Meta-analysis comparing progesterone therapy with placebo concluded mean change in weight was not significant (mean difference (MD) 1.56, 95% CI -0.36 to 3.52, p=0.12). There was little evidence to show significant impact on LBM, and no trials looked at muscle strength. There was a paucity of evidence looking at appetite and HRQOL; however, results were generally positive. Current evidence does not support the use of progesterone therapies for non-cancer cachexia. There may however be a limited role for its use as an appetite stimulant in a palliative context on a case-by-case basis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Pre-cachexia in patients with stages I-III non-small cell lung cancer: systemic inflammation and functional impairment without activation of skeletal muscle ubiquitin proteasome system.

PubMed

Op den Kamp, C M; Langen, R C; Minnaard, R; Kelders, M C; Snepvangers, F J; Hesselink, M K; Dingemans, A C; Schols, A M

2012-04-01

Cachexia is a prevalent phenomenon of non-small cell lung cancer (NSCLC) which is responsible for increased mortality and deterioration of physical performance. Preclinical research indicates that systemic inflammation induces cachexia-related muscle wasting through muscular Nuclear Factor-kappa B (NF-κB) signaling and subsequent ubiquitin proteasome system (UPS)-mediated proteolysis. As these pathways could be a target for early intervention strategies, it needs to be elucidated whether increased activation of these pathways is already present in early stage NSCLC cachexia. The aim of the present study was therefore to assess muscular NF-κB and UPS activation in patients with NSCLC pre-cachexia. Sixteen patients with newly diagnosed stages I-III NSCLC having <10% weight loss and ten healthy controls were studied. Body composition, systemic inflammation and exercise capacity were assessed in all subjects and NF-κB and UPS activity in vastus lateralis muscle biopsies in a subset. Patients showed increased plasma levels of C-reactive protein (CRP) (P<0.001), soluble Tumor Necrosis Factor receptor 1 (sTNF-R1) (P<0.05), fibrinogen (P<0.001) and decreased levels of albumin (P<0.001). No changes in fat free body mass or skeletal muscle NF-κB and UPS activity were observed, while peak oxygen consumption ( [Formula: see text] ) was significantly decreased in patients compared with healthy controls. In conclusion, this exploratory study demonstrates significantly reduced exercise capacity in NSCLC pre-cachexia despite maintenance of muscle mass and unaltered indices of UPS activation. The absence of muscular NF-κB-dependent inflammatory signaling supports the notion that transition of systemic to local inflammation is required to initiate UPS-dependent muscle wasting characteristic for (experimental) cachexia. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia.

PubMed

Ebadi, Maryam; Mazurak, Vera C

2015-01-01

Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers.

The role of ghrelin in anorexia-cachexia syndromes.

PubMed

Guillory, Bobby; Splenser, Andres; Garcia, Jose

2013-01-01

Anorexia, sarcopenia, and cachexia are common complications of many chronic conditions including cancer, rheumatoid arthritis, HIV infection, aging, and chronic lung, heart, or kidney disease. Currently, there is no effective treatment for muscle atrophy or wasting conditions although they typically take a significant toll on the quality of life of patients and are associated with poor prognosis and decreased survival. Ghrelin affects multiple key pathways in the regulation of body weight, body composition, and appetite in the setting of cachexia that may lead to an increase in appetite and growth hormone secretion and a reduction in energy expenditure and inflammation. The net effect is increased lean body mass and fat mass preservation. In this chapter, we review the mechanisms of action of ghrelin and present the available data in animal models and human trials using ghrelin or ghrelin mimetics in different settings of cachexia. Copyright © 2013 Published by Elsevier Inc. Published by Elsevier Science & Technology.. All rights reserved.

Calpain inhibitors ameliorate muscle wasting in a cachectic mouse model bearing CT26 colorectal adenocarcinoma.

PubMed

Lin, Xing-Yu; Chen, Si-Zeng

2017-03-01

Cancer-related cachexia involves increased protein breakdown through various proteolytic pathways, including the ubiquitin-proteasome pathway (UPP). We hypothesized that a calcium- and calpain-dependent pathway might play a crucial role during the proteolytic procedure, and that pathway interventions would ameliorate cancer cachexia in vivo. After being inoculated with CT26 adenocarcinoma cell culture subcutaneously, BALB/c mice developed cachexia in 12 days. They were then administered with different types of calpain inhibitors individually or in combination for 7 consecutive days. Eighteen healthy mice were also assessed as a control group. Changes in body weight, gastrocnemius muscle mass, tumor volume, food intake, survival time, and serum nutritional markers were monitored. Also measured were the levels of calpains, E3 ubiquitin ligases, and apoptosis-associated markers in gastrocnemius muscle. Our study showed that the intraperitoneal administration of calpain inhibitors significantly improved tumor-free body weight and gastrocnemius muscle mass in all treatment groups. Treatment with calpain inhibitors also ameliorated cachexia-associated negative effects in metabolic profiles and increased survival time in most of the tumor-bearing mice compared with the cachexia controls. Furthermore, calpain inhibitors reduced the calpain activity and the expression of MuRF-1 and atrogin-1 in all treatment groups, while increasing the level of cleaved caspase-3 and BAX and lowering the level of BCL-2 in some groups. These results justify further evaluation of calpain inhibitors both alone and in combination with other candidate agents as a potential new therapeutic strategy for treating cancer cachexia.

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia--can findings from animal models be translated to humans?

PubMed

Mueller, Tara C; Bachmann, Jeannine; Prokopchuk, Olga; Friess, Helmut; Martignoni, Marc E

2016-02-08

Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research. A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically. More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future.

Detection of Pancreatic Cancer-Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance.

PubMed

Winnard, Paul T; Bharti, Santosh K; Penet, Marie-France; Marik, Radharani; Mironchik, Yelena; Wildes, Flonne; Maitra, Anirban; Bhujwalla, Zaver M

2016-03-15

The dire effects of cancer-induced cachexia undermine treatment and contribute to decreased survival rates. Therapeutic options for this syndrome are limited, and therefore efforts to identify signs of precachexia in cancer patients are necessary for early intervention. The applications of molecular and functional imaging that would enable a whole-body "holistic" approach to this problem may lead to new insights and advances for diagnosis and treatment of this syndrome. Here we have developed a myoblast optical reporter system with the purpose of identifying early cachectic events. We generated a myoblast cell line expressing a dual tdTomato:GFP construct that was grafted onto the muscle of mice-bearing human pancreatic cancer xenografts to provide noninvasive live imaging of events associated with cancer-induced cachexia (i.e., weight loss). Real-time optical imaging detected a strong tdTomato fluorescent signal from skeletal muscle grafts in mice with weight losses of only 1.2% to 2.7% and tumor burdens of only approximately 79 to 170 mm(3). Weight loss in cachectic animals was also associated with a depletion of lipid, cholesterol, valine, and alanine levels, which may provide informative biomarkers of cachexia. Taken together, our findings demonstrate the utility of a reporter system that is capable of tracking tumor-induced weight loss, an early marker of cachexia. Future studies incorporating resected tissue from human pancreatic ductal adenocarcinoma into a reporter-carrying mouse may be able to provide a risk assessment of cachexia, with possible implications for therapeutic development. ©2015 American Association for Cancer Research.

Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia.

PubMed

Tsoli, Maria; Swarbrick, Michael M; Robertson, Graham R

2016-06-01

Although muscle wasting is the obvious manifestation of cancer cachexia that impacts on patient quality of life, the loss of lipid reserves and metabolic imbalance in adipose tissue also contribute to the devastating impact of cachexia. Depletion of fat depots in cancer patients is more pronounced than loss of muscle and often precedes, or even occurs in the absence of, reduced lean body mass. Rapid mobilisation of triglycerides stored within adipocytes to supply the body with fatty acids in periods of high-energy demand is normally mediated through a well-defined process of lipolysis involving the lipases ATGL, HSL and MGL. Studies into how these lipases contribute to fat loss in cancer cachexia have revealed the prominent role for ATGL in initiating lipolysis during adipose tissue atrophy, together with links between tumour-derived factors and the signalling pathways that control lipid flux within fat cells. The recent findings of increased thermogenesis in brown fat during cancer cachexia indicate that metabolically active adipose tissue contributes to the imbalance in energy homeostasis involved in catabolic wasting. Such energetically futile use of fatty acids liberated from adipose tissue to generate heat represents a maladaptive response in conjunction with anorexia experienced by cancer patients. As IL-6 release by tumours provokes lipolysis and activates the thermogenic programme in brown fat, this review explores the overlap in dysregulated metabolic processes due to inflammatory mediators in cancer cachexia and other disease states characterised by elevated cytokines such as obesity and diabetes. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Unsatisfactory knowledge and use of terminology regarding malnutrition, starvation, cachexia and sarcopenia among dietitians.

PubMed

Ter Beek, Lies; Vanhauwaert, Erika; Slinde, Frode; Orrevall, Ylva; Henriksen, Christine; Johansson, Madelene; Vereecken, Carine; Rothenberg, Elisabet; Jager-Wittenaar, Harriët

2016-12-01

Clinical signs of malnutrition, starvation, cachexia and sarcopenia overlap, as they all imply muscle wasting to a various extent. However, the underlying mechanisms differ fundamentally and therefore distinction between these phenomena has therapeutic and prognostic implications. We aimed to determine whether dietitians in selected European countries have 'sufficient knowledge' regarding malnutrition, starvation, cachexia and sarcopenia, and use these terms in their daily clinical work. An anonymous online survey was performed among dietitians in Belgium, the Netherlands, Norway and Sweden. 'Sufficient knowledge' was defined as having mentioned at least two of the three common domains of malnutrition according to ESPEN definition of malnutrition (2011): 'nutritional balance', 'body composition' and 'functionality and clinical outcome', and a correct answer to three cases on starvation, cachexia and sarcopenia. Chi-square test was used to analyse differences in experience, work place and number of malnourished patients treated between dietitians with 'sufficient knowledge' vs. 'less sufficient knowledge'. 712/7186 responded to the questionnaire, of which data of 369 dietitians were included in the analysis (5%). The term 'malnutrition' is being used in clinical practice by 88% of the respondents. Starvation, cachexia and sarcopenia is being used by 3%, 30% and 12% respectively. The cases on starvation, cachexia and sarcopenia were correctly identified by 58%, 43% and 74% respectively. 13% of the respondents had 'sufficient knowledge'. 31% of the respondents identified all cases correctly. The proportion of respondents with 'sufficient knowledge' was significantly higher in those working in a hospital or in municipality (16%, P < 0.041), as compared to those working in other settings (7%). The results of our survey among dietitians in four European countries show that the percentage of dietitians with 'sufficient knowledge' regarding malnutrition, starvation, cachexia and sarcopenia is unsatisfactory (13%). The terms starvation, cachexia and sarcopenia are not often used by dietitians in daily clinical work. As only one-third (31%) of dietitians identified all cases correctly, the results of this study seem to indicate that nutrition-related disorders are suboptimally recognized in clinical practice, which might have a negative impact on nutritional treatment. The results of our study require confirmation in a larger sample of dietitians. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia

PubMed Central

Bindels, Laure B; Neyrinck, Audrey M; Claus, Sandrine P; Le Roy, Caroline I; Grangette, Corinne; Pot, Bruno; Martinez, Inés; Walter, Jens; Cani, Patrice D; Delzenne, Nathalie M

2016-01-01

Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia. PMID:26613342

Therapy insight: Cancer anorexia-cachexia syndrome--when all you can eat is yourself.

PubMed

Laviano, Alessandro; Meguid, Michael M; Inui, Akio; Muscaritoli, Maurizio; Rossi-Fanelli, Filippo

2005-03-01

Tumor growth is associated with profound metabolic and neurochemical alterations, which can lead to the onset of anorexia-cachexia syndrome. Anorexia is defined as the loss of the desire to eat, while cachexia results from progressive wasting of skeletal muscle mass--and to a lesser extent adipose tissue--occurring even before weight loss becomes apparent. Cancer anorexia-cachexia syndrome is highly prevalent among cancer patients, has a large impact on morbidity and mortality, and impinges on patient quality of life. However, its clinical relevance is frequently overlooked, and treatments are usually only attempted during advanced stages of the disease. The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumor-derived factors have a significant role, thereby representing a suitable therapeutic target. Energy expenditure in anorexia is frequently increased while energy intake is decreased, which further exacerbates the progressive deterioration of nutritional status. The optimal therapeutic approach to anorectic-cachectic cancer patients should be based on both changes in dietary habits, achieved via nutritional counseling; and drug therapy, aimed at interfering with cytokine expression or activity. Our improved understanding of the influence a tumor has on the host's metabolism is advancing new therapeutic approaches, which are likely to result in better preservation of nutritional status if started concurrently with specific antineoplastic treatment.

Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia.

PubMed

Bindels, Laure B; Neyrinck, Audrey M; Claus, Sandrine P; Le Roy, Caroline I; Grangette, Corinne; Pot, Bruno; Martinez, Inés; Walter, Jens; Cani, Patrice D; Delzenne, Nathalie M

2016-06-01

Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia.

Prevalence, incidence and clinical impact of cachexia: facts and numbers-update 2014.

PubMed

von Haehling, Stephan; Anker, Stefan D

2014-12-01

Cachexia is a serious but underrecognised consequence of many chronic diseases. Its prevalence ranges from 5-15 % in end-stage chronic heart failure to 50-80 % in advanced cancer. Cachexia is also part of the terminal course of many patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis. Mortality rates of patients with cachexia range from 10-15 % per year in COPD through 20-30 % per year in chronic heart failure and chronic kidney disease to 80 % in cancer. The condition is also associated with poor quality of life. In the industrialised world, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing and it currently affects around 1 % of the patient population, i.e. around 9 million people. It is also a significant health problem in other parts of the globe. Recently there have been advances in our understanding of the multifactorial nature of the condition, and particularly of the role of inflammatory mediators and the imbalance of anabolism and catabolism. Several promising approaches to treatment have failed to live up to the challenge of phase III clinical trials, but the ghrelin receptor agonist anamorelin seems to have fulfilled at least some early promise. Further advances are urgently needed.

[Chronic heart failure and cachexia: role of endocrine system].

PubMed

Dei Cas, A; Muoio, A; Zavaroni, I

2011-12-01

Chronic heart failure (CHF) is a major health problem that carries a devastating prognosis. The prognosis worsens considerably once cardiac cachexia has been diagnosed. Neurohormonal, metabolic, hemodynamic and immunological alterations are involved in the initiation and progression of cardiac cachexia. Cachexia is characterized by a hypothalamic inappropriate response to the mechanisms controlling energy homeostasis. Levels of the anorexigenic hormone leptin are decreased whereas the orexigenic gherlin hormone levels are normal or elevated. Nevertheless, energy intake is not increased as expected due to a persistent activation of the proopiomelanocortin (POMC) system (anorexigenic) paralleled by a decreased activity of the neuropeptide Y (NPY, orexigenic) neurons. Cachexia is also characterized by an imbalance in anabolic (impairment in the growth hormone/insulin-like growth factor-I axis, insulin resistance) and catabolic (increased levels of catecholamines, increased cortisol/dehydroepiandrosterone ratio and activation of proinflammatory cytokines such as tumor necrosis factor-alpha, interleuchin-6, interleuchin-1') at the basis of the wasting process. This review discusses the complex role of the endocrine system in modulating energy balance, appetite and metabolism in patients with chronic heart failure. A joint multidisciplinary effort of the cardiologists, immunologists and endocrinologists might be useful to identify the precise mechanisms involved in the neuroendocrine alteration and to develop therapeutic strategies able to improve the prognosis of CHF patients.

Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase.

PubMed

Julienne, Cloé Mimsy; Tardieu, Marine; Chevalier, Stéphan; Pinault, Michelle; Bougnoux, Philippe; Labarthe, François; Couet, Charles; Servais, Stéphane; Dumas, Jean-François

2014-05-01

Cancer-induced cachexia describes the progressive skeletal muscle wasting associated with many cancers leading to shortened survival time in cancer patients. We previously reported that cardiolipin content and energy-wasting processes were both increased in liver mitochondria in a rat model of peritoneal carcinosis (PC)-induced cachexia. To increase the understanding of the cellular biology of cancer cachexia, we investigated the involvement of adenine nucleotide translocator (ANT) in mitochondrial energy-wasting processes in liver mitochondria of PC and pair-fed control rats and its interactions with cardiolipin in isolated liver mitochondria from healthy rats exposed to cardiolipin-enriched liposomes. We showed in this study that functional ANT content was decreased in liver mitochondria from PC rats but without any effects on the efficiency of ATP synthesis. Moreover, non-phosphorylating energy wasting was not affected by saturating concentrations of carboxyatractylate (CAT), a potent inhibitor of ANT, in liver mitochondria from PC rats. Decreased efficiency of ATP synthesis was found in normal liver mitochondria exposed to cardiolipin-enriched liposomes, with increased non-phosphorylating energy wasting, thus mimicking mitochondria from PC rats. However, the functional ANT content in these cardiolipin-enriched mitochondria was unchanged, although non-phosphorylating energy wasting was reduced by CAT-induced inhibition of ANT. Finally, non-phosphorylating energy wasting was increased in cardiolipin-enriched mitochondria with substrates for complexes 1 and 2, but not for complex 4. In conclusion, increased energy wasting measured in liver mitochondria from rats with cancer cachexia is dependent on cardiolipin but independent of ANT. Interactions between ANT and cardiolipin are modified when cancer cachexia occurs. Copyright © 2014 Elsevier B.V. All rights reserved.

Protein metabolism in the small intestine during cancer cachexia and chemotherapy in mice.

PubMed

Samuels, S E; Knowles, A L; Tilignac, T; Debiton, E; Madelmont, J C; Attaix, D

2000-09-01

The impact of cancer cachexia and chemotherapy on small intestinal protein metabolism and its subsequent recovery was investigated. Cancer cachexia was induced in mice with colon 26 adenocarcinoma, which is a small and slow-growing tumor characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12ClN3O4S). Both healthy mice and tumor-bearing mice were given a single i.p. injection of cystemustine (20 mg/kg) 3 days after the onset of cachexia. Cancer cachexia led to a reduced in vivo rate of protein synthesis in the small intestine relative to healthy mice (-13 to -34%; P < 0.05), resulting in a 25% loss of protein mass (P < 0.05), and decreased villus width and crypt depth (P < 0.05). In treated mice, acute cytotoxicity of chemotherapy did not promote further wasting of small intestinal protein mass, nor did it result in further damage to intestinal morphology. In contrast, mucosal damage and a 17% reduction in small intestinal protein mass (P < 0.05) were evident in healthy mice treated with cystemustine, suggesting that the effects of chemotherapy on the small intestine in a state of cancer cachexia are not additive, which was an unexpected finding. Complete and rapid recovery of small intestinal protein mass in cured mice resulted from an increase in the rate of protein synthesis compared with healthy mice (23-34%; P < 0.05). Northern hybridizations of mRNA encoding components of the major proteolytic systems suggested that proteolysis may not have mediated intestinal wasting or recovery. A major clinical goal should be to design methods to improve small intestinal protein metabolism before the initiation of chemotherapy.

Clinical outcomes and contributors to weight loss in a cancer cachexia clinic.

PubMed

Del Fabbro, Egidio; Hui, David; Dalal, Shalini; Dev, Rony; Nooruddin, Zohra I; Noorhuddin, Zohra; Bruera, Eduardo

2011-09-01

Cancer cachexia is considered intractable, with few therapeutic options. Secondary nutrition impact symptoms (S-NIS) such as nausea may further contribute to weight loss by decreasing nutrient intake. In addition, treatable metabolic abnormalities such as hypogonadism, vitamin B12 deficiency, hypothyroidism, and hypoadrenalism could exacerbate anorexia and muscle wasting in patients with cancer cachexia. We determined the frequency and type of contributors to appetite and weight loss, and the effect of the cachexia clinic on clinical outcomes. Review of 151 consecutive patients referred to a cachexia clinic. All received dietary counseling and exercise recommendations. Assessments included weight, body mass index (BMI), S-NIS, resting energy expenditure by indirect calorimetry, serum thyroid stimulating hormone (TSH), cortisol, total testosterone, and vitamin B12. Median weight loss in the 100 days before referral was 9% (4%-13%); median BMI at presentation was 20.8. Median number of S-NIS was 3 (2-4), most commonly treated by metoclopramide, laxatives, and antidepressants. Forty-one percent (24/59) of patients were hypermetabolic and 73% (52/71) of males hypogonadic, whereas hypoadrenalism (0/101, 0%), hypothyroidism (4/113, 4%), and low vitamin B12 (3/107, 3%) were uncommon. Poor appetite and weight loss before referral (r = 0.18, p = 0.036) were associated with increased S-NIS (r = 0.22, p = 0.008). Appetite improved (p < 0.001) and 31/92 (34%) of patients returning for a second visit gained weight. Patients had a high frequency of multiple S-NIS, hypogonadism, and hypermetabolism. A combination of simple pharmacological and nonpharmacological interventions improved appetite significantly, and increased weight in one third of patients who were able to return for follow-up. Cachexia clinics are feasible and effective for many patients with advanced cancer.

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia.

PubMed

Bonetto, Andrea; Rupert, Joseph E; Barreto, Rafael; Zimmers, Teresa A

2016-11-30

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality 1 . Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma 2-4 . Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength 3-5 . Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6) 3 , which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism 2 . Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.

Endoplasmic Reticulum Stress, Calcium Dysregulation and Altered Protein Translation: Intersection of Processes That Contribute to Cancer Cachexia Induced Skeletal Muscle Wasting.

PubMed

Isaac, Stephanie T; Tan, Timothy C; Polly, Patsie

2016-01-01

Cancer cachexia is a debilitating paraneoplastic wasting syndrome characterized by skeletal muscle depletion and unintentional weight loss. It affects up to 50-80% of patients with cancer and directly accounts for one-quarter of cancer-related deaths due to cardio-respiratory failure. Muscle weakness, one of the hallmarks of this syndrome, has been postulated to be due to a combination of muscle breakdown, dysfunction and decrease in the ability to repair, with effective treatment strategies presently limited. Excessive inflammatory cytokine levels due to the host-tumor interaction, such as Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α, are hypothesised to drive this pathological process but the specific mechanisms by which these cytokines produce skeletal muscle dysfunction in cancer cachexia remain undefined. Endoplasmic Reticulum (ER) stress and the associated disruptions in calcium signaling have been implicated in cytokine-mediated disruptions in skeletal muscle and function. Disrupted ER stress-related processes such as the Unfolded Protein Response (UPR), calcium homeostasis and altered muscle protein synthesis have been reported in clinical and experimental cachexia and other inflammation-driven muscle diseases such as myositis, potentially suggesting a link between increased IL-6 and TNF-α and ER stress in skeletal muscle cells. As the concept of upregulated ER stress in skeletal muscle cells due to elevated cytokines is novel and potentially very relevant to our understanding of cancer cachexia, this review aims to examine the potential relationship between inflammatory cytokine mediated muscle breakdown and ER stress, in the context of cancer cachexia, and to discuss the molecular signaling pathways underpinning this pathology.

Tandospirone reduces wasting and improves cardiac function in experimental cancer cachexia.

PubMed

Elkina, Yulia; Palus, Sandra; Tschirner, Anika; Hartmann, Kai; von Haehling, Stephan; Doehner, Wolfram; Mayer, Ulrike; Coats, Andrew J S; Beadle, John; Anker, Stefan D; Springer, Jochen

2013-12-10

Cancer cachexia is thought to be the cause of >20% of cancer related deaths. Symptoms of cancer cachexia patients include depression and anorexia significantly worsening their quality of life. Moreover, in rodent models of cancer cachexia atrophy of the heart has been shown to impair cardiac function. Here, we characterize the effects of the antidepressant and anxiolytic drug tandospirone on wasting, cardiac function and survival in experimental cancer cachexia. The well-established Yoshida hepatoma rat model was used and tumor-bearing rats were treated with 1mg/kg/d (LD), 10mg/kg/d (HD) tandospirone or placebo. Weight, body composition (NMR), cardiac function (echocardiography), activity and food intake were assessed. Noradrenalin and cortisol were measured in plasma and caspase activity in skeletal muscle. Ten mg/kg/d tandospirone decreased the loss of body weight (p=0.0003) compared to placebo animals, mainly due to preservation of muscle mass (p<0.001), while 1mg/kg/d tandospirone was not effective. Locomotor activity (p=0.0007) and food intake (p=0.0001) were increased by HD tandospirone. The weight (p=0.0277) and function of heart (left ventricular mass, fractional shortening, stroke volume, ejection fraction, all p<0.05) were significantly improved. In the HD tandospirone group, plasma levels of noradrenalin and cortisol were significantly reduced by 49% and 52%, respectively, which may have contributed to the lower caspase activity in the gastrocnemius muscle. Most importantly, HD tandospirone significantly improved survival compared to placebo rats (HR: 0.34; 95% CI: 0.13-0.86; p=0.0495). Tandospirone showed significant beneficial effects in the Yoshida hepatoma cancer cachexia model and should be further examined as a prospective drug for this syndrome. © 2013.

Understanding cachexia as a cancer metabolism syndrome

PubMed Central

Porporato, P E

2016-01-01

Metabolic reprogramming occurs in tumors to foster cancer cell proliferation, survival and metastasis, but as well at a systemic level affecting the whole organism, eventually leading to cancer cachexia. Indeed, as cancer cells rely on external sources of nitrogen and carbon skeleton to grow, systemic metabolic deregulation promoting tissue wasting and metabolites mobilization ultimately supports tumor growth. Cachectic patients experience a wide range of symptoms affecting several organ functions such as muscle, liver, brain, immune system and heart, collectively decreasing patients' quality of life and worsening their prognosis. Moreover, cachexia is estimated to be the direct cause of at least 20% of cancer deaths. The main aspect of cachexia syndrome is the unstoppable skeletal muscle and fat storage wasting, even with an adequate caloric intake, resulting in nutrient mobilization – both directly as lipid and amino acids and indirectly as glucose derived from the exploitation of liver gluconeogenesis – that reaches the tumor through the bloodstream. From a metabolic standpoint, cachectic host develops a wide range of dysfunctions, from increased insulin and IGF-1 resistance to induction of mitochondrial uncoupling proteins and fat tissue browning resulting in an increased energy expenditure and heat generation, even at rest. For a long time, cachexia has been merely considered an epiphenomenon of end-stage tumors. However, in specific tumor types, such as pancreatic cancers, it is now clear that patients present markers of tissue wasting at a stage in which tumor is not yet clinically detectable, and that host amino acid supply is required for tumor growth. Indeed, tumor cells actively promote tissue wasting by secreting specific factors such as parathyroid hormone-related protein and micro RNAs. Understanding the molecular and metabolic mediators of cachexia will not only advance therapeutic approaches against cancer, but also improve patients' quality of life. PMID:26900952

Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

PubMed Central

Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

2011-01-01

Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia. PMID:22832525

Mechanisms of Anorexia Cancer Cachexia Syndrome and Potential Benefits of Traditional Medicine and Natural Herbs.

PubMed

Ming-Hua, Cong; Bao-Hua, Zou; Lei, Yu

Anorexia cancer cachexia syndrome is prevalent in advanced cancer patients, which is featured by anorexia, decreased dietary intake, body weight loss (skeletal muscle mass loss), and is unable to be reversed by routine nutritional support therapy. Up to now, the main mechanisms involved in cancer cachexia include excessive systemic inflammation, which is represented by increased plasma levels of IL-1, IL-6, TNF-alpha, tumor-induced factors, such as PIF and LMF. These factors eventually act on orexigenic and anorexigenicneurons located in the hypothalamus or protein and lipid metabolism of peripheral tissues, which lead to anorexia, decreased dietary intake, enhanced basic metabolism rate and hypercatabolism. The treatment modality includes early nutritional intervention, physical activity and drug treatment. However, studies about drugs used to treat cachexia are always controversial or merely effective in stimulating appetite and increasing body weight, though not lean body mass. The main target of pharmaceutical treatment is to improve appetite, decrease systemic inflammation and promote anabolic metabolism. Nevertheless, the treatment effectiveness of chemical drugs are not reaching consensus by existing cachexia guidelines. Complementary and alternative medicine (CAM) is recently known as a promising treatment to improve cachaxia status and quality of life of cancer patients. Traditional Chinese medicine (TCM) and natural herbal medicines have been used in the treatment of cancer for thousands of years worldwide, particularly in China. More and more research show that traditional Hanfang (Chinese medicines) and some natural herbs with less side reactions, have the effects of antagonizing pro-inflammatory cytokines, enhancing immune system, inhibiting protein catabolism, boosting the appetite and body weight, which maybe a promising treatment strategy and development tendency for anorexia cancer cachexia syndrome.

Use of ghrelin in cachexia syndrome: a systematic review of clinical trials.

PubMed

Mansson, Jéssica V; Alves, Fernanda D; Biolo, Andréia; Souza, Gabriela C

2016-11-01

Ghrelin is a hormone that stimulates weight gain and increases appetite. For these reasons, it has been used for treatment of cachexia syndrome. The aim of this systematic review was to examine the use of ghrelin in cachexia patients to better understand the most prevalent clinical outcomes, particularly since the type and dosage of hormone used and the route and duration of administration often varies. A search of electronic databases (MEDLINE, SciELO, Embase, Cochrane Library, and Clinical Trials.gov) was limited to original articles describing interventions in adult humans, with no limits for publication date or language. Articles were searched independently by 2 reviewers, from October 2013 to April 2015. Studies were eligible for inclusion if they were conducted in adult patients with a diagnosis of cachexia and provided information on type of ghrelin or analogue used, route of administration and dose administered, duration of intervention, outcomes, and clinical trial study design. Data were extracted independently by 2 reviewers using a preconstructed spreadsheet. Initially, 573 references were identified. Seven articles describing 379 participants were selected for review. Ghrelin was found to have a predominantly positive effect on growth hormone plasma levels, weight gain, increases in lean mass, and reductions in loss of adipose tissue. Although the studies reviewed here report positive results, there is still little evidence available on the use of ghrelin to treat cachexia. Further research is required to determine conclusively whether the use of ghrelin in patients with cachexia is a viable therapy. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Historical Perspectives in the Care of Patients with Enterocutaneous Fistula

DTIC Science & Technology

2010-09-01

correct hypercatabolism and cachexia that are frequently present. Phase 2, or the investigational phase, involves imaging such as a fistulo- gram and...fluid losses, electrolytes, or nutrients, although they highlight how far we have come. The adverse results of malnutrition to include cachexia

Pay attention to cardiac remodeling in cancer cachexia.

PubMed

Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

2016-07-01

Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

IL-4 mRNA Is Downregulated in the Liver of Pancreatic Cancer Patients Suffering from Cachexia.

PubMed

Prokopchuk, Olga; Steinacker, Jürgen M; Nitsche, Ulrich; Otto, Stephanie; Bachmann, Jeannine; Schubert, Elaine C; Friess, Helmut; Martignoni, Marc E

2017-01-01

Interleukin-4 (IL-4) together with interleukin-13 (IL-13) play an important role in inflammation and wound repair, and are known to be upregulated in human skeletal muscle after strenuous physical exercise. Additionally, these cytokines may act as autocrine growth factors in pancreatic cancer cells. We hypothesize that IL-4, IL-13, and their corresponding receptors are involved in mechanism of cancer cachexia. Tissue samples from human skeletal muscle, white fat, liver, healthy pancreas, and pancreatic ductal adenocarcinoma were analyzed by quantitative real-time polymerase chain reaction for mRNA expression levels of IL-4, IL-13, IL-4 receptor α, and IL-13 receptor α1. We demonstrate for the first time that liver IL-4 mRNA is downregulated in vivo in patients with pancreatic cancer and cachexia. Additionally, IL-4 mRNA in the liver inversely correlated with musculus psoas thickness. We speculate that suppression of IL-4 is involved in cancer cachexia, although the exact mechanisms have to be further elucidated.

Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin-6 dependent.

PubMed

Reddel, C J; Allen, J D; Ehteda, A; Taylor, R; Chen, V M Y; Curnow, J L; Kritharides, L; Robertson, G

2017-03-01

Essentials Cancer cachexia and cancer-associated thrombosis have not previously been mechanistically linked. We assessed thrombin generation and coagulation parameters in cachectic C26 tumor-bearing mice. C26 mice are hypercoagulable, partially corrected by blocking tumor derived interleukin-6. Coagulability and anti-inflammatory interventions may be clinically important in cancer cachexia. Background Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer, which have not previously been mechanistically linked. The colon 26 (C26) carcinoma is a well-established mouse model of complications of advanced cancer cachexia, partially dependent on high levels of interleukin-6 (IL-6) produced by the tumor. Objectives To assess if cancer cachexia altered the coagulation state and if this was attributable to tumor IL-6 production. Methods In male BALB/c*DBA2 (F1 hybrid) mice with a C26 tumor we used modified calibrated automated thrombogram and fibrin generation (based on overall hemostatic potential) assays to assess the functional coagulation state, and also examined fibrinogen, erythrocyte sedimentation rate (ESR), platelet count, tissue factor pathway inhibitor (TFPI) and hepatic expression of coagulation factors by microarray. C26 mice were compared with non-cachectic NC26, pair-fed and sham control mice. IL-6 expression in C26 cells was knocked down by lentiviral shRNA constructs. Results C26 mice with significant weight loss and highly elevated IL-6 had elevated thrombin generation, fibrinogen, ESR, platelets and TFPI compared with all control groups. Fibrin generation was elevated compared with pair-fed and sham controls but not compared with NC26 tumor mice. Hepatic expression of coagulation factors and fibrinolytic inhibitors was increased. Silencing IL-6 in the tumor significantly, but incompletely, attenuated the increased thrombin generation, fibrinogen and TFPI. Conclusions Cachectic C26 tumor-bearing mice are in a hypercoagulable state, which is partly attributable to IL-6 release by the tumor. The findings support the importance of the coagulation state in cancer cachexia and the clinical utility of anti-inflammatory interventions. © 2017 International Society on Thrombosis and Haemostasis.

ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments.

PubMed

Hatakeyama, Shinji; Summermatter, Serge; Jourdain, Marie; Melly, Stefan; Minetti, Giulia C; Lach-Trifilieff, Estelle

2016-01-01

Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients.

Cancer cachexia: mediators, signaling, and metabolic pathways.

PubMed

Fearon, Kenneth C H; Glass, David J; Guttridge, Denis C

2012-08-08

Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.

[A rare case of diencephalic cachexia in an adult female with cranio-pharyngioma].

PubMed

Klochkova, I S; Astaf'eva, L I; Konovalov, A N; Kadashev, B A; Kalinin, P L; Sharipov, O I; Kutin, M A; Sidneva, Yu G; Shishkina, L V; Pronin, I N

Diencephalic cachexia (DС) is progressive weight loss despite a normal caloric intake and a satisfactory state of health, which is caused by hypothalamic lesions. This is a rare (about 100 cases were reported) and potentially fatal disorder of unknown pathogenesis. At present, there is no effective pharmacological therapy for the disorder. Cachexia may regress only if the tumor reduces in size, therefore the timely diagnosis and treatment are of vital importance for the patient. DС is typical of early childhood, and only a few cases have been reported in adults. We present a rare case of DС in a 24-year-old female with papillary craniopharyngioma.

Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia.

PubMed

Peyta, Laure; Jarnouen, Kathleen; Pinault, Michelle; Coulouarn, Cedric; Guimaraes, Cyrille; Goupille, Caroline; de Barros, Jean-Paul Pais; Chevalier, Stephan; Dumas, Jean-François; Maillot, François; Hatch, Grant M; Loyer, Pascal; Servais, Stephane

2015-11-01

Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p<0.02) and cardiolipin synthase (CLS) activity decreased 44% (p<0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p<0.01) and 50% (p<0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p<0.05), mitochondrial oxygen consumption 33% (p<0.05), PGPS gene expression 44% (p<0.05) and MLCL AT-1 activity 20% (p<0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.

Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle.

PubMed

Pretto, Francesca; Ghilardi, Carmen; Moschetta, Michele; Bassi, Andrea; Rovida, Alessandra; Scarlato, Valentina; Talamini, Laura; Fiordaliso, Fabio; Bisighini, Cinzia; Damia, Giovanna; Bani, Maria Rosa; Piccirillo, Rosanna; Giavazzi, Raffaella

2015-02-20

Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome. We used the RXF393 human renal carcinoma xenograft that recapitulates the characteristics of the disease, including the growth in the mouse kidney (orthotopic implantation), and the induction of cachexia with subsequent premature death. Sunitinib prevents body weight loss and muscle wasting and significantly improves the survival of RXF393-bearing nude mice. The anti-cachectic effect was not associated to direct anti-tumor activity of the drug. Most relevant is the ability of sunitinib to reverse the cachectic phenotype and rescue the animals from the loss of fat tissue. Body weight loss is prevented also in mice bearing the C26 colon carcinoma, classically reported to induce cachexia in immunocompetent mice. Among the mechanisms, we herein show that sunitinib is able to restrain the overactivation of STAT3 and MuRF-1 pathways, involved in enhanced muscle protein catabolism during cancer cachexia. We suggest that off-target effects of angiogenesis inhibitors targeting STAT3 are worth considering as a therapeutic option for patients who develop cachexia, independently of their anti-tumor activity.

Highlights of the mechanistic and therapeutic cachexia and sarcopenia research 2010 to 2012 and their relevance for cardiology.

PubMed

Anker, Markus S; von Haehling, Stephan; Springer, Jochen; Banach, Maciej; Anker, Stefan D

2013-01-10

Sarcopenia and cachexia are significant medical problems with a high disease related burden in cardiovascular illness. Muscle wasting and weight loss are very frequent particularly in chronic heart failure and they relate to poor prognosis. Although clinically largely underestimated, the fields of cachexia and sarcopenia are of great relevance to cardiologists. In cachexia and sarcopenia a significant number of research publications related to basic science questions of muscle wasting and lipolysis were published between 2010 and 2012. Recently, the two processes of muscle wasting and lipolysis were found to be closely linked. Treatment research in pre-clinical models involves studies on a number of different therapeutic entities, including ghrelin, selective androgen receptor modulators (SARMs), as well as drugs targeting myostatin or melanocortin-4. In the human setting, studies using enobosarm (a SARM) and anamorelin (ghrelin) are in phase III. The last 3 years has seen significant efforts to define the field using consensus statements. In the future, these definitions should also be considered for guidelines and treatment trials in cardiovascular medicine. The current review aims to summarize important information and development in the fields of muscle wasting, sarcopenia and cachexia focussing on findings in cardiovascular research, in order for cardiologists to have a better understanding of the progress in the still not well enough known field. Copyright © 2012. Published by Elsevier Ireland Ltd.

Experimental Cancer Cachexia Changes Neuron Numbers and Peptide Levels in the Intestine: Partial Protective Effects after Dietary Supplementation with L-Glutamine

PubMed Central

Vicentini, Geraldo E.; Fracaro, Luciane; de Souza, Sara R. G.; Martins, Heber A.; Guarnier, Flávia A.; Zanoni, Jacqueline N.

2016-01-01

Gastrointestinal dysmotility frequently occurs in cancer cachexia and may result from damage to enteric innervation caused by oxidative stress, especially due to glutathione depletion. We assessed the effect of dietary supplementation with 20 g/kg l-glutamine (a glutathione precursor) on the intrinsic innervation of the enteric nervous system in healthy and Walker 256 tumor-bearing Wistar rats during the development of experimental cachexia (14 days), in comparison with non-supplemented rats, by using immunohistochemical methods and Western blotting. The total neural population and cholinergic subpopulation densities in the myenteric plexus, as well as the total population and VIPergic subpopulation in the submucosal plexus of the jejunum and ileum, were reduced in cachectic rats, resulting in adaptive morphometric alterations and an increase in vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) expression, suggesting a neuroplastic response. l-glutamine supplementation prevented decrease in myenteric neuronal density in the ileum, morphometric alterations in the neurons and nerve fibers (in both the plexuses of the jejunum and ileum), and the overexpression of VIP and CGRP. Cancer cachexia severely affected the intrinsic innervation of the jejunum and ileum to various degrees and this injury seems to be associated with adaptive neural plasticity. l-glutamine supplementation presented partial protective effects on the enteric innervation against cancer cachexia, possibly by attenuating oxidative stress. PMID:27635657

Experimental Cancer Cachexia Changes Neuron Numbers and Peptide Levels in the Intestine: Partial Protective Effects after Dietary Supplementation with L-Glutamine.

PubMed

Vicentini, Geraldo E; Fracaro, Luciane; de Souza, Sara R G; Martins, Heber A; Guarnier, Flávia A; Zanoni, Jacqueline N

2016-01-01

Gastrointestinal dysmotility frequently occurs in cancer cachexia and may result from damage to enteric innervation caused by oxidative stress, especially due to glutathione depletion. We assessed the effect of dietary supplementation with 20 g/kg l-glutamine (a glutathione precursor) on the intrinsic innervation of the enteric nervous system in healthy and Walker 256 tumor-bearing Wistar rats during the development of experimental cachexia (14 days), in comparison with non-supplemented rats, by using immunohistochemical methods and Western blotting. The total neural population and cholinergic subpopulation densities in the myenteric plexus, as well as the total population and VIPergic subpopulation in the submucosal plexus of the jejunum and ileum, were reduced in cachectic rats, resulting in adaptive morphometric alterations and an increase in vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) expression, suggesting a neuroplastic response. l-glutamine supplementation prevented decrease in myenteric neuronal density in the ileum, morphometric alterations in the neurons and nerve fibers (in both the plexuses of the jejunum and ileum), and the overexpression of VIP and CGRP. Cancer cachexia severely affected the intrinsic innervation of the jejunum and ileum to various degrees and this injury seems to be associated with adaptive neural plasticity. l-glutamine supplementation presented partial protective effects on the enteric innervation against cancer cachexia, possibly by attenuating oxidative stress.

[Cardiac cachexia].

PubMed

Miján, Alberto; Martín, Elvira; de Mateo, Beatriz

2006-05-01

Chronic heart failure (CHF), especially affecting the right heart, frequently leads to malnutrition. If the latter is severe and is combined to other factors, it may lead to cardiac cachexia. This one is associated to increased mortality and lower survival of patients suffering from it. The causes of cardiac cachexia are diverse, generally associated to maintenance of a negative energy balance, with increasing evidence of its multifactorial origin. Neurohumoral, inflammatory, immunological, and metabolic factors, among others, are superimposed in the patient with CHF, leading to involvement and deterioration of several organs and systems, since this condition affects both lean (or active cellular) mass and adipose and bone tissue osteoporosis. Among all, the most pronounced deterioration may be seen at skeletal muscle tissue, at both structural and functional levels, the heart not being spared. As for treatment, it should be based on available scientific evidence. Assessment of nutritional status of any patient with CHF is a must, with the requirement of nutritional intervention in case of malnutrition. In this situation, especially if accompanied by cardiac cachexia, it is required to modify energy intake and oral diet quality, and to consider the indication of specific complementary or alternative artificial nutrition. Besides, the causal relationship of the beneficial role of moderate physical exertion is increasing, as well as modulation of metabolic and inflammatory impairments observed in cardiac cachexia with several drugs, leading to a favorable functional and structural response in CHF patients.

Update on clinical trials of growth factors and anabolic steroids in cachexia and wasting1234

PubMed Central

Gullett, Norleena P; Hebbar, Gautam

2010-01-01

This article and others that focused on the clinical features, mechanisms, and epidemiology of skeletal muscle loss and wasting in chronic diseases, which include chronic kidney disease, cancer, and AIDS, were presented at a symposium entitled "Cachexia and Wasting: Recent Breakthroughs in Understanding and Opportunities for Intervention," held at Experimental Biology 2009. The clinical and anabolic efficacy of specific growth factors and anabolic steroids (eg, growth hormone, testosterone, megestrol acetate) in malnutrition and other catabolic states has been the subject of considerable research during the past several decades. Research on the effects of these agents in cachexia or wasting conditions, characterized by progressive loss of skeletal muscle and adipose tissue, focused on patients with AIDS in the early 1990s, when the devastating effects of the loss of body weight, lean body mass, and adipose tissue were recognized as contributors to these patients' mortality. These same agents have also been studied as methods to attenuate the catabolic responses observed in cancer-induced cachexia and in wasting induced by chronic obstructive pulmonary disease, congestive heart failure, renal failure, and other conditions. This article provides an updated review of recent clinical trials that specifically examined the potential therapeutic roles of growth hormone, testosterone, oxandrolone, and megestrol acetate and emerging data on the orexigenic peptide ghrelin, in human cachexia and wasting. PMID:20164318

Update on clinical trials of growth factors and anabolic steroids in cachexia and wasting.

PubMed

Gullett, Norleena P; Hebbar, Gautam; Ziegler, Thomas R

2010-04-01

This article and others that focused on the clinical features, mechanisms, and epidemiology of skeletal muscle loss and wasting in chronic diseases, which include chronic kidney disease, cancer, and AIDS, were presented at a symposium entitled "Cachexia and Wasting: Recent Breakthroughs in Understanding and Opportunities for Intervention," held at Experimental Biology 2009. The clinical and anabolic efficacy of specific growth factors and anabolic steroids (eg, growth hormone, testosterone, megestrol acetate) in malnutrition and other catabolic states has been the subject of considerable research during the past several decades. Research on the effects of these agents in cachexia or wasting conditions, characterized by progressive loss of skeletal muscle and adipose tissue, focused on patients with AIDS in the early 1990s, when the devastating effects of the loss of body weight, lean body mass, and adipose tissue were recognized as contributors to these patients' mortality. These same agents have also been studied as methods to attenuate the catabolic responses observed in cancer-induced cachexia and in wasting induced by chronic obstructive pulmonary disease, congestive heart failure, renal failure, and other conditions. This article provides an updated review of recent clinical trials that specifically examined the potential therapeutic roles of growth hormone, testosterone, oxandrolone, and megestrol acetate and emerging data on the orexigenic peptide ghrelin, in human cachexia and wasting.

Hypothalamic Mechanisms in Cachexia

PubMed Central

Grossberg, Aaron J.; Scarlett, Jarrad M.; Marks, Daniel L.

2010-01-01

The role of nutrition and balanced metabolism in normal growth, development, and health maintenance is well known. Patients affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Other common features that are not required for the diagnosis include decreases in voluntary movement, insulin resistance, and anhedonia. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, renal failure, and Alzheimer's disease. The severity of cachexia in these illnesses is often the primary determining factor in both quality of life, and in eventual mortality. Indeed, body mass retention in AIDS patients has a stronger association with survival than any other current measure of the disease. This has led to intense investigation of cachexia and the proposal of numerous hypotheses regarding its etiology. Most authors suggest that cytokines released during inflammation and malignancy act on the central nervous system to alter the release and function of a number of neurotransmitters, thereby altering both appetite and metabolic rate. This review will discuss the salient features of cachexia in human diseases, and review the mechanisms whereby inflammation alters the function of key brain regions to produce stereotypical illness behavior. PMID:20346963

Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF(V600E).

PubMed

Husain, Amjad; Hu, Nina; Sadow, Peter M; Nucera, Carmelo

2016-10-01

Cachexia is the result of complex metabolic alterations which cause morbidity and mortality in patients with advanced cancers including undifferentiated (anaplastic) thyroid carcinoma (ATC). ATC is a lethal disease with limited therapeutic options and unclear etiology for cachexia. We hypothesize that the BRAF(V600E) oncoprotein triggers microvascular endothelial cell tubule formation (in vitro angiogenesis) by means of factors which play a crucial role in angiogenic switch, inflammation/immune response and cachexia. We use human ATC cells and applied multiplex ELISA assay to screen for and measure angiogenic/cachectic and pro-inflammatory factors in the ATC-derived secretome. We find that vemurafenib anti-BRAF(V600E) therapy significantly reduces secreted VEGFA, VEGFC and IL6 protein levels compared to vehicle-treated ATC cells. As a result, the secretome from vemurafenib-treated ATC cells inhibits microvascular endothelial cell-related in vitro angiogenesis. Furthermore, ATC clinical samples express VEGFA, VEGFC and IL6 proteins. Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAF(V600E)-positive human ATC aggressiveness. Understanding the extent to which microenvironment-associated angiogenic factors participate in cachexia and cancer metabolism in advanced thyroid cancers will reveal new biomarkers and foster novel therapeutic approaches. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Hemodialysis and nutritional status in children: malnutrition and cachexia.

PubMed

Fischbach, Michel; Dheu, Céline; Seuge, Laure; Orfanos, Nadia

2009-01-01

Malnutrition is a common state in chronic hemodialyzed children. More than malnutrition, which infers that dietary supplementation would be curative, cachexia, which implies loss of protein stores, are combined factors of impaired linear growth and reduced muscle mass in uremic patients. Adequate diet to prevent malnutrition is of major importance. But to avoid cachexia in children on chronic hemodialysis, the management of acidosis, inflammation, abnormal metabolic rate, and endocrine disturbances should not, be forgotten. Daily hemodialysis regimen using convective flow therapy and ultrapure dialysate, i.e., on line hemodiafiltration together with growth hormone therapy, appears as a hopeful strategy for the chronic dialyzed child to achieve catch-up growth, a parameter of optimal nutrition.

Does nutrition support have a role in managing cancer cachexia?

PubMed

Laviano, Alessandro; Di Lazzaro Giraldi, Gianluca; Koverech, Angela

2016-12-01

Cachexia is a negative prognostic factor in cancer patients. The pathogenesis is related to a variable combination of reduced food intake and metabolic changes. However, whether nutritional support may contribute to effectively prevent and treat cachexia remains a debated issue. Consistent evidence demonstrates that anabolic windows of opportunity occur during the clinical trajectory of cancer patients. Also, the use of specific nutrients, namely omega-3 fatty acids, may enhance the efficacy of nutritional support when tumor-driven inflammatory response is high. Of greater interest, it is now becoming clearer that the use of nutritional support at key time points in the clinical journey of cancer patients (i.e., perioperative period) may extend its clinical benefits beyond those on nutritional status. Nutritional support plays a role in managing cancer cachexia, when it is timely delivered, when it provides adequate amounts of calories and proteins, and when it is part of a concurrent palliative care approach. Specific nutrients, that is, omega-3 fatty acids, may help in those cancer patients with high-inflammatory response, and may also contribute to positively influence long-term clinical outcomes.

Clinical application of ghrelin for chronic respiratory failure.

PubMed

Matsumoto, Nobuhiro; Tsubouchi, Hironobu; Imazu, Yoshifumi; Arimura, Yasuji; Yanagi, Shigehisa; Iiboshi, Hirotoshi; Nakazato, Masamitsu

2017-01-01

Chronic respiratory failure, which is often caused by chronic obstructive pulmonary disease, chronic lower respiratory tract infection, or interstitial pneumonia, often leads to cachexia with disease progression. Patients who have chronic respiratory failure with cachexia exhibit increased morbidity. Although cachectic status is an important clinical problem, there are no effective therapies for cachexia. Ghrelin has various effects, including increasing food intake, attenuating sympathetic nerve activity, inhibiting inflammation, increasing cardiac output, and controlling fat utilization. These effects of ghrelin are ideal targets for the treatment of severely wasting chronic respiratory disease. In a few clinical studies, including a small randomized controlled trial, ghrelin administration to cachectic patients with chronic respiratory failure improved exercise tolerance, dyspnea, and appetite. The patients in these studies gained muscle mass and weight. In another study of chronic lower respiratory tract infection with cachexia, ghrelin suppressed airway inflammation by decreasing neutrophil accumulation in the airway, resulting in improvements in oxygenation and exercise tolerance. Although further clinical investigations are needed to clarify its usefulness, ghrelin is expected to become a novel therapy for cachectic patients with chronic respiratory failure.

Dietary treatment of weight loss in patients with advanced cancer and cachexia: a systematic literature review.

PubMed

Balstad, Trude R; Solheim, Tora S; Strasser, Florian; Kaasa, Stein; Bye, Asta

2014-08-01

A systematical literature review evaluating the effect of dietary counseling in treating weight loss and improving energy intake in patients with advanced cancer with different stages of cachexia. Five publications were retrieved, of which three were randomized. Two out of five studies showed less weight loss with dietary counseling (+1% weight gain vs. -1.5% weight loss, p=0.03, 1.4kg vs. -2kg, p<0.05), two presented positive effect on energy intake (92% of total caloric need vs. 73%, p<0.01, 1865±317kcal vs. 1556±497kcal, ns). Dietary counseling can effect energy intake and body weight, however, apparent heterogeneity between studies is present. Based on these results there is not enough proof of evidence that dietary counseling given to patients with cancer is beneficial for improving weight or energy balance in the different cachexia stages. Nutrition is an essential part of cachexia treatment as it is not considered possible to increase or stabilize weight if nutritional needs are not met. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Contribution of anorexia to tissue wasting in cachexia.

PubMed

Molfino, Alessio; Laviano, Alessandro; Rossi Fanelli, Filippo

2010-12-01

Anorexia is a severe debilitating symptom characterizing the clinical course of several chronic diseases. It negatively impacts on patient outcome by contributing to weight loss, lean body mass catabolism and adipose tissue wasting. Although disease-associated anorexia may stand alone as a clinically relevant symptom, it is now considered as a component of the cachexia syndrome. The present review discusses experimental and clinical data indicating that the pathogenic mechanisms of anorexia may also suggest a neural control of tissue wasting in cachexia. Consistent data show that selective melanocortin receptor antagonism modulates food intake and reduces wasting in experimental models of chronic disease. Consequently, ghrelin administration, whose prophagic effects are related to melanocortin antagonism, has been tested both in animal studies and human trials, with promising effects, although restoration of lean body mass has been not achieved. More interest is driven by the use of small molecules selectively antagonising hypothalamic melanocortin receptors. The 'brain-muscle axis' coordinated by the hypothalamus seems to mediate the onset of not only anorexia but also tissue wasting in cachexia, by centrally influencing energy homeostasis and the balance between anabolism and catabolism.

Enobosarm (GTx-024, S-22): a potential treatment for cachexia.

PubMed

Srinath, Reshmi; Dobs, Adrian

2014-02-01

Muscle loss and wasting occurs with aging and in multiple disease states including cancer, heart failure, chronic obstructive pulmonary disease, end-stage liver disease, end-stage renal disease and HIV. Cachexia is defined as a multifactorial syndrome that is associated with anorexia, weight loss and increased catabolism, with increased morbidity and mortality. Currently no therapy is approved for the treatment or prevention of cachexia. Different treatment options have been suggested but many have proven to be ineffective or associated with adverse events. Nonsteroidal selective androgen receptor modulators (SARMs) are a new class of anabolic agents that bind the androgen receptor and exhibit tissue selectivity. Enobosarm (GTx-024, S-22) is a recently developed SARM, developed by GTx, Inc. (TN, USA), which has been tested in Phase I, II and III trials with promising results in terms of improving lean body mass and measurements of physical function and power. Enobosarm has received fast track designation by the US FDA and results from the Phase III trials POWER1 and POWER2 will help determine approval for use in the prevention and treatment of muscle wasting in patients with non-small-cell lung cancer. This article provides an introduction to enobosarm as a new therapeutic strategy for the prevention and treatment of cachexia. A review of the literature was performed using search terms 'cachexia', 'sarcopenia', 'SARM', 'enobosarm' and 'GTx-024' in September 2013 using multiple databases as well as online resources.

The mechanisms of cachexia underlying muscle dysfunction in COPD.

PubMed

Remels, A H V; Gosker, H R; Langen, R C J; Schols, A M W J

2013-05-01

Pulmonary cachexia is a prevalent, debilitating, and well-recognized feature of COPD associated with increased mortality and loss of peripheral and respiratory muscle function. The exact cause and underlying mechanisms of cachexia in COPD are still poorly understood. Increasing evidence, however, shows that pathological changes in intracellular mechanisms of muscle mass maintenance (i.e., protein turnover and myonuclear turnover) are likely involved. Potential factors triggering alterations in these mechanisms in COPD include oxidative stress, myostatin, and inflammation. In addition to muscle wasting, peripheral muscle in COPD is characterized by a fiber-type shift toward a more type II, glycolytic phenotype and an impaired oxidative capacity (collectively referred to as an impaired oxidative phenotype). Atrophied diaphragm muscle in COPD, however, displays an enhanced oxidative phenotype. Interestingly, intrinsic abnormalities in (lower limb) peripheral muscle seem more pronounced in either cachectic patients or weight loss-susceptible emphysema patients, suggesting that muscle wasting and intrinsic changes in peripheral muscle's oxidative phenotype are somehow intertwined. In this manuscript, we will review alterations in mechanisms of muscle mass maintenance in COPD and discuss the involvement of oxidative stress, inflammation, and myostatin as potential triggers of cachexia. Moreover, we postulate that an impaired muscle oxidative phenotype in COPD can accelerate the process of cachexia, as it renders muscle in COPD less energy efficient, thereby contributing to an energy deficit and weight loss when not dietary compensated. Furthermore, loss of peripheral muscle oxidative phenotype may increase the muscle's susceptibility to inflammation- and oxidative stress-induced muscle damage and wasting.

Early recognition of malnutrition and cachexia in the cancer patient: a position paper of a European School of Oncology Task Force.

PubMed

Aapro, M; Arends, J; Bozzetti, F; Fearon, K; Grunberg, S M; Herrstedt, J; Hopkinson, J; Jacquelin-Ravel, N; Jatoi, A; Kaasa, S; Strasser, F

2014-08-01

Weight loss and cachexia are common, reduce tolerance of cancer treatment and the likelihood of response, and independently predict poor outcome. A group of experts met under the auspices of the European School of Oncology to review the literature and-on the basis of the limited evidence at present-make recommendations for malnutrition and cachexia management and future research. Our focus should move from end-stage wasting to supporting patients' nutritional and functional state throughout the increasingly complex and prolonged course of anti-cancer treatment. When inadequate nutrient intake predominates (malnutrition), this can be managed by conventional nutritional support. In the presence of systemic inflammation/altered metabolism (cachexia), a multi-modal approach including novel therapeutic agents is required. For all patients, oncologists should consider three supportive care issues: ensuring sufficient energy and protein intake, maintaining physical activity to maintain muscle mass and (if present) reducing systemic inflammation. The results of phase II/III trials based on novel drug targets (e.g. cytokines, ghrelin receptor, androgen receptor, myostatin) are expected in the next 2 years. If effective therapies emerge, early detection of malnutrition and cachexia will be increasingly important in the hope that timely intervention can improve both patient-centered and oncology outcomes. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The central role of hypothalamic inflammation in the acute illness response and cachexia.

PubMed

Burfeind, Kevin G; Michaelis, Katherine A; Marks, Daniel L

2016-06-01

When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15.

PubMed

Tsai, V W W; Lin, S; Brown, D A; Salis, A; Breit, S N

2016-02-01

Anorexia-cachexia associated with cancer and other diseases is a common and often fatal condition representing a large area of unmet medical need. It occurs most commonly in advanced cancer and is probably a consequence of molecules released by tumour cells, or tumour-associated interstitial or immune cells. These may then act directly on muscle to cause atrophy and/or may cause anorexia, which then leads to loss of both fat and lean mass. Although the aetiological triggers for this syndrome are not well characterized, recent data suggest that MIC-1/GDF15, a transforming growth factor-beta superfamily cytokine produced in large amounts by cancer cells and as a part of other disease processes, may be an important trigger. This cytokine acts on feeding centres in the hypothalamus and brainstem to cause anorexia leading to loss of lean and fat mass and eventually cachexia. In animal studies, the circulating concentrations of MIC-1/GDF15 required to cause this syndrome are similar to those seen in patients with advanced cancer, and at least some epidemiological studies support an association between MIC-1/GDF15 serum levels and measures of nutrition. This article will discuss its mechanisms of central appetite regulation, and the available data linking this action to anorexia-cachexia syndromes that suggest it is a potential target for therapy of cancer anorexia-cachexia and conversely may also be useful for the treatment of severe obesity.

Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer.

PubMed

Bye, Asta; Wesseltoft-Rao, Nima; Iversen, Per Ole; Skjegstad, Grete; Holven, Kirsten B; Ulven, Stine; Hjermstad, Marianne J

2016-06-01

Chronic systemic inflammatory response is proposed as an underlying mechanism for development of cancer cachexia. We conducted a prospective study to examine changes in inflammatory biomarkers during the disease course and the relationship between inflammatory biomarkers and cachexia in patients with inoperable pancreatic cancer. Twenty patients, median (range) age 67.5 (35-79) years, 5 females, were followed for median 5.5 (1-12) months. Cachexia was diagnosed according to the 2011 consensus-based classification system (weight loss >5 % past six months, BMI < 20 kg/m(2) and weight loss >2 %, or sarcopenia) and the modified Glasgow Prognostic score (mGPS) that combines CRP and albumin levels. Inflammatory biomarkers were measured by enzyme immunoassays. The patients had increased levels of most inflammatory biomarkers, albeit not all statistically significant, both at study entry and close to death, indicating ongoing inflammation. According to the consensus-based classification system, eleven (55 %) patients were classified as cachectic upon inclusion. They did not differ from non-cachectic patients with regard to inflammatory biomarkers or energy intake. According to the mGPS, seven (35 %) were defined as cachectic and had a higher IL-6 (p < 0.001) than the non-cachectic patients. They also had a slightly, but insignificantly longer survival than non-cachectic patients (p = 0.08). The mGPS should be considered as an additional framework for identification of cancer cachexia.

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review).

PubMed

Belloum, Yassine; Rannou-Bekono, Françoise; Favier, François B

2017-05-01

Cachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactivation of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia.

Continuous Release of Tumor-Derived Factors Improves the Modeling of Cachexia in Muscle Cell Culture.

PubMed

Jackman, Robert W; Floro, Jess; Yoshimine, Rei; Zitin, Brian; Eiampikul, Maythita; El-Jack, Kahlid; Seto, Danielle N; Kandarian, Susan C

2017-01-01

Cachexia is strongly associated with a poor prognosis in cancer patients but the biological trigger is unknown and therefore no therapeutics exist. The loss of skeletal muscle is the most deleterious aspect of cachexia and it appears to depend on secretions from tumor cells. Models for studying wasting in cell culture consist of experiments where skeletal muscle cells are incubated with medium conditioned by tumor cells. This has led to candidates for cachectic factors but some of the features of cachexia in vivo are not yet well-modeled in cell culture experiments. Mouse myotube atrophy measured by myotube diameter in response to medium conditioned by mouse colon carcinoma cells (C26) is consistently less than what is seen in muscles of mice bearing C26 tumors with moderate to severe cachexia. One possible reason for this discrepancy is that in vivo the C26 tumor and skeletal muscle share a circulatory system exposing the muscle to tumor factors in a constant and increasing way. We have applied Transwell®-adapted cell culture conditions to more closely simulate conditions found in vivo where muscle is exposed to the ongoing kinetics of constant tumor secretion of active factors. C26 cells were incubated on a microporous membrane (a Transwell® insert) that constitutes the upper compartment of wells containing plated myotubes. In this model, myotubes are exposed to a constant supply of cancer cell secretions in the medium but without direct contact with the cancer cells, analogous to a shared circulation of muscle and cancer cells in tumor-bearing animals. The results for myotube diameter support the idea that the use of Transwell® inserts serves as a more physiological model of the muscle wasting associated with cancer cachexia than the bolus addition of cancer cell conditioned medium. The Transwell® model supports the notion that the dose and kinetics of cachectic factor delivery to muscle play a significant role in the extent of pathology.

[Systemic and local mechanisms leading to cachexia in cancer].

PubMed

Grabiec, Kamil; Burchert, Marta; Milewska, Marta; Błaszczyk, Maciej; Grzelkowska-Kowalczyk, Katarzyna

2013-12-31

Cachexia is a multifactorial syndrome of atrophy of skeletal muscle and adipose tissue, resulting in progressive loss of body weight associated with low quality of life and poor prognosis in cancer. Studies on experimental animal models and observations on patients have shown that the soluble factors secreted by tumor cells and tissues of the patient can participate in regulation of the wasting process. Cachexia is often accompanied by anorexia, which is caused by predominance of signals inhibiting appetite in the hypothalamus, such as release of proopiomelanocortin and anorexigenic action of proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α). Cachexia is also accompanied by extensive metabolic changes consisting of increase of resting energy expenditure and disturbance of carbohydrate, protein and lipid metabolism. Increased expression of protein uncoupling phosphorylation leads to increased thermogenesis in skeletal muscle. Tumor tissue hypoxia caused by its growth beyond blood vessels activates the transcription factor HIF-1, which results in increase in glycolysis, and leads to lactic acid accumulation and activation of the energy inefficient Cori cycle. Loss of fat tissue is caused by increase of lipolysis induced by lipid-mobilizing factor (LMF) and proinflammatory cytokines. Skeletal muscle wasting in cachexia is caused by a reduction of protein synthesis at the stage of initiation and elongation of translation and the simultaneous increase of protein degradation via ubiquitin-dependent and lysosomal pathways. The main mediators of skeletal muscle wasting in cancer are proteolysis-inducing factor (PIF), proinflammatory cytokines, and angiotensin II acting through increased levels of reactive oxygen species (ROS) and nuclear factor NF-κB activation, as well as glucocorticoid activated FOXO transcription factors and myostatin. Understanding of the complexity of the interaction of factors produced by the tumor and the patient's body may form the basis for the development of effective treatments for cachexia in cancer and other pathological conditions.

Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals.

PubMed

Toneto, Aline Tatiane; Ferreira Ramos, Luiz Alberto; Salomão, Emilianne Miguel; Tomasin, Rebeka; Aereas, Miguel Arcanjo; Gomes-Marcondes, Maria Cristina Cintra

2016-12-01

The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart. Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity. Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity. Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.

Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial.

PubMed

Clark, Andrew L; Coats, Andrew J S; Krum, Henry; Katus, Hugo A; Mohacsi, Paul; Salekin, Damien; Schultz, Melissa K; Packer, Milton; Anker, Stefan D

2017-08-01

Cardiac cachexia frequently accompanies the progression of heart failure despite the use of effective therapies for left ventricular dysfunction. Activation of the sympathetic nervous system has been implicated in the pathogenesis of weight loss, but the effects of sympathetic antagonism on cachexia are not well defined. We prospectively evaluated changes in body weight in 2289 patients with heart failure who had dyspnoea at rest or on minimal exertion and a left ventricular ejection fraction <25%. Patients were randomly assigned (double-blind) to receive either placebo (n = 1133) or carvedilol (n = 1156) and were followed for the occurrence of major clinical events for up to 29 months (COPERNICUS trial). Patients were not enrolled if they had signs of clinically significant fluid retention due to heart failure. Patients in the carvedilol group were 33% less likely than patients in the placebo group to experience a further significant loss of weight (>6%) (95% confidence interval: 14-48%, P = 0.002) and were 37% more likely to experience a significant gain in weight (≥5%) (95% confidence interval: 12-66%, P = 0.002). Carvedilol's ability to prevent weight loss was most marked in patients with increased body mass index at baseline, whereas its ability to promote weight gain was most marked in patients with decreased body mass index at baseline. Increases in weight were not accompanied by evidence of fluid retention. Baseline values for body mass index and change in body weight were significant predictors of survival regardless of treatment. Carvedilol attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

The study on mechanism of the modified Chinese herbal compound, jianpijiedu, on a mouse model of hepatic carcinoma cachexia.

PubMed

Sun, Baoguo; Luo, Haoxuan; Deng, Liuxiang; Zhang, Shijun; Chen, Zexiong

2016-10-01

Various studies have investigated hepatic carcinoma cachexia, however, there is little published information regarding the effect of Chinese Medicine carcinoma cachexia. The present study was performed to investigate the effect of modified Chinese herbal compound jianpijiedu (MJPJD) on a mouse model of ascites‑induced hepatic carcinoma cachexia. C57BL/6 mice were randomized to five groups: Control (Group A); xenograft tumor (Group B); low concentration of MJPJD (Group C); high concentration of MJPJD (Group D) and medroxyprogesterone (MPA) combined with indometacin (IND; Group E). The mouse model of ascites‑induced hepatic carcinoma cachexia was established by abdominal injection of H22 hepatic carcinoma cells. Subsequently, the body weight, food intake and gastrocnemius weight were recorded, and the levels of interleukin (IL)‑lα, IL‑6, tumor necrosis factor‑α (TNF‑α) in ascites were detected by enzyme‑linked immunosorbent assay. The protein expression levels of muscle RING‑finger protein‑1 (MU‑RF1) and atrogin 1 were detected by western blotting and immunohistochemistry, and the mRNA levels in gastrocnemius were detected by reverse transcription‑quantitative polymerase chain reaction. Compared with the xenograft tumor group, the administration of MJPJD inhibited the increase in body weight and the volume of ascites, the consumption of gastrocnemius was reduced, the net weight of ascites was maintained, the food intake was enhanced and the levels of the cytokines IL‑lα, IL‑6, TNF‑α in ascites and the levels of MU‑RF1 and atrogin 1 proteins were reduced. These results indicated that MJPJD delays the pathological process of ascites‑induced hepatic carcinoma cachexia, and the mechanism of action may be correlated with a reduction in the levels of IL‑lα, IL‑6, TNF‑α and inhibiting the activation of the ubiquitin proteosome pathway.

Rheumatoid cachexia is associated with dyslipidemia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study.

PubMed

Elkan, Ann-Charlotte; Håkansson, Niclas; Frostegård, Johan; Cederholm, Tommy; Hafström, Ingiäld

2009-01-01

Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD) independent of traditional risk factors. The aim of this study was to analyze the associations between diet, body composition, lipids and atheroprotective natural antibodies against phosphorylcholine (anti-PC) in patients with RA. A total of 80 RA patients (76% women), mean age (standard deviation (SD)) 61.4 (12) years and median disease duration of 6 years, were assessed by food frequency questionnaire (FFQ), fatty acid profile in adipose tissue and whole-body dual energy x ray absorptiometry (DXA). Rheumatoid cachexia was defined as fat free mass index below the 25th percentile and fat mass index above the 50th percentile of a reference population. Blood lipids, oxidized low-density lipoprotein (oxLDL) and anti-PC levels were determined. The mean body mass index for the women and men was 25.0 and 27.0, respectively. Central obesity was found in 57% of the women (waist circumference >80 cm) and in 89% of the men (waist circumference >94 cm). In all, 18% of the women and 26% of the men had rheumatoid cachexia. These patients had significantly higher total cholesterol (P < 0.033), LDL (P < 0.029), and trendwise oxLDL (P = 0.056) as well as lower anti-PC IgM (P = 0.040), higher frequency of hypertension (69%) and metabolic syndrome (25%) than those without. The patients reported a high dietary intake of saturated fat, which partly correlated with fatty acid composition in adipose tissue and significantly with disease activity. However, patients with or without cachexia did not differ with respect to dietary fat intake or intake of Mediterranean-like diet. Additionally, patients on a Mediterranean-like diet had high levels of anti-PC (P < 0.001). About one in five patients with low-active RA displayed rheumatoid cachexia. This condition was associated with high levels of LDL cholesterol, low levels of atheroprotective anti-PC and high frequency of hypertension, which is of interest in the context of CVD in RA. The cachexia could not be related to diet fat intake. However, patients on a Mediterranean-like diet had high anti-PC levels in spite of similar frequency of cachexia. High anti-PC levels may provide some protection against CVD.

The abridged patient-generated subjective global assessment is a useful tool for early detection and characterization of cancer cachexia.

PubMed

Vigano, Antonio L; di Tomasso, Jonathan; Kilgour, Robert D; Trutschnigg, Barbara; Lucar, Enriqueta; Morais, José A; Borod, Manuel

2014-07-01

Cancer cachexia (CC) is a syndrome characterized by wasting of lean body mass and fat, often driven by decreased food intake, hypermetabolism, and inflammation resulting in decreased lifespan and quality of life. Classification of cancer cachexia has improved, but few clinically relevant diagnostic tools exist for its early identification and characterization. The abridged Patient-Generated Subjective Global Assessment (aPG-SGA) is a modification of the original Patient-Generated Subjective Global Assessment, and consists of a four-part questionnaire that scores patients' weight history, food intake, appetite, and performance status. The purpose of this study was to determine whether the aPG-SGA is associated with both features and clinical sequelae of cancer cachexia. In this prospective cohort study, 207 advanced lung and gastrointestinal cancer patients completed the following tests: aPG-SGA, Edmonton Symptom Assessment System, handgrip strength, a complete blood count, albumin, apolipoprotein A and B, and C-reactive protein. Ninety-four participants with good performance status as assessed by the Eastern Cooperative Oncology Group Performance Status completed additional questionnaires and underwent body composition testing. Of these, 68 patients tested for quadriceps strength and completed a 3-day food recall. Multivariable regression models revealed that higher aPG-SGA scores (≥9 vs 0 to 1) are significantly associated (P<0.05) with the following: unfavorable biological markers of cancer cachexia, such as higher white blood cell counts (10.0 vs 6.7×10(9)/L; lower hemoglobin (115.6 vs 127.7 g/L), elevated C-reactive protein (42.7 vs 18.2 mg/L [406.7 vs 173.3 nmol/L]); decreased anthropometric and physical measures, such as body mass index (22.5 vs 27.1); fat mass (14.4 vs 26.0 kg), handgrip (24.7 vs 34.9 kg) and leg strength; an average 12% greater length of hospital stay; a dose reduction in chemotherapy; and increased mortality. Given its association with the main features of cancer cachexia and its ease of use, the aPG-SGA appears to be a useful tool for detecting and predicting outcomes of cancer cachexia. Additional research is required to determine what impact the aPG-SGA has on quality of care when used in the clinical setting. Copyright © 2014 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Relationship between TNF-α -1031T/C gene polymorphism, plasma level of TNF-α, and risk of cachexia in head and neck cancer patients.

PubMed

Powrózek, Tomasz; Mlak, Radosław; Brzozowska, Anna; Mazurek, Marcin; Gołębiowski, Paweł; Małecka-Massalska, Teresa

2018-05-25

Malnutrition and cachexia are frequent among head and neck cancer (HNC) patients and these syndromes are associated with both poor quality of life and unfavorable disease prognosis. Unfortunately, there are still no established biomarkers that could predict the development of cachexia. Among potential molecular alterations related to cancer cachexia, there are single-nucleotide polymorphisms (SNPs) within genes encoding pro-inflammatory cytokines such as TNF-α. To investigate TNF-α -1031T/C SNP as a risk factor of cachexia in 62 HNC patients subjected to radiotherapy. DNA was isolated from whole blood samples and genotyping was conducted using real-time PCR method by means of TaqMan SNP Genotyping Assay. TNF-alpha Human ELISA Kit was used to determine TNF-α concentration in each extracted plasma sample. Moreover, the relationship between genotype variants of TNF-α and plasma level of TNF-α was examined. Detailed clinical-demographic and nutritional data were collected from each study participant. CC genotype carriers were at a significantly higher risk of being qualified as cachectic compared with other genotype carriers (p = 0.044; HR = 3.724). Subjects, who carried CC genotype had significantly lower body mass compared to patients with TT and CT genotype (p = 0.045). Moreover, CC individuals had the highest TNF-α plasma level (median 10.70 ± 0.72 pg/mL, p = 0.006) among the studied cases. We also noted, that CC genotype carriers had significantly higher risk of early death incidence compared to other genotype carriers [overall survival (OS): 28 vs 38 months (HR = 3.630, p = 0.013)]. Despite the differences between SGA and NRS scoring, the presence of CC genotype could be a useful objective marker allowing for the prediction of cachexia development in both parenterally nourished and non-parenterally nourished patients. Patients with CC genotype had also the highest risk of early death incidence; therefore, such individuals should be qualified for parenteral nutrition and supportive care at the time of diagnosis to improve further therapy outcomes. Moreover, this is the first study demonstrating the relationship between TNF-α -1031T/C polymorphism and plasma level of TNF-α. This is also the first paper investigating the role of TNF-α -1031T/C in cancer cachexia.

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin‐induced cachexia

PubMed Central

Conte, Elena; Camerino, Giulia Maria; Mele, Antonietta; De Bellis, Michela; Pierno, Sabata; Rana, Francesco; Fonzino, Adriano; Caloiero, Roberta; Rizzi, Laura; Bresciani, Elena; Ben Haj Salah, Khoubaib; Fehrentz, Jean‐Alain; Martinez, Jean; Giustino, Arcangela; Mariggiò, Maria Addolorata; Coluccia, Mauro; Tricarico, Domenico; Lograno, Marcello Diego; De Luca, Annamaria; Torsello, Antonio; Conte, Diana

2017-01-01

Abstract Background Cachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose‐limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium‐dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS‐R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood. Methods By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast‐twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin‐induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention. Results Cisplatin‐treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up‐regulation of atrogin1/Murf‐1 genes and a down‐regulation of Pgc1‐a gene, all indexes of muscle atrophy, and by a two‐fold increase in resting intracellular calcium, [Ca2+]i, compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store‐operated calcium entry were ~50% significantly reduced in cisplatin‐treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin‐induced alteration of calcium homeostasis by both common as well as drug‐specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis. Conclusions Our findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin‐induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin‐induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy‐associated cachexia. PMID:28294567

Megestrol acetate in cachexia and anorexia

PubMed Central

Yeh, Shing-shing; Schuster, Michael W

2006-01-01

The aim is to review major clinical trials that have used megestrol acetate (MA) in the treatment of cachexia across several disease states. A review of general usage and potential side-effects are discussed. A theory that the newly approved nanocrystal formation of MA can better deliver this potent medication for treatment will also be reviewed. PMID:17722275

Satellite Cell Functional Alterations Following Cutaneous Burn in rats Include an Increase in Their Osteogenic Potential

DTIC Science & Technology

2013-10-07

response to local injury [3]. They have also been recognized as having a role in diseases, including cachexia and sarcopenia, where muscle mass may be...1961;9:493. [4] Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia Sarcopenia Muscle 2012;3:225. [5] Glass DJ. Signaling pathways that mediate

Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice.

PubMed

Samuels, S E; Knowles, A L; Tilignac, T; Debiton, E; Madelmont, J C; Attaix, D

2001-07-01

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C(6)H(12)CIN(3)O(4)S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower (P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (-38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (~-54 to -69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (-80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

Prevalence of rheumatoid cachexia assessed by bioelectrical impedance vector analysis and its relation with physical function.

PubMed

Santillán-Díaz, Cira; Ramírez-Sánchez, Noemi; Espinosa-Morales, Rolando; Orea-Tejeda, Arturo; Llorente, Luis; Rodríguez-Guevara, Gerardo; Castillo-Martínez, Lilia

2018-03-01

Rheumatoid arthritis (RA) patients frequently have changes in their body composition, with a decrease in muscle mass and an increase in fat mass, a syndrome that is termed rheumatoid cachexia (RC). The prevalence of this nutritional alteration is not well known; there is as yet no consensus, seeing as it depends on the methods, techniques, and cutoff points that are used for its diagnosis. The main aim of this study was to identify RC through assessment by bioelectrical impedance vector analysis (BIVA) and its association with metabolic causes, physical function, and the main disease status, among others. The prevalence of RC was identified in those subjects who fell outside the right lower quadrant of the reference curve of RXc graph of BIVA. Clinical, anthropometric, biochemical and physical activity, emotional status, and diet markers were also evaluated. Ninety-four patients were included (92.55% women). The prevalence of RC assessed by BIVA was 21.28%. BIVA-cachexia patients had a lesser value of handgrip strength vs. patients without BIVA-cachexia 10.2 kg (7.2-13.4) vs. 14.7 kg (9.6-19), p = 0.0062. Disability and folic acid with methotrexate consumption are related to BIVA-cachexia ((OR 4.69, 95% CI 1.33, 16.54, p = 0.016) and (OR 0.19, 95%CI 0.058, 0.651, p = 0.008), respectively). BIVA could represent a valuable tool to assess presence of RC. It is important that RA patients have physical therapy to improve their nutritional status.

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line.

PubMed

Terawaki, Kiyoshi; Sawada, Yumi; Kashiwase, Yohei; Hashimoto, Hirofumi; Yoshimura, Mitsuhiro; Suzuki, Masami; Miyano, Kanako; Sudo, Yuka; Shiraishi, Seiji; Higami, Yoshikazu; Yanagihara, Kazuyoshi; Kase, Yoshio; Ueta, Yoichi; Uezono, Yasuhito

2014-02-15

Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC.

Differential Effects of IL6 and Activin A in the Development of Cancer-Associated Cachexia.

PubMed

Chen, Justin L; Walton, Kelly L; Qian, Hongwei; Colgan, Timothy D; Hagg, Adam; Watt, Matthew J; Harrison, Craig A; Gregorevic, Paul

2016-09-15

Cachexia is a life-threatening wasting syndrome lacking effective treatment, which arises in many cancer patients. Although ostensibly induced by multiple tumor-produced cytokines (tumorkines), their functional contribution to initiation and progression of this syndrome has proven difficult to determine. In this study, we used adeno-associated viral vectors to elevate circulating levels of the tumorkines IL6 and/or activin A in animals in the absence of tumors as a tactic to evaluate hypothesized roles in cachexia development. Mice with elevated levels of IL6 exhibited 8.1% weight loss after 9 weeks, whereas mice with elevated levels of activin A lost 11% of their body weight. Co-elevation of both tumorkines to levels approximating those observed in cancer cachexia models induced a more rapid and profound body weight loss of 15.4%. Analysis of body composition revealed that activin A primarily triggered loss of lean mass, whereas IL6 was a major mediator of fat loss. Histologic and transcriptional analysis of affected organs/tissues (skeletal muscle, fat, and liver) identified interactions between the activin A and IL6 signaling pathways. For example, IL6 exacerbated the detrimental effects of activin A in skeletal muscle, whereas activin A curbed the IL6-induced acute-phase response in liver. This study presents a useful model to deconstruct cachexia, opening a pathway to determining which tumorkines are best targeted to slow/reverse this devastating condition in cancer patients. Cancer Res; 76(18); 5372-82. ©2016 AACR. ©2016 American Association for Cancer Research.

Current concepts in cancer: effects of cancer and cancer treatment on the nutrition of the host

DOE Office of Scientific and Technical Information (OSTI.GOV)

Costa, G.; Donaldson, S.S.

1979-06-28

The growth of cancer in man leads to destruction of tissues and alterations of functions. The consequences of this process, culminating in overt cachexia and death, are so varied that cancer has replaced syphilis as the great imitator. Many of the manifestations of cachexia (weakness, anorexia, depletion and translocation of host component, and loss of immunocompetence) resemble malnutrition and are accountable for, in many patients, by poor nutritional intake, neoplastic invasion of the gastrointestinal tract or creation by the tumor of abnormal routes through which nutrients can be lost. The development of cachexia, nevertheless, bears no simple relation to caloricmore » intake, tumor burden, tumor cell type or anatomic site of involvement. Indeed, it has long been apparent that, in many patients succumbing to cancer, if the same lesions were composed of scar tissue rather than neoplastic cells, the affected individuals might not only be alive but in reasonably good health. Distant metabolic effects of cancers have therefore come into focus, are well documented and are known collectively as paraneoplastic syndromes. They imply release by the tumor of chemically identifiable toxic mediators. Recently, a third mechanism has been recognized as an important determinant of cachexia and malnutrition: cancer treatment. As our tools have become more powerful and our philosophies more agressive,the effects of therapy on normal cell populations have become visible. The present paper discusses the most important manifestations of cachexia that resemble malnutrition. Technics of nutritional assessment and intervention that have proved successful in patients with cancer are also briefly discussed.« less

Development of the EORTC QLQ-CAX24, A Questionnaire for Cancer Patients With Cachexia.

PubMed

Wheelwright, Sally J; Hopkinson, Jane B; Darlington, Anne-Sophie; Fitzsimmons, Deborah F; Fayers, Peter; Balstad, Trude R; Bredart, Anne; Hammerlid, Eva; Kaasa, Stein; Nicolatou-Galitis, Ourania; Pinto, Monica; Schmidt, Heike; Solheim, Tora S; Strasser, Florian; Tomaszewska, Iwona M; Johnson, Colin D

2017-02-01

Cachexia is commonly found in cancer patients and has profound consequences; yet there is only one questionnaire that examines the patient's perspective. To report a rigorously developed module for patient self-reported impact of cancer cachexia. Module development followed published guidelines. Patients from across the cancer cachexia trajectory were included. In Phase 1, health-related quality of life (HRQOL) issues were generated from a literature review and interviews with patients in four countries. The issues were revised based on patient and health care professional (HCP) input. In Phase 2, questionnaire items were formulated and translated into the languages required for Phase 3, the pilot phase, in which patients from eight countries scored the relevance and importance of each item, and provided qualitative feedback. A total of 39 patients and 12 HCPs took part in Phase 1. The literature review produced 68 HRQOL issues, with 22 new issues arising from the patient interviews. After patient and HCP input, 44 issues were formulated into questionnaire items in Phase 2. One hundred ten patients took part in Phase 3. One item was reworded, and 20 items were deleted as a consequence of patient feedback. The QLQ-CAX24 is a cancer cachexia-specific questionnaire, comprising 24 items, for HRQOL assessment in clinical trials and practice. It contains five multi-item scales (food aversion, eating and weight-loss worry, eating difficulties, loss of control, and physical decline) and four single items. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Extracellular Superoxide Dismutase Ameliorates Skeletal Muscle Abnormalities, Cachexia and Exercise Intolerance in Mice with Congestive Heart Failure

PubMed Central

Okutsu, Mitsuharu; Call, Jarrod A.; Lira, Vitor A.; Zhang, Mei; Donet, Jean A.; French, Brent A.; Martin, Kyle S.; Peirce-Cottler, Shayn M.; Rembold, Christopher M.; Annex, Brian H.; Yan, Zhen

2014-01-01

Background Congestive heart failure (CHF) is a leading cause of morbidity and mortality, and oxidative stress has been implicated in the pathogenesis of cachexia (muscle wasting) and the hallmark symptom, exercise intolerance. We have previously shown that a nitric oxide (NO)-dependent antioxidant defense renders oxidative skeletal muscle resistant to catabolic wasting. Here, we aimed to identify and determine the functional role of the NO-inducible antioxidant enzyme(s) in protection against cardiac cachexia and exercise intolerance in CHF. Methods and Results We demonstrated that systemic administration of endogenous nitric oxide donor S-Nitrosoglutathione in mice blocked the reduction of extracellular superoxide dismutase (EcSOD) protein expression, the induction of MAFbx/Atrogin-1 mRNA expression and muscle atrophy induced by glucocorticoid. We further showed that endogenous EcSOD, expressed primarily by type IId/x and IIa myofibers and enriched at endothelial cells, is induced by exercise training. Muscle-specific overexpression of EcSOD by somatic gene transfer or transgenesis [muscle creatine kinase (MCK)-EcSOD] in mice significantly attenuated muscle atrophy. Importantly, when crossbred into a mouse genetic model of CHF [α-myosin heavy chain (MHC)-calsequestrin] MCK-EcSOD transgenic mice had significant attenuation of cachexia with preserved whole body muscle strength and endurance capacity in the absence of reduced heart failure. Enhanced EcSOD expression significantly ameliorated CHF-induced oxidative stress, MAFbx/Atrogin-1 mRNA expression, loss of mitochondria and vascular rarefaction in skeletal muscle. Conclusions EcSOD plays an important antioxidant defense function in skeletal muscle against cardiac cachexia and exercise intolerance in CHF. PMID:24523418

Rapid differentiation of citrus Hop stunt viroid variants by real-time RT-PCR and high resolution melting analysis.

PubMed

Loconsole, Giuliana; Onelge, Nuket; Yokomi, Raymond K; Kubaa, Raied Abou; Savino, Vito; Saponari, Maria

2013-01-01

The RNA genome of pathogenic and non-pathogenic variants of citrus Hop stunt viroid (HSVd) differ by five to six nucleotides located within the variable (V) domain referred to as the "cachexia expression motif". Sensitive hosts such as mandarin and its hybrids are seriously affected by cachexia disease. Current methods to differentiate HSVd variants rely on lengthy greenhouse biological indexing on Parson's Special mandarin and/or direct nucleotide sequence analysis of amplicons from RT-PCR of HSVd-infected plants. Two independent high throughput assays to segregate HSVd variants by real-time RT-PCR and High-Resolution Melting Temperature (HRM) analysis were developed: one based on EVAGreen dye; the other based on TaqMan probes. Primers for both assays targeted three differentiating nucleotides in the V domain which separated HSVd variants into three clusters by distinct melting temperatures with a confidence level higher than 98%. The accuracy of the HRM assays were validated by nucleotide sequencing of representative samples within each HRM cluster and by testing 45 HSVd-infected field trees from California, Italy, Spain, Syria and Turkey. To our knowledge, this is the first report of a rapid and sensitive approach to detect and differentiate HSVd variants associated with different biological behaviors. Although, HSVd is found in several crops including citrus, cachexia variants are restricted to some citrus-growing areas, particularly the Mediterranean Region. Rapid diagnosis for cachexia and non-cachexia variants is, thus, important for the management of HSVd in citrus and reduces the need for bioindexing and sequencing analysis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Cardiac cachexia: hic et nunc: "hic et nunc" - here and now.

PubMed

Loncar, Goran; Springer, Jochen; Anker, Markus; Doehner, Wolfram; Lainscak, Mitja

2015-12-15

Cardiac cachexia (CC) is the clinical entity at the end of chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. Better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick-up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF.

Tumor inoculation site affects the development of cancer cachexia and muscle wasting.

PubMed

Matsuyama, Tatsuzo; Ishikawa, Takeshi; Okayama, Tetsuya; Oka, Kaname; Adachi, Satoko; Mizushima, Katsura; Kimura, Reiko; Okajima, Manabu; Sakai, Hiromi; Sakamoto, Naoyuki; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Kokura, Satoshi; Naito, Yuji; Itoh, Yoshito

2015-12-01

The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor-bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF-β family, and found that levels of IL-6, TNF-α and activin A increased in both groups of tumor-bearing mice. Eotaxin and G-CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor-bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment. © 2015 UICC.

Cardiac cachexia: hic et nunc

PubMed Central

Loncar, Goran; Springer, Jochen; Anker, Markus; Doehner, Wolfram

2016-01-01

Abstract Cardiac cachexia (CC) is the clinical entity at the end of the chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely, the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. A better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia, and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF. PMID:27386168

Mechanisms to explain wasting of muscle and fat in cancer cachexia.

PubMed

Argilés, Josep M; López-Soriano, Francisco J; Busquets, Sílvia

2007-12-01

To describe the most relevant recent findings concerning the molecular mechanisms involved in both fat and muscle tissues in cachectic cancer patients. Relevant progress has been made in the mechanism of signalling protein metabolism in skeletal muscle. PI3K has a dual role inhibiting protein degradation by inhibition of Atrogin-1 and MuRF1 gene expression and facilitating AKT phosphorylation, leading to increased protein synthesis. Interestingly, Caspase-3 activity is intimately associated with myofibrillar protein degradation in muscle tissue. With respect to fat metabolism, increased lipolysis in human cancer cachexia seems to be directly connected to increased hormone-sensitive lipase activity. The results and findings described in this review represent important progress in wasting disease mechanisms and may provide hints for future therapeutic approaches in cancer cachexia.

Muscle atrophy in cachexia: can dietary protein tip the balance?

PubMed

Op den Kamp, Céline M; Langen, Ramon C; Haegens, Astrid; Schols, Annemie M

2009-11-01

To review the efficacy of dietary protein supplementation in attenuating muscle atrophy in cachexia. Only very few recent randomized controlled trials have studied the effects of protein supplementation in clinical cachexia. It appears that supplementation of dietary protein (>1.5 g/kg per day) alone or in combination with other anabolic stimuli such as exercise training maintains or even improves muscle mass, but results on muscle function are controversial and no clinical studies have yet directly linked alterations in cellular signaling or metabolic signatures of protein intake-induced muscle anabolism to muscle weight gain. To elucidate the role of dietary protein supplementation in attenuating muscle atrophy in cachectic patients, randomized clinical trials are needed in adequately phenotyped patients using sensitive measures of muscle mass and function.

Cancer cachexia, sarcopenia and biochemical markers in patients with advanced non-small cell lung cancer-chemotherapy toxicity and prognostic value.

PubMed

Srdic, Drazena; Plestina, Sanja; Sverko-Peternac, Ana; Nikolac, Nora; Simundic, Ana-Maria; Samarzija, Miroslav

2016-11-01

Cancer cachexia and sarcopenia are frequently observed in cancer patients and associated with poor survival. The majority of studies of cancer cachexia and sarcopenia have been done in patients with solid tumors of different origins, and there are currently no good predictors of the benefit of chemotherapy or factors that predict survival in advanced cancer. The purpose of our prospective study was to evaluate prevalence of cachexia and sarcopenia using international consensus definition and criteria for diagnosis in patients with diagnosed advanced non-small cell lung cancer (NSCLC) stage IIIB and IV and their relation to chemotherapy toxicity and survival prediction. A secondary aim was to compare several biochemical markers (CRP, IL-6, protein, and albumin) with time to tumor progression in order to assess prognostic value or to guide a treatment. Between December 2013 and April 2015, the prospective cohort study of 100 Caucasian patients with advanced NSCLC stage IIIB or IV, who were referred consecutively to Department for Respiratory Diseases "Jordanovac," was evaluated. Anthropometric measurements and biochemical data (CRP, albumin, protein, IL-6, haemoglobin) together with body composition measurements (total muscle cross-sectional area, lumbar skeletal muscle index) were obtained for each patient before starting with platinum-doublet therapy. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment and time-to-tumor progression was determined prospectively. One hundred patients with advanced lung cancer were recruited: 67 were male and median age was 64 years. The median time to disease progression was 187 days. The prevalence of cachexia and sarcopenia in study cohort was 69 and 47 %, respectively. CRP, IL-6, and albumin concentration in cachectic compared to non-cachectic patients demonstrated statistically significant difference (p = 0.020, p = 0.040, p = 0.003). Cachexia and sarcopenia were not found to be predictors of chemotoxicity nor was time to tumor progression. On the contrary, albumin concentration with established cutoff point of 37.5 g/L was clearly proved as the predictive factor of both chemotoxicity (OR (95 % CI) = 0.85; p < 0.001) and survival (HR (95 % CI) = 0.55). Albumin level has been shown to be more important predictive marker of chemotherapy toxicity and survival than cachexia and sarcopenia are. This approach in clinical settings can be used to guide the choice of oncologic treatment.

STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia.

PubMed

Bonetto, Andrea; Aydogdu, Tufan; Kunzevitzky, Noelia; Guttridge, Denis C; Khuri, Sawsan; Koniaris, Leonidas G; Zimmers, Teresa A

2011-01-01

Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia. Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer. These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood.

Weight loss versus muscle loss: re-evaluating inclusion criteria for future cancer cachexia interventional trials.

PubMed

Roeland, Eric J; Ma, Joseph D; Nelson, Sandahl H; Seibert, Tyler; Heavey, Sean; Revta, Carolyn; Gallivan, Andrea; Baracos, Vickie E

2017-02-01

Participation in cancer cachexia clinical trials requires a defined weight loss (WL) over time. A loss in skeletal muscle mass, measured by cross-sectional computed tomography (CT) image analysis, represents a possible alternative. Our aim was to compare WL versus muscle loss in patients who were screened to participate in a cancer cachexia clinical trial. This was a single-center, retrospective analysis in metastatic colorectal cancer patients screened for an interventional cancer cachexia trial requiring a ≥5 % WL over the preceding 6 months. Concurrent CT images obtained as part of standard oncology care were analyzed for changes in total muscle and fat (visceral, subcutaneous, and total). Of patients screened (n = 36), 3 (8 %) enrolled in the trial, 17 (47 %) were excluded due to insufficient WL (<5 %), 3 (8 %) were excluded due to excessive WL (>20 %), and 16 (44 %) met inclusion criteria for WL. Patients who met screening criteria for WL (5-20 %) had a mean ± SD of 7.7 ± 8.7 % muscle loss, 24.4 ± 37.5 % visceral adipose loss, 21.6 ± 22.3 % subcutaneous adipose loss, and 22.1 ± 24.7 % total adipose loss. Patients excluded due to insufficient WL had 2 ± 6.4 % muscle loss, but a gain of 8.5 ± 39.8 % visceral adipose, and 4.2 ± 28.2 % subcutaneous adipose loss and 0.8 ± 28.4 % total adipose loss. Of the patients excluded due to WL <5 % (n = 17), 7 (41 %) had a skeletal muscle loss >5 %. Defining cancer cachexia by WL over time may be limited as it does not capture skeletal muscle loss. Cross-sectional CT body composition analysis may improve early detection of muscle loss and patient participation in future cancer cachexia clinical trials.

STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

PubMed Central

Kunzevitzky, Noelia; Guttridge, Denis C.; Khuri, Sawsan; Koniaris, Leonidas G.; Zimmers, Teresa A.

2011-01-01

Background Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia. Methodology/Principal Findings Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer. Conclusions/Significance These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood. PMID:21799891

Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway.

PubMed

Alves, Michele Joana; Figuerêdo, Raquel Galvão; Azevedo, Flavia Figueiredo; Cavallaro, Diego Alexandre; Neto, Nelson Inácio Pinto; Lima, Joanna Darck Carola; Matos-Neto, Emidio; Radloff, Katrin; Riccardi, Daniela Mendes; Camargo, Rodolfo Gonzalez; De Alcântara, Paulo Sérgio Martins; Otoch, José Pinhata; Junior, Miguel Luiz Batista; Seelaender, Marília

2017-03-14

Cancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGFβ) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGFβ in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGFβ pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients. After signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGFβ isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (αSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay. There was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of αSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGFβ1 and TGFβ3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas of CC adipose tissue. Cancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.

Pro-inflammatory cytokines and oxidative stress/antioxidant parameters characterize the bio-humoral profile of early cachexia in lung cancer patients.

PubMed

Fortunati, Nicoletta; Manti, Roberta; Birocco, Nadia; Pugliese, Mariateresa; Brignardello, Enrico; Ciuffreda, Libero; Catalano, Maria G; Aragno, Manuela; Boccuzzi, Giuseppe

2007-12-01

Cancer-related cachexia, that is present in about 50% of cancer patients and accounts for 20% of all cancer deaths, is clinically characterized by progressive weight loss, anorexia, metabolic alterations, asthenia, depletion of lipid stores and severe loss of skeletal muscle proteins. The main biochemical and molecular alterations that are responsible for the syndrome are prematurely present in the progress of the disease and the identification of the early stages of cachexia can be useful in targetting patients who will benefit from early treatment. The aim of the present study was to delineate the bio-humoral profile of a group of lung cancer patients either non-cachectic or cachectic by evaluating serum pro-inflammatory cytokines and oxidative stress/antioxidant parameters (both recognized to be involved in cachexia pathogenesis) and pro-inflammatory cytokine gene expression in PBMC (Peripheral blood mononuclear cells) of cancer patients. All serum pro-inflammatory cytokines and oxidative stress/antioxidant parameters significantly increased in neoplastic patients, but only TNF-alpha, ROS, GSH and vitamin E showed a significantly greater increase in cachectic patients. Pro-inflammatory cytokine gene expression mirrored serum level behaviour except for IL-6 that was increased in serum but not as gene expression, suggesting its provenience from tumour tissue. Our data support that the simultaneous determination of ROS, GSH, vitamin E, together with TNF-alpha allows the identification of a lung cancer patient developing cancer-related cachexia. This bio-humoral profile should be used for the early diagnosis and follow-up of the syndrome. Moreover, the evaluation of gene expression in patient PBMC was helpful in differentiating tumour vs host factors, therefore being useful in the study of pathogenetic mechanisms in neoplastic cachectic patients.

Nutritional treatment of cancer cachexia in rats. Use of a diet formulated with a crayfish enzymatic extract.

PubMed

Cremades, Olga; Parrado, Juan; Jover, María; Collantes de Terán, Laura; Gutiérrez, Juan Francisco; Bautista Palomas, Juan D

2007-09-01

Terminal cancer-associated cachexia, characterized by a marked weight loss, anorexia, asthenia and anemia, is usually associated with a malnutrition status. To investigate whether a diet formulated with a crayfish enzymatic extract, enriched in essential amino acids, omega-3 fatty acids, and astaxanthin, would be effective for the treatment of cancer-associated cachexias, by decreasing mortality and morbidity rates in cachectic rats and/or improving survival. Two types of diet were used: a standard diet and one formulated with crayfish enzymatic extract. Rats were divided into two groups (24 animals per group): one without tumor (T-) and the other with tumor (T+) (AH-130 Yoshida ascites hepatoma). Each group was further divided into two subgroups (12 animals per subgroup). Two subgroups (T-(standard) and T+(standard)) were fed the standard diet and the other two (T-(CFEE) and T+(CFEE)) the crayfish enzymatic extract one for four weeks, after which different tissue and plasma parameters were studied. The implantation of the tumor resulted in a considerable loss of muscle and adipose tissue mass in both groups, but the loss of muscle and fat was lower in the group fed the crayfish enzymatic extract diet. There was also a concomitant increase in the plasma concentration of TNF-alpha, although the increase was smaller in the crayfish enzymatic extract-treated group. This study shows that although the treatment of cachetic rats with the crayfish enzymatic extract diet did not revert the cachexia, it increased survival (57.1% vs. 25.9% in the group treated with crayfish enzymatic extract and standard diets, respectively) and meliorated the cachexia symptoms--anorexia and body mass loss (muscle and adipose tissue).

Loss of strength capacity is associated with mortality, but resistance exercise training promotes only modest effects during cachexia progression.

PubMed

das Neves, Willian; Alves, Christiano Robles Rodrigues; de Almeida, Ney Robson; Guimarães, Fátima Lúcia Rodrigues; Ramires, Paulo Rizzo; Brum, Patricia Chakur; Lancha, Antonio Herbert

2016-10-15

Resistance exercise training (RET) has been adopted as non-pharmacological anti-catabolic strategy. However, the role of RET to counteract cancer cachexia is still speculative. This study aimed to verify whether short-term RET would counteract skeletal muscle wasting in a severe cancer cachexia rat model. Wistar rats were randomly allocated into four experimental groups; 1) untrained control rats (control), 2) rats submitted to RET (control+RET), 3) untrained rats injected with Walker 256 tumor cells in the bone marrow (tumor) and 4) rats injected with Walker 256 tumor cells in the bone marrow and submitted to RET (tumor+RET). Tumor group displayed skeletal muscle atrophy fifteen days post tumor cells injection as assessed by plantaris (-20.5%) and EDL (-20.0%) muscle mass. EDL atrophy was confirmed showing 43.8% decline in the fiber cross sectional area. Even though RET increased the lactate dehydrogenase protein content and fully restored phosphorylated form of 4EBP-1 to the control levels in skeletal muscle, it failed to rescue muscle morphology in tumor-bearing rats. Indeed, RET did not mitigated loss of muscle function, anorexia, tumor growth or mortality rate. However, loss of strength capacity (assessed by 1-RM test performance) demonstrated a negative correlation with rats' survival (p=0.02; r=0.40), suggesting that loss of strength capacity might predict cancer mortality. These results demonstrated that bone marrow injection of Walker 256 tumor cells in rats induces cancer cachexia, strength capacity is associated with cancer survival and short-term RET promotes only modest effects during cachexia progression. Copyright © 2016 Elsevier Inc. All rights reserved.

Expression of NF-kappaB and IkappaB proteins in skeletal muscle of gastric cancer patients

PubMed Central

Rhoads, Mary G.; Kandarian, Susan C.; Pacelli, Fabio; Doglietto, Giovan Battista; Bossola, Maurizio

2011-01-01

The mechanisms eliciting cancer cachexia are not well understood. Wasting of skeletal muscle is problematic because it is responsible for the clinical deterioration in cancer patients and the ability to tolerate cancer treatment. Animal studies suggest that nuclear factor of kappa B (NF-κB) signaling is important in the progression of muscle wasting due to several types of tumors. However, there are no published studies in humans on a role for NF-κB in cancer cachexia. In this project we studied the rectus abdominis muscle from patients with gastric tumors (n=14) and age matched control subjects (n=10) for markers of NF-κB activation. Nuclear levels of p65, p50, and Bcl-3 were the same in both groups of subjects. However, phospho-p65 was elevated by 25% in muscles of cancer patients. In addition, expression of the inhibitor of kappa B alpha (IκBα), was decreased by 25% in cancer patients. Decreased expression of IκBα reflects its degradation by one of the IκBα kinases and is a marker of NF-κB activation. Interestingly, there was no correlation between the stage of cancer and the extent of IκBα decrease, nor was there a correlation between the degree of cachexia and decreased IκBα levels. This suggests that the activation of NF-κB is an early and sustained event in gastric cancer. The work implicates the NF-κB signaling in the initiation and progression of cancer cachexia in humans and demonstrates the need for additional study of this pathway; it also recommends NF-κB signaling as a therapeutic target for the amelioration of cachexia as has been suggested from rodent studies. PMID:19857958

Cachexia induces head and neck changes in locally advanced oropharyngeal carcinoma during definitive cisplatin and image-guided volumetric-modulated arc radiation therapy.

PubMed

Mazzola, R; Ricchetti, F; Fiorentino, A; Di Paola, G; Fersino, S; Giaj Levra, N; Ruggieri, R; Alongi, F

2016-06-01

Cancer cachexia is a syndrome characterized by weight loss (WL) and sarcopenia. Aim of the study was to assess the impact of cachexia on head and neck changes during definitive cisplatin and image-guided volumetric-modulated arc radiation therapy in a series of locally advanced oropharyngeal cancer. Volume variations of sternocleidomastoid muscle (SCM) were considered as surrogate of muscle changes related to sarcopenia. Two head and neck diameters, encompassing the cranial limits of II and III nodal levels (defined as 'head diameter' and 'neck diameter', respectively), were measured. All parameters were defined retrospectively by means of on-board cone beam computed tomography images at 1-8th to 15-22th and at last fraction (fx) of radiotherapy (RT). Cachexia was defined as WL >5% during treatment. Analysis was conducted correlating the parameter changes with three WL ranges: <5, 5-9 and>10%. Thirty patients were evaluated. One hundred and fifty contoured SCMs and three hundred diameters were collected. Median WL was 6.5% (range, 0-16%). The most significant SCM shrinkage was recorded at 15th fx (mean 1.6 cc) related to WL 5-9% and WL >10% (P 0.001). For 'head diameter', the peak reduction was recorded at the 15th fx (mean 8 mm), statistically correlated to WL >10% (P 0.001). The peak reduction in 'neck diameter' was registered at the 22th fx (mean 6 mm), with a gradual reduction until the end of treatment for WL >5%. In a homogeneous cohort of patients, present study quantified the impact of cachexia on head and neck changes. Present data could provide adaptive RT implications for further investigations.

Validation and real-world assessment of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in patients with advanced non-small cell lung cancer and the cancer anorexia-cachexia syndrome (CACS).

PubMed

LeBlanc, Thomas W; Samsa, Greg P; Wolf, Steven P; Locke, Susan C; Cella, David F; Abernethy, Amy P

2015-08-01

Patients with cancer anorexia-cachexia syndrome (CACS) suffer a significant symptom burden, impaired quality of life (QoL), and shorter survival. Measurement of QoL impairments related to CACS is thereby important both in clinical practice and in research. We aimed to further validate the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in an advanced lung cancer population. We tested the performance of the FAACT and its anorexia-cachexia subscale (ACS) within a dataset of patients with advanced non-small cell lung cancer (aNSCLC), using standard statistical methods. We then compared the performance of commonly used QoL measures stratified by CACS status and by patient self-report of appetite and weight loss. The FAACT and its ACS demonstrate internal validity consistent with acceptable published ranges for other QoL scales (Cronbach alpha = 0.9 and 0.79, respectively). Correlation coefficients demonstrate moderate correlations in the expected directions between FAACT and ACS and scales that measure related constructs. Comparing patients with and without CACS, the ACS is more sensitive to change than other QoL instruments (mean score 33.1 vs. 37.2, p = 0.011, ES = 0.58). In patients with aNSCLC, the FAACT and its ACS performed well compared with other instruments, further supporting their validity and value in clinical research. FAACT and ACS scores covaried with symptoms and other QoL changes that are typical hallmarks of CACS, lending further support to their use as QoL endpoints in clinical trials among patients with CACS.

A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients.

PubMed

Fogelman, David R; Morris, J; Xiao, L; Hassan, M; Vadhan, S; Overman, M; Javle, S; Shroff, R; Varadhachary, G; Wolff, R; Vence, L; Maitra, A; Cleeland, C; Wang, X S

2017-06-01

Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients. Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy. Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker. Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome.

Publication trends in cachexia and sarcopenia in elderly heart failure patients.

PubMed

Springer, Jochen; Anker, Stefan D

2016-12-01

The loss of skeletal mass - sarcopenia and cachexia - is considered to be a major contributor to morbidity and mortality in chronic heart failure (CHF). Unfortunately, sarcopenia is generally considered to be a geriatric syndrome, but not necessarily seen as a comorbidity in CHF, even though it has a wide range of adverse health outcomes. While there were 15,574 publication with the title word "heart failure" in PubMed in the 5‑year period from 1 June 2011 to 31 May 2016, only 22 or 71 publications were found with the search combination "sarcopenia" or "cachexia" (title word) and "heart failure" (all fields), respectively. This shows very clearly that loss of muscle quality and function due to heart failure is still an underappreciated problem in the medical field.

Erlotinib plus parenteral nutrition: an opportunity to get through the hardest days of advanced non-small cell lung cancer with cancer anorexia-cachexia syndrome.

PubMed

Zang, Yuan-Sheng; Fang, Zheng; Li, Bing

2013-03-01

This case study details the poor performance status of a patient with non-small cell lung cancer and cancer anorexia-cachexia syndrome got through the hardest days of high tumor burden and malnutrition, by using a combined therapy of lung cancer-targeted therapy drug and parenteral nutrition. The related literatures were reviewed.

The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

PubMed Central

Rébillard, Amélie

2016-01-01

Chronic inflammation and excessive loss of skeletal muscle usually occur during cancer cachexia, leading to functional impairment and delaying the cure of cancer. The release of cytokines by tumor promotes the formation of reactive oxygen species (ROS), which in turn regulate catabolic pathways involved in muscle atrophy. ROS also exert a dual role within tumor itself, as they can either promote proliferation and vascularization or induce senescence and apoptosis. Accordingly, previous studies that used antioxidants to modulate these ROS-dependent mechanisms, in cancer and cancer cachexia, have obtained contradictory results, hence the need to gather the main findings of these studies and draw global conclusions in order to stimulate more oriented research in this field. Based on the literature reviewed in this paper, it appears that antioxidant supplementation is (1) beneficial in cancer cachectic patients with antioxidant deficiencies, (2) most likely harmful in cancer patients with adequate antioxidant status (i.e., lung, gastrointestinal, head and neck, and esophageal), and (3) not recommended when undergoing radiotherapy. At the moment, measuring the blood levels of antioxidants may help to identify patients with systemic deficiencies. This approach is simple to realize but could not be a gold standard method for cachexia, as it does not necessarily reflect the redox state in other organs, like muscle. PMID:27642498

The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts.

PubMed

Assi, Mohamad; Rébillard, Amélie

2016-01-01

Chronic inflammation and excessive loss of skeletal muscle usually occur during cancer cachexia, leading to functional impairment and delaying the cure of cancer. The release of cytokines by tumor promotes the formation of reactive oxygen species (ROS), which in turn regulate catabolic pathways involved in muscle atrophy. ROS also exert a dual role within tumor itself, as they can either promote proliferation and vascularization or induce senescence and apoptosis. Accordingly, previous studies that used antioxidants to modulate these ROS-dependent mechanisms, in cancer and cancer cachexia, have obtained contradictory results, hence the need to gather the main findings of these studies and draw global conclusions in order to stimulate more oriented research in this field. Based on the literature reviewed in this paper, it appears that antioxidant supplementation is (1) beneficial in cancer cachectic patients with antioxidant deficiencies, (2) most likely harmful in cancer patients with adequate antioxidant status (i.e., lung, gastrointestinal, head and neck, and esophageal), and (3) not recommended when undergoing radiotherapy. At the moment, measuring the blood levels of antioxidants may help to identify patients with systemic deficiencies. This approach is simple to realize but could not be a gold standard method for cachexia, as it does not necessarily reflect the redox state in other organs, like muscle.

Physiological and functional failure in chronic obstructive pulmonary disease, congestive heart failure and cancer: a debilitating intersection of sarcopenia, cachexia and breathlessness.

PubMed

Dudgeon, Deborah; Baracos, Vickie E

2016-09-01

Loss of skeletal muscle mass and cachexia are important manifestations of chronic obstructive pulmonary disease and have been associated with breathlessness, functional limitation and poor prognosis. A number of other life-limiting illnesses, including cancer and chronic heart failure as well as acute conditions seen in ICU such as sepsis, are characteristically associated with cachexia and sarcopenia. These conditions may have respiratory muscle atrophy of sufficient magnitude to contribute to the development of breathlessness and associated functional limitation. The purpose of this review is to summarize findings related to a direct role for severe respiratory muscle wasting in the etiology of breathlessness in advanced, life limiting illness. Localized wasting of respiratory muscles appears to be part of systemic wasting of skeletal muscles, driven by deconditioning, nutritional insufficiencies and inflammation, and because of disease-specific factors (tumor factors and exacerbations), anabolic insufficiency, autonomic dysfunction, drugs (such as corticosteroids and chemotherapy agents), mechanical ventilation and comorbidities. Marked morphological and biochemical abnormalities have been noted in diaphragm muscle biopsies. Older patients with multiple comorbidities associated with muscle loss and cachexia are likely to be at elevated risk of respiratory muscle atrophy and functional loss, because of the presence of multiple, interacting etiologic factors.

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training

PubMed Central

Bowen, T Scott; Schuler, Gerhard; Adams, Volker

2015-01-01

Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Transmission of external stimuli to intracellular effector proteins via signalling pathways is a highly regulated and controlled process that determines muscle mass by balancing protein synthesis and protein degradation. An impaired balance between protein synthesis and breakdown leads to the development of specific myopathies. Sarcopenia and cachexia represent two distinct muscle wasting diseases characterized by inflammation and oxidative stress, where specific regulating molecules associated with wasting are either activated (e.g. members of the ubiquitin-proteasome system and myostatin) or repressed (e.g. insulin-like growth factor 1 and PGC-1α). At present, no therapeutic interventions are established to successfully treat muscle wasting in sarcopenia and cachexia. Exercise training, however, represents an intervention that can attenuate or even reverse the process of muscle wasting, by exerting anti-inflammatory and anti-oxidative effects that are able to attenuate signalling pathways associated with protein degradation and activate molecules associated with protein synthesis. This review will therefore discuss the molecular mechanisms associated with the pathology of muscle wasting in both sarcopenia and cachexia, as well as highlighting the intracellular effects of exercise training in attenuating the debilitating loss of muscle mass in these specific conditions. PMID:26401465

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training.

PubMed

Bowen, T Scott; Schuler, Gerhard; Adams, Volker

2015-09-01

Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Transmission of external stimuli to intracellular effector proteins via signalling pathways is a highly regulated and controlled process that determines muscle mass by balancing protein synthesis and protein degradation. An impaired balance between protein synthesis and breakdown leads to the development of specific myopathies. Sarcopenia and cachexia represent two distinct muscle wasting diseases characterized by inflammation and oxidative stress, where specific regulating molecules associated with wasting are either activated (e.g. members of the ubiquitin-proteasome system and myostatin) or repressed (e.g. insulin-like growth factor 1 and PGC-1α). At present, no therapeutic interventions are established to successfully treat muscle wasting in sarcopenia and cachexia. Exercise training, however, represents an intervention that can attenuate or even reverse the process of muscle wasting, by exerting anti-inflammatory and anti-oxidative effects that are able to attenuate signalling pathways associated with protein degradation and activate molecules associated with protein synthesis. This review will therefore discuss the molecular mechanisms associated with the pathology of muscle wasting in both sarcopenia and cachexia, as well as highlighting the intracellular effects of exercise training in attenuating the debilitating loss of muscle mass in these specific conditions.

Inhibition of cisplatin-induced lipid catabolism and weight loss by ghrelin in male mice.

PubMed

Garcia, Jose M; Scherer, Thomas; Chen, Ji-an; Guillory, Bobby; Nassif, Anriada; Papusha, Victor; Smiechowska, Joanna; Asnicar, Mark; Buettner, Christoph; Smith, Roy G

2013-09-01

Cachexia, defined as an involuntary weight loss ≥ 5%, is a serious and dose-limiting side effect of chemotherapy that decreases survival in cancer patients. Alterations in lipid metabolism are thought to cause the lipodystrophy commonly associated with cachexia. Ghrelin has been proposed to ameliorate the alterations in lipid metabolism due to its orexigenic and anabolic properties. However, the mechanisms of action through which ghrelin could potentially ameliorate chemotherapy-associated cachexia have not been elucidated. The objectives of this study were to identify mechanisms by which the chemotherapeutic agent cisplatin alters lipid metabolism and to establish the role of ghrelin in reversing cachexia. Cisplatin-induced weight and fat loss were prevented by ghrelin. Cisplatin increased markers of lipolysis in white adipose tissue (WAT) and of β-oxidation in liver and WAT and suppressed lipogenesis in liver, WAT, and muscle. Ghrelin prevented the imbalance between lipolysis, β-oxidation, and lipogenesis in WAT and muscle. Pair-feeding experiments demonstrated that the effects of cisplatin and ghrelin on lipogenesis, but not on lipolysis and β-oxidation, were due to a reduction in food intake. Thus, ghrelin prevents cisplatin-induced weight and fat loss by restoring adipose tissue functionality. An increase in caloric intake further enhances the anabolic effects of ghrelin.

Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer

PubMed Central

Pigna, Eva; Berardi, Emanuele; Aulino, Paola; Rizzuto, Emanuele; Zampieri, Sandra; Carraro, Ugo; Kern, Helmut; Merigliano, Stefano; Gruppo, Mario; Mericskay, Mathias; Li, Zhenlin; Rocchi, Marco; Barone, Rosario; Macaluso, Filippo; Di Felice, Valentina; Adamo, Sergio; Coletti, Dario; Moresi, Viviana

2016-01-01

Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed. PMID:27244599

Myostatin - From the Mighty Mouse to cardiovascular disease and cachexia.

PubMed

Dschietzig, Thomas Bernd

2014-06-10

In 1997, McPherron et al. created the so-called Mighty Mouse: owing to the knock-out of a new member of the TGF-β superfamily of peptides, this mouse line was extremely hypermuscular and also characterized by very low body fat. The new peptide, a powerful negative muscle regulator, was named myostatin. Apart from regulating skeletal muscle growth, myostatin has recently been reported to be significantly involved in different cardio-vascular and metabolic pathologies. This review is focused on these non-muscular myostatin actions. First, myostatin is intricately involved in regulating metabolism: it causes insulin resistance, and the advantageous metabolic profile achieved by myostatin inhibition is mainly attributable to its effects on skeletal muscle. Myostatin is further expressed in myocardium where it exerts anti-hypertrophic, but pro-fibrotic effects. Circulating and local myostatin is elevated in chronic heart failure and poses a major player in cardiac cachexia. Eventually, the current body of evidence regarding myostatin's significant involvement in different entities of the cachexia syndrome is summarized. Activin type-2 receptor antagonism and/or inhibitory myostatin antibodies have emerged as a promising therapeutic approach to treat the cachexia syndrome although the general applicability of this therapeutic approach to the human clinical situation has still to be demonstrated. Copyright © 2014 Elsevier B.V. All rights reserved.

Rheumatoid cachexia and other nutritional alterations in rheumatologic diseases.

PubMed

Hurtado-Torres, Gilberto Fabián; González-Baranda, Lourdes Larisa; Abud-Mendoza, Carlos

2015-01-01

The prevalence of nutritional alterations in rheumatologic diseases ranges from 4 to 95%, depending on the detection method used. Formerly described as the single term rheumatoid cachexia, nutritional alterations can currently be grouped and subdivided based on the physiopathological mechanisms involved: chronic disease-related inflammatory conditions (cachexia), malnutrition associated to acute malnutrition inflammatory conditions (protein-caloric malnutrition) and starvation-related malnutrition. Clinical manifestations of malnutrition associated to rheumatic diseases vary from the patient with low weight or overweight and obesity; with lean body mass depletion as well as functional repercussions, and impact of quality of life as a common denominator. Additionally, the associated increase in body fat mass increases the risk for cardiovascular morbidity. A multidisciplinary approach towards rheumatic diseases should include aspects oriented towards prevention, early identification, diagnosis and correction of nutritional alterations. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Protective effect of Panax ginseng in cisplatin-induced cachexia in rats.

PubMed

Lobina, Carla; Carai, Mauro A M; Loi, Barbara; Gessa, Gian Luigi; Riva, Antonella; Cabri, Walter; Petrangolini, Giovanna; Morazzoni, Paolo; Colombo, Giancarlo

2014-05-01

This study investigated the protective effect of a standardized extract of Panax ginseng on multiple cisplatin-induced 'sickness behaviors' (model of cancer-induced cachexia) in rats. Cisplatin was administered twice weekly (1-2 mg/kg, intraperitoneal) for 5 consecutive weeks. Panax ginseng extract (0, 25 and 50 mg/kg, intragastric) was administered daily over the 5-week period of cisplatin exposure. Malaise, bodyweight and temperature, pain sensitivity, and endurance running were recorded at baseline and at 5 weekly intervals. Treatment with cisplatin produced severe signs of malaise, marked loss of bodyweight, hypothermia, hyperalgesia and reduction in running time. Treatment with Panax ginseng extract completely prevented all cisplatin-induced alterations. These data indicate that treatment with Panax ginseng extract exerted a protective effect in a rat model of cachexia and suggest that Panax ginseng extract may be a therapeutic promising tool for supportive care in oncology.

[Recent development in research and management of cancer anorexia-cachexia syndrome].

PubMed

Inui, Akio

2005-06-01

Cachexia is among the most debilitating and life-threatening aspects of cancer, and is more common in children and elderly patients. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. This could be done by persistent inhibition of feeding-stimulatory circuitry including neuropeptide Y. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a 3-6-month period. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide-all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. Communication among physicians and other health care professionals provides the patient with a multidisciplinary approach to care. The patient record will be an excellent resource to document a plan of care and patient responses to treatment. Psychological distress and psychiatric disorders are common among cancer patients. These problems are also as common among the family members of people with cancer. The use of psychological and behavioral interventions in cancer is increasing, and recent studies have suggested that some of these techniques may affect quality of life and, perhaps, survival rates. Evaluations of relaxation, hypnosis, and short-term group psychotherapy have suggested some benefit with regard to anorexia and fatigue, although the population most likely to benefit from these interventions has not yet been determined. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life.

Multiplatform plasma fingerprinting in cancer cachexia: a pilot observational and translational study

PubMed Central

Cala, Mónica Patricia; Agulló‐Ortuño, María Teresa; Prieto‐García, Elena; González‐Riano, Carolina; Parrilla‐Rubio, Lucía; Barbas, Coral; Díaz‐García, Carmen Vanesa; García, Antonia; Pernaut, Cristina; Adeva, Jorge; Riesco, María Carmen; Rupérez, Francisco Javier

2018-01-01

Abstract Background Cachexia is a metabolic syndrome that affects up to 50–80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The ‘omics’ technologies provide a global view of biological systems. We hypothesize that blood‐based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge on its pathophysiology, and eventually postulate new therapeutic strategies. Methods This is a cross‐sectional observational study in two cohorts of cancer patients, with and without cachexia. Patients were consecutively recruited from routine clinical practice of a General Oncology Department at ‘12 de Octubre’ University Hospital. Selected clinical and biochemical features were collected. Blood metabolite fingerprinting was performed using three analytical platforms, gas chromatography coupled to mass spectrometry (GC–MS), capillary electrophoresis coupled to mass spectrometry (CE–MS), and liquid chromatography coupled to mass spectrometry (LC–MS). Besides, we performed pathway‐based metabolite analyses to obtain more information on biological functions. Results A total of 15 subjects were included in this study, 8 cachectic and 7 non‐cachectic patients. Metabolomic analyses were able to correctly classify their samples in 80% (GC–MS), 97% (CE–MS), 96% [LC–MS (positive mode)], and 89% [LC–MS (negative mode)] of the cases. The most prominent metabolic alteration in plasma of cachectic patients was the decrease of amino acids and derivatives [especially arginine, tryptophan, indolelactic acid, and threonine, with 0.4‐fold change (FC) compared with non‐cachectic patients], along with the reduction of glycerophospholipids [mainly lysophosphatidylcholines(O‐16:0) and lysophosphatidylcholines(20:3) sn‐1, FC = 0.1] and sphingolipids [SM(d30:0), FC = 0.5]. The metabolite with the highest increase was cortisol (FC = 1.6). Such alterations suggest a role of the following metabolic pathways in the pathophysiology of cancer cachexia: arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; phenylalanine metabolism; lysine degradation; aminoacyl‐tRNA biosynthesis; fatty acid elongation in mitochondria; tricarboxylic acids cycle; among others. Conclusions These findings suggest that plasma amino acids and lipids profiling has great potential to find the mechanisms involved in the pathogenesis of cachexia. Metabolic profiling of plasma from cancer patients show differences between cachexia and non‐cachexia in amino acids and lipids that might be related to mechanisms involved in its pathophysiology. A better understanding of these mechanisms might identify novel therapeutic approaches to palliate this unmet medical condition. PMID:29464940

Ghrelin for the management of cachexia associated with cancer.

PubMed

Khatib, Mahalaqua Nazli; Shankar, Anuraj H; Kirubakaran, Richard; Gaidhane, Abhay; Gaidhane, Shilpa; Simkhada, Padam; Quazi Syed, Zahiruddin

2018-02-28

Cancer sufferers are amongst the most malnourished of all the patient groups. Studies have shown that ghrelin, a gut hormone can be a potential therapeutic agent for cachexia (wasting syndrome) associated with cancer. A variety of mechanisms of action of ghrelin in people with cancer cachexia have been proposed. However, safety and efficacy of ghrelin for cancer-associated cachexia have not been systematically reviewed. The aim of this review was to assess whether ghrelin is associated with better food intake, body composition and survival than other options for adults with cancer cachexia. To assess the efficacy and safety of ghrelin in improving food intake, body composition and survival in people with cachexia associated with cancer. We searched CENTRAL, MEDLINE and Embase without language restrictions up to July 2017. We also searched for ongoing studies in trials registers, performed handsearching, checked bibliographic references of relevant articles and contacted authors and experts in the field to seek potentially relevant research. We applied no restrictions on language, date, or publication status. We included randomised controlled (parallel-group or cross-over) trials comparing ghrelin (any formulation or route of administration) with placebo or an active comparator in adults (aged 18 years and over) who met any of the international criteria for cancer cachexia. Two review authors independently assessed studies for eligibility. Two review authors then extracted data and assessed the risk of bias for individual studies using standard Cochrane methodology. For dichotomous variables, we planned to calculate risk ratio with 95% confidence intervals (CI) and for continuous data, we planned to calculate mean differences (MD) with 95% CI. We assessed the evidence using GRADE and created 'Summary of findings' tables. We screened 926 individual references and identified three studies that satisfied the inclusion criteria. Fifty-nine participants (37 men and 22 women) aged between 54 and 78 years were randomised initially, 47 participants completed the treatment. One study had a parallel design and two had a cross-over design. The studies included people with a variety of cancers and also differed in the dosage, route of administration, frequency and duration of treatment.One trial, which compared ghrelin with placebo, found that ghrelin improved food intake (very low-quality evidence) and had no adverse events (very low-quality evidence). Due to unavailability of data we were unable to report on comparisons for ghrelin versus no treatment or alternative experimental treatment modalities, or ghrelin in combination with other treatments or ghrelin analogues/ghrelin mimetics/ghrelin potentiators. Two studies compared a higher dose of ghrelin with a lower dose of ghrelin, however due to differences in study designs and great diversity in the treatment provided we did not pool the results. In both trials, food intake did not differ between participants on higher-dose and lower-dose ghrelin. None of the included studies assessed data on body weight. One study reported higher adverse events with a higher dose as compared to a lower dose of ghrelin.All studies were at high risk of attrition bias and bias for size of the study. Risk of bias in other domains was unclear or low.We rated the overall quality of the evidence for primary outcomes (food intake, body weight, adverse events) as very low. We downgraded the quality of the evidence due to lack of data, high or unclear risk of bias of the studies and small study size. There is insufficient evidence to be able to support or refute the use of ghrelin in people with cancer cachexia. Adequately powered randomised controlled trials focusing on evaluation of safety and efficacy of ghrelin in people with cancer cachexia is warranted.

Myostatin gene inactivation prevents skeletal muscle wasting in cancer.

PubMed

Gallot, Yann S; Durieux, Anne-Cécile; Castells, Josiane; Desgeorges, Marine M; Vernus, Barbara; Plantureux, Léa; Rémond, Didier; Jahnke, Vanessa E; Lefai, Etienne; Dardevet, Dominique; Nemoz, Georges; Schaeffer, Laurent; Bonnieu, Anne; Freyssenet, Damien G

2014-12-15

Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc(Min) (/+) mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc(Min) (/+) mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease. ©2014 American Association for Cancer Research.

Protein calorie malnutrition, nutritional intervention and personalized cancer care.

PubMed

Gangadharan, Anju; Choi, Sung Eun; Hassan, Ahmed; Ayoub, Nehad M; Durante, Gina; Balwani, Sakshi; Kim, Young Hee; Pecora, Andrew; Goy, Andre; Suh, K Stephen

2017-04-04

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.

An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

PubMed

Nakamura, Kentaro; Sasayama, Akina; Takahashi, Takeshi; Yamaji, Taketo

2015-01-01

Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E2 levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.

Elevated expression of activins promotes muscle wasting and cachexia.

PubMed

Chen, Justin L; Walton, Kelly L; Winbanks, Catherine E; Murphy, Kate T; Thomson, Rachel E; Makanji, Yogeshwar; Qian, Hongwei; Lynch, Gordon S; Harrison, Craig A; Gregorevic, Paul

2014-04-01

In models of cancer cachexia, inhibiting type IIB activin receptors (ActRIIBs) reverse muscle wasting and prolongs survival, even with continued tumor growth. ActRIIB mediates signaling of numerous TGF-β proteins; of these, we demonstrate that activins are the most potent negative regulators of muscle mass. To determine whether activin signaling in the absence of tumor-derived factors induces cachexia, we used recombinant serotype 6 adeno-associated virus (rAAV6) vectors to increase circulating activin A levels in C57BL/6 mice. While mice injected with control vector gained ~10% of their starting body mass (3.8±0.4 g) over 10 wk, mice injected with increasing doses of rAAV6:activin A exhibited weight loss in a dose-dependent manner, to a maximum of -12.4% (-4.2±1.1 g). These reductions in body mass in rAAV6:activin-injected mice correlated inversely with elevated serum activin A levels (7- to 24-fold). Mechanistically, we show that activin A reduces muscle mass and function by stimulating the ActRIIB pathway, leading to deleterious consequences, including increased transcription of atrophy-related ubiquitin ligases, decreased Akt/mTOR-mediated protein synthesis, and a profibrotic response. Critically, we demonstrate that the muscle wasting and fibrosis that ensues in response to excessive activin levels is fully reversible. These findings highlight the therapeutic potential of targeting activins in cachexia.

Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90.

PubMed

Zhang, Guohua; Liu, Zhelong; Ding, Hui; Zhou, Yong; Doan, Hoang Anh; Sin, Ka Wai Thomas; Zhu, Zhiren J; Flores, Rene; Wen, Yefei; Gong, Xing; Liu, Qingyun; Li, Yi-Ping

2017-09-19

Cachexia, characterized by muscle wasting, is a major contributor to cancer-related mortality. However, the key cachexins that mediate cancer-induced muscle wasting remain elusive. Here, we show that tumor-released extracellular Hsp70 and Hsp90 are responsible for tumor's capacity to induce muscle wasting. We detected high-level constitutive release of Hsp70 and Hsp90 associated with extracellular vesicles (EVs) from diverse cachexia-inducing tumor cells, resulting in elevated serum levels in mice. Neutralizing extracellular Hsp70/90 or silencing Hsp70/90 expression in tumor cells abrogates tumor-induced muscle catabolism and wasting in cultured myotubes and in mice. Conversely, administration of recombinant Hsp70 and Hsp90 recapitulates the catabolic effects of tumor. In addition, tumor-released Hsp70/90-expressing EVs are necessary and sufficient for tumor-induced muscle wasting. Further, Hsp70 and Hsp90 induce muscle catabolism by activating TLR4, and are responsible for elevation of circulating cytokines. These findings identify tumor-released circulating Hsp70 and Hsp90 as key cachexins causing muscle wasting in mice.Cachexia affects many cancer patients causing weight loss and increasing mortality. Here, the authors identify extracellular Hsp70 and Hsp90, either in soluble form or secreted as part of exosomes from tumor cells, to be responsible for tumor induction of cachexia.

Functional Body Composition and Related Aspects in Research on Obesity and Cachexia

PubMed Central

Müller, M.J.; Baracos, V.; Bosy-Westphal, A.; Dulloo, A.; Eckel, J.; Fearon, K.C.H.; Hall, K.D.; Pietrobelli, A.; Sørensen, T.I.A.; Speakman, J.; Trayhurn, P.; Visser, M.; Heymsfield, S.B.

2014-01-01

The 12th Stock Conference addressed body composition and related functions in two extreme situations, obesity and cancer cachexia. The concept of “functional body composition” integrates body components into regulatory systems relating the mass of organs and tissues to corresponding in vivo functions and metabolic processes. This concept adds to an understanding of organ/tissue mass and function in the context of metabolic adaptations to weight change and disease. During weight gain and loss there are associated changes in individual body components while the relationships between organ and tissue mass are fixed. Thus, an understanding of weight regulation involves an examination of organ-tissue regulation rather than of individual organ mass. The between organ/tissue mass relationships are associated with and explained by cross-talk between organs and tissues mediated by cytokines, hormones, and metabolites that are coupled with changes in body weight, composition, and function as observed in obesity and cancer cachexia. In addition to established roles in intermediary metabolism, cell function and inflammation, organ-tissue cross-talk mediators are determinants of body composition and its’ change with weight gain and loss. The 12th Stock Conference supported Michael Stocks’ concept of gaining new insights by integrating research ideas from obesity and cancer cachexia. The conference presentations provide an in-depth understanding of body composition and metabolism. PMID:24835453

Protein calorie malnutrition, nutritional intervention and personalized cancer care

PubMed Central

Gangadharan, Anju; Choi, Sung Eun; Hassan, Ahmed; Ayoub, Nehad M.; Durante, Gina; Balwani, Sakshi; Kim, Young Hee; Pecora, Andrew; Goy, Andre; Suh, K. Stephen

2017-01-01

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients. PMID:28177923

Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia.

PubMed

DeBoer, Mark D; Zhu, Xin Xia; Levasseur, Peter; Meguid, Michael M; Suzuki, Susumu; Inui, Akio; Taylor, John E; Halem, Heather A; Dong, Jesse Z; Datta, Rakesh; Culler, Michael D; Marks, Daniel L

2007-06-01

Cancer cachexia is a debilitating syndrome of anorexia and loss of lean body mass that accompanies many malignancies. Ghrelin is an orexigenic hormone with a short half-life that has been shown to improve food intake and weight gain in human and animal subjects with cancer cachexia. We used a rat model of cancer cachexia and administered human ghrelin and a synthetic ghrelin analog BIM-28131 via continuous infusion using sc osmotic minipumps. Tumor-implanted rats receiving human ghrelin or BIM-28131 exhibited a significant increase in food consumption and weight gain vs. saline-treated animals. We used dual-energy x-ray absorptiometry scans to show that the increased weight was due to maintenance of lean mass vs. a loss of lean mass in saline-treated animals. Also, BIM-28131 significantly limited the loss of fat mass normally observed in tumor-implanted rats. We further performed real-time PCR analysis of the hypothalami and brainstems and found that ghrelin-treated animals exhibited a significant increase in expression of orexigenic peptides agouti-related peptide and neuropeptide Y in the hypothalamus and a significant decrease in the expression of IL-1 receptor-I transcript in the hypothalamus and brainstem. We conclude that ghrelin and a synthetic ghrelin receptor agonist improve weight gain and lean body mass retention via effects involving orexigenic neuropeptides and antiinflammatory changes.

Is there a relation between pre-sarcopenia, sarcopenia, cachexia and osteoporosis in patients with ankylosing spondylitis?

PubMed

El Maghraoui, Abdellah; Ebo'o, François Bertin; Sadni, Siham; Majjad, Abderrahim; Hamza, Toufik; Mounach, Aziza

2016-07-11

Osteoporosis is a well-known complication of ankylosing spondylitis (AS). However, data about body composition modifications and muscle performance showed conflicting results. The aim of the study was to determine the prevalence and risk factors of pre-sarcopenia, sarcopenia and cachexia in patients with AS and analyze its relationship with bone loss and symptomatic and severity parameters of the disease. Sixty-seven consecutive male patients with AS (mean age of 40.9 ± 11.0 years) and 67 healthy controls were studied. Body composition and bone mineral density (BMD) scans were obtained using DXA. The fat-free mass index (FFMI; fat-free mass divided by height squared) and the percent of fat mass (%FM) were calculated. Pre-sarcopenia was defined by low skeletal muscle mass (SMI <7.25 kg/m(2)), sarcopenia by the combined presence of the two following criteria: SMI <7.25 kg/m(2) and a low muscle strength (handgrip strength <30 kg) or a low muscle performance (timed get-up-and-go test >10 s) and cachexia by a BMI <20 kg/m(2) plus 3 from the 5 following parameters: anorexia, fatigue, handgrip strength <30 kg, CRP >5 mg/l, SMI <7.25 kg/m(2). Pre-sarcopenia, sarcopenia, cachexia, and osteoporosis prevalences were (50.4, 34.3, 11.9, and 16.0) respectively. Patients had a mean 3 kg significant decrease in FFM and a 1 kg/m(2) decrease in appendicular mass vs. healthy controls. Pre-sarcopenia, sarcopenia and cachexia were significantly associated to higher BASDAI levels and low BMD. Our study showed that men with AS had a statistically significant reduction in total and appendicular lean mass that is related to higher disease activity and significantly associated to bone loss.

A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project.

PubMed

Mochamat; Cuhls, Henning; Marinova, Milka; Kaasa, Stein; Stieber, Christiane; Conrad, Rupert; Radbruch, Lukas; Mücke, Martin

2017-02-01

We provide a systematic review to support the European Palliative Care Research Collaboration development of clinical guidelines for cancer patients suffering from cachexia. CENTRAL, MEDLINE, PsycINFO, ClinicalTrials.gov, and a selection of cancer journals have been searched up until 15 April 2016. The systematic literature research yielded 4214 publications with 21 of these included in the final evaluation. Regarding minerals, our search identified only one study examining the use of magnesium with no effect on weight loss. As far as vitamins are concerned, vitamin E in combination with omega-3 fatty acids displayed an effect on survival in a single study, vitamin D showed improvement of muscle weakness in prostate cancer patients, and vitamin C supplementation led to an improvement of various quality of life aspects in a sample with a variety of cancer diagnoses. For proteins, a combination therapy of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. L-carnitine led to an increase of body mass index and an increase in overall survival in advanced pancreatic cancer patients. Adverse effects of food supplementation were rare and showed mild intensity. There is not enough solid evidence for the use of minerals, vitamins, proteins, or other supplements in cancer. No serious adverse effects have been reported with dietary supplementation. © 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

Relation between hypermetabolism, cachexia, and survival in cancer patients: a prospective study in 390 cancer patients before initiation of anticancer therapy.

PubMed

Vazeille, Clara; Jouinot, Anne; Durand, Jean-Philippe; Neveux, Nathalie; Boudou-Rouquette, Pascaline; Huillard, Olivier; Alexandre, Jérôme; Cynober, Luc; Goldwasser, François

2017-05-01

Background: Cachexia is a major cause of death in cancer patients. The role of hypermetabolism in cancer cachexia remains unclear. Objective: We studied the relation between resting energy expenditure (REE), the estimated energy balance, clinical and biological markers of cachexia, and survival. Design: REE was measured with the use of indirect calorimetry in cancer patients before the initiation of anticancer therapies. Hypermetabolic, normometabolic, and hypometabolic patients were identified with the use of Boothby's standard. Weight loss, performance status (PS), C-reactive protein (CRP), albumin, the nutritional risk index, daily energy intake, energy balance (equal to daily energy intakes minus the REE), and survival were recorded. Results: Of 390 enrolled patients, 49% of subjects were hypermetabolic, 30% of subjects were normometabolic, and 21% of subjects were hypometabolic. Mean daily energy intakes did not differ significantly between the 3 groups. Hypermetabolic patients, compared with normometabolic patients, were more likely to have a negative energy balance [45% compared with 32%, respectively; OR: 1.74 (95% CI: 1.05, 2.91); P = 0.024], weight loss >5% [48% compared with 34%, respectively; OR: 1.83 (95% CI: 1.11, 3.04); P = 0.013], PS ≥2 [40% compared with 29%, respectively; OR: 1.70 (95% CI: 1.01, 2.88); P = 0.038], and CRP concentrations ≥10 mg/L [52% compared with 33%, respectively; OR: 2.2 (95% CI: 1.33, 3.66); P = 0.001]. In metastatic patients, compared with normometabolism, hypermetabolism was associated with a reduced median survival [14.6 compared with 21.4 mo, respectively; OR: 1.48 (95% CI: 1.01, 2.17); P = 0.044]. Conclusions: Hypermetabolism is correlated with clinical and biological markers of cancer cachexia and is associated with a shorter survival in metastatic cancer patients. The development of therapeutic strategies that aim to blunt hypermetabolism appears warranted. This trial was registered at www.controlled-trials.com as ISRCTN46152275. © 2017 American Society for Nutrition.

Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation.

PubMed

Musolino, Vincenzo; Palus, Sandra; Tschirner, Anika; Drescher, Cathleen; Gliozzi, Micaela; Carresi, Cristina; Vitale, Cristiana; Muscoli, Carolina; Doehner, Wolfram; von Haehling, Stephan; Anker, Stefan D; Mollace, Vincenzo; Springer, Jochen

2016-12-01

Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia. In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis. Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (-9 ± 12%, P  < 0.05) and the wasting of lean and fat mass (-7.0 ± 6% and -22.4 ± 3 %, P  < 0.001 and P  < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 ± 30 mg vs. placebo 474 ± 13 mg, P  < 0.001). Tumour-bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular end systolic volume. Western blotting analysis showed an upregulation of the autophagic pathway in the gastrocnemius and hearts of the placebo-treated tumour-bearing rats. Treatment with MA, however, was able to modulate the autophagic markers (e.g. Beclin-1, p62, TRAF6, and LC3) in the gastrocnemius and in the hearts of tumour-bearing rats. Most importantly, 100 mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20-1.00; P  = 0.0486]. Megestrol acetate improved survival and reduced wasting through a marked downregulation of autophagy, occurring in both skeletal and heart muscle, the latter effect leading to a significant improvement of cardiac function. Our data suggest that MA might represent a valuable strategy to counteract the development of cancer cachexia-induced cardiomyopathy.

A comparison of long-chain triglycerides and medium-chain triglycerides on weight loss and tumour size in a cachexia model.

PubMed Central

Tisdale, M. J.; Brennan, R. A.

1988-01-01

A comparison has been made between the ability of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) to prevent weight loss induced by the cachexia-inducing colon adenocarcinoma (MAC16) and to reduce tumour size. There was no difference in calorie consumption or nitrogen intake between the various groups. When compared with a normal control high carbohydrate, low fat diet, animals fed MCT showed a reduced weight loss and a marked reduction in tumour size. In contrast neither weight loss nor tumour size differed significantly from the controls in animals fed the LCT diet. An elevated plasma level of 3-hydroxybuturate was found only in the animals fed the MCT diets. Administration of LCT caused an increase in the plasma level of FFA, which was not observed in the MCT group. These results suggest that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size. PMID:3219268

[Treatment with nutrition and fluids in patients with non-curable cancer].

PubMed

Nordøy, Tone; Thoresen, Lene; Kvikstad, Anne; Svensen, Rune

2006-02-23

Patients with non-curable cancer represent a large and heterogeneous group in which malnutrition and weight loss is a frequent finding. This article is based on relevant literature and our own clinical experience. For every patient a thorough examination of possible underlying causes should be explored and corrected as soon as possible (secondary cachexia). However, in many patients primary cachexia is the cause, a catabolic condition where muscle protein and lipids are degraded and even aggressive nutrition will not reverse the process. This condition is very different from starvation. Metoclopramide, corticosteroids and gestagens can relieve symptoms as anorexia, chronic nausea and asthenia which frequently occur in patients with cachexia. Treatments that may maintain or increase muscle function and modulate inflammatory processes are new approaches, such as eicosapentaneoic acid, adenosine triphosphate, specific amino acids and nonsteroidal antiinflammatory drugs. Nutrition is an integrated part of supportive therapy to all cancer patients, unless expected survival is short. At this time in life, nutrition will not influence survival and focus should be on symptom control.

Is clarithromycin a potential treatment for cachexia in people with lung cancer? A feasibility study.

PubMed

Awan, Sarah; Crosby, Vincent; Potter, Vanessa; Hennig, Ivo; Baldwin, David; Ndlovu, Mehluli; Paradine, Sharon; Wilcock, Andrew

2017-02-01

Clarithromycin may improve cachexia and survival in non-small cell lung cancer (NSCLC), but adequately controlled data are lacking. This study was undertaken primarily to inform the feasibility and scale of a phase III trial. Eligible consenting patients with stage IV NSCLC and cachexia were to be randomized to receive either clarithromycin 250mg twice daily or placebo for eight weeks. Aspects of trial feasibility recorded included numbers eligible, approached and recruited, together with adherence and completion of treatment and assessments. Over 6 months, none of 125 patients identified fulfilled the entry criteria. The commonest reasons for ineligibility were the use of an excluded concurrent drug (45, 36%), brain metastases (22, 18%), poor performance status (21, 17%) and current chemotherapy (15, 12%). A phase III trial of clarithromycin using these entry criteria is not feasible in this setting. Other macrolides that have a lower risk of a drug-drug interaction may be more practical to pursue. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A differential pattern of gene expression in skeletal muscle of tumor-bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations.

PubMed

Fontes-Oliveira, Cibely Cristine; Busquets, Sílvia; Fuster, Gemma; Ametller, Elisabet; Figueras, Maite; Olivan, Mireia; Toledo, Míriam; López-Soriano, Francisco J; Qu, Xiaoyan; Demuth, Jeffrey; Stevens, Paula; Varbanov, Alex; Wang, Feng; Isfort, Robert J; Argilés, Josep M

2014-02-01

Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals. The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome.

Effect of Feeding Status on Adjuvant Arthritis Severity, Cachexia, and Insulin Sensitivity in Male Lewis Rats

PubMed Central

Stofkova, Andrea; Zelezna, Blanka; Romzova, Marianna; Ulicna, Olga; Kiss, Alexander; Skurlova, Martina; Jurcovicova, Jana

2010-01-01

We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA) in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART) in the arcuate nucleus (ARC) does not play a primary role. The overexpression of IL-1β mRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats. PMID:20953376

A Prospective Randomized Controlled Trial to Study the Impact of a Nutrition-Sensitive Intervention on Adult Women With Cancer Cachexia Undergoing Palliative Care in India.

PubMed

Kapoor, Neha; Naufahu, Jane; Tewfik, Sundus; Bhatnagar, Sushma; Garg, Rakesh; Tewfik, Ihab

2017-03-01

Advanced cancer patients with disease progression develop cachexia. Nevertheless, cancer patients at nutritional risk have shown improved body weight and quality of life with oral nutritional supplements. This was a randomized controlled trial in adult female cancer patients (n = 63) attending palliative clinics, with symptoms of cachexia. Eligible patients were randomly distributed into control (n = 33) and intervention (n = 30) groups. Both groups were provided with nutritional and physical activity counseling, but the intervention group received an additional 100 g of Improved Atta (IAtta) for 6 months daily consumption. This study was designed to assess the efficacy of IAtta (with counseling) in enhancing the health status of cachexic patients. Anthropometric measurements, dietary intake, physical activity level and quality of life parameters were assessed at baseline, after 3 months, and at the end of 6 months. Patients in the control group (n = 15) had significantly decreased body weight ( P = .003), mid-upper-arm circumference ( P = .002), and body fat ( P = .002) by the end of intervention. A trend of body weight gain in the intervention group (n = 17; P = .08) and significant increase of body fat ( P = .002) was observed; moreover, patients reported a significant improvement in fatigue ( P = .002) and appetite scores ( P = .006) under quality-of-life domains at the end of intervention. Embedding a nutrition-sensitive intervention ( IAtta ) within Indian palliative care therapy may improve quality of life and stabilize body weight in cancer cachexia patients.

The clinical picture of cachexia: a mosaic of different parameters (experience of 503 patients).

PubMed

Schwarz, S; Prokopchuk, O; Esefeld, K; Gröschel, S; Bachmann, J; Lorenzen, S; Friess, H; Halle, M; Martignoni, M E

2017-02-14

Despite our growing knowledge about the pathomechanisms of cancer cachexia, a whole clinical picture of the cachectic patient is still missing. Our objective was to evaluate the clinical characteristics in cancer patients with and without cachexia to get the whole picture of a cachectic patient. Cancer patients of the University Clinic "Klinikum rechts der Isar" with gastrointestinal, gynecological, hematopoietic, lung and some other tumors were offered the possibility to take part in the treatment concept including a nutrition intervention and an individual training program according to their capability. We now report on the first 503 patients at the time of inclusion in the program between March 2011 and October 2015. We described clinical characteristics such as physical activity, quality of life, clinical dates and food intake. Of 503 patients with cancer, 131 patients (26.0%) were identified as cachectic, 369 (73.4%) as non-cachectic. The change in cachexia were 23% reduced capacity performance (108 Watt for non-cachectic-patients and 83 Watt for cachectic patients) and 12% reduced relative performance (1.53 Watt/kg for non-cachectic and 1.34 Watt/kg for cachectic patients) in ergometry test. 75.6% of non-cachectic and 54.3% of cachectic patients still received curative treatment. Cancer cachectic patients have multiple symptoms such as anemia, impaired kidney function and impaired liver function with elements of mild cholestasis, lower performance and a poorer quality of life in the EORTC questionnaire. Our study reveals biochemical and clinical specific features of cancer cachectic patients.

Collagen-induced arthritis as an animal model of rheumatoid cachexia.

PubMed

Alabarse, Paulo V G; Lora, Priscila S; Silva, Jordana M S; Santo, Rafaela C E; Freitas, Eduarda C; de Oliveira, Mayara S; Almeida, Andrelise S; Immig, Mônica; Teixeira, Vivian O N; Filippin, Lidiane I; Xavier, Ricardo M

2018-03-25

Rheumatoid arthritis is characterized by chronic polyarticular synovitis and presents systemic changes that impact quality of life, such as impaired muscle function, seen in up to 66% of the patients. This can progress to severely debilitating state known as rheumatoid cachexia-without loss of fat mass and body weight-for which there is little consensus in terms of diagnosis or treatment. This study aims to evaluate whether the collagen-induced arthritis (CIA) animal model also develops clinical and functional features characteristic of rheumatoid cachexia. Male DBA1/J mice were randomly divided into 2 groups: healthy animals (CO, n = 11) and CIA animals (n = 13). The clinical score and edema size, animal weight and food intake, free exploratory locomotion, grip strength, and endurance exercise performance were tested 0, 18, 35, 45, 55, and 65 days after disease induction. After euthanasia, several organs, visceral and brown fat, and muscles were dissected and weighed. Muscles were used to assess myofiber diameter. Ankle joint was used to assess arthritis severity by histological score. Statistical analysis were performed using one-way and two-way analyses of variance followed by Tukey's and Bonferroni's test or t-test of Pearson and statistical difference were assumed for a P value under 0.05. The CIA had significantly higher arthritis scores and larger hind paw edema volumes than CO. The CIA had decreased endurance exercise performance total time (fatigue; 23, 22, 24, and 21% at 35, 45, 55, and 65 days, respectively), grip strength (27, 55, 63, 60, and 66% at 25, 35, 45, 55, and 65 days, respectively), free locomotion (43, 57, 59, and 66% at 35, 45, 55, and 65 days, respectively), and tibialis anterior and gastrocnemius muscle weight (25 and 24%, respectively) compared with CO. Sarcoplasmic ratios were also reduced in CIA (TA: 23 and GA: 22% less sarcoplasmic ratio), confirming the atrophy of skeletal muscle mass in these animals than in CO. Myofiber diameter was also reduced 45% in TA and 41% in GA in CIA when compared with the CO. Visceral and brown fat were lighter in CIA (54 and 39%, respectively) than CO group. The CIA model is a valid experimental model for rheumatoid cachexia given that the clinical changes observed were similar to those described in patients with rheumatoid arthritis. © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Glycine administration attenuates skeletal muscle wasting in a mouse model of cancer cachexia.

PubMed

Ham, Daniel J; Murphy, Kate T; Chee, Annabel; Lynch, Gordon S; Koopman, René

2014-06-01

The non-essential amino acid, glycine, is often considered biologically neutral, but some studies indicate that it could be an effective anti-inflammatory agent. Since inflammation is central to the development of cancer cachexia, glycine supplementation represents a simple, safe and promising treatment. We tested the hypothesis that glycine supplementation reduces skeletal muscle inflammation and preserves muscle mass in tumor-bearing mice. To induce cachexia, CD2F1 mice received a subcutaneous injection of PBS (control, n = 12) or C26 tumor cells (n = 32) in accordance with the protocols developed by Murphy et al. [Murphy KT, Chee A, Trieu J, Naim T, Lynch GS. Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia. Dis Models Mech 2012;5(4):533-545.]. Subcutaneous injections of glycine (n = 16) or PBS (n = 16) were administered daily for 21 days and at the conclusion of treatment, selected muscles, tumor and adipose tissue were collected and prepared for Real-Time RT-PCR or western blot analysis. Glycine attenuated the loss of fat and muscle mass, blunted increases in markers of inflammation (F4/80, P = 0.01 & IL-6 mRNA, P = 0.01) and atrophic signaling (MuRF, P = 0.047; atrogin-1, P = 0.04; LC3B, P = 0.06 and; BNIP3, P = 0.10) and tended to attenuate the loss of body mass (P = 0.07), muscle function (P = 0.06), and oxidative stress (GSSG/GSH, P = 0.06 and DHE, P = 0.07) seen in tumor-bearing mice. Preliminary studies that compared the effect of glycine administration with isonitrogenous doses of alanine or citrulline showed that the observed protective effect was specific to glycine. Glycine protects skeletal muscle from cancer-induced wasting and loss of function, reduces the oxidative and inflammatory burden, and reduces the expression of genes associated with muscle protein breakdown in cancer cachexia. Importantly, these effects were glycine specific. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia

PubMed Central

Murphy, Kate T.; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S.

2012-01-01

SUMMARY Cancer cachexia describes the progressive skeletal muscle wasting and weakness that is associated with many cancers. It impairs quality of life and accounts for >20% of all cancer-related deaths. The main outcome that affects quality of life and mortality is loss of skeletal muscle function and so preclinical models should exhibit similar functional impairments in order to maximize translational outcomes. Mice bearing colon-26 (C-26) tumors are commonly used in cancer cachexia studies but few studies have provided comprehensive assessments of physiological and metabolic impairment, especially those factors that impact quality of life. Our aim was to characterize functional impairments in mildly and severely affected cachectic mice, and determine the suitability of these mice as a preclinical model. Metabolic abnormalities are also evident in cachectic patients and we investigated whether C-26-tumor-bearing mice had similar metabolic aberrations. Twelve-week-old CD2F1 mice received a subcutaneous injection of PBS (control) or C-26 tumor cells. After 18–20 days, assessments were made of grip strength, rotarod performance, locomotor activity, whole body metabolism, and contractile properties of tibialis anterior (TA) muscles (in situ) and diaphragm muscle strips (in vitro). Injection of C-26 cells reduced body and muscle mass, and epididymal fat mass. C-26-tumor-bearing mice exhibited lower grip strength and rotarod performance. Locomotor activity was impaired following C-26 injection, with reductions in movement distance, duration and speed compared with controls. TA muscles from C-26-tumor-bearing mice had lower maximum force (−27%) and were more susceptible to fatigue. Maximum specific (normalized) force of diaphragm muscle strips was reduced (−10%) with C-26 injection, and force during fatiguing stimulation was also lower. C-26-tumor-bearing mice had reduced carbohydrate oxidation and increased fat oxidation compared with controls. The range and consistency of functional and metabolic impairments in C-26-tumor-bearing mice confirm their suitability as a preclinical model for cancer cachexia. We recommend the use of these comprehensive functional assessments to maximize the translation of findings to more accurately identify effective treatments for cancer cachexia. PMID:22563056

Mechanisms of Cachexia in Chronic Disease States

PubMed Central

Yoshida, Tadashi; Delafontaine, Patrice

2015-01-01

Sarcopenia and cachexia are muscle wasting syndromes associated with aging and with many chronic diseases such as congestive heart failure (CHF), diabetes, cancer, chronic obstructive pulmonary disease and chronic kidney disease (CKD). While mechanisms are complex these conditions are often accompanied by elevated angiotensin II (Ang II). Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. We found that Ang II infusion in rodents leads to skeletal muscle wasting. Ang II increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A and glucocorticoids, which regulate muscle protein synthesis and degradation. Ang II-induced muscle wasting is caused by alterations in insulin-like growth factor-1 signaling, enhanced muscle protein breakdown via the ubiquitin-proteasome system, and decreased appetite resulting from downregulation of hypothalamic orexigenic neuropeptides such as Npy and orexin. Ang II also inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance via activation of AMPK phosphatase PP2Cα. Furthermore, Ang II inhibits skeletal muscle stem (satellite) cell proliferation, leading to lowered muscle regenerative capacity. Distinct satellite cell angiotensin receptor subtypes have different effects on different stages of differentiation and are critical for regulation of muscle regeneration. These data suggest that the renin-angiotensin system (RAS) plays a critical role in mechanisms underlying cachexia in chronic disease states, and is a promising target for the treatment of muscle atrophy in patients with diseases such as CHF and CKD. PMID:26083652

Mechanisms of Cachexia in Chronic Disease States.

PubMed

Yoshida, Tadashi; Delafontaine, Patrice

2015-10-01

Sarcopenia and cachexia are muscle wasting syndromes associated with aging and with many chronic diseases, such as congestive heart failure (CHF), diabetes, cancer, chronic obstructive pulmonary disease and chronic kidney disease (CKD). While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme inhibitor treatment improves weight loss. It was found that Ang II infusion in rodents leads to skeletal muscle wasting. Ang II increases cytokines and circulating hormones, such as tumor necrosis factor-α, interleukin-6, serum amyloid-A and glucocorticoids, which regulate muscle protein synthesis and degradation. Ang II-induced muscle wasting is caused by alterations in insulin-like growth factor-1 signaling, enhanced muscle protein breakdown via the ubiquitin-proteasome system and decreased appetite resulting from the downregulation of hypothalamic orexigenic neuropeptides, such as Npy and orexin. Ang II also inhibits 5' adenosine monophosphate-activated protein kinase activity and disrupts normal energy balance via the activation of 5' adenosine monophosphate-activated protein kinase phosphatase PP2Cα. Furthermore, Ang II inhibits skeletal muscle stem (satellite) cell proliferation, leading to lowered muscle regenerative capacity. Distinct satellite cell angiotensin receptor subtypes have different effects on different stages of differentiation and are critical for the regulation of muscle regeneration. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states, and it is a promising target for the treatment of muscle atrophy in patients with diseases such as CHF and CKD.

A multifactorial anti‐cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

PubMed Central

Toledo, Míriam; Penna, Fabio; Oliva, Francesc; Luque, Melania; Betancourt, Angelica; Marmonti, Enrica; López‐Soriano, Francisco J.; Argilés, Josep M.

2015-01-01

Abstract Background The effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre‐clinical rodent models, where only the tumour‐induced alterations are taken into account, excluding the co‐presence of anti‐tumour molecules that could worsen the scenario and/or interfere with the treatment. Methods The aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour‐bearing rats (Yoshida AH‐130, a highly cachectic tumour) undergoing chemotherapy (sorafenib). Results Treatment of cachectic tumour‐bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi‐factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour‐bearing animals. The effects of the multi‐factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems. Conclusions The combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre‐clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients. PMID:27066318

A Prospective Randomized Controlled Trial to Study the Impact of a Nutrition-Sensitive Intervention on Adult Women With Cancer Cachexia Undergoing Palliative Care in India

PubMed Central

Kapoor, Neha; Naufahu, Jane; Tewfik, Sundus; Bhatnagar, Sushma; Garg, Rakesh; Tewfik, Ihab

2016-01-01

Purpose. Advanced cancer patients with disease progression develop cachexia. Nevertheless, cancer patients at nutritional risk have shown improved body weight and quality of life with oral nutritional supplements. Method. This was a randomized controlled trial in adult female cancer patients (n = 63) attending palliative clinics, with symptoms of cachexia. Eligible patients were randomly distributed into control (n = 33) and intervention (n = 30) groups. Both groups were provided with nutritional and physical activity counseling, but the intervention group received an additional 100 g of Improved Atta (IAtta) for 6 months daily consumption. This study was designed to assess the efficacy of IAtta (with counseling) in enhancing the health status of cachexic patients. Anthropometric measurements, dietary intake, physical activity level and quality of life parameters were assessed at baseline, after 3 months, and at the end of 6 months. Results. Patients in the control group (n = 15) had significantly decreased body weight (P = .003), mid–upper-arm circumference (P = .002), and body fat (P = .002) by the end of intervention. A trend of body weight gain in the intervention group (n = 17; P = .08) and significant increase of body fat (P = .002) was observed; moreover, patients reported a significant improvement in fatigue (P = .002) and appetite scores (P = .006) under quality-of-life domains at the end of intervention. Conclusions. Embedding a nutrition-sensitive intervention ( IAtta ) within Indian palliative care therapy may improve quality of life and stabilize body weight in cancer cachexia patients. PMID:27252077

Erythropoietin improves cardiac wasting and outcomes in a rat model of liver cancer cachexia.

PubMed

Saitoh, Masakazu; Hatanaka, Michiyoshi; Konishi, Masaaki; Ishida, Junichi; Palus, Sandra; Ebner, Nicole; Döhner, Wolfram; von Haehling, Stephan; Anker, Stefan D; Springer, Jochen

2016-09-01

Erythropoietin administration, which is clinically used in cancer patients with cancer-induced anemia, has also potentially beneficial effects on nonhematopoietic organs. We assessed the effects of erythropoietin on cancer cachexia progression and cardiac wasting compared with placebo using the Yoshida hepatoma model. Wistar rats were divided in a sham group (n=10) and a tumor-bearing group (n=60). The tumor-bearing group was further randomized to placebo (n=28), 500Unit/kg/day (n=16) or 5000Unit/kg/day of erythropoietin (n=16). Body composition was measured using nuclear magnetic resonance spectroscopy, cardiac function using echocardiography, physical activity using infrared monitoring system. Tumor-bearing rats with high dose erythropoietin led to a significant improvement on survival compared with placebo (hazard ratio: 0.43, 95%CI: 0.20-0.92, p=0.030), though low dose erythropoietin did not reach significance (hazard ratio: 0.46, 95%CI: 0.22-1.02, p=0.056). Loss of body weight, wasting of lean mass, fat mass, and reduced physical activity were ameliorated in rats treated with both low and high doses of erythropoietin (p<0.05, all). Moreover, reduced left ventricular mass and left ventricular systolic function were also ameliorated in rats treated with low and high doses of erythropoietin (p<0.05, respectively). Overall, the present data support that cardiac wasting induced by cancer cachexia plays an important role which leads to impaired survival, provided that the erythropoietin could be an effective therapeutic approach for cancer cachexia progression and cardiac wasting. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Transmission of chronic wasting disease identifies a prion strain causing cachexia and heart infection in hamsters.

PubMed

Bessen, Richard A; Robinson, Cameron J; Seelig, Davis M; Watschke, Christopher P; Lowe, Diana; Shearin, Harold; Martinka, Scott; Babcock, Alex M

2011-01-01

Chronic wasting disease (CWD) is an emerging prion disease of free-ranging and captive cervids in North America. In this study we established a rodent model for CWD in Syrian golden hamsters that resemble key features of the disease in cervids including cachexia and infection of cardiac muscle. Following one to three serial passages of CWD from white-tailed deer into transgenic mice expressing the hamster prion protein gene, CWD was subsequently passaged into Syrian golden hamsters. In one passage line there were preclinical changes in locomotor activity and a loss of body mass prior to onset of subtle neurological symptoms around 340 days. The clinical symptoms included a prominent wasting disease, similar to cachexia, with a prolonged duration. Other features of CWD in hamsters that were similar to cervid CWD included the brain distribution of the disease-specific isoform of the prion protein, PrP(Sc), prion infection of the central and peripheral neuroendocrine system, and PrP(Sc) deposition in cardiac muscle. There was also prominent PrP(Sc) deposition in the nasal mucosa on the edge of the olfactory sensory epithelium with the lumen of the nasal airway that could have implications for CWD shedding into nasal secretions and disease transmission. Since the mechanism of wasting disease in prion diseases is unknown this hamster CWD model could provide a means to investigate the physiological basis of cachexia, which we propose is due to a prion-induced endocrinopathy. This prion disease phenotype has not been described in hamsters and we designate it as the 'wasting' or WST strain of hamster CWD.

Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia

PubMed Central

Hall, Derek T.; Ma, Jennifer F.; Di Marco, Sergio; Gallouzi, Imed-Eddine

2011-01-01

Muscle atrophy—also known as muscle wasting—is a debilitating syndrome that slowly develops with age (sarcopenia) or rapidly appears at the late stages of deadly diseases such as cancer, AIDS, and sepsis (cachexia). Despite the prevalence and the drastic detrimental effects of these two syndromes, there are currently no widely used, effective treatment options for those suffering from muscle wasting. In an attempt to identify potential therapeutic targets, the molecular mechanisms of sarcopenia and cachexia have begun to be elucidated. Growing evidence suggests that inflammatory cytokines may play an important role in the pathology of both syndromes. As one of the key cytokines involved in both sarcopenic and cachectic muscle wasting, tumor necrosis factor α (TNFα) and its downstream effectors provide an enticing target for pharmacological intervention. However, to date, no drugs targeting the TNFα signaling pathway have been successful as a remedial option for the treatment of muscle wasting. Thus, there is a need to identify new effectors in this important pathway that might prove to be more efficacious targets. Inducible nitric oxide synthase (iNOS) has recently been shown to be an important mediator of TNFα-induced cachectic muscle loss, and studies suggest that it may also play a role in sarcopenia. In addition, investigations into the mechanism of iNOS-mediated muscle loss have begun to reveal potential therapeutic strategies. In this review, we will highlight the potential for targeting the iNOS/NO pathway in the treatment of muscle loss and discuss its functional relevance in sarcopenia and cachexia. PMID:21832306

Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia

PubMed Central

Yoshida, Tadashi; Tabony, A. Michael; Galvez, Sarah; Mitch, William E.; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

2013-01-01

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. PMID:23769949

Nutritional status and interventions in hospice: physician assessment of cancer patients.

PubMed

Flynn, B; Barrett, M; Sui, J; Halpin, C; Paz, G; Walsh, D

2018-06-07

Cancer cachexia is a multifactorial syndrome characterised by a progressive loss of skeletal muscle mass. It adversely influences quality of life, treatment response and survival. Early identification and multimodal interventions can potentially treat cancer cachexia. However, healthcare professionals demonstrate a lack of understanding and the ability to identify cancer cachexia early. The present study aimed to evaluate the assessment by physicians of nutritional status in cancer patients admitted to hospice. A retrospective medical record review was conducted on all cancer admissions to a specialist in-patient palliative care unit over a 4-month period between October 2016 and January 2017. Charts were reviewed for evidence of documented nutritional assessment by physicians. Data were collected from the referral letter, admission notes, drug kardex and discharge letter. The information extracted included: (i) patient demographics and characteristics; (ii) terms used by physicians to describe nutritional status; (iii) any record of nutritional impact symptoms (NIS) experienced by the patient; and (iv) nutritional interventions prescribed. One hundred and forty admissions were evaluated. Nutritional terminology and NIS were most commonly documented on the admission notes. Only 41% of documents recorded any nutritional term used by physicians to assess nutritional status. Furthermore, 71% of documents recorded at least one NIS experienced by the patient. Fatigue was the most frequent NIS. We identified an inadequate nutritional assessment of cancer patients admitted to hospice. Implementation of a nutritional symptom checklist and nutrition screening tools, along with enhanced physician education and multidisciplinary nutrition care, could improve the identification and management of cancer cachexia in the palliative care setting. © 2018 The British Dietetic Association Ltd.

Patients with established cancer cachexia lack the motivation and self-efficacy to undertake regular structured exercise.

PubMed

Wasley, David; Gale, Nichola; Roberts, Sioned; Backx, Karianne; Nelson, Annmarie; van Deursen, Robert; Byrne, Anthony

2018-02-01

Patients with advanced cancer frequently suffer a decline in activities associated with involuntary loss of weight and muscle mass (cachexia). This can profoundly affect function and quality of life. Although exercise participation can maintain physical and psychological function in patients with cancer, uptake is low in cachectic patients who are underrepresented in exercise studies. To understand how such patients' experiences are associated with exercise participation, we investigated exercise history, self-confidence, and exercise motivations in patients with established cancer cachexia, and relationships between relevant variables. Lung and gastrointestinal cancer outpatients with established cancer cachexia (n = 196) completed a questionnaire exploring exercise history and key constructs of the Theory of Planned Behaviour relating to perceived control, psychological adjustment, and motivational attitudes. Patients reported low physical activity levels, and few undertook regular structured exercise. Exercise self-efficacy was very low with concerns it could worsen symptoms and cause harm. Patients showed poor perceived control and a strong need for approval but received little advice from health care professionals. Preferences were for low intensity activities, on their own, in the home setting. Regression analysis revealed no significant factors related to the independent variables. Frequently employed higher intensity, group exercise models do not address the motivational and behavioural concerns of cachectic cancer patients in this study. Developing exercise interventions which match perceived abilities and skills is required to address challenges of self-efficacy and perceived control identified. Greater engagement of health professionals with this group is required to explore potential benefits of exercise. Copyright © 2017 John Wiley & Sons, Ltd.

High Serum Essential Amino Acids as a Predictor of Skeletal Muscle Depletion in Patients With Cachexia and Advanced Gastrointestinal Cancers.

PubMed

Kitagawa, Moeko; Haji, Seiji; Amagai, Teruyoshi

2017-10-01

In recent years, the number of patients with cancer has increased. These patients are prone to sarcopenia as a result of the decrease in muscle mass and muscle weakness that occur in cancer cachexia. Amino Index Cancer Screening is carried out to evaluate cancer cachexia risk by examining amino acid concentration and analyzing amino acid balance. We conducted a retrospective chart review of consecutive patients with unresectable advanced gastrointestinal cancer (stage IV) receiving chemotherapy treatment (December 2012-September 2015) in an outpatient or in-hospital setting at our institution (N = 46). Data included characteristics, psoas muscle area per computed tomography, and biochemical blood test and serum amino acid profiles. Method 1: Comparison of biomarkers between 2 groups: psoas muscle index change rate (ΔPMI) decrease vs increase. Method 2.1: Correlation between ΔPMI and biomarkers. Method 2.2: Multiple regression of ΔPMI and biomarkers. EAA/TAA ratio (essential amino acids/total amino acids) in the decrease group was significantly higher than that in the increase group. Among all parameters, serum C-reactive protein (CRP), leucine, and isoleucine were negatively related to ΔPMI (correlation coefficients = -0.604, -0.540, -0.518; P = .004, .011, .016, respectively). On multiple regression analysis, serum CRP value was strongly related to ΔPMI ( r 2 = 0.452, β = -0.672, P = .001). Higher serum EAA/TAA ratio and CRP were associated with depletion in psoas muscle area, which led to a diagnosis of sarcopenia, in patients with advanced gastrointestinal cancers. These parameters at baseline could be predictors of cancer cachexia.

Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through Both Tumor Extrinsic and Intrinsic Activities

PubMed Central

Mace, Thomas A.; Farren, Matthew R.; Farris, Alton B.; Young, Gregory S.; Elnaggar, Omar; Che, Zheng; Timmers, Cynthia D.; Rajasekera, Priyani; Maskarinec, Jennifer M.; Bloomston, Mark; Bekaii-Saab, Tanios; Guttridge, Denis C.; Lesinski, Gregory B.

2016-01-01

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating co-morbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses, but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anti-cachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK is at least in part independent of the tumor. Because single agent MEK inhibitors have been limited as a front-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent anti-tumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia. PMID:27811010

Novel targeted therapies for cancer cachexia.

PubMed

Argilés, Josep M; López-Soriano, Francisco Javier; Stemmler, Britta; Busquets, Sílvia

2017-07-27

Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, β-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Aerobic Exercise Modulates the Free Fatty Acids and Inflammatory Response During Obesity and Cancer Cachexia.

PubMed

Teixeira, Alexandre Abilio de Souza; Lira, Fábio Santos; Pimentel, Gustavo D; Oliveira de Souza, Camila; Batatinha, Helena; Biondo, Luana A; Yamashita, Alex S; Junior, Edson A Lima; Neto, José Cesar Rosa

2016-01-01

White adipose tissue (WAT) is no longer considered a tissue whose main function is the storage of TAG. Since the discovery of leptin in 1994, several studies have elucidated the important role of WAT as an endocrine organ, the source of the adipokines. The low-grade inflammation observed in obese and cancer cachexia patients is explained, at least partially, by the exacerbated release of proinflammatory adipokines. Despite of the recent progress in the characterization of the various adipokines and lipokines produced by WAT, little is known about the mechanisms regulating the secretion of these molecules in different physiological and pathological circumstances. Chronic exercise is a nonpharmacological therapy employed in several chronic diseases and shows an anti-inflammatory effect through the regulation of the cytokine network. In this review, we address the potential mechanisms by which the aerobic physical exercise modulate the production and release of inflammatory adipokines, as well as the inflammation-lipolysis axis in WAT, with special focus in the therapeutic role of exercise in obesity-associated insulin resistance and cancer cachexia.

Muscle wasting in cancer: the role of mitochondria.

PubMed

Argilés, Josep M; López-Soriano, Francisco J; Busquets, Silvia

2015-05-01

The aim of the present review is to examine the impact of mitochondrial dysfunction in cancer cachexia. Oxidative pathways are altered in this tissue during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. An alteration of energy balance is the immediate cause of cachexia. Both alterations in energy intake and expenditure are responsible for the wasting syndrome associated with different types of pathological conditions, such as cancer. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss, one of which is mitochondrial dysfunction.

Cancer as a Proinflammatory Environment: Metastasis and Cachexia

PubMed Central

Inácio Pinto, Nelson; Carnier, June; Oyama, Lila M.; Otoch, Jose Pinhata; Alcântara, Paulo Sergio; Tokeshi, Flavio; Nascimento, Claudia M.

2015-01-01

The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. PMID:26508818

Megestrol acetate for treatment of anorexia-cachexia syndrome.

PubMed

Ruiz Garcia, Vicente; López-Briz, Eduardo; Carbonell Sanchis, Rafael; Gonzalvez Perales, Jose Luis; Bort-Marti, Sylvia

2013-03-28

This is an updated version of a previously published review in The Cochrane Library (2005, Issue 2) on 'Megestrol acetate for the treatment of anorexia-cachexia syndrome'. Megestrol acetate (MA) is currently used to improve appetite and to increase weight in cancer-associated anorexia. In 1993, MA was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia or unexplained weight loss in patients with AIDS. The mechanism by which MA increases appetite is unknown and its effectiveness for anorexia and cachexia in neoplastic and AIDS (acquired immunodeficiency syndrome) patients is under investigation. To evaluate the efficacy, effectiveness and safety of MA in palliating anorexia-cachexia syndrome in patients with cancer, AIDS and other underlying pathologies. We sought studies through an extensive search of electronic databases, journals, reference lists, contact with investigators and other search strategies outlined in the methods. The most recent search for this update was carried out in May 2012. Studies were included in the review if they assessed MA compared to placebo or other drug treatments in randomised controlled trials of patients with a clinical diagnosis of anorexia-cachexia syndrome related to cancer, AIDS or any other underlying pathology. Two independent review authors conducted data extraction and evaluated methodological quality. We performed quantitative analyses using appetite and quality of life as a dichotomous variable, and analysed weight gain as continuous and dichotomous variables. We included 35 trials in this update, the same number but not the same trials as in the previous version of the review. The trials comprised 3963 patients for effectiveness and 3180 for safety. Sixteen trials compared MA at different doses with placebo, seven trials compared different doses of MA with other drug treatments and 10 trials compared different doses of MA. Meta-analysis showed a benefit of MA compared with placebo, particularly with regard to appetite improvement and weight gain in cancer, AIDS and other underlying conditions, and lack of benefit in the same patients when MA was compared to other drugs. There was insufficient information to define the optimal dose of MA, but higher doses were more related to weight improvement than lower doses. Quality of life improvement in patients was seen only when comparing MA versus placebo but not other drugs in both subcategories: cancer and AIDS. Oedema, thromboembolic phenomena and deaths were more frequent in the patients treated with MA. More than 40 side effects were studied. This review shows that MA improves appetite and is associated with slight weight gain in cancer, AIDS and in patients with other underlying pathology. Despite the fact that these patients are receiving palliative care they should be informed of the risks involved in taking MA.

Deletion of the gene encoding MyD88 protects from anorexia in a mouse tumor model.

PubMed

Ruud, Johan; Bäckhed, Fredrik; Engblom, David; Blomqvist, Anders

2010-05-01

The anorexia-cachexia syndrome, characterized by a rise in energy expenditure and loss of body weight that paradoxically are associated with loss of appetite and decreased food intake, contributes significantly to the morbidity and mortality in cancer. While the pathophysiology of cancer anorexia-cachexia is poorly understood, evidence indicates that pro-inflammatory cytokines are key mediators of this response. Although inflammation hence is recognized as an important component of cancer anorexia-cachexia, the molecular pathways involved are largely unknown. We addressed this issue in mice carrying a deletion of the gene encoding MyD88, the key intracellular adaptor molecule in Toll-like and interleukin-1 family receptor signaling. Wild-type and MyD88-deficient mice were transplanted subcutaneously with a syngenic methylcholanthrene-induced tumor (MCG 101) and daily food intake and body weight were recorded. Wild-type mice showed progressively reduced food intake from about 5days after tumor transplantation and displayed a slight body weight loss after 10days when the experiment was terminated. In contrast, MyD88-deficient mice did not develop anorexia, and displayed a positive body weight development during the observation period. While the MyD88-deficient mice on average developed somewhat smaller tumors than wild-type mice, this did not explain the absence of anorexia, because anorexia was seen in wild-type mice with similar tumor mass as non-anorexic knock-out mice. These data suggest that MyD88-dependent mechanisms are involved in the metabolic derangement during cancer anorexia-cachexia and that innate immune signaling is important for the development of this syndrome. Copyright 2010 Elsevier Inc. All rights reserved.

A longitudinal study of muscle strength and function in patients with cancer cachexia.

PubMed

Gale, Nichola; Wasley, David; Roberts, Sioned; Backx, Karianne; Nelson, Annemarie; van Deursen, Robert; Byrne, Anthony

2018-06-02

Patients with cancer frequently experience an involuntary loss of weight (in particular loss of muscle mass), defined as cachexia, with profound implications for independence and quality of life. The rate at which such patients' physical performance declines has not been well established. The aim of this study was to determine the change in muscle strength and function over 8 weeks in patients with already established cancer cachexia, to help inform the design and duration of physical activity interventions applicable to this patient group. Patients with thoracic and gastrointestinal cancer and with unintentional weight loss of > 5% in 6 months or BMI < 20 plus 2% weight loss were included. Physical and functional assessments (baseline, 4 weeks, 8 weeks) included isometric quadriceps and hamstring strength, handgrip, standing balance, 10-m walk time and timed up and go. Fifty patients (32 male), mean ± SD age 65 ± 10 years and BMI 24.9 ± 4.3 kg/m 2 , were recruited. Thoracic cancer patients had lower muscle strength and function (p < 0.05). Despite notable attrition, in patients who completed all assessments (8 thoracic and 12 gastrointestinal), there was little change in performance over 8 weeks (p > 0.05). Baseline variables did not differentiate between completers and non-completers (p > 0.05). More than a third of patients with established cancer cachexia in our study were stable over 8 weeks, suggesting a subgroup who may benefit from targeted interventions of reasonable duration. Better understanding the physical performance parameters which characterise and differentiate these patients has important clinical implications for cancer multidisciplinary team practice.

Myostatin is a novel tumoral factor that induces cancer cachexia

PubMed Central

Lokireddy, Sudarsanareddy; Wijesoma, Isuru Wijerupage; Bonala, Sabeera; Wei, Meng; Sze, Siu Kwan; McFarlane, Craig; Kambadur, Ravi; Sharma, Mridula

2012-01-01

Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice. PMID:22621320

Rosiglitazone reduces body wasting and improves survival in a rat model of cancer cachexia.

PubMed

Trobec, Katja; Palus, Sandra; Tschirner, Anika; von Haehling, Stephan; Doehner, Wolfram; Lainscak, Mitja; Anker, Stefan D; Springer, Jochen

2014-09-01

Rosiglitazone improves insulin sensitivity and promotes weight gain in patients with type 2 diabetes mellitus, which could be useful in wasting and cachexia. However, its effects on cardiac function are controversial. The aim of this study was to investigate the effects of rosiglitazone on body wasting, body composition, cardiac function, and survival in a rat model of cancer cachexia. Rats were injected with Yoshida AH-130 hepatoma tumor cells and randomized to receive placebo or rosiglitazone 4 mg/kg daily. Treatment started 1 d after tumor inoculation and the rats were sacrificed 14 d thereafter. Body weight and body composition was measured at baseline and after removal of tumor. Echocardiography was performed at baseline and on day 11. At the end of the study, organs were weighed and the proteasome activity in gastrocnemius muscle was measured. Survival analysis showed a significant benefit from treatment with rosiglitazone (hazard ratio = 0.38, 95% confidence interval: 0.15-0.86). Rosiglitazone reduced average daily weight loss (2.33 g/d rosiglitazone versus 3.93 g/d placebo; P < 0.05) as a result of both fat and lean mass preservation. It decelerated white and brown tissue wasting, but had no effect on skeletal muscle mass and heart mass. However, peptidyl-glutamyl-protein-hydrolysing and trypsin-like activity in gastrocnemius muscle was significantly reduced by rosiglitazone. Finally, it increased left ventricular ejection fraction, fractional shortening, and systolic volume and improved cardiac output in cachectic cancer rats. Rosiglitazone prevents weight loss and improves survival in a rat model of cancer cachexia. It exerts beneficial effects on cardiac function. Copyright © 2014 Elsevier Inc. All rights reserved.

The complexity of treating wasting in ambulatory rehabilitation: Is it starvation, sarcopenia, cachexia or a combination of these conditions?

PubMed

Yaxley, Alison; Miller, Michelle D; Fraser, Robert J; Cobiac, Lynne; Crotty, Maria

2012-01-01

Nutritional status is often impaired in ambulatory rehabilitation patients. Wasting conditions can be classified as starvation, sarcopenia or cachexia but differences between these are not well defined, and misdiagnosis may lead to inappropriate intervention. A secondary analysis of data from 187 ambulatory rehabilitation patients aged >=60 years aimed to identify patients with one or more wasting condition, and investigate the impact on common rehabilitation outcomes. Starvation was defined by fat-free mass index and the Council on Nutrition Appetite Questionnaire score; sarcopenia by fat-free mass index and quadriceps strength; and cachexia by fat-free mass index and serum C-reactive protein. Selected rehabilitation outcomes were compared for those who were, and those who were not, identified as having one or more wasting condition. Of those identified with starvation (n=30), all were also identified as sarcopenic and 20 as cachectic; of those identified as sarcopenic (n=75), 30 had starvation and 37 were cachectic; and of those identified as cachectic (n=37), 20 had starvation and all were sarcopenic. Twenty participants were identified as having all three conditions. Those with starvation had higher level of depression (p=0.003), lower self-rated health (p=0.032), and lower levels of physical function (motor p=0.006; process p=0.004) than those with no evidence of a wasting condition. Those who had sarcopenia had lower physical function (motor p=0.012; process p=0.003) as did those with cachexia (motor p=0.025; process p=0.042). Results suggest problems in operationalising definitions in an ambulatory clinical setting. The overlap identified in this analysis suggests that up to 40% (75/187) of patients could be misidentified and prescribed inappropriate nutritional support.

c9t11-Conjugated linoleic acid-rich oil fails to attenuate wasting in colon-26 tumor-induced late-stage cancer cachexia in male CD2F1 mice.

PubMed

Tian, Min; Kliewer, Kara L; Asp, Michelle L; Stout, Michael B; Belury, Martha A

2011-02-01

Cancer cachexia is characterized by muscle and adipose tissue wasting caused partly by chronic, systemic inflammation. Conjugated linoleic acids (CLAs) are a group of fatty acids with various properties including anti-inflammatory cis9, trans11 (c9t11)-CLA and lipid-mobilizing trans10, cis12 (t10c12)-CLA. The purpose of this study was to test whether dietary supplementation of a c9t11-CLA-rich oil (6:1 c9t11:t10c12) could attenuate wasting of muscle and adipose tissue in colon-26 adenocarcinoma-induced cachexia in mice. Loss of body weight, muscle and adipose tissue mass caused by tumors were not rescued by supplementation with the c9t11-CLA-rich oil. In quadriceps muscle, c9t11-CLA-rich oil exacerbated tumor-induced gene expression of inflammatory markers tumor necrosis factor-α, IL-6 receptor and the E3 ligase MuRF-1 involved in muscle proteolysis. In epididymal adipose tissue, tumor-driven delipidation and atrophy was aggravated by the c9,t11-CLA-rich oil, demonstrated by further reduced adipocyte size and lower adiponectin expression. However, expression of inflammatory cytokines and macrophage markers were not altered by tumors, or CLA supplementation. These data suggest that addition of c9t11-CLA-rich oil (0.6% c9t11, 0.1% t10c12) in diet did not ameliorate wasting in mice with cancer cachexia. Instead, it increased expression of inflammatory markers in the muscle and increased adipose delipidation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs.

PubMed

Barreto, Rafael; Waning, David L; Gao, Hongyu; Liu, Yunlong; Zimmers, Teresa A; Bonetto, Andrea

2016-07-12

Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.

Role of Exosomal MicroRNAs and myomiRs in the Development of Cancer Cachexia-Associated Muscle Wasting.

PubMed

Marinho, Rodolfo; Alcântara, Paulo S M; Ottoch, José P; Seelaender, Marilia

2017-01-01

Cachexia is a complex metabolic syndrome that promotes great weight loss, with marked muscle mass wasting. In the last years, many efforts have been directed to improve the understanding of the mechanisms involved in the disease. This syndrome is present in up to 80% of cancer patients and, despite its clinical relevance, is underdiagnosed. The orchestration of the molecular and biochemical disruptions observed in cachexia is paralleled by inflammation and the communication among the different body compartments, including the tumor and the skeletal muscle, is still not completely described. One of the mechanisms that may be involved in the transduction of the inflammatory signals and the activation of catabolic status in muscle is the participation of exosomes containing microRNAs (miRNAs) and muscle-specific miRNAs (myomiRs). Exosomes are nanovesicles, measuring from 30 to 100 µm, and able to carry miRNAs in the circulation, promoting cell-cell and tissue-tissue communication in an autocrine, paracrine, and endocrine manner. miRNAs transported in exosomes are preserved from degradation, while these nanoparticles deliver the cargo to specific cell targets, making communication more efficient. Several miRNAs are known to modulate inflammatory pathways, to induce metastasis, to mediate cancer aggressiveness and even to participate in the regulation of protein synthesis and degradation pathways in the skeletal muscle. The aim of this mini-review is to describe the present knowledge about the role of exosomal miRNAs and myomiRs in the induction of muscle mass wasting in cancer cachexia state and to explain which transcription factors, proteins, and pathways are regulated by these molecules.

Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and β-2 agonist.

PubMed

Toledo, Míriam; Busquets, Sílvia; Penna, Fabio; Zhou, Xiaolan; Marmonti, Enrica; Betancourt, Angelica; Massa, David; López-Soriano, Francisco J; Han, H Q; Argilés, Josep M

2016-04-15

Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer. © 2015 UICC.

Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.

PubMed

Yoshida, Tadashi; Tabony, A Michael; Galvez, Sarah; Mitch, William E; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

2013-10-01

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5' AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and -Intrinsic Activities.

PubMed

Talbert, Erin E; Yang, Jennifer; Mace, Thomas A; Farren, Matthew R; Farris, Alton B; Young, Gregory S; Elnaggar, Omar; Che, Zheng; Timmers, Cynthia D; Rajasekera, Priyani; Maskarinec, Jennifer M; Bloomston, Mark; Bekaii-Saab, Tanios; Guttridge, Denis C; Lesinski, Gregory B

2017-02-01

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK are at least in part independent of the tumor. Because single-agent MEK inhibitors have been limited as a first-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy, MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent antitumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia. Mol Cancer Ther; 16(2); 344-56. ©2016 AACRSee related article by Kobayashi et al., p. 357. ©2016 American Association for Cancer Research.

Pharmacological strategies in lung cancer-induced cachexia: effects on muscle proteolysis, autophagy, structure, and weakness.

PubMed

Chacon-Cabrera, Alba; Fermoselle, Clara; Urtreger, Alejandro J; Mateu-Jimenez, Mercè; Diament, Miriam J; de Kier Joffé, Elisa D Bal; Sandri, Marco; Barreiro, Esther

2014-11-01

Cachexia is a relevant comorbid condition of chronic diseases including cancer. Inflammation, oxidative stress, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) are involved in the pathophysiology of cancer cachexia. Currently available treatment is limited and data demonstrating effectiveness in in vivo models are lacking. Our objectives were to explore in respiratory and limb muscles of lung cancer (LC) cachectic mice whether proteasome, NF-κB, and MAPK inhibitors improve muscle mass and function loss through several molecular mechanisms. Body and muscle weights, limb muscle force, protein degradation and the ubiquitin-proteasome system, signaling pathways, oxidative stress and inflammation, autophagy, contractile and functional proteins, myostatin and myogenin, and muscle structure were evaluated in the diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing cachectic mice (BALB/c), with and without concomitant treatment with NF-κB (sulfasalazine), MAPK (U0126), and proteasome (bortezomib) inhibitors. Compared to control animals, in both respiratory and limb muscles of LC cachectic mice: muscle proteolysis, ubiquitinated proteins, autophagy, myostatin, protein oxidation, FoxO-1, NF-κB and MAPK signaling pathways, and muscle abnormalities were increased, while myosin, creatine kinase, myogenin, and slow- and fast-twitch muscle fiber size were decreased. Pharmacological inhibition of NF-κB and MAPK, but not the proteasome system, induced in cancer cachectic animals, a substantial restoration of muscle mass and force through a decrease in muscle protein oxidation and catabolism, myostatin, and autophagy, together with a greater content of myogenin, and contractile and functional proteins. Attenuation of MAPK and NF-κB signaling pathway effects on muscles is beneficial in cancer-induced cachexia. © 2014 Wiley Periodicals, Inc.

Altered mitochondrial quality control signaling in muscle of old gastric cancer patients with cachexia.

PubMed

Marzetti, Emanuele; Lorenzi, Maria; Landi, Francesco; Picca, Anna; Rosa, Fausto; Tanganelli, Fabiana; Galli, Marco; Doglietto, Giovanni Battista; Pacelli, Fabio; Cesari, Matteo; Bernabei, Roberto; Calvani, Riccardo; Bossola, Maurizio

2017-01-01

Mitochondrial dysfunction is involved in the loss of muscle featuring both aging and cancer cachexia (CC). Whether mitochondrial quality control (MQC) is altered in skeletal myocytes of old patients with CC is unclear. The present investigation therefore sought to preliminarily characterize MQC pathways in muscle of old gastric cancer patients with cachexia. The study followed a case-control cross-sectional design. Intraoperative biopsies of the rectus abdominis muscle were obtained from 18 patients with gastric adenocarcinoma (nine with CC and nine non-cachectic) and nine controls, and assayed for the expression of a set of MQC mediators. The mitofusin 2 expression was reduced in cancer patients compared with controls, independent of CC. Fission protein 1 was instead up-regulated in CC patients relative to the other groups. The mitophagy regulators PTEN-induced putative kinase 1 and Parkin were both down-regulated in cancer patients compared with controls. The ratio between the protein content of the lipidated and non-lipidated forms of microtubule-associated protein 1 light chain 3B was lower in CC patients relative to controls and non-cachectic cancer patients. Finally, the expression of autophagy-associated protein 7, lysosome-associated membrane protein 2, peroxisome proliferator-activated receptor-γ coactivator-1α, and mitochondrial transcription factor A was unvarying among groups. Collectively, our findings indicate that, in old patients with gastric cancer, cachexia is associated with derangements of the muscular MQC axis at several checkpoints: mitochondrial dynamics, mitochondrial tagging for disposal, and mitophagy signaling. Further investigations are needed to corroborate these preliminary findings and determine whether MQC pathways may become target for future interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

The mitochondrial metabolic reprogramming agent trimetazidine as an ‘exercise mimetic’ in cachectic C26‐bearing mice

PubMed Central

Molinari, Francesca; Pin, Fabrizio; Gorini, Stefania; Chiandotto, Sergio; Pontecorvo, Laura; Penna, Fabio; Rizzuto, Emanuele; Pisu, Simona; Musarò, Antonio; Costelli, Paola

2017-01-01

Abstract Background Cancer cachexia is characterized by muscle depletion and exercise intolerance caused by an imbalance between protein synthesis and degradation and by impaired myogenesis. Myofibre metabolic efficiency is crucial so as to assure optimal muscle function. Some drugs are able to reprogram cell metabolism and, in some cases, to enhance metabolic efficiency. Based on these premises, we chose to investigate the ability of the metabolic modulator trimetazidine (TMZ) to counteract skeletal muscle dysfunctions and wasting occurring in cancer cachexia. Methods For this purpose, we used mice bearing the C26 colon carcinoma as a model of cancer cachexia. Mice received 5 mg/kg TMZ (i.p.) once a day for 12 consecutive days. A forelimb grip strength test was performed and tibialis anterior, and gastrocnemius muscles were excised for analysis. Ex vivo measurement of skeletal muscle contractile properties was also performed. Results Our data showed that TMZ induces some effects typically achieved through exercise, among which is grip strength increase, an enhanced fast‐to slow myofibre phenotype shift, reduced glycaemia, PGC1α up‐regulation, oxidative metabolism, and mitochondrial biogenesis. TMZ also partially restores the myofibre cross‐sectional area in C26‐bearing mice, while modulation of autophagy and apoptosis were excluded as mediators of TMZ effects. Conclusions In conclusion, our data show that TMZ acts like an ‘exercise mimetic’ and is able to enhance some mechanisms of adaptation to stress in cancer cachexia. This makes the modulation of the metabolism, and in particular TMZ, a suitable candidate for a therapeutic rehabilitative protocol design, particularly considering that TMZ has already been approved for clinical use. PMID:29130633

Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia.

PubMed

Biolo, Gianni; Cederholm, Tommy; Muscaritoli, Maurizio

2014-10-01

Skeletal muscle is the most abundant body tissue accounting for many physiological functions. However, muscle mass and functions are not routinely assessed. Sarcopenia is defined as skeletal muscle loss and dysfunction in aging and chronic diseases. Inactivity, inflammation, age-related factors, anorexia and unbalanced nutrition affect changes in skeletal muscle. Mechanisms are difficult to distinguish in individual subjects due to the multifactorial character of the condition. Sarcopenia includes both muscle loss and dysfunction which induce contractile impairment and metabolic and endocrine abnormalities, affecting whole-body metabolism and immune/inflammatory response. There are different metabolic trajectories for muscle loss versus fat changes in aging and chronic diseases. Appetite regulation and physical activity affect energy balance and changes in body fat mass. Appetite regulation by inflammatory mediators is poorly understood. In some patients, inflammation induces anorexia and fat loss in combination with sarcopenia. In others, appetite is maintained, despite activation of systemic inflammation, leading to sarcopenia with normal or increased BMI. Inactivity contributes to sarcopenia and increased fat tissue in aging and diseases. At the end of the metabolic trajectories, cachexia and sarcopenic obesity are paradigms of the two patient categories. Pre-cachexia and cachexia are observed in patients with cancer, chronic heart failure or liver cirrhosis. Sarcopenic obesity and sarcopenia with normal/increased BMI are observed in rheumatoid arthritis, breast cancer patients with adjuvant chemotherapy and in most of patients with COPD or chronic kidney disease. In these conditions, sarcopenia is a powerful prognostic factor for morbidity and mortality, independent of BMI. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma*

PubMed Central

Muqaku, Besnik; Eisinger, Martin; Meier, Samuel M.; Tahir, Ammar; Pukrop, Tobias; Haferkamp, Sebastian; Slany, Astrid; Reichle, Albrecht

2017-01-01

Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified as important source of serum protein and lipid alterations in late stage melanoma patients. As a result, the proposed model describes the crosstalk between lipolysis of fat tissue and muscle wasting mediated by oxidative stress, resulting in the metabolic deregulations characteristic for cachexia. PMID:27879288

Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs

PubMed Central

Barreto, Rafael; Waning, David L.; Gao, Hongyu; Liu, Yunlong; Zimmers, Teresa A.; Bonetto, Andrea

2016-01-01

Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy. PMID:27259276

Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia.

PubMed

Sun, Rulin; Zhang, Santao; Hu, Wenjun; Lu, Xing; Lou, Ning; Yang, Zhende; Chen, Shaoyong; Zhang, Xiaoping; Yang, Hongmei

2016-07-01

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. Copyright © 2016 the American Physiological Society.

The role of adipose tissue in cancer-associated cachexia.

PubMed

Vaitkus, Janina A; Celi, Francesco S

2017-03-01

Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype - "beige" or "brite" adipose tissue - in a process referred to as "browning." While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots - white, brown, and beige - to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials.

Role of PARP activity in lung cancer-induced cachexia: Effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype.

PubMed

Chacon-Cabrera, Alba; Mateu-Jimenez, Mercè; Langohr, Klaus; Fermoselle, Clara; García-Arumí, Elena; Andreu, Antoni L; Yelamos, Jose; Barreiro, Esther

2017-12-01

Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1 -/- ) and Parp-2 -/- mice. In diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing mice (wild type, Parp-1 -/- , and Parp-2 -/- ), PARP activity (ADP-ribose polymers, pADPr), redox balance, muscle fiber phenotype, apoptotic nuclei, tyrosine release, protein ubiquitination, muscle-specific E3 ligases, NF-κB signaling pathway, markers of muscle anabolism (Akt, mTOR, p70S6K, and mitochondrial DNA) were evaluated along with body and muscle weights, and limb muscle force. Compared to wild type cachectic animals, in both respiratory and limb muscles of Parp-1 -/- and Parp-2 -/- cachectic mice: cancer induced-muscle wasting characterized by increased PARP activity, protein oxidation, tyrosine release, and ubiquitin-proteasome system (total protein ubiquitination, atrogin-1, and 20S proteasome C8 subunit) were blunted, the reduction in contractile myosin and atrophy of the fibers was attenuated, while no effects were seen in other structural features (inflammatory cells, internal or apoptotic nuclei), and markers of muscle anabolism partly improved. Activation of either PARP-1 or -2 is likely to play a role in muscle protein catabolism via oxidative stress, NF-κB signaling, and enhanced proteasomal degradation in cancer-induced cachexia. Therapeutic potential of PARP activity inhibition deserves attention. © 2017 Wiley Periodicals, Inc.

Association of cardiac cachexia and atrial fibrillation in heart failure patients.

PubMed

Arámbula-Garza, Estefanía; Castillo-Martínez, Lilia; González-Islas, Dulce; Orea-Tejeda, Arturo; Santellano-Juárez, Brenda; Keirns-Davies, Candace; Peláez-Hernández, Viridiana; Sánchez-Santillán, Rocío; Pineda-Juárez, Juan; Cintora-Martínez, Carlos; Pablo-Santiago, Ruth

2016-11-15

Cachexia is a common complication in patients with advanced heart failure (HF) associated with inflammatory response activation. Atrial fibrillation (AF) is the most frequent arrhythmia (26%), probably both exacerbate the cardiac cachexia (CC). Evaluate the association of cardiac cachexia and atrial fibrillation in heart failure patients. In a case control study, CC was diagnosed by electrical bioimpedance with vectorial analysis (BIVA). Subjects with congenital heart disease, cancer, HIV, drug use and other causes than HF were excluded. Of the 359 subjects analyzed (men: 52.9%) median age 65years (55-74). Those with CC were older [72 (61-67)] vs. without [62 (52-70) years old, p<0.01]. During follow-up 47.8% of subjects developed CC and 17.27% AF, this was significantly more frequent in cachectic patients CC (23% vs 12.11%, OR: 2.17, 95% CI: 1.19-4.01, p=0.006). Subjects, with AF had lower left ventricular ejection fraction (25.49±12.96 vs. 32.01±15.02, p=0.08), lower posterior wall thickness (10.03±2.12 vs. 11.00±2.47, p=0.007), larger diameter of the left atrium (49.87±9.84 vs. 42.66±7.56, p<0.001), and a higher prevalence of CC (85.42% vs. 69.77%, p=0.028). The 50.58% of was in NYHA class I. In NYHA III, 22.95% were in AF vs. 12.10% with not AF (p=0.027). The frequent coexistence of CC and AF as HF complications indicate greater severity of HF, regardless of its type of HF. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome.

PubMed

Reuter, Stephanie E; Martin, Jennifer H

2016-07-01

Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population.

Elevated myocardial enzymes and natriuretic peptides in anorexia nervosa: prototypic condition for the pathophysiology of cachexia?

PubMed

Zastrow, Arne; Wolf, Johanna; Giannitsis, Evangelos; Katus, Hugo; Herzog, Wolfgang; Friederich, Hans-Christoph; Mussler, Christina

2011-01-01

We report on a patient suffering from chronic anorexia nervosa who in the course of treatment showed elevated high-sensitive troponin T, creatine kinase and most markedly N-terminal pro-brain natriuretic peptide (NT-proBNP). Elevated enzymes improved significantly throughout the course of treatment without cardiac specific medication but exceeded the normal range for weeks. Abnormally high myocardial enzymes and NT-proBNP in cachectic anorectic patients might resemble conditions of cardiac cachexia. A review of the available literature is provided. Further research is required to explain the pathophysiological meaning of the abnormal laboratory findings. Copyright © 2011 S. Karger AG, Basel.

[Cancer and Malnutrition].

PubMed

Tsuzuki, Norimasa; Higashiguchi, Takashi; Ito, Akihiro; Ohara, Hiroshi; Futamura, Akihiko

2015-07-01

A Japanese proverb says that a balanced diet leads to a healthy body. However, the relation between healthy life and nutrition has not been established precisely and quantitatively. Cancer cachexia, which is malnutrition in cancer patients, has been studied extensively. Appropriate nutrition support can prevent the progression of malnutrition in cancer patients and advance the tolerance for anticancer therapy. In refractory cachexia (terminally cancer patients), we will judge the necessity of reduction of nutrition support, what it is called "gear-change", because the support is burden for the body. It is important to restrict the quantity of nutrition and to give medical treatment to retain bodily function in these patients.

Anorexia of ageing: a key component in the pathogenesis of both sarcopenia and cachexia

PubMed Central

2017-01-01

Abstract The anorexia of aging was first recognized as a physiological syndrome 30 years ago. Its major causes are an alteration in fundal compliance with an increase in antral stretch and enhanced cholecystokinin activity leading to increased satiation.This anorexia leads to weight loss in aging persons and is one of the component causes of the aging related sarcopenia. This physiological anorexia also increases the risk of more severe anorexia when an older person has an increase in inflammatory cytokines such as occurs when they have an illness. This results in an increase in the anorexia due to cachexia in older persons. PMID:28452130

Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome: design, development, and potential place in therapy.

PubMed

Graf, Solomon A; Garcia, Jose M

2017-01-01

Cancer anorexia-cachexia syndrome (CACS) is a complex and largely untreatable paraneoplastic complication common in advanced cancer. It is associated with profoundly deleterious effects on quality of life and survival. Since its discovery over a decade ago, anamorelin hydrochloride (anamorelin), a mimetic of the growth hormone secretagogue ghrelin, has shown considerable promise in ameliorating components of CACS when administered to patients with advanced cancer, including loss of lean body mass and reversal of anorexia. This review summarizes the development of anamorelin and its safety and efficacy in clinical investigations. The potential future role of anamorelin in treating CACS is also discussed.

Muscle wasting and cachexia in heart failure: mechanisms and therapies.

PubMed

von Haehling, Stephan; Ebner, Nicole; Dos Santos, Marcelo R; Springer, Jochen; Anker, Stefan D

2017-06-01

Body wasting is a serious complication that affects a large proportion of patients with heart failure. Muscle wasting, also known as sarcopenia, is the loss of muscle mass and strength, whereas cachexia describes loss of weight. After reaching guideline-recommended doses of heart failure therapies, the most promising approach to treating body wasting seems to be combined therapy that includes exercise, nutritional counselling, and drug treatment. Nutritional considerations include avoiding excessive salt and fluid intake, and replenishment of deficiencies in trace elements. Administration of omega-3 polyunsaturated fatty acids is beneficial in selected patients. High-calorific nutritional supplements can also be useful. The prescription of aerobic exercise training that provokes mild or moderate breathlessness has good scientific support. Drugs with potential benefit in the treatment of body wasting that have been tested in clinical studies in patients with heart failure include testosterone, ghrelin, recombinant human growth hormone, essential amino acids, and β 2 -adrenergic receptor agonists. In this Review, we summarize the pathophysiological mechanisms of muscle wasting and cachexia in heart failure, and highlight the potential treatment strategies. We aim to provide clinicians with the relevant information on body wasting to understand and treat these conditions in patients with heart failure.

Serum sialyltransferase and liver catalase activity in cachectic nude mice bearing a human malignant melanoma.

PubMed

Kondo, Y; Sato, K; Ueyama, Y; Ohsawa, N

1981-07-01

Cachexia is rare in nude mice bearing human malignant tumors even when the transplanted tumors become as large as the body size of the host. In our series on heterotransplantation of a variety of human malignant tumors into nude mice, a malignant melanoma (SEKI) was found to induce severe body weight loss in the host at the early stage of transplantation. There was no electrolyte disturbance, hyper- or hypoadrenocorticism, hyperthyroidism, or destruction of cells of vital organs to account for the weight loss. Moreover, no evidence was obtained for concomitant infection with bacteria, Mycoplasma or fungi. These cachectic mice revealed remarkably increased levels of serum sialyltransferase and decreased liver catalase activity. The removal of tumor tissues from these mice resulted in prompt recovery of body weight, serum sialyltransferase, and liver catalase activity within 1 to 2 weeks. On the basis of the results obtained, the SEKI melanoma was thought to have produced a pathophysiological state in host nude mice which was very similar to that of cachexia in cancer patients. Nude mice bearing transplants of SEKI melanoma may provide a useful system for the study of cancer cachexia in humans.

Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model.

PubMed

Palus, Sandra; Schur, Robert; Akashi, Yoshihiro J; Bockmeyer, Barbara; Datta, Rakesh; Halem, Heather; Dong, Jesse; Culler, Michael D; Adams, Volker; Anker, Stefan D; Springer, Jochen

2011-01-01

Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10-16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output. Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a rat model of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics. Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p<0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9±0.07 for BIM-28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76±0.07 for BIM-28131, 0.68±0.12 for BIM-28125, and 0.48±0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment. Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM-131) being the most effective compound.

ROMANA 3: a phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia.

PubMed

Currow, D; Temel, J S; Abernethy, A; Milanowski, J; Friend, J; Fearon, K C

2017-08-01

Cancer anorexia-cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities. ROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0-12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12-24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12-24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0-24 weeks). Of the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment-emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia-cachexia symptoms observed in the original trials were consistently maintained over 12-24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P < 0.0001) and improved anorexia-cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group. During the 12-24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0-24w treatment period, body weight and symptom burden were improved with anamorelin. ROMANA 1 (NCT01387269), ROMANA 2 (NCT01387282), and ROMANA 3 (NCT01395914). © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

A Ketogenic Formula Prevents Tumor Progression and Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice

PubMed Central

Tonouchi, Hidekazu; Sasayama, Akina

2018-01-01

Low-carbohydrate, high-fat diets (ketogenic diets) might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF) is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR), tumor-bearing (TB), and ketogenic formula (KF) groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia. PMID:29443873

Nutritional support for malnourished patients with cancer.

PubMed

Baldwin, Christine

2011-03-01

Cancer and its treatments frequently have a negative impact on the weight and nutritional status of patients. Weight loss is associated with reduced survival and poorer outcomes of treatment but is not well characterized and frequently confused with cachexia, which may complicate the interpretation of studies of nutritional support. The aims of this review were to examine the impact of cancer on nutritional status and to review the role of simple oral nutritional interventions and novel agents. The terms weight loss, malnutrition and cachexia refer to different entities and new definitions have recently been proposed that take account of the role of the underlying inflammatory processes. Oral nutritional interventions are widely recommended for malnourished cancer patients, but the evidence for their benefits to clinical, nutritional and patient-centred outcomes is limited. Meta-analysis has highlighted the variability in response to simple nutritional interventions of different cohorts of cancer patients and suggested that improvements in nutritional endpoints and aspects of quality of life may be achieved in some patients. Recent research has largely focused on treatments aiming to modulate the inflammatory processes associated with cachexia, but to date has not identified a single treatment with clear efficacy. Studies characterizing the potential for nutritional support in combination with anti-inflammatory agents in defined patient groups are defined to advance the evidence base in this area.

Beneficial immune modulatory effects of a specific nutritional combination in a murine model for cancer cachexia

PubMed Central

Faber, J; Vos, P; Kegler, D; van Norren, K; Argilés, J M; Laviano, A; Garssen, J; van Helvoort, A

2008-01-01

The majority of patients with advanced cancer are recognised by impaired immune competence influenced by several factors, including the type and stage of the tumour and the presence of cachexia. Recently, a specific nutritional combination containing fish oil, specific oligosaccharide mixture, high protein content and leucine has been developed aimed to support the immune system of cancer patients in order to reduce the frequency and severity of (infectious) complications. In a recently modified animal model cachexia is induced by inoculation of C26 tumour cells in mice. In a pre-cachectic state, no effect was observed on contact hypersensitivity, a validated in vivo method to measure Th1-mediated immune function, after adding the individual nutritional ingredients to the diet of tumour-bearing mice. However, the complete mixture resulted in significantly improved Th1 immunity. Moreover, in a cachectic state, the complete mixture reduced plasma levels of pro-inflammatory cytokines and beneficially affected ex vivo immune function. Accordingly, the combination of the nutritional ingredients is required to obtain a synergistic effect, leading to a reduced inflammatory state and improved immune competence. From this, it can be concluded that the specific nutritional combination has potential as immune-supporting nutritional intervention to reduce the risk of (infectious) complications in cancer patients. PMID:19018259

Molecular mechanisms and treatment targets of muscle wasting and cachexia in heart failure: an overview.

PubMed

Ebner, Nicole; Elsner, Sebastian; Springer, Jochen; von Haehling, Stephan

2014-03-01

This article aims to describe molecular pathways involved in the development of muscle wasting and cachexia, diagnostic possibilities, and potential treatments that have seen clinical testing in recent heart failure trials. An understanding of the specific changes that cause an anabolic-catabolic imbalance is an essential first step in the development of pharmaceutical intervention strategies aimed at blocking muscle wasting. Skeletal muscle mass and muscle strength are the most important determinants of exercise capacity in patients with heart failure. In contrast to cachexia, muscle wasting is not usually associated with weight loss, implying the need for sophisticated assessment methods to correctly diagnose muscle wasting, for example the use of computed tomography, magnetic resonance imaging, or dual energy X-ray absorptiometry. Simpler techniques such as handgrip strength, exercise testing, or even a biomarker may help in determining patients with a high pre-test probability of muscle wasting. Despite intensive research efforts in the field of muscle wasting during the last couple of decades, no effective treatment of muscle wasting currently exists other than exercise training. This situation remains true even though study of the molecular pathways involved in muscle wasting suggests many therapeutic targets. Easily applicable diagnostic tools may help to identify patients at risk of developing muscle wasting.

NF-κB–mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia

PubMed Central

He, Wei A.; Berardi, Emanuele; Cardillo, Veronica M.; Acharyya, Swarnali; Aulino, Paola; Thomas-Ahner, Jennifer; Wang, Jingxin; Bloomston, Mark; Muscarella, Peter; Nau, Peter; Shah, Nilay; Butchbach, Matthew E.R.; Ladner, Katherine; Adamo, Sergio; Rudnicki, Michael A.; Keller, Charles; Coletti, Dario; Montanaro, Federica; Guttridge, Denis C.

2013-01-01

Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7 was induced by serum factors from cachectic mice and patients, in an NF-κB–dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer. PMID:24084740

Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia

PubMed Central

Roberts, Edward W.; Deonarine, Andrew; Jones, James O.; Denton, Alice E.; Feig, Christine; Lyons, Scott K.; Espeli, Marion; Kraman, Matthew; McKenna, Brendan; Wells, Richard J.B.; Zhao, Qi; Caballero, Otavia L.; Larder, Rachel; Coll, Anthony P.; O’Rahilly, Stephen; Brindle, Kevin M.; Teichmann, Sarah A.; Tuveson, David A.

2013-01-01

Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP+ cells, we find that they reside in most tissues of the adult mouse. FAP+ cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP+ cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP+ stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia. PMID:23712428

Pancreatic cancer-induced cachexia is Jak2-dependent in mice.

PubMed

Gilabert, Marine; Calvo, Ezequiel; Airoldi, Ana; Hamidi, Tewfik; Moutardier, Vincent; Turrini, Olivier; Iovanna, Juan

2014-10-01

Cancer cachexia syndrome is observed in 80% of patients with advanced-stage cancer, and it is one of the most frequent causes of death. Severe wasting accounts for more than 80% in patients with advanced pancreatic cancer. Here we wanted to define, by using an microarray approach and the Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) mice model, the pathways involved in muscle, liver, and white adipose tissue wasting. These mice, which develop systematically pancreatic cancer, successfully reproduced many human symptoms afflicted with this disease, and particularly cachexia. Using the profiling analysis of pancreatic cancer-dependent cachectic tissues we found that Jak2/Stat3 pathways, p53 and NFkB results activated. Thus, our interest was focused on the Jak2 pathways because it is pharmacologically targetable with low toxicity and FDA approved drugs are available. Therefore, Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) mice were treated with the Jak2 inhibitor AG490 compound daily starting at 7 weeks old and for a period of 3 weeks and animals were sacrificed at 10 weeks old. Body weight for control mice was 27.84 ± 2.14 g, for untreated Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) was 14.97 ± 1.99 g, whereas in animals treated with the AG490 compound the weight loss was significantly less to 24.53 ± 2.04 g. Treatment with AG490 compound was efficient since phosphorylation of Jak2 and circulating interleukin-6 (IL6) levels were significantly reduced in cachectic tissues and in mice respectively. In conclusion, we found that Jak2/Stat3-dependent intracellular pathway plays an essential role since its pharmacological inhibition strongly attenuates cachexia progression in a lethal transgenic pancreatic cancer model. © 2014 Wiley Periodicals, Inc.

MicroRNA expression and protein acetylation pattern in respiratory and limb muscles of Parp-1(-/-) and Parp-2(-/-) mice with lung cancer cachexia.

PubMed

Chacon-Cabrera, Alba; Fermoselle, Clara; Salmela, Ida; Yelamos, Jose; Barreiro, Esther

2015-12-01

Current treatment options for cachexia, which impairs disease prognosis, are limited. Muscle-enriched microRNAs and protein acetylation are involved in muscle wasting including lung cancer (LC) cachexia. Poly(ADP-ribose) polymerases (PARP) are involved in muscle metabolism. We hypothesized that muscle-enriched microRNA, protein hyperacetylation, and expression levels of myogenic transcription factors (MTFs) and downstream targets, muscle loss and function improve in LC cachectic Parp-1(−/−) and Parp-2(−/−) mice. Body and muscle weights, grip strength, muscle phenotype, muscle-enriched microRNAs (miR-1, -133, -206, and -486), protein acetylation, acetylated levels of FoxO1, FoxO3, and PGC-1α, histone deacetylases (HDACs) including SIRT1, MTFs, and downstream targets (α-actin, PGC-1α, and creatine kinase) were evaluated in diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) wild type (WT), Parp-1(−/−) and Parp-2−/− mice. Compared to WT cachectic animals, in both respiratory and limb muscles of Parp-1(−/−) and Parp-2(−/−) cachectic mice: downregulation of muscle-specific microRNAs was counterbalanced especially in gastrocnemius of Parp-1(−/−) mice; increased protein acetylation was attenuated (improvement in HDAC3, SIRT-1, and acetylated FoxO3 levels in both muscles, acetylated FoxO1 levels in the diaphragm); reduced MTFs and creatine kinase levels were mitigated; body and muscle weights, strength, and muscle fiber sizes improved, while tumor weight and growth decreased. These molecular findings may explain the improvements seen in body and muscle weights, limb muscle force and fiber sizes in both Parp-1(−/−) and Parp-2(−/−) cachectic mice. PARP-1 and -2 play a role in cancer-induced cachexia, thus selective pharmacological inhibition of PARP-1 and -2 may be of interest in clinical settings. Copyright © 2015 Elsevier B.V. All rights reserved.

Defining the role of dietary intake in determining weight change in patients with cancer cachexia.

PubMed

Nasrah, R; Kanbalian, M; Van Der Borch, C; Swinton, N; Wing, S; Jagoe, R T

2018-02-01

Weight loss is a cardinal feature of cachexia and is frequently associated with reduced food intake and anorexia. It is still unclear how much reduced food intake contributes to cancer-related weight loss and how effective increasing dietary energy and protein is in combating this weight loss. The relationship between weight change and both diet and change in dietary intake, was examined in patients with advanced stage cancer referred to a multidisciplinary clinic for management of cancer cachexia. A retrospective study of data for each of the first three clinic visits for patients seen between 2009 and 2015. Data on weight change, dietary intake and change in dietary intake were compared. Regression analysis was used to determine independent explanatory factors for weight change, including the impact of appetite level and a marker of systemic inflammation. Of 405 eligible patients, 320 had data on dietary intake available. Dietary intake varied widely at baseline: 26.9% reported very poor diet and only 17% were consuming recommended levels of energy and protein. A highly significant positive correlation was found between dietary energy or protein intake and weight change, both before and after being seen in the clinic. Anorexia was also significantly correlated with weight loss at each clinic visit. However, there was no similar overall correlation between change in dietary intake and change in weight. Many patients with advanced cancer and weight loss are consuming diets that would likely be insufficient to maintain weight even in healthy individuals. Higher consumption of protein and energy correlates with greater weight gain, but it is impossible to predict the response to increased nutritional intake when patients are first assessed. There is a pressing need to improve understanding of factors that modulate metabolic responses to dietary intake in patients with cancer cachexia. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia.

PubMed

Silva, Kleiton Augusto Santos; Dong, Jiangling; Dong, Yanjun; Dong, Yanlan; Schor, Nestor; Tweardy, David J; Zhang, Liping; Mitch, William E

2015-04-24

Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial, and clinically reliable therapies are not available. A trigger of muscle protein loss is the Jak/Stat pathway, and indeed, we found that conditioned medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates Stat3 (p-Stat3) in C2C12 myotubes. We identified two proteolytic pathways that are activated in muscle by p-Stat3; one is activation of caspase-3, and the other is p-Stat3 to myostatin, MAFbx/Atrogin-1, and MuRF-1 via CAAT/enhancer-binding protein δ (C/EBPδ). Using sequential deletions of the caspase-3 promoter and CHIP assays, we determined that Stat3 activation increases caspase-3 expression in C2C12 cells. Caspase-3 expression and proteolytic activity were stimulated by p-Stat3 in muscles of tumor-bearing mice. In mice with cachexia caused by Lewis lung carcinoma or C26 tumors, knock-out of p-Stat3 in muscle or with a small chemical inhibitor of p-Stat3 suppressed muscle mass losses, improved protein synthesis and degradation in muscle, and increased body weight and grip strength. Activation of p-Stat3 stimulates a pathway from C/EBPδ to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBPδ KO decreases the expression of MAFbx/Atrogin-1 and myostatin, while increasing muscle mass and grip strength. In conclusion, cancer stimulates p-Stat3 in muscle, activating protein loss by stimulating caspase-3, myostatin, and the ubiquitin-proteasome system. These results could lead to novel strategies for preventing cancer-induced muscle wasting. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia*

PubMed Central

Silva, Kleiton Augusto Santos; Dong, Jiangling; Dong, Yanjun; Dong, Yanlan; Schor, Nestor; Tweardy, David J.; Zhang, Liping; Mitch, William E.

2015-01-01

Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial, and clinically reliable therapies are not available. A trigger of muscle protein loss is the Jak/Stat pathway, and indeed, we found that conditioned medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates Stat3 (p-Stat3) in C2C12 myotubes. We identified two proteolytic pathways that are activated in muscle by p-Stat3; one is activation of caspase-3, and the other is p-Stat3 to myostatin, MAFbx/Atrogin-1, and MuRF-1 via CAAT/enhancer-binding protein δ (C/EBPδ). Using sequential deletions of the caspase-3 promoter and CHIP assays, we determined that Stat3 activation increases caspase-3 expression in C2C12 cells. Caspase-3 expression and proteolytic activity were stimulated by p-Stat3 in muscles of tumor-bearing mice. In mice with cachexia caused by Lewis lung carcinoma or C26 tumors, knock-out of p-Stat3 in muscle or with a small chemical inhibitor of p-Stat3 suppressed muscle mass losses, improved protein synthesis and degradation in muscle, and increased body weight and grip strength. Activation of p-Stat3 stimulates a pathway from C/EBPδ to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBPδ KO decreases the expression of MAFbx/Atrogin-1 and myostatin, while increasing muscle mass and grip strength. In conclusion, cancer stimulates p-Stat3 in muscle, activating protein loss by stimulating caspase-3, myostatin, and the ubiquitin-proteasome system. These results could lead to novel strategies for preventing cancer-induced muscle wasting. PMID:25787076

Small RNAome profiling from human skeletal muscle: novel miRNAs and their targets associated with cancer cachexia.

PubMed

Narasimhan, Ashok; Ghosh, Sunita; Stretch, Cynthia; Greiner, Russell; Bathe, Oliver F; Baracos, Vickie; Damaraju, Sambasivarao

2017-06-01

MicroRNAs (miRs) are small non-coding RNAs that regulate gene (mRNA) expression. Although the pathological role of miRs have been studied in muscle wasting conditions such as myotonic and muscular dystrophy, their roles in cancer cachexia (CC) are still emerging. The objectives are (i) to profile human skeletal muscle expressed miRs; (ii) to identify differentially expressed (DE) miRs between cachectic and non-cachectic cancer patients; (iii) to identify mRNA targets for the DE miRs to gain mechanistic insights; and (iv) to investigate if miRs show potential prognostic and predictive value. Study subjects were classified based on the international consensus diagnostic criteria for CC. Forty-two cancer patients were included, of which 22 were cachectic cases and 20 were non-cachectic cancer controls. Total RNA isolated from muscle biopsies were subjected to next-generation sequencing. A total of 777 miRs were profiled, and 82 miRs with read counts of ≥5 in 80% of samples were retained for analysis. We identified eight DE miRs (up-regulated, fold change of ≥1.4 at P < 0.05). A total of 191 potential mRNA targets were identified for the DE miRs using previously described human skeletal muscle mRNA expression data (n = 90), and a majority of them were also confirmed in an independent mRNA transcriptome dataset. Ingenuity pathway analysis identified pathways related to myogenesis and inflammation. qRT-PCR analysis of representative miRs showed similar direction of effect (P < 0.05), as observed in next-generation sequencing. The identified miRs also showed prognostic and predictive value. In all, we identified eight novel miRs associated with CC. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Health-Related Quality of Life, Cachexia and Overall Survival After Major Upper Abdominal Surgery: A Prospective Cohort Study.

PubMed

Aahlin, E K; Tranø, G; Johns, N; Horn, A; Søreide, J A; Fearon, K C; Revhaug, A; Lassen, K

2017-03-01

Major upper abdominal surgery is often associated with reduced health-related quality of life and reduced survival. Patients with upper abdominal malignancies often suffer from cachexia, represented by preoperative weight loss and sarcopenia (low skeletal muscle mass) and this might affect both health-related quality of life and survival. We aimed to investigate how health-related quality of life is affected by cachexia and how health-related quality of life relates to long-term survival after major upper abdominal surgery. From 2001 to 2006, 447 patients were included in a Norwegian multicenter randomized controlled trial in major upper abdominal surgery. In this study, six years later, these patients were analyzed as a single prospective cohort and survival data were retrieved from the National Population Registry. Cachexia was derived from patient-reported preoperative weight loss and sarcopenia as assessed from computed tomography images taken within three months preoperatively. In the original trial, self-reported health-related quality of life was assessed preoperatively at trial enrollment and eight weeks postoperatively with the health-related quality of life questionnaire Short Form 36. A majority of the patients experienced improved mental health-related quality of life and, to a lesser extent, deteriorated physical health-related quality of life following surgery. There was a significant association between preoperative weight loss and reduced physical health-related quality of life. No association between sarcopenia and health-related quality of life was observed. Overall survival was significantly associated with physical health-related quality of life both pre- and postoperatively, and with postoperative mental health-related quality of life. The association between health-related quality of life and survival was particularly strong for postoperative physical health-related quality of life. Postoperative physical health-related quality of life strongly correlates with overall survival after major upper abdominal surgery.

Regulation of pathogenicity in hop stunt viroid-related group II citrus viroids.

PubMed

Reanwarakorn, K; Semancik, J S

1998-12-01

Nucleotide sequences were determined for two hop stunt viroid-related Group II citrus viroids characterized as either a cachexia disease non-pathogenic variant (CVd-IIa) or a pathogenic variant (CVd-IIb). Sequence identity between the two variants of 95.6% indicated a conserved genome with the principal region of nucleotide difference clustered in the variable (V) domain. Full-length viroid RT-PCR cDNA products were cloned into plasmid SP72. Viroid cDNA clones as well as derived RNA transcripts were transmissible to citron (Citrus medica L.) and Luffa aegyptiaca Mill. To determine the locus of cachexia pathogenicity as well as symptom expression in Luffa, chimeric viroid cDNA clones were constructed from segments of either the left terminal, pathogenic and conserved (T1-P-C) domains or the conserved, variable and right terminal (C-V-T2) domains of CVd-IIa or CVd-IIb in reciprocal exchanges. Symptoms induced by the various chimeric constructs on the two bioassay hosts reflected the differential response observed with CVd-IIa and -IIb. Constructs with the C-V-T2 domains region from clone-IIa induced severe symptoms on Luffa typical of CVd-IIa, but were non-symptomatic on mandarin as a bioassay host for the cachexia disease. Constructs with the same region (C-V-T2) from the clone-IIb genome induced only mild symptoms on Luffa, but produced a severe reaction on mandarin, as observed for CVd-IIb. Specific site-directed mutations were introduced into the V domain of the CVd-IIa clone to construct viroid cDNA clones with either partial or complete conversions to the CVd-IIb sequence. With the introduction of six site-specific changes into the V domain of the clone-IIa genome, cachexia pathogenicity was acquired as well as a moderation of severe symptoms on Luffa.

Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15.

PubMed

Borner, Tito; Arnold, Myrtha; Ruud, Johan; Breit, Samuel N; Langhans, Wolfgang; Lutz, Thomas A; Blomqvist, Anders; Riediger, Thomas

2017-06-01

The cancer-anorexia-cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour-derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour-derived macrophage inhibitory cytokine-1 (MIC-1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC-1 in mice. Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC-1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response. In tumour-bearing sham-operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer-induced anorexia or body weight loss. Tumour-bearing rats had substantially increased MIC-1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake. These findings demonstrate the importance of the AP in the mediation of cancer-dependent anorexia and body weight loss and support a pathological role of MIC-1 as a tumour-derived factor mediating CACS, possibly via an AP-dependent action. © 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium

PubMed Central

Wang, Hang; Li, Tsung-Lin; Hsia, Simon; Su, I-Li; Chan, Yi-Lin; Wu, Chang-Jer

2015-01-01

Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, remained unclear. In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy. PMID:25797259

The "parallel pathway": a novel nutritional and metabolic approach to cancer patients.

PubMed

Muscaritoli, Maurizio; Molfino, Alessio; Gioia, Gianfranco; Laviano, Alessandro; Rossi Fanelli, Filippo

2011-04-01

Cancer-associated malnutrition results from a deadly combination of anorexia, which leads to reduced food intake, and derangements of host metabolism inducing body weight loss, and hindering its reversal with nutrient supplementation. Cancer patients often experience both anorexia and weight loss, contributing to the onset of the clinical feature named as anorexia-cachexia syndrome. This condition has a negative impact upon patients' nutritional status. The pathogenesis of the anorexia-cachexia syndrome is multifactorial, and is related to: tumour-derived factors, host-derived factors inducing metabolic derangements, and side effects of anticancer therapies. In addition, the lack of awareness of cancer patients' nutritional issues and status by many oncologists, frequently results in progressive weight loss going undiagnosed until it becomes severe. The critical involvement of host inflammatory response in the development of weight loss, and, in particular, lean body mass depletion, limits the response to the provision of standard nutrition support. A novel nutritional and metabolic approach, named "parallel pathway", has been devised that may help maintain or improve nutritional status, and prevent or delay the onset of cancer cachexia. Such an approach may improve tolerance to aggressive anticancer therapies, and ameliorate the functional capacity and quality of life even in advanced disease stages. The "parallel pathway" implies a multiprofessional and multimodal approach aimed at ensuring early, appropriate and continuous nutritional and metabolic support to cancer patients in any phase of their cancer journey.

Prevention of liver cancer cachexia-induced cardiac wasting and heart failure.

PubMed

Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J S; Beadle, John; Argiles, Josep M; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D

2014-04-01

Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats.

PubMed

Taksande, Brijesh G; Gawande, Dinesh Y; Chopde, Chandrabhan T; Umekar, Milind J; Kotagale, Nandkishor R

2017-02-01

The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis. Day 8 onwards of CFA administration, rats were injected daily with agmatine for next 7days, and arthritis score, body weights and food intake were monitored daily (g). Since cachexia is known to produce severe inflammation, malnutrition and inhibition of albumin gene expression, we have also monitored the total proteins, albumin, TNF-α and IL-6 levels in arthritic rats and its modulation by agmatine. In the present study, CFA treated rats showed a progressive reduction in both food intake and body weight. In addition analysis of blood serum of arthritis animals showed a significant reduction in proteins and albumin and significant elevation in tumor necrosis factor (TNF)-α and Interleukins (IL)-6. Chronic agmatine (20-40mg/kg, ip) treatment not only attenuated the signs of arthritis but also reverses anorexia and body weight loss in CFA treated rats. In addition, agmatine restored total protein and albumin and reduces TNF-α and IL-6 levels in arthritis rats. These results suggest that agmatine administration can prevent the body weights loss and symptoms of arthritis via inhibition of inflammatory cytokines. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

PubMed

Elattar, Sawsan; Dimri, Manali; Satyanarayana, Ande

2018-03-23

Cachexia is a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia. Browning of white adipose tissue (WAT) is one of the significant factors that contribute to energy wasting in cachexia. By utilizing a cell implantation model, we demonstrate here that the lipid mobilizing factor zinc-α 2 -glycoprotein (ZAG) induces WAT browning in mice. Increased circulating levels of ZAG not only induced lipolysis in adipose tissues but also caused robust browning in WAT. Stimulating WAT progenitors with ZAG recombinant protein or expression of ZAG in mouse embryonic fibroblasts (MEFs) strongly enhanced brown-like differentiation. At the molecular level, ZAG stimulated peroxisome proliferator-activated receptor γ (PPARγ) and early B cell factor 2 expression and promoted their recruitment to the PR/SET domain 16 (Prdm16) promoter, leading to enhanced expression of Prdm16, which determines brown cell fate. In brown adipose tissue, ZAG stimulated the expression of PPARγ and PPARγ coactivator 1α and promoted recruitment of PPARγ to the uncoupling protein 1 (Ucp1) promoter, leading to increased expression of Ucp1. Overall, our results reveal a novel function of ZAG in WAT browning and highlight the targeting of ZAG as a potential therapeutic application in humans with cachexia.-Elattar, S., Dimri, M., Satyanarayana, A. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia.

PubMed

Shirai, Yumiko; Okugawa, Yoshinaga; Hishida, Asahi; Ogawa, Aki; Okamoto, Kyoko; Shintani, Miki; Morimoto, Yuki; Nishikawa, Ryutaro; Yokoe, Takeshi; Tanaka, Koji; Urata, Hisashi; Toiyama, Yuji; Inoue, Yasuhiro; Tanaka, Motoyoshi; Mohri, Yasuhiko; Goel, Ajay; Kusunoki, Masato; McMillan, Donald C; Miki, Chikao

2017-07-06

Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2).

Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle: update 2017.

PubMed

von Haehling, Stephan; Morley, John E; Coats, Andrew J S; Anker, Stefan D

2017-12-01

This article details an updated version of the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM). At the time of submission to JCSM, the corresponding author, on behalf of all co-authors, needs to certify adherence to these principles. The principles are as follows: All authors listed on a manuscript considered for publication have approved its submission and (if accepted) publication as provided to JCSM. No person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript. Each author has made a material and independent contribution to the work submitted for publication. The submitted work is original and is neither under consideration elsewhere nor that it has been published previously in whole or in part other than in abstract form. All authors certify that the work is original and does not contain excessive overlap with prior or contemporaneous publication elsewhere, and where the publication reports on cohorts, trials, or data that have been reported on before these other publications must be referenced. All original research work has been approved by the relevant bodies such as institutional review boards or ethics committees. All conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively, and relevant sources of funding have been duly declared in the manuscript. The manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true. If any of the aforementioned statements ceases to be true, the authors have a duty to notify the Editors of JCSM as soon as possible so that the available information regarding the published article can be updated and/or the manuscript can be withdrawn. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1.

PubMed

McDonald, Merry-Lynn Noelle; Won, Sungho; Mattheisen, Manuel; Castaldi, Peter J; Cho, Michael H; Rutten, Erica; Hardin, Megan; Yip, Wai-Ki; Rennard, Stephen I; Lomas, David A; Wouters, Emiel F M; Agusti, Alvar; Casaburi, Richard; Lange, Christoph P; O'Connor, George; Hersh, Craig P; Silverman, Edwin K

2017-06-01

There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study. A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years of age with three consecutive BMI time points (n = 4162). Four GWAS of ΔBMI using generalized estimating equations were performed among 1085 participants with a cancer diagnosis, 204 with gastrointestinal (GI) cancer, 112 with lung cancer, and 237 with COPD to test for association with 418 365 single-nucleotide polymorphisms (SNPs). Two SNPs reached a level of genome-wide significance (P < 5 × 10 -8 ) with ΔBMI: (i) rs41526344 within the CNTN4 gene, among COPD cases (β = 0.13, P = 4.3 × 10 -8 ); and (ii) rs4751240 in the gene Dedicator of Cytokinesis 1 (DOCK1) among GI cancer cases (β = 0.10, P = 1.9 × 10 -8 ). The DOCK1 SNP association replicated in the ΔBMI GWAS among COPD cases (β meta-analyis  = 0.10, P meta-analyis  = 9.3 × 10 -10 ). The DOCK1 gene codes for the dedicator of cytokinesis 1 protein, which has a role in myoblast fusion. In sum, one statistically significant common variant in the DOCK1 gene was associated with ΔBMI in GI cancer and COPD cases providing support for at least partially shared aetiology of ΔBMI in complex diseases. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

The role of thalidomide and placebo for the treatment of cancer-related anorexia-cachexia symptoms: results of a double-blind placebo-controlled randomized study.

PubMed

Yennurajalingam, Sriram; Willey, Jie S; Palmer, J Lynn; Allo, Julio; Del Fabbro, Egidio; Cohen, Evan N; Tin, Sanda; Reuben, James M; Bruera, Eduardo

2012-10-01

To determine the effects of thalidomide and placebo on anorexia-cachexia and its related symptoms, body composition, resting metabolic rate, and serum cytokines and their receptors in patients with advanced cancer. Included in the study were patients with advanced cancer with weight loss greater than 5% in 6 months and who reported anorexia, fatigue, and one of the following: anxiety, depression, or sleep disturbances. Patients on chemotherapy within 2 weeks prior or during the study were excluded from the study. Patients were randomly assigned to either 100 mg thalidomide or placebo once a day for 14 days. The Edmonton Symptom Assessment Scale (ESAS), Functional Assessment of Anorexia/Cachexia Therapy (FAACT), Functional Assessment of Cancer Illness Therapy (FACIT-F), Hospital Anxiety Depression Scale (HADS) Pittsburgh Sleep Quality Index (PSQI) were utilized, and in addition body composition, Resting Energy Expenditure (REE), and serum cytokine levels were assessed. Of the 31 patients entered in the study, 15 were assigned to the thalidomide group and 16 to the placebo group. However only 21/31 patients were able to complete the study. Compared with their baseline values, both the thalidomide and the placebo groups showed significant reduction in cytokines. Tumor necrosis factor (TNF)-α (p=0.04) and its receptors TNFR1 (p=0.04), TNFR2 (p=0.04), and interleukin (IL)-8 (p=0.04) were statistically significant in the thalidomide group. In the placebo group, TNF-α (p=0.008), TNFR1 (p=0.005), TNFR2 (p=0.005), IL-RA (p=0.005), IL-6 (p=0.005), and IL-8 (p=0.005) were statistically significant. However, improvement in these symptoms and cytokine levels were not significantly different in the thalidomide group compared with the placebo group. None of the patients withdrew from the study because of toxicity of either thalidomide or placebo. Based on the poor accrual rate and attrition observed in this study, it is important that future research on thalidomide as a treatment for cancer-related anorexia-cachexia symptoms (ACS) in patients with advanced cancer use less stringent entry criteria and less exhaustive outcome measures.

Total parenteral nutrition in a neonatal llama.

PubMed

Hovda, L R; McGuirk, S M; Lunn, D P

1990-01-15

Total parenteral nutrition reversed cachexia, dehydration, and electrolyte abnormalities in a neonatal llama suffering from prolonged diarrhea. Complications were not observed during the 8 days that IV-administered fluids and nutritional support were provided.

Are cannabinoids an alternative for cachexia-anorexia syndrome in patients with advanced cancer?

PubMed

Cabeza, Claudia; Corsi, Oscar; Pérez-Cruz, Pedro

2017-12-29

Cachexia and anorexia are among the most frequent symptoms in patients with cancer. Cannabinoids have been used in patients with advanced cancer; however, their role is still controversial. To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, and generated a summary of findings table using the GRADE approach. We identified ten systematic reviews including three studies overall, of which two were randomized trials. We concluded it is not clear whether cannabinoids have any positive effect on increasing weight because the certainty of the evidence is very low. They might not have any effect on appetite, and are probably associated to frequent adverse effects.

Of Faeces and Sweat. How Much a Mouse is Willing to Run: Having a Hard Time Measuring Spontaneous Physical Activity in Different Mouse Sub-Strains.

PubMed

Coletti, Dario; Adamo, Sergio; Moresi, Viviana

2017-02-24

Invited Letter to the Editor. Physical activity has multiple beneficial effects in the physiology and pathology of the organism. In particular, we and other groups have shown that running counteracts cancer cachexia in both humans and rodents. The latter are prone to exercise in wheel-equipped cages even at advanced stages of cachexia. However, when we wanted to replicate the experimental model routinely used at the University of Rome in a different laboratory (i.e. at Paris 6 University), we had to struggle with puzzling results due to unpredicted mouse behavior. Here we report the experience and offer the explanation underlying these apparently irreproducible results. The original data are currently used for teaching purposes in undergraduate student classes of biological sciences.

Can the use of creatine supplementation attenuate muscle loss in cachexia and wasting?

PubMed

Sakkas, Giorgos K; Schambelan, Morris; Mulligan, Kathleen

2009-11-01

Weight loss and low BMI due to an underlying illness have been associated with increased mortality, reduced functional capacity, and diminished quality of life. There is a need for well tolerated, long-term approaches to maintain body weight in patients with cachexia or wasting. The purpose of this review is to highlight the scientific and clinical evidence derived from the recent literature investigating the rationale for and potential medical use of creatine supplementation in patients with cachexia or wasting. Some studies have demonstrated that supplementation with creatine can increase creatine reserves in skeletal muscle and increase muscle mass and performance in various disease states that affect muscle size and function. The mechanisms underlying these effects are not clear. It has been suggested that creatine supplementation may increase intramuscular phosphocreatine stores and promote more rapid recovery of adenosine triphosphate levels following exercise, thus allowing users to exercise for longer periods or at higher intensity levels. Other hypothesized mechanisms include attenuation of proinflammatory cytokines, stimulation of satellite cell proliferation and upregulation of genes that promote protein synthesis and cell repair. Creatine is a generally well tolerated, low-cost, over-the-counter nutritional supplement that shows potential in improving lean body mass and functionality in patients with wasting diseases. However, placebo-controlled studies have shown variable effects, with improvements in some and not in others. Additional studies with longer follow-up are required to identify the populations that might benefit most from creatine supplementation.

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors.

PubMed

Villars, Fabienne O; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

2017-05-05

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.

The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting.

PubMed

Carson, James A; Hardee, Justin P; VanderVeen, Brandon N

2016-06-01

While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle's metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prevention of liver cancer cachexia-induced cardiac wasting and heart failure

PubMed Central

Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J.S.; Beadle, John; Argiles, Josep M.; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D.

2014-01-01

Aims Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Methods and results Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Conclusion Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer. PMID:23990596

The Emerging Role of Skeletal Muscle Metabolism as a Biological Target and Cellular Regulator of Cancer-Induced Muscle Wasting

PubMed Central

Carson, James A.; Hardee, Justin P.; VanderVeen, Brandon N.

2015-01-01

While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle’s metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function regulation, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed. PMID:26593326

Mechanism and novel therapeutic approaches to wasting in chronic disease.

PubMed

Ebner, Nicole; Springer, Jochen; Kalantar-Zadeh, Kamyar; Lainscak, Mitja; Doehner, Wolfram; Anker, Stefan D; von Haehling, Stephan

2013-07-01

Cachexia is a multifactorial syndrome defined by continuous loss of skeletal muscle mass - with or without loss of fat mass - which cannot be fully reversed by conventional nutritional support and which may lead to progressive functional impairment and increased death risk. Its pathophysiology is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Muscle wasting is encountered in virtually all chronic disease states in particular during advanced stages of the respective illness. Several pre-clinical and clinical studies are ongoing to ameliorate this clinical problem. The mechanisms of muscle wasting and cachexia in chronic diseases such as cancer, chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease are described. We discuss therapeutic targets and such potential modulators as appetite stimulants, selective androgen receptor modulators, amino acids and naturally occurring peptide hormones. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Polioencephalomalacia and Heart Failure Secondary to Presumptive Thiamine Deficiency, Hepatic Lipidosis, and Starvation in 2 Abandoned Siamese Cats.

PubMed

Anholt, H; Himsworth, C; Britton, A

2016-07-01

Two 4-year-old spayed female Siamese cats were seized by the British Columbia Society for the Prevention of Cruelty to Animals after confinement to an abandoned housing unit without food for 9 weeks. One cat was found dead, and the second was euthanized within 24 hours due to neurologic deterioration despite therapy. Polioencephalomalacia of the caudal colliculus, hepatic lipidosis, cachexia, and congestive heart failure with cardiomyocyte atrophy were identified in both cats through postmortem examination and attributed to a prolonged period of starvation. Brain lesions were likely the result of thiamine deficiency (Chastek paralysis), which can be associated with both malnutrition and liver disease. This case highlights the importance of thiamine supplementation during realimentation of cats with hepatic lipidosis. Heart failure resulting from cachexia may have contributed to the death of the first cat and the morbidity of the second cat. © The Author(s) 2016.

Dietary protein content for an optimal diet: a clinical view.

PubMed

Santarpia, Lidia; Contaldo, Franco; Pasanisi, Fabrizio

2017-06-01

The dietary protein role in different clinical nutritional conditions and some physio-pathological perspectives is a current and hot topic to discuss. Recent Proceedings of the Protein Summit 2, joining more than 60 nutrition scientists, health experts, and nutrition educators, suggest to increase plant but, in particular, animal protein intake because richer in leucine and consequently more effective to influence anabolic protein metabolism. The Panel conclusions are in apparent contradiction with the nutritional ecology statements, which strongly sustain the reduction of animal origin foods in the human diet and are currently concerned about the excessive, mainly animal protein intake in western and westernized Countries. In conclusion, it is time to carefully evaluate protein and aminoacid intake accurately considering quality, digestibility, daily distribution and individual characteristics. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment.

PubMed

Drescher, Cathleen; Konishi, Masaaki; Ebner, Nicole; Springer, Jochen

2016-01-01

Loss of muscle mass arises from an imbalance of protein synthesis and protein degradation. Potential triggers of muscle wasting and function are immobilization, loss of appetite, dystrophies and chronic diseases as well as aging. All these conditions lead to increased morbidity and mortality in patients, which makes it a timely matter to find new biomarkers to get a fast clinical diagnosis and to develop new therapies. This mini-review covers current developments in the field of biomarkers and drugs on cachexia and sarcopenia. Here, we reported about promising markers, e.g. tartrate-resistant acid phosphatase 5a (TRACP5a), and novel substances like Epigallocatechin-3-gallate (EGCg). In summary, the progress to combat muscle wasting is in full swing and perhaps diagnosis of muscle atrophy and of course patient treatments could be soon supported by improved and more helpful strategies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia.

PubMed

Nagaya, Noritoshi; Kojima, Masakazu; Kangawa, Kenji

2006-01-01

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for GH secretagogue receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. This peptide also stimulates food intake and induces adiposity through GH-independent mechanisms. In addition, ghrelin acts directly on the central nervous system to decrease sympathetic nerve activity. Thus, ghrelin plays important roles for maintaining GH release and energy homeostasis. Repeated administration of ghrelin improves body composition, muscle wasting, functional capacity, and sympathetic augmentation in cachectic patients with heart failure or chronic obstructive pulmonary disease. These results suggest that ghrelin has anti-cachectic effects through GH-dependent and independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of cardiopulmonary-associated cachexia.

White adipose tissue cells and the progression of cachexia: inflammatory pathways

PubMed Central

Neves, Rodrigo X.; Rosa‐Neto, José Cesar; Yamashita, Alex S.; Matos‐Neto, Emidio M.; Riccardi, Daniela M. R.; Lira, Fabio S.; Batista, Miguel L.

2015-01-01

Abstract Background Cachexia is a systemic syndrome leading to body wasting, systemic inflammation, and to metabolic chaos. It is a progressive condition, and little is known about its dynamics. Detection of the early signs of the disease may lead to the attenuation of the associated symptoms. The white adipose tissue is an organ with endocrine functions, capable of synthesising and secreting a plethora of proteins, including cytokines, chemokines, and adipokines. It is well established that different adipose tissue depots demonstrate heterogeneous responses to physiological and pathological stimuli. The present study aimed at providing insight into adipocyte involvement in inflammation along the progression of cachexia. Methods Eight‐weeks‐old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour‐bearing, T) or Phosphate‐buffered saline (control, C). The retroperitoneal, epididymal, and mesenteric adipose pads were excised on Days 0, 7, and 14 post‐tumour cell injection, and the adipocytes were isolated. Results Mesenteric and epididymal adipocytes showed up‐regulation of IL‐1β protein expression and activation of the inflammasome pathway, contributing for whole tissue inflammation. The stromal vascular fraction of the retroperitoneal adipose tissue, on the other hand, seems to be the major contributor for the inflammation in this specific pad. Conclusion Adipocytes seem to play a relevant role in the establishment of white adipose tissue inflammation, through the activation of the NF‐κB and inflammasome pathways. In epididymal adipocytes, induction of the inflammasome may be detected already on Day 7 post‐tumour cell inoculation. PMID:27493872

Reactive Oxygen Species/Nitric Oxide Mediated Inter-Organ Communication in Skeletal Muscle Wasting Diseases

PubMed Central

Leitner, Lucia M.; Wilson, Rebecca J.; Yan, Zhen

2017-01-01

Abstract Significance: Cachexia is defined as a complex metabolic syndrome that is associated with underlying illness and a loss of muscle with or without loss of fat mass. This disease is associated with a high incidence with chronic diseases such as heart failure, cancer, chronic obstructive pulmonary disease (COPD), and acquired immunodeficiency syndrome (AIDS), among others. Since there is currently no effective treatment available, cachectic patients have a poor prognosis. Elucidation of the underlying mechanisms is, therefore, an important medical task. Recent Advances: There is accumulating evidence that the diseased organs such as heart, lung, kidney, or cancer tissue secrete soluble factors, including Angiotensin II, myostatin (growth differentiation factor 8 [GDF8]), GDF11, tumor growth factor beta (TGFβ), which act on skeletal muscle. There, they induce a set of genes called atrogenes, which, among others, induce the ubiquitin-proteasome system, leading to protein degradation. Moreover, elevated reactive oxygen species (ROS) levels due to modulation of NADPH oxidases (Nox) and mitochondrial function contribute to disease progression, which is characterized by loss of muscle mass, exercise resistance, and frailty. Critical issues: Although substantial progress was achieved to elucidate the pathophysiology of cachexia, effectice therapeutic strategies are urgently needed. Future Directions: With the identification of key components of the aberrant inter-organ communication leading to cachexia, studies in mice and men to inhibit ROS formation, induction of anti-oxidative superoxide dismutases, and upregulation of muscular nitric oxide (NO) formation either by pharmacological tools or by exercise are promising approaches to reduce the extent of skeletal muscle wasting. Antioxid. Redox Signal. 26, 700–717. PMID:27835923

Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats.

PubMed

Oliveira, André G; Gomes-Marcondes, Maria Cristina C

2016-07-07

Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition. Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays. Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste. Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats.

Hydrazine Sulfate (PDQ®)—Health Professional Version

Cancer.gov

Hydrazine sulfate has shown no anticancer activity in randomized clinical trials. Data on its effectiveness in cancer-related cachexia are inconclusive. Get detailed information about hydrazine sulfate as a treatment for people with cancer in this summary for clinicians.

The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.

PubMed

Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Pavlides, Stephanos; Chiavarina, Barbara; Bonuccelli, Gloria; Casey, Trimmer; Tsirigos, Aristotelis; Migneco, Gemma; Witkiewicz, Agnieszka; Balliet, Renee; Mercier, Isabelle; Wang, Chengwang; Flomenberg, Neal; Howell, Anthony; Lin, Zhao; Caro, Jaime; Pestell, Richard G; Sotgia, Federica; Lisanti, Michael P

2010-11-01

The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a "lethal" aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.

Pulmonary Rehabilitation in Improving Lung Function in Patients With Locally Advanced Non-Small Cell Lung Cancer Undergoing Chemoradiation

ClinicalTrials.gov

2017-04-12

Cachexia; Fatigue; Pulmonary Complications; Radiation Toxicity; Recurrent Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

Supplementation of Magnolol Attenuates Skeletal Muscle Atrophy in Bladder Cancer-Bearing Mice Undergoing Chemotherapy via Suppression of FoxO3 Activation and Induction of IGF-1.

PubMed

Chen, Meng-Chuan; Chen, Yen-Lin; Lee, Chi-Feng; Hung, Chih-Huang; Chou, Tz-Chong

2015-01-01

Skeletal muscle atrophy, the most prominent phenotypic feature of cancer cachexia, is often observed in cancer patients undergoing chemotherapy. Magnolol (M) extracted from Magnolia officinalis exhibits several pharmacological effects including anti-inflammatory and anticancer activities. In this study, we investigated whether magnolol supplementation protects against the development of cachexia symptoms in bladder cancer-bearing mice undergoing chemotherapy. Combined treatment of magnolol with chemotherapeutic drugs, such as gemcitabine and cisplatin (TGCM) or gemcitabine (TGM), markedly attenuates the body weight loss and skeletal muscle atrophy compared with conventional chemotherapy (TGC). The antiatrophic effect of magnolol may be associated with inhibition of myostatin and activin A formation, as well as FoxO3 transcriptional activity resulting from Akt activation, thereby suppressing ubiquitin ligases MuRF-1 and MAFbx/atrogin-1 expression, as well as proteasomal enzyme activity. Notably, magnolol-induced insulin-like growth factor 1 (IGF-1) production and related protein synthesis may also contribute to its protective effects. The decreased food intake, and intestinal injury and dysfunction observed in the mice of TGC group were significantly improved in the TGCM and TGM groups. Moreover, the increased inflammatory responses evidenced by elevation of proinflammatory cytokine formation and NF-κB activation occurred in the atrophying muscle of TGC group were markedly inhibited in mice of combined treatment with magnolol. In summary, these findings support that magnolol is a promising chemopreventive supplement for preventing chemotherapy-induced skeletal muscle atrophy associated with cancer cachexia by suppressing muscle protein degradation, and inflammatory responses, as well as increasing IGF-1-mediated protein synthesis.

Supplementation of Magnolol Attenuates Skeletal Muscle Atrophy in Bladder Cancer-Bearing Mice Undergoing Chemotherapy via Suppression of FoxO3 Activation and Induction of IGF-1

PubMed Central

Chen, Meng-Chuan; Chen, Yen-Lin; Lee, Chi-Feng; Hung, Chih-Huang; Chou, Tz-Chong

2015-01-01

Skeletal muscle atrophy, the most prominent phenotypic feature of cancer cachexia, is often observed in cancer patients undergoing chemotherapy. Magnolol (M) extracted from Magnolia officinalis exhibits several pharmacological effects including anti-inflammatory and anticancer activities. In this study, we investigated whether magnolol supplementation protects against the development of cachexia symptoms in bladder cancer-bearing mice undergoing chemotherapy. Combined treatment of magnolol with chemotherapeutic drugs, such as gemcitabine and cisplatin (TGCM) or gemcitabine (TGM), markedly attenuates the body weight loss and skeletal muscle atrophy compared with conventional chemotherapy (TGC). The antiatrophic effect of magnolol may be associated with inhibition of myostatin and activin A formation, as well as FoxO3 transcriptional activity resulting from Akt activation, thereby suppressing ubiquitin ligases MuRF-1 and MAFbx/atrogin-1 expression, as well as proteasomal enzyme activity. Notably, magnolol-induced insulin-like growth factor 1 (IGF-1) production and related protein synthesis may also contribute to its protective effects. The decreased food intake, and intestinal injury and dysfunction observed in the mice of TGC group were significantly improved in the TGCM and TGM groups. Moreover, the increased inflammatory responses evidenced by elevation of proinflammatory cytokine formation and NF-κB activation occurred in the atrophying muscle of TGC group were markedly inhibited in mice of combined treatment with magnolol. In summary, these findings support that magnolol is a promising chemopreventive supplement for preventing chemotherapy-induced skeletal muscle atrophy associated with cancer cachexia by suppressing muscle protein degradation, and inflammatory responses, as well as increasing IGF-1-mediated protein synthesis. PMID:26600425

Zinc-α2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia

PubMed Central

Bing, Chen; Bao, Yi; Jenkins, John; Sanders, Paul; Manieri, Monia; Cinti, Saverio; Tisdale, Michael J.; Trayhurn, Paul

2004-01-01

Zinc-α2-glycoprotein (ZAG), a 43-kDa protein, is overexpressed in certain human malignant tumors and acts as a lipid-mobilizing factor to stimulate lipolysis in adipocytes leading to cachexia in mice implanted with ZAG-producing tumors. Because white adipose tissue (WAT) is an endocrine organ secreting a wide range of protein factors, including those involved in lipid metabolism, we have investigated whether ZAG is produced locally by adipocytes. ZAG mRNA was detected by RT-PCR in the mouse WAT depots examined (epididymal, perirenal, s.c., and mammary gland) and in interscapular brown fat. In WAT, ZAG gene expression was evident in mature adipocytes and in stromal-vascular cells. Using a ZAG Ab, ZAG protein was located in WAT by Western blotting and immunohistochemistry. Mice bearing the MAC16-tumor displayed substantial losses of body weight and fat mass, which was accompanied by major increases in ZAG mRNA and protein levels in WAT and brown fat. ZAG mRNA was detected in 3T3-L1 cells, before and after the induction of differentiation, with the level increasing progressively after differentiation with a peak at days 8–10. Both dexamethasone and a β3 agonist, BRL 37344, increased ZAG mRNA levels in 3T3-L1 adipocytes. ZAG gene expression and protein were also detected in human adipose tissue (visceral and s.c.). It is suggested that ZAG is a new adipose tissue protein factor, which may be involved in the modulation of lipolysis in adipocytes. Overexpression in WAT of tumor-bearing mice suggests a local role for adipocyte-derived ZAG in the substantial reduction of adiposity of cancer cachexia. PMID:14983038

The influence of DNA repair on neurological degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D)

PubMed Central

2013-01-01

Background To investigate the association of DNA nucleotide excision repair (NER) defects with neurological degeneration, cachexia and cancer, we performed autopsies on 4 adult xeroderma pigmentosum (XP) patients with different clinical features and defects in NER complementation groups XP-A, XP-C or XP-D. Results The XP-A (XP12BE) and XP-D (XP18BE) patients exhibited progressive neurological deterioration with sensorineural hearing loss. The clinical spectrum encompassed severe cachexia in the XP-A (XP12BE) patient, numerous skin cancers in the XP-A and two XP-C (XP24BE and XP1BE) patients and only few skin cancers in the XP-D patient. Two XP-C patients developed internal neoplasms including glioblastoma in XP24BE and uterine adenocarcinoma in XP1BE. At autopsy, the brains of the 44 yr XP-A and the 45 yr XP-D patients were profoundly atrophic and characterized microscopically by diffuse neuronal loss, myelin pallor and gliosis. Unlike the XP-A patient, the XP-D patient had a thickened calvarium, and the brain showed vacuolization of the neuropil in the cerebrum, cerebellum and brainstem, and patchy Purkinje cell loss. Axonal neuropathy and chronic denervation atrophy of the skeletal muscles were observed in the XP-A patient, but not in the XP-D patient. Conclusions These clinical manifestations and autopsy findings indicate advanced involvement of the central and peripheral nervous system. Despite similar defects in DNA repair, different clinicopathological phenotypes are seen in the four cases, and therefore distinct patterns of neurodegeneration characterize XP-D, XP-A and XP-C patients. PMID:24252196

A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project

PubMed Central

Mochamat; Cuhls, Henning; Marinova, Milka; Kaasa, Stein; Stieber, Christiane; Conrad, Rupert; Radbruch, Lukas

2016-01-01

Abstract We provide a systematic review to support the European Palliative Care Research Collaboration development of clinical guidelines for cancer patients suffering from cachexia. CENTRAL, MEDLINE, PsycINFO, ClinicalTrials.gov, and a selection of cancer journals have been searched up until 15 April 2016. The systematic literature research yielded 4214 publications with 21 of these included in the final evaluation. Regarding minerals, our search identified only one study examining the use of magnesium with no effect on weight loss. As far as vitamins are concerned, vitamin E in combination with omega‐3 fatty acids displayed an effect on survival in a single study, vitamin D showed improvement of muscle weakness in prostate cancer patients, and vitamin C supplementation led to an improvement of various quality of life aspects in a sample with a variety of cancer diagnoses. For proteins, a combination therapy of β‐hydroxy‐β‐methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. L‐carnitine led to an increase of body mass index and an increase in overall survival in advanced pancreatic cancer patients. Adverse effects of food supplementation were rare and showed mild intensity. There is not enough solid evidence for the use of minerals, vitamins, proteins, or other supplements in cancer. No serious adverse effects have been reported with dietary supplementation. PMID:27897391

Supplementation with L-glutamine prevents tumor growth and cancer-induced cachexia as well as restores cell proliferation of intestinal mucosa of Walker-256 tumor-bearing rats.

PubMed

Martins, Heber Amilcar; Sehaber, Camila Caviquioli; Hermes-Uliana, Catchia; Mariani, Fernando Augusto; Guarnier, Flavia Alessandra; Vicentini, Geraldo Emílio; Bossolani, Gleison Daion Piovezana; Jussani, Laraine Almeida; Lima, Mariana Machado; Bazotte, Roberto Barbosa; Zanoni, Jacqueline Nelisis

2016-12-01

This study aimed to evaluate the intestinal mucosa of the duodenum and jejunum of Walker-256 tumor-bearing rats supplemented with L-glutamine. Thirty-two male 50-day-old Wistar rats (Rattus norvegicus) were randomly divided into four groups: control (C), control supplemented with 2 % L-glutamine (GC), Walker-256 tumor (WT), and Walker-256 tumor supplemented with 2 % L-glutamine (TWG). Walker-256 tumor was induced by inoculation viable tumor cells in the right rear flank. After 10 days, celiotomy was performed and duodenal and jejunal tissues were removed and processed. We evaluated the cachexia index, proliferation index, villus height, crypt depth, total height of the intestinal wall, and number of goblet cells by the technique of periodic acid-Schiff (PAS). Induction of Walker-256 tumor promoted a reduction of metaphase index in the TW group animals, which was accompanied by a reduction in the villous height and crypt depths, resulting in atrophy of the intestinal wall as well as increased PAS-positive goblet cells. Supplementation with L-glutamine reduced the tumor growth and inhibited the development of the cachectic syndrome in animals of the TWG group. Furthermore, amino acid supplementation promoted beneficial effects on the intestinal mucosa in the TWG animals through restoration of the number of PAS-positive goblet cells. Therefore, supplementation with 2 % L-glutamine exhibited a promising role in the prevention of tumor growth and cancer-associated cachexia as well as restoring the intestinal mucosa in the duodenum and jejunum of Walker-256 tumor-bearing rats.

L-carnitine and cancer cachexia. I. L-carnitine distribution and metabolic disorders in cancer cachexia.

PubMed

Szefel, Jarosław; Kruszewski, Wiesław Janusz; Ciesielski, Maciej; Szajewski, Mariusz; Kawecki, Krzysztof; Aleksandrowicz-Wrona, Ewa; Jankun, Jerzy; Lysiak-Szydłowska, Wiesława

2012-07-01

Cancer cachexia (CC), a progressive loss of body mass, is associated with decreased energy production. Abnormally low levels of L-carnitine (LC) in skeletal muscle means that mitochondrial β-oxidation of long-chain fatty acids (LCFA) does not occur efficiently in patients with CC. We assessed the influence of CC on LC distribution and the effects of parenteral lipid emulsions on plasma LC levels and urinary excretion. Fifty patients with CC were randomly assigned to total parenteral nutrition (TPN) with long-chain triglycerides (LCTs), or LCTs plus medium-chain triglycerides (MCTs) as 50/50. Patients were further separated into those with body-mass index (BMI) ≤ 19 kg/m(2) and BMI >19 kg/m(2). Plasma concentrations of total LC (TC) and free LC (FC) and their urinary excretion were measured, along with skeletal muscle LC levels. On average, plasma FC and TC were higher than reference values in all patients. Patients with BMI ≤ 19 kg/m(2) had lower plasma FC and TC than those with BMI >19 kg/m(2). Skeletal muscle FC in the BMI ≤ 19 kg/m(2) group was lower than reference value, but within the normal range in others. LC and FC urinary excretion was higher than reference values. Plasma LC and its urinary excretion were higher in patients administered pure LCTs relative to those given MCTs/LCTs. A decrease in skeletal muscle LC in cancer patients with CC (BMI ≤ 19 kg/m(2)) correlates with an increase in its plasma levels and increased renal excretion. A diet of MCTs/LCTs reduces LC release from muscle to plasma and urine more effectively than LCTs.

Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia.

PubMed

Burney, Basil O; Hayes, Teresa G; Smiechowska, Joanna; Cardwell, Gina; Papusha, Victor; Bhargava, Peeyush; Konda, Bhavana; Auchus, Richard J; Garcia, Jose M

2012-05-01

Male cancer patients suffer from fatigue, sexual dysfunction, and decreased functional performance and muscle mass. These symptoms are seen in men with hypogonadism and/or inflammatory conditions. However, the relative contribution of testosterone and inflammation to symptom burden in cancer has not been well-established. The aim of this study was to measure testosterone levels in male cancer patients and determine the relationship between testosterone, inflammation, and symptom burden. This cross-sectional study enrolled patients from a tertiary-care center. SUBJECTS/OUTCOME MEASURES: Subjects included males with cancer-cachexia (CC; n = 45) and cancer without cachexia (CNC; n = 50), as well as noncancer controls (CO; n = 45). Total testosterone (TT), bioavailable testosterone, C-reactive protein (CRP), and IL-6 were measured in plasma. Functional performance was assessed by the ECOG (Eastern Cooperative Oncology Group) and KPS (Karnofsky Performance Scales), and sexual function was assessed by the IIEF (International Index of Erectile Function). Low testosterone levels were seen in more than 70% of CC cases. TT was lower in CC compared to CNC (P < 0.05). Also, CC had lower bioavailable testosterone, grip strength, IIEF scores, appendicular lean body mass, and fat mass and higher IL-6 and CRP compared to controls (P ≤ 0.05). ECOG and KPS were lower in CC and CNC compared to controls (P ≤ 0.05). On multiple regression analysis, TT, albumin, and CRP predicted symptoms differentially in cancer patients. CC patients have higher inflammation and lower testosterone, grip strength, functional status, erectile function, fat mass, and appendicular lean body mass. Inflammation, TT, and albumin are associated with heavier symptom burden in this population. Interventional trials are needed to determine whether testosterone replacement and/or antiinflammatory agents benefit cancer patients.

Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial.

PubMed

Del Fabbro, Egidio; Dev, Rony; Hui, David; Palmer, Lynn; Bruera, Eduardo

2013-04-01

Prior studies have suggested that melatonin, a frequently used integrative medicine, can attenuate weight loss, anorexia, and fatigue in patients with cancer. These studies were limited by a lack of blinding and absence of placebo controls. The primary purpose of this study was to compare melatonin with placebo for appetite improvement in patients with cancer cachexia. We performed a randomized, double-blind, 28-day trial of melatonin 20 mg versus placebo in patients with advanced lung or GI cancer, appetite scores ≥ 4 on a 0 to 10 scale (10 = worst appetite), and history of weight loss ≥ 5%. Assessments included weight, symptoms by the Edmonton Symptom Assessment Scale, and quality of life by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Differences between groups from baseline to day 28 were analyzed using one-sided, two-sample t tests or Wilcoxon two-sample tests. Interim analysis halfway through the trial had a Lan-DeMets monitoring boundary with an O'Brien-Fleming stopping rule. Decision boundaries were to accept the null hypothesis of futility if the test statistic z < 0.39 (P ≥ .348) and reject the null hypothesis if z > 2.54 (P ≤ .0056). After interim analysis of 48 patients, the study was closed for futility. There were no significant differences between groups for appetite (P = .78) or other symptoms, weight (P = .17), FAACT score (P = .95), toxicity, or survival from baseline to day 28. In cachectic patients with advanced cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo.

Insulin, not glutamine dipeptide, reduces lipases expression and prevents fat wasting and weight loss in Walker 256 tumor-bearing rats.

PubMed

de Morais, Hely; de Fatima Silva, Flaviane; da Silva, Francemilson Goulart; Silva, Milene Ortiz; Graciano, Maria Fernanda Rodrigues; Martins, Maria Isabel Lovo; Carpinelli, Ângelo Rafael; Mazucco, Tânia Longo; Bazotte, Roberto Barbosa; de Souza, Helenir Medri

2017-07-05

Cachexia is the main cause of mortality in advanced cancer patients. We investigated the effects of insulin (INS) and glutamine dipeptide (GDP), isolated or associated, on cachexia and metabolic changes induced by Walker 256 tumor in rats. INS (NPH, 40 UI/kg, sc) or GDP (1.5g/kg, oral gavage) was once-daily administered during 11 days after tumor cell inoculation. GDP, INS or INS+GDP treatments did not influence the tumor growth. However, INS and INS+GDP prevented retroperitoneal fat wasting and body weight loss of tumor-bearing rats. In consistency, INS and INS+GDP prevented the increased expression of triacylglycerol lipase (ATGL) and hormone sensitive lipase (HSL), without changing the expression of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in the retroperitoneal adipose tissue of tumor-bearing rats. INS and INS+GDP also prevented anorexia and hyperlactatemia of tumor-bearing rats. However, INS and INS+GDP accentuated the loss of muscle mass (gastrocnemius, soleus and long digital extensor) without affecting the myostatin expression in the gastrocnemius muscle and blood corticosterone. GDP treatment did not promote beneficial effects. It can be concluded that treatment with INS (INS or INS+GDP), not with GDP, prevented fat wasting and weight loss in tumor-bearing rats without reducing tumor growth. These effects might be attributed to the reduction of lipases expression (ATGL and LHS) and increased food intake. The results show the physiological function of INS in the suppression of lipolysis induced by cachexia mediators in tumor-bearing rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Consequences of Late-Stage Non-Small-Cell Lung Cancer Cachexia on Muscle Metabolic Processes.

PubMed

Murton, Andrew J; Maddocks, Matthew; Stephens, Francis B; Marimuthu, Kanagaraj; England, Ruth; Wilcock, Andrew

2017-01-01

The loss of muscle is common in patients with advanced non-small-cell lung cancer (NSCLC) and contributes to the high morbidity and mortality of this group. The exact mechanisms behind the muscle loss are unclear. To investigate this, 4 patients with stage IV NSCLC who met the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age-matched healthy volunteers. After an overnight fast, biopsy specimens were obtained from the vastus lateralis, and the key components associated with inflammation and the control of muscle protein, carbohydrate, and fat metabolism were assessed. Compared with the healthy volunteers, significant increases in mRNA levels for interleukin-6 and NF-κB signaling and lower intramyocellular lipid content in slow-twitch fibers were observed in NSCLC patients. Although a significant decrease in phosphorylation of the mechanistic target of rapamycin (mTOR) signaling protein 4E-BP1 (Ser 65 ) was observed, along with a trend toward reduced p70 S6K (Thr 389 ) phosphorylation (P = .06), no difference was found between groups for the mRNA levels of MAFbx (muscle atrophy F box) and MuRF1 (muscle ring finger protein 1), chymotrypsin-like activity of the proteasome, or protein levels of multiple proteasome subunits. Moreover, despite decreases in intramyocellular lipid content, no robust changes in mRNA levels for key proteins involved in insulin signaling, glycolysis, oxidative metabolism, or fat metabolism were observed. These findings suggest that examining the contribution of suppressed mTOR signaling in the loss of muscle mass in late-stage NSCLC patients is warranted and reinforces our need to understand the potential contribution of impaired fat metabolism and muscle protein synthesis in the etiology of cancer cachexia. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacological interference with tissue hypercatabolism in tumour-bearing rats.

PubMed Central

Tessitore, L; Costelli, P; Baccino, F M

1994-01-01

Marked loss of body weight and profound waste of both skeletal muscle and white adipose tissue occur in rats into which the ascites hepatoma Yoshida AH-130 has been transplanted, associated with marked perturbations in the hormonal homoeostasis and the presence of circulating tumour necrosis factor and high plasma levels of prostaglandin E2 [Tessitore, Costelli and Baccino (1993) Br. J. Cancer 67, 15-23]. On the basis of previous findings, the present study examined whether the development of cachexia in this model system could be significantly affected by adrenalectomy or by pharmacological treatments that may interfere with proximal or distal mediators of tissue hypercatabolism. In no instance was tumour growth modified. Medroxyprogesterone acetate, an anabolic-hormone-like drug, was completely ineffective. In adrenalectomized animals, although changes such as the elevation of plasma triacylglycerols and corticosterone were corrected, the general course of cachexia was not modified. A partial prevention of muscle waste was observed with acetylsalicylic acid, a non-steroidal anti-inflammatory drug, or with leupeptin, a proteinase inhibitor. Insulin afforded the most significant preservation of muscle protein and adipose-tissue mass, which were maintained close to control values even 10 days after transplantation. The effects of insulin on gastrocnemius muscle and liver protein content were exerted by slowing down protein turnover, mainly enhancing synthesis. Consistently, the total free amino acid concentration in the gastrocnemius of insulin-treated rats 10 days after tumour transplantation was close to that of controls. Although treatment with insulin decreased plasma corticosterone to normal values, it did not modify the circulating level of tumour necrosis factor. On the whole these data show that it seems possible to prevent, at least in part, the tissue waste that characterizes cancer cachexia by purely pharmacological means. PMID:8166661

Perspectives of health care professionals on cancer cachexia: results from three global surveys

PubMed Central

Muscaritoli, M.; Rossi Fanelli, F.; Molfino, A.

2016-01-01

Background Cachexia has a high prevalence in cancer patients and negatively impacts prognosis, quality of life (QOL), and tolerance/response to treatments. This study reports the results of three surveys designed to gain insights into cancer cachexia (CC) awareness, understanding, and treatment practices among health care professionals (HCPs). Methods Surveys were conducted globally among HCPs involved in CC management. Topics evaluated included definitions and synonyms of CC, diagnosis and treatment practices, and goals and desired improvements of CC treatment. Results In total, 742 HCPs from 14 different countries participated in the surveys. The majority (97%) of participants were medical oncologists or hematologists. CC was most frequently defined as weight loss (86%) and loss of appetite (46%). The terms loss of weight and decreased appetite (51% and 34%, respectively) were often provided as synonyms of CC. Almost half (46%) of the participants reported diagnosing CC and beginning treatment if a patient experienced a weight loss of 10%. However, 48% of the participants would wait until weight loss was ≥15% to diagnose CC and start treatment. HCPs also reported that 61%–77% of cancer patients do not receive any prescription medication for CC before Stage IV of disease is reached. Ability to promote weight gain was rated as the most important factor for selecting CC treatment. Key goals of treatment included ensuring that patients can cope with the cancer and treatment and have a QOL benefit. HCPs expressed desire for treatments with a more CC-specific mode of action and therapies that enhance QOL. Conclusions These surveys underscore the need for increased awareness among HCPs of CC and its management. PMID:28007753

Ghrelin Partially Protects Against Cisplatin-Induced Male Murine Gonadal Toxicity in a GHSR-1a-Dependent Manner1

PubMed Central

Whirledge, Shannon D.; Garcia, Jose M.; Smith, Roy G.; Lamb, Dolores J.

2015-01-01

ABSTRACT The chemotherapeutic drug cisplatin causes a number of dose-dependent side effects, including cachexia and testicular damage. Patients receiving a high cumulative dose of cisplatin may develop permanent azoospermia and subsequent infertility. Thus, the development of chemotherapeutic regimens with the optimal postsurvival quality of life (fertility) is of high importance. This study tested the hypothesis that ghrelin administration can prevent or minimize cisplatin-induced testicular damage and cachexia. Ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR-1a), are expressed and function in the testis. Targeted deletion of ghrelin, or its receptor, significantly increases the rate of cell death in the testis, suggesting a protective role. Intraperitoneal administration of vehicle, ghrelin, or cisplatin alone or in combination with ghrelin, in cycles of 9 or 18 days, to adult male C57Bl/6 mice was performed. Body weight was measured daily and testicular and epididymal weight, sperm density and motility, testicular histology, and testicular cell death were analyzed at the time of euthanization. Ghrelin coadministration decreased the severity of cisplatin-induced cachexia and gonadal toxicity. Body, testicular, and epididymal weights significantly increased as testicular cell death decreased with ghrelin coadministration. The widespread damage to the seminiferous epithelium induced by cisplatin administration was less severe in mice simultaneously treated with ghrelin. Furthermore, ghrelin diminished the deleterious effects of cisplatin on testis and body weight homeostasis in wild-type but not Ghsr−/− mice, showing that ghrelin's actions are mediated via GHSR. Ghrelin or more stable GHSR agonists potentially offer a novel therapeutic approach to minimize the testicular damage that occurs after gonadotoxin exposure. PMID:25631345

Psychosocial consequences of cancer cachexia: the development of an item bank.

PubMed

Häne, Hanspeter; Oberholzer, Rolf; Walker, Jochen; Hopkinson, Jane B; de Wolf-Linder, Susanne; Strasser, Florian

2013-12-01

Cancer cachexia syndrome (CCS) is often accompanied by psychosocial consequences (PSC). To alleviate PSC, a systematic assessment method is required. Currently, few assessment tools are available (e.g., Functional Assessment of Anorexia/Cachexia Therapy). There is no systematic assessment tool that captures the PSC of CCS. To develop a pilot item bank to assess the PSC of CCS. A total of 132 questions, generated from patient answers in a previous study, were reduced to 121 items by content analysis and evaluation by multidisciplinary experts (doctor, nutritionists, and nurses). In our two-step, cross-sectional study, patients, judged by staff to have PSC of CCS, were included, and the questions were randomly allocated to the patients. Questions were evaluated for understandability and triggering emotions, and patients were asked to provide a response using a four-point Likert scale. Subsequently, problematic questions were revised, reformulated, and retested. A total of 20 patients with a variety of tumor types participated. Of the 121 questions, 31 had to be reformulated after Step 1 and were retested in Step 2, after which seven were again evaluated as not being perfectly comprehensible. In Step 1, 22 questions were found to trigger emotions, but no item required remodeling. Item performance using the Likert scale revealed no consistent floor or ceiling effects. Our final pilot question bank comprised 117 questions. The final item bank contains questions that are understood and accepted by the patients. This item bank now needs to be developed into a measurement tool that groups items into domains and can be used in future research studies. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Decreased hepatic response to glucagon, adrenergic agonists, and cAMP in glycogenolysis, gluconeogenesis, and glycolysis in tumor-bearing rats.

PubMed

Biazi, Giuliana R; Frasson, Isabele G; Miksza, Daniele R; de Morais, Hely; de Fatima Silva, Flaviane; Bertolini, Gisele L; de Souza, Helenir M

2018-05-15

The response to glucagon and adrenaline in cancer cachexia is poorly known. The aim of this study was to investigate the response to glucagon, adrenergic agonists (α and β) and cyclic adenosine monophosphate (cAMP) on glycogenolysis, gluconeogenesis, and glycolysis in liver perfusion of Walker-256 tumor-bearing rats with advanced cachexia. Liver ATP content was also investigated. Rats without tumor (healthy) were used as controls. Agonists α (phenylephrine) and β (isoproterenol) adrenergic, instead of adrenaline, and cAMP, the second messenger of glucagon and isoproterenol, were used in an attempt to identify mechanisms involved in the responses. Glucagon (1 nM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in the liver of healthy and tumor-bearing rats, but their effects were lower in tumor-bearing rats. Isoproterenol (20 µM) stimulated glycogenolysis, gluconeogenesis, and glycolysis in healthy rats and had virtually no effect in tumor-bearing rats. cAMP (9 µM) also stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in healthy rats but had practically no effect in tumor-bearing rats. Phenylephrine (2 µM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis and these effects were also lower in tumor-bearing rats than in healthy. Liver ATP content was lower in tumor-bearing rats. In conclusion, tumor-bearing rats with advanced cachexia showed a decreased hepatic response to glucagon, adrenergic agonists (α and β), and cAMP in glycogenolysis, gluconeogenesis, and glycolysis, which may be due to a reduced rate of regulatory enzyme phosphorylation caused by the low ATP levels in the liver. © 2018 Wiley Periodicals, Inc.

Powerful signals for weak muscles.

PubMed

Saini, Amarjit; Faulkner, Steve; Al-Shanti, Nasser; Stewart, Claire

2009-10-01

The aim of the present review is to summarise, evaluate and critique the different mechanisms involved in anabolic growth of skeletal muscle and the catabolic processes involved in cancer cachexia and sarcopenia of ageing. This is highly relevant, since they represent targets for future promising clinical investigations. Sarcopenia is an inevitable process associated with a gradual reduction in muscle mass and strength, associated with a reduction in motor unit number and atrophy of muscle fibres, especially the fast type IIa fibres. The loss of muscle mass with ageing is clinically important because it leads to diminished functional ability and associated complications. Cachexia is widely recognised as severe and rapid wasting accompanying disease states such as cancer or immunodeficiency disease. One of the main characteristics of cancer cachexia is asthenia or lack of strength, which is directly related to the muscle loss. Indeed, apart from the speed of loss, muscle wasting during cancer and ageing share many common metabolic pathways and mediators. In healthy young individuals, muscles maintain their mass and function because of a balance between protein synthesis and protein degradation associated with rates of anabolic and catabolic processes, respectively. Muscles grow (hypertrophy) when protein synthesis exceeds protein degradation. Conversely, muscles shrink (atrophy) when protein degradation dominates. These processes are not occurring independently of each other, but are finely coordinated by a web of intricate signalling networks. Such signalling networks are in charge of executing environmental and cellular cues that ultimately determine whether muscle proteins are synthesised or degraded. Increasing our understanding for the pathways involved in hypertrophy and atrophy and particularly the interaction of these pathways is essential in designing therapeutic strategies for both prevention and treatment of muscle wasting conditions with age and with disease.

Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia.

PubMed

Tenk, Judit; Rostás, Ildikó; Füredi, Nóra; Mikó, Alexandra; Solymár, Margit; Soós, Szilvia; Gaszner, Balázs; Feller, Diana; Székely, Miklós; Pétervári, Erika; Balaskó, Márta

2017-02-01

Hypothalamic corticotropin-releasing factor (CRF) lays downstream to catabolic melanocortins and at least partly mediates their catabolic effects. Age-related changes in the melanocortin system (weak responsiveness in middle-aged and a strong one in old rats) have been shown to contribute to middle-aged obesity and later to aging anorexia and cachexia of old age groups. We hypothesized that catabolic (anorexigenic and hypermetabolic) CRF effects vary with aging similarly to those of melanocortins. Thus, we aimed to test whether age-related variations of CRF effects may also contribute to middle-aged obesity and aging anorexia leading to weight loss of old age groups. Food intake, body weight, core temperature, heart rate, and activity were recorded in male Wistar rats of young, middle-aged, aging, and old age groups (from 3 to 24 months) during a 7-day intracerebroventricular CRF infusion (0.2 μg/μl/h) in a biotelemetric system. In addition, CRF gene expression was also assessed by quantitative RT-PCR in the paraventricular nucleus (PVN) of intact animals of the same age groups. The infusion suppressed body weight in the young, aging, and old rats, but not in middle-aged animals. Weak anorexigenic and hypermetabolic effects were detected in the young, whereas strong anorexia (without hypermetabolism) developed in the oldest age groups in which post mortem analysis showed also a reduction of retroperitoneal fat mass. CRF gene expression in the PVN increased with aging. Our results support the potential contribution of age-related changes in CRF effects to aging anorexia and cachexia. The role of the peptide in middle-aged obesity cannot be confirmed.

The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats.

PubMed

Borner, Tito; Loi, Laura; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

2016-07-01

The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia. Copyright © 2016 the American Physiological Society.

Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice.

PubMed

Murphy, Kate T; Chee, Annabel; Gleeson, Ben G; Naim, Timur; Swiderski, Kristy; Koopman, René; Lynch, Gordon S

2011-09-01

Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg·kg⁻¹·wk⁻¹, LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment (P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P < 0.05) but was not improved with PF-354 treatment (P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice (P < 0.05) but was not different in PF-354-treated tumor-bearing mice (P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.

Nutrition in Cancer Care (PDQ®)—Health Professional Version

Cancer.gov

Nutrition in cancer care can be affected by the tumor or by treatment and result in weight loss, malnutrition, anorexia, cachexia, and sarcopenia. Get information about strategies to screen, assess, and treat nutritional problems, including through diet and supplements, in this clinician summary.

THE RENIN-ANGIOTENSIN SYSTEM AND THE BIOLOGY OF SKELETAL MUSCLE: MECHANISMS OF MUSCLE WASTING IN CHRONIC DISEASE STATES.

PubMed

Delafontaine, Patrice; Yoshida, Tadashi

2016-01-01

Sarcopenia and cachexia are muscle-wasting syndromes associated with aging and with many chronic diseases such as congestive heart failure, diabetes, cancer, chronic obstructive pulmonary disease, and renal failure. While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). We found that Ang II infusion in rodents leads to skeletal muscle wasting via alterations in insulin-like growth factor-1 signaling, increased apoptosis, enhanced muscle protein breakdown via the ubiquitin-proteasome system, and decreased appetite resulting from downregulation of hypothalamic orexigenic neuropeptides orexin and neuropeptide Y. Furthermore, Ang II inhibits skeletal muscle stem cell proliferation, leading to lowered muscle regenerative capacity. Distinct stem cell Ang II receptor subtypes are critical for regulation of muscle regeneration. In ischemic mouse congestive heart failure model skeletal muscle wasting and attenuated muscle regeneration are Ang II dependent. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states.

Nutritional issues in heart transplant candidates and recipients.

PubMed

Amarelli, Cristiano; Buonocore, Marianna; Romano, Gianpaolo; Maiello, Ciro; De Santo, Luca Salvatore

2012-01-01

Heart transplant is the golden standard in the management of end-stage heart failure. Recent studies have pointed out the role of nutritional issues in patients evaluated for heart transplant listing. In particular, extremes in body habitus, cachexia and obesity, have been characterized and identified as independent prognostic factors and clinically relevant target for therapeutic interventions. Effects of such conditions exert a prognostic implication well beyond waiting time up to early post transplant setting. Changes in posttransplant clinical conditions and nutritional status have been recently described in their pattern of presentation and implications on weight gain, reversal of preoperative cachexia and early and late morbidity and mortality. New onset diabetes mellitus and metabolic syndrome have been disclosed as relevant clinical conditions in this setting. Implications for tailoring of immunosuppressive therapy and dietary prescription emerged as main stem of long term recipient management. All this issues have been reviewed focusing on the clinical relevance of this growing body of knowledge and emphasizing the role of a multidisciplinary approach for selection and management of heart transplant recipients.

The 2014 ESPEN Arvid Wretlind Lecture: Metabolism & nutrition: Shifting paradigms in COPD management.

PubMed

Schols, Annemie M W J

2015-12-01

COPD is a chronic disease of the lungs, but heterogeneous with respect to clinical manifestations and disease progression. This has consequences for health risk assessment, stratification and management. Heterogeneity can be driven by pulmonary events but also by systemic consequences (e.g. cachexia and muscle weakness) and co-morbidity (e.g. osteoporosis, diabetes and cardiovascular disease). This paper shows how a metabolic perspective on COPD has contributed significantly to understanding clinical heterogeneity and the need for a paradigm shift from reactive medicine towards predictive, preventive, personalized and participatory medicine. These insights have also lead to a paradigm shift in nutritional therapy for COPD from initial ignorance or focusing on putative adverse effects of carbohydrate overload on the ventilatory system to beneficial effects of nutritional intervention on body composition and physical functioning as integral part of disease management. The wider implications beyond COPD as disease have been as clinical model for translational cachexia research. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Beyond anorexia -cachexia. Nutrition and modulation of cancer patients' metabolism: supplementary, complementary or alternative anti-neoplastic therapy?

PubMed

Laviano, Alessandro; Seelaender, Marilia; Sanchez-Lara, Karla; Gioulbasanis, Ioannis; Molfino, Alessio; Rossi Fanelli, Filippo

2011-09-01

Anorexia and muscle wasting are frequently observed in cancer patients and influence their clinical outcome. The better understanding of the mechanisms underlying behavioral changes and altered metabolism yielded to the development of specialized nutritional support, which enhances utilization of provided calories and proteins by counteracting some of the metabolic derangements occurring during tumor growth. Inflammation appears to be a key factor determining the cancer-associated biochemical abnormalities eventually leading to anorexia and cachexia. Interestingly, inflammation is also involved in carcinogenesis, cancer progression and metastasis by impairing immune surveillance, among other mechanisms. Therefore, nutritional interventions aiming at modulating inflammation to restore nutritional status may also result in improved response to pharmacological anti-cancer therapies. Recent clinical data show that supplementation with nutrients targeting inflammation and immune system increases response rate and survival in cancer patients. This suggests that nutrition therapy should be considered as an important adjuvant strategy in the multidimensional approach to cancer patients. Copyright © 2011 Elsevier B.V. All rights reserved.

Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia.

PubMed

Yeh, Kun-Yun; Wang, Hung-Ming; Chang, John W-C; Huang, Jen-Seng; Lai, Chien-Hong; Lan, Yii-Jenq; Wu, Tsung-Han; Chang, Pei-Hung; Wang, Hang; Wu, Chang-Jer; Hsia, Simon; Wang, Cheng-Hsu

2013-07-01

To evaluate whether an oral nutritional supplement enriched with omega-3 fatty acids, micronutrients, and probiotics affected body weight (BW) changes, serum albumin and prealbumin levels in patients with head and neck cancer (HNC) cachexia. Sixty-eight HNC patients were randomly assigned to receive either an Ethanwell/Ethanzyme (EE) regimen enriched with omega-3 fatty acids, micronutrients, and probiotics, or control (Isocal) for a 3-month period. Analysis of covariance was used to examine the association between BW change and variables. Patients with body mass index (BMI) <19 and those receiving the EE regimen consumed fewer daily calories but showed significantly increased BW and maintained higher serum albumin and prealbumin levels than other patients (P<.05). Their BW changes were significantly associated with changes in serum albumin and prealbumin levels. EE regimen improved BW as well as serum albumin and prealbumin levels in HNC patients with BMI <19. Copyright © 2013 Elsevier Inc. All rights reserved.

Lentinan: hematopoietic, immunological, and efficacy studies in a syngeneic model of acute myeloid leukemia.

PubMed

McCormack, Emmet; Skavland, Jørn; Mujic, Maja; Bruserud, Øystein; Gjertsen, Bjørn Tore

2010-01-01

Lentinan, a beta-glucan nutritional supplement isolated from the shitake mushroom (Lentula edodes), is a biological response modifier with immunostimulatory properties. Concomitantly, the role of beta-glucans as chemoimmunotherapeutic in a number of solid cancers has been widely documented. We investigated the effects of nutritional grade lentinan upon BN rats and in a preclinical syngeneic model of acute myeloid leukemia. BN rats supplemented daily with lentinan exhibited weight gains, increased white blood cells, monocytes, and circulating cytotoxic T-cells; and had a reduction in anti-inflammatory cytokines IL-4, IL-10, and additionally IL-6. Lentinan treatment of BN rats with BNML leukemia resulted in improved cage-side health and reduced cachexia in the terminal stage of this aggressive disease. Combination of lentinan with standards of care in acute myeloid leukemia, idarubicin, and cytarabine increased average survival compared with monotherapy and reduced cachexia. These results indicate that nutritional supplementation of cancer patients with lentinan should be further investigated.

Impact of cancer anorexia-cachexia syndrome on health-related quality of life and resource utilisation: A systematic review.

PubMed

Tarricone, Rosanna; Ricca, Giada; Nyanzi-Wakholi, Barbara; Medina-Lara, Antonieta

2016-03-01

Cancer anorexia-cachexia syndrome (CACS) negatively impacts patients' quality of life (QoL) and increases the burden on healthcare resources. To review published CACS data regarding health-related QOL (HRQoL) and its economic impact on the healthcare system. Searches were conducted in MEDLINE, EMBASE, DARE, and NHS EED databases. A total of 458 HRQoL and 189 healthcare resources utilisation abstracts were screened, and 42 and 2 full-text articles were included, respectively. The EORTC QLQ-C30 and FAACT instruments were most favoured for assessing HRQOL but none of the current tools cover all domains affected by CACS. Economic estimates for managing CACS are scarce, with studies lacking a breakdown of healthcare resource utilisation items. HRQoL instruments that can better assess and incorporate all the domains affected by CACS are required. Rigorous assessment of costs and benefits of treatment are needed to understand the magnitude of the impact of CACS. Copyright © 2016. Published by Elsevier Ireland Ltd.

Cachexia and adiposity in rheumatoid arthritis. Relevance for disease management and clinical outcomes.

PubMed

Challal, Salima; Minichiello, Emeline; Boissier, Marie-Christophe; Semerano, Luca

2016-03-01

Altered body composition is a frequent finding in rheumatoid arthritis and is associated with the two major outcomes of the disease: disability and cardiovascular mortality. It is estimated that up to two thirds of patients may be affected by loss of lean mass, the so-called rheumatoid cachexia. Hence, body weight being equal, the relative amount of lean mass is lower and that of body fat is higher in rheumatoid arthritis patients vs. healthy controls. Both disease-related factors and other factors, like drug treatments, physical activity and nutrition contribute to modify body composition in rheumatoid arthritis. The effect of pharmacological treatments, and notably of anti-TNF drugs, on body composition is controversial. Conversely, training programs to stimulate muscle growth can restore lean mass and reduce adiposity. There is good evidence that amelioration of body composition ameliorates function and reduces disability. Currently, there is no evidence that interventions that modify body composition can reduce cardiovascular morbidity and mortality in rheumatoid arthritis. Copyright © 2015. Published by Elsevier SAS.

Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

USDA-ARS?s Scientific Manuscript database

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghreli...

Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions.

PubMed

Holeček, Milan

2017-08-01

Beta-hydroxy-beta-methylbutyrate (HMB) is a metabolite of the essential amino acid leucine that has been reported to have anabolic effects on protein metabolism. The aims of this article were to summarize the results of studies of the effects of HMB on skeletal muscle and to examine the evidence for the rationale to use HMB as a nutritional supplement to exert beneficial effects on muscle mass and function in various conditions of health and disease. The data presented here indicate that the beneficial effects of HMB have been well characterized in strength-power and endurance exercise. HMB attenuates exercise-induced muscle damage and enhances muscle hypertrophy and strength, aerobic performance, resistance to fatigue, and regenerative capacity. HMB is particularly effective in untrained individuals who are exposed to strenuous exercise and in trained individuals who are exposed to periods of high physical stress. The low effectiveness of HMB in strength-trained athletes could be due to the suppression of the proteolysis that is induced by the adaptation to training, which may blunt the effects of HMB. Studies performed with older people have demonstrated that HMB can attenuate the development of sarcopenia in elderly subjects and that the optimal effects of HMB on muscle growth and strength occur when it is combined with exercise. Studies performed under in vitro conditions and in various animal models suggest that HMB may be effective in treatment of muscle wasting in various forms of cachexia. However, there are few clinical reports of the effects of HMB on muscle wasting in cachexia; in addition, most of these studies evaluated the therapeutic potential of combinations of various agents. Therefore, it has not been possible to determine whether HMB was effective or if there was a synergistic effect. Although most of the endogenous HMB is produced in the liver, there are no reports regarding the levels and the effects of HMB supplementation in subjects with liver disease. Several studies have suggested that anabolic effects of HMB supplementation on skeletal muscle do not occur in healthy, non-exercising subjects. It is concluded that (i) HMB may be applied to enhance increases in the mass and strength of skeletal muscles in subjects who exercise and in the elderly and (ii) studies examining the effects of HMB administered alone are needed to obtain conclusions regarding the specific effectiveness in attenuating muscle wasting in various muscle-wasting disorders. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Aerobic and resistance training dependent skeletal muscle plasticity in the colon-26 murine model of cancer cachexia.

PubMed

Khamoui, Andy V; Park, Bong-Sup; Kim, Do-Houn; Yeh, Ming-Chia; Oh, Seung-Lyul; Elam, Marcus L; Jo, Edward; Arjmandi, Bahram H; Salazar, Gloria; Grant, Samuel C; Contreras, Robert J; Lee, Won Jun; Kim, Jeong-Su

2016-05-01

The appropriate mode of exercise training for cancer cachexia is not well-established. Using the colon-26 (C26) mouse model of cancer cachexia, we defined and compared the skeletal muscle responses to aerobic and resistance training. Twelve-month old Balb/c mice were initially assigned to control, aerobic training (AT; wheel running), or resistance training (RT; ladder climbing) (n=16-17/group). After 8weeks of training, half of each group was injected with C26 tumor cells, followed by 3 additional weeks of training. Body composition and neuromuscular function was evaluated pre- and post-training. Muscles were collected post-training and analyzed for fiber cross-sectional area (CSA), Akt-mTOR signaling, and expression of insulin-like growth factor-I (IGF-I) and myogenic regulatory factors. Total body mass decreased (p<0.05) in C26 (-8%), AT+C26 (-18%), and RT+C26 (-15%) but not control. Sensorimotor function declined (p<0.05) in control (-16%), C26 (-13%), and RT+C26 (-23%) but not AT+C26. Similarly, strength/body weight decreased (p<0.05) in control (-7%), C26 (-21%), and RT+C26 (-10%) but not AT+C26. Gastrocnemius mass/body weight tended to be greater in AT+C26 vs. C26 (+6%, p=0.09). Enlargement of the spleen was partially corrected in AT+C26 (-27% vs. C26, p<0.05). Fiber CSA was lower in all C26 groups vs. control (-32% to 46%, p<0.05); however, the effect size calculated from C26 and AT+C26 was large (+24%, d=1.04). Phosphorylated levels of mTOR in AT+C26 exceeded C26 (+32%, p<0.05). RT+C26 showed greater mRNA expression (p<0.05) of IGF-IEa (+79%) and myogenin (+126%) with a strong tendency for greater IGF-IEb (+127%, p=0.069) vs. Aerobic or resistance training was unable to prevent tumor-induced body weight loss. However, aerobic training may have preserved function, reduced the inflammatory response of the spleen, and marginally rescued muscle mass possibly through activation of mTOR. Aerobic training may therefore have therapeutic value for patients with cancer cachexia. In contrast, resistance training induced the expression of genes associated with muscle damage and repair. This gene response may be supportive of excessive stress generated by high resistance loading in a tumor-bearing state. Copyright © 2016 Elsevier Inc. All rights reserved.

Differentiation of citrus Hop stunt viroid variants by real-time RT-PCR and high resolution melting analysis

USDA-ARS?s Scientific Manuscript database

Viroids are small, infectious, single-stranded RNA molecules that cause several important citrus diseases. Viroids are transmitted primarily in budwood, however, spread can also occur mechanically on pruning equipment, budding knives, hedging and topping equipment. Exocortis and cachexia are two we...

Mammary tumorigenesis causes bone loss and dietary selenium supplementation does not affect such bone loss in male MMTV-PyMT mice

USDA-ARS?s Scientific Manuscript database

Cancer progression is accompanied by wasting that eventually results in cachexia characterized by significant weight loss and multi-organ functional failures. Limited clinical trials indicate that bone is adversely affected by cancer-associated wasting. To determine the effects of breast cancer on...

Fatigue and gynecologic cancer.

PubMed

Olt, George J

2003-02-01

Fatigue is common in women with gynecologic cancers and is thought to be multifactorial. Anemia, cachexia, pain, and depression are frequently associated with cancer and treatment-related fatigue and should be evaluated and treated. The National Comprehensive Cancer Network Fatigue Practice Guidelines are helpful in the assessment and treatment of women with gynecologic cancer-related fatigue.

Deletion variant near ZNF389 is associated with control of ovine lentivirus in multiple flocks of sheep

USDA-ARS?s Scientific Manuscript database

Ovine lentivirus (OvLV) is a macrophage-tropic lentivirus found in many countries that causes interstitial pneumonia, mastitis, arthritis and cachexia in sheep. There is no preventive vaccine and no cure, but breed differences suggest marker-assisted selective breeding might improve odds of infectio...

First report of citrus exocortis viroid and two citrus variants of the hop stunt viroid on lemon in Azerbaijan

USDA-ARS?s Scientific Manuscript database

Budwood received from a lemon tree growing at the Bioresources Institute Nakhichivan, Azerbaijan, produced symptoms corresponding with citrus viroids and cachexia on biological indicators ‘S-1’ citron and ‘Parson’s Special’ (PSM) mandarin, respectively. Sequential poly acrylamide gel electrophoresis...

Heteroplasmic mutation in the anticodon-stem of mitochondrial tRNA(Val) causing MNGIE-like gastrointestinal dysmotility and cachexia.

PubMed

Horváth, Rita; Bender, Andreas; Abicht, Angela; Holinski-Feder, Elke; Czermin, Birgit; Trips, Tobias; Schneiderat, Peter; Lochmüller, Hanns; Klopstock, Thomas

2009-05-01

While mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is typically associated with mutations in the nuclear gene encoding for thymidine phosphorylase (ECGF1, TYMP), a similar clinical phenotype was described in patients carrying mutations in the nuclear-encoded polymerase gamma (POLG1) as well as a few mitochondrial tRNA genes. Here we report a novel mutation in the mitochondrial tRNA(Val) (MTTV) gene in a girl presenting with clinical symptoms of MNGIE-like gastrointestinal dysmotility and cachexia. Clinical, histological, biochemical and single cell investigations were performed. The heteroplasmic m.1630A>G mutation was detected in the mitochondrial tRNA(Val) (MTTV) gene in the patient's muscle, blood leukocytes and myoblasts, as well as in blood DNA of the unaffected mother. We provide clinical, biochemical, histological, and molecular genetic evidence on the single cell level for the pathogenicity of this mutation. Our finding adds to the genetic heterogeneity of MNGIE-like gastrointestinal symptoms and highlights the importance of a thorough genetic workup in case of suspected mitochondrial disease.

Using polyphenol derivatives to prevent muscle wasting.

PubMed

Francaux, Marc; Deldicque, Louise

2018-05-01

To highlight recent evidence for the ability of polyphenols and their derivatives to reduce muscle wasting in different pathological states. From January 2016 to August 2017, four articles dealt with the effects of polyphenols on muscle wasting, which were all carried out in mice. The four studies found that polyphenols reduced muscle mass loss associated with cancer cachexia, acute inflammation or sciatic nerve section. One study even showed that muscle mass was totally preserved when rutin was added to the diet of mice undergoing cancer cachexia. The beneficial effects of polyphenols on muscle wasting were mainly due to a reduction in the activation of the nuclear factor-kappa B pathway, a lower oxidative stress level and a better mitochondrial function. In addition, urolithin B was found to have a testosterone-like effect and to favorably regulate muscle protein balance. During the last 20 months, additional data have been collected about the beneficial effects of rutin, curcumin, quercetin, ellagitanins and urolithin B to limit the loss of muscle mass associated with several pathological states. However, currently, scientific evidence lacks for their use as nutraceuticals in human.

Therapeutic Potential of Targeting the Ghrelin Pathway.

PubMed

Colldén, Gustav; Tschöp, Matthias H; Müller, Timo D

2017-04-11

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems' metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.

Therapeutic Potential of Targeting the Ghrelin Pathway

PubMed Central

Colldén, Gustav; Tschöp, Matthias H.; Müller, Timo D.

2017-01-01

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome. PMID:28398233

Linking Cancer Cachexia-Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism

PubMed Central

Montalvo, Ryan N.

2017-01-01

Cancer cachexia, a wasting syndrome characterized by skeletal muscle depletion, contributes to increased patient morbidity and mortality. While the intricate balance between protein synthesis and breakdown regulates skeletal muscle mass, the suppression of basal protein synthesis may not account for the severe wasting induced by cancer. Therefore, recent research has shifted to the regulation of “anabolic resistance,” which is the impaired ability of nutrition and exercise to stimulate protein synthesis. Emerging evidence suggests that oxidative metabolism can regulate both basal and induced muscle protein synthesis. While disrupted protein turnover and oxidative metabolism in cachectic muscle have been examined independently, evidence suggests a linkage between these processes for the regulation of cancer-induced wasting. The primary objective of this review is to highlight the connection between dysfunctional oxidative metabolism and cancer-induced anabolic resistance in skeletal muscle. First, we review oxidative metabolism regulation of muscle protein synthesis. Second, we describe cancer-induced alterations in the response to an anabolic stimulus. Finally, we review a role for exercise to inhibit cancer-induced anabolic suppression and mitochondrial dysfunction. PMID:29375734

Tight control of disease activity fails to improve body composition or physical function in rheumatoid arthritis patients.

PubMed

Lemmey, Andrew B; Wilkinson, Thomas J; Clayton, Rebecca J; Sheikh, Fazal; Whale, John; Jones, Hope S J; Ahmad, Yasmeen A; Chitale, Sarang; Jones, Jeremy G; Maddison, Peter J; O'Brien, Thomas D

2016-10-01

RA typically features rheumatoid cachexia [loss of muscle mass (MM) and excessive total fat mass (TFM), especially trunk FM], which contributes to physical disability. Since rheumatoid cachexia is driven by inflammation, it would be anticipated that the success of tight control of disease activity, such as treat-to-target (T2T), in attenuating inflammation would benefit body composition and physical function. This aim of this cross-sectional study was to assess the impact of T2T on body composition and objectively assessed function in RA patients. A total of 82 RA patients exclusively treated by T2T, were compared with 85 matched sedentary healthy controls (HCs). Body composition was estimated by DXA, with appendicular lean mass the surrogate measure of total MM. Physical function was assessed by knee extensor strength, handgrip strength, 30 s sit-to-stands, 8' up and go, and 50' walk (tests which reflect the ability to perform activities of daily living). Although generally well treated (mean DAS28 = 2.8, with 49% in remission), RA patients had ∼10% proportionally less appendicular lean mass and were considerably fatter (by ∼27%), particularly in the trunk (∼32%), than HCs. All measures of function were 24-34% poorer in the RA patients relative to HC. Despite marked improvements in disease control (most patients achieving or approaching remission), the relative loss of MM and increased adiposity in RA patients compared with matched HCs was similar to that observed pre-T2T. Additionally, performance of objective function tests was unchanged from that reported by our group for pre-T2T RA patients. Thus T2T, even in responsive RA patients, did not attenuate rheumatoid cachexia or improve objectively assessed function. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Medium-chain triglycerides/long-chain triglycerides versus long-chain triglycerides in treatment of cancer patients with major body mass loss. Survival in patients with refractory cachexia.

PubMed

Szefel, Jarosław; Kruszewski, Wiesław J; Szajewski, Mariusz; Ciesielski, Maciej; Sobczak, Ewa; Czerepko, Maksymilian; Łysiak-Szydłowska, Wiesława

2016-01-01

Currently there are no established guidelines regarding the use of long-chain triglycerides (LCT) vs. medium-chain triglycerides medium-chain triglycerides (MCT)/long-chain triglycerides (LCT) in total parenteral nutrition (TPN). Severe malnutrition of patients with refractory cachexia (RC) often causes their disqualification from invasive methods of treatment thus decreasing their quality of life and survival time. To compare the changes in nutritional state of patients with RC receiving PN with LCT and LCT/MCT lipid emulsions and to assess the influence of enteral nutrition on their survival time. The study group comprised of 50 patients (23 female, 27 male) with a median age of 66 years. Refractory cachexia was diagnosed in them due to dysphagia secondary to solid tumours causing obstruction of the gastrointestinal tract (GT). All patients were qualified for surgical gastrostomy due to contraindications to percutaneous endoscopic gastrostomy. The patients were randomly assigned into one of two groups and perioperatively received either LCT or LCT/MCT. Blood samples were collected four times and tested for: total protein, albumin, prealbumin, and C-reactive protein concentration. Patients received Home Enteral Nutrition after discharge from hospital. Changes in nutritional status parameters were similar among patients receiving lipid emulsions LCT vs. MCT/LCT in TPN for 11 days. The mean survival time of all patients operated to gain enteral access to nutrition was 192 ±268 days, and the median survival was 98 days. Regarding the short-term TPN, the results of the study do not demonstrate any superiority of MCT/LCT lipid emulsions over LCT, or vice versa. The inability to eat significantly accelerates unintended body mass loss among patients with RC. Disqualification from invasive treatment options deprives some patients of the benefits they might have obtained from the surgical access to GT and enteral nutrition.

A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women.

PubMed

Wright, Traver J; Dillon, E Lichar; Durham, William J; Chamberlain, Albert; Randolph, Kathleen M; Danesi, Christopher; Horstman, Astrid M; Gilkison, Charles R; Willis, Maurice; Richardson, Gwyn; Hatch, Sandra S; Jupiter, Daniel C; McCammon, Susan; Urban, Randall J; Sheffield-Moore, Melinda

2018-06-01

Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment. A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival. A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0-7%) whereas those receiving placebo lost 3.3% (95% CI, -7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups. In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo. © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Medium-chain triglycerides/long-chain triglycerides versus long-chain triglycerides in treatment of cancer patients with major body mass loss. Survival in patients with refractory cachexia

PubMed Central

Kruszewski, Wiesław J.; Szajewski, Mariusz; Ciesielski, Maciej; Sobczak, Ewa; Czerepko, Maksymilian; Łysiak-Szydłowska, Wiesława

2016-01-01

Introduction Currently there are no established guidelines regarding the use of long-chain triglycerides (LCT) vs. medium-chain triglycerides medium-chain triglycerides (MCT)/long-chain triglycerides (LCT) in total parenteral nutrition (TPN). Severe malnutrition of patients with refractory cachexia (RC) often causes their disqualification from invasive methods of treatment thus decreasing their quality of life and survival time. Aim To compare the changes in nutritional state of patients with RC receiving PN with LCT and LCT/MCT lipid emulsions and to assess the influence of enteral nutrition on their survival time. Material and methods The study group comprised of 50 patients (23 female, 27 male) with a median age of 66 years. Refractory cachexia was diagnosed in them due to dysphagia secondary to solid tumours causing obstruction of the gastrointestinal tract (GT). All patients were qualified for surgical gastrostomy due to contraindications to percutaneous endoscopic gastrostomy. The patients were randomly assigned into one of two groups and perioperatively received either LCT or LCT/MCT. Blood samples were collected four times and tested for: total protein, albumin, prealbumin, and C-reactive protein concentration. Patients received Home Enteral Nutrition after discharge from hospital. Results Changes in nutritional status parameters were similar among patients receiving lipid emulsions LCT vs. MCT/LCT in TPN for 11 days. The mean survival time of all patients operated to gain enteral access to nutrition was 192 ±268 days, and the median survival was 98 days. Conclusions Regarding the short-term TPN, the results of the study do not demonstrate any superiority of MCT/LCT lipid emulsions over LCT, or vice versa. The inability to eat significantly accelerates unintended body mass loss among patients with RC. Disqualification from invasive treatment options deprives some patients of the benefits they might have obtained from the surgical access to GT and enteral nutrition. PMID:27713780

Decrease of serum carnitine levels in patients with or without gastrointestinal cancer cachexia.

PubMed

Malaguarnera, Mariano; Risino, Corrado; Gargante, Maria Pia; Oreste, Giovanni; Barone, Gloria; Tomasello, Anna Veronica; Costanzo, Mario; Cannizzaro, Matteo Angelo

2006-07-28

To evaluate the levels of serum carnitine in patients with cancer in digestive organs and to compare them with other cancers in order to provide new insights into the mechanisms of cachexia. Fifty-five cachectic patients with or without gastrointestinal cancer were enrolled in the present study. They underwent routine laboratory investigations, including examination of the levels of various forms of carnitine present in serum (i.e., long-chain acylcarnitine, short-chain acylcarnitine, free carnitine, and total carnitine). These values were compared with those found in 60 cancer patients in good nutritional status as well as with those of 30 healthy control subjects. When the cachectic patients with gastro-intestinal cancer were compared with the cachectic patients without gastrointestinal cancer, the difference was -6.8 micromol/L in free carnitine (P < 0.005), 0.04 micromol/L in long chain acylcarnitine (P < 0.05), 8.7 micromol/L in total carnitine (P < 0.001). In the cachectic patients with or without gastrointestinal cancer, the difference was 12.2 micromol/L in free carnitine (P < 0.001), 4.60 micromol/L in short chain acylcarnitine (P < 0.001), and 0.60 micromol /L in long-chain acylcarnitine (P < 0.005) and 17.4 micromol/L in total carnitine (P < 0.001). In the cachectic patients with gastrointestinal cancer and the healthy control subjects, the difference was 15.5 micromol/L in free carnitine (P < 0.001), 5.2 micromol /L in short-chain acylcarnitine (P < 0.001), 1.0 micromol/L in long chain acylcarnitine (P < 0.001), and 21.8 micromol/L in total carnitine (P < 0.001). Low serum levels of carnitine in terminal neoplastic patients are decreased greatly due to the decreased dietary intake and impaired endogenous synthesis of this substance. These low serum carnitine levels also contribute to the progression of cachexia in cancer patients.

Cardiac muscle wasting in individuals with cancer cachexia.

PubMed

Barkhudaryan, Anush; Scherbakov, Nadja; Springer, Jochen; Doehner, Wolfram

2017-11-01

Cachexia is a severe complication of cancer that adversely affects the course of the disease and is associated with high rates of mortality. Patients with cancer manifest symptoms, such as fatigue, shortness of breath, and impaired exercise tolerance, which are clinical signs of chronic heart failure. The aim of this study was to evaluate cardiac muscle wasting in cancer individuals. We retrospectively analysed 177 individuals who died of cancer, including 58 lung, 60 pancreatic, and 59 gastrointestinal (GI) cancers, and 42 cancer-free controls who died of other, non-cardiovascular reasons. Cancer cachexia (CC) was defined based on clinical and/or pathological diagnosis, body mass index (BMI) <20.0 kg/m 2 and/or oedema-free body weight loss of 5.0% during the previous year or less. The pathology reports were analysed for BMI, heart weight (HW), and left and right ventricular wall thicknesses (LVWT and RVWT, respectively). The analysis of clinical data included recording of biochemical parameters and medication data of study patients. CC was detected in 54 (30.5%) subjects. Individuals with CC had a significantly lower HW than non-cachectic subjects (363.1 ± 86.2 vs. 447.0 ± 128.9 g, P < 0.001) and control group (412.9 ± 75.8 g, P < 0.05). BMI correlated with HW in cases with GI cancer (r = 0.44, P < 0.001), lung cancer (r = 0.53, P < 0.0001), and pancreatic cancer (r = 0.39, P < 0.01). Body weight loss in individuals with lung, pancreatic, and GI cancers is accompanied by a decrease in HW. In patients with CC who receive cancer treatment, screening for cardiac muscle wasting may have clinical importance. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Decrease of serum carnitine levels in patients with or without gastrointestinal cancer cachexia

PubMed Central

Malaguarnera, Mariano; Risino, Corrado; Gargante, Maria Pia; Oreste, Giovanni; Barone, Gloria; Tomasello, Anna Veronica; Costanzo, Mario; Cannizzaro, Matteo Angelo

2006-01-01

AIM: To evaluate the levels of serum carnitine in patients with cancer in digestive organs and to compare them with other cancers in order to provide new insights into the mechanisms of cachexia. METHODS: Fifty-five cachectic patients with or without gastrointestinal cancer were enrolled in the present study. They underwent routine laboratory investigations, including examination of the levels of various forms of carnitine present in serum (i.e., long-chain acylcarnitine, short-chain acylcarnitine, free carnitine, and total carnitine). These values were compared with those found in 60 cancer patients in good nutritional status as well as with those of 30 healthy control subjects. RESULTS: When the cachectic patients with gastro-intestinal cancer were compared with the cachectic patients without gastrointestinal cancer, the difference was -6.8 μmol/L in free carnitine (P < 0.005), 0.04 μmol/L in long chain acylcarnitine (P < 0.05), 8.7 μmol/L in total carnitine (P < 0.001). In the cachectic patients with or without gastrointestinal cancer, the difference was 12.2 μmol/L in free carnitine (P < 0.001), 4.60 μmol/L in short chain acylcarnitine (P < 0.001), and 0.60 μmol /L in long-chain acylcarnitine (P < 0.005) and 17.4 μmol/L in total carnitine (P < 0.001). In the cachectic patients with gastrointestinal cancer and the healthy control subjects, the difference was 15.5 μmol/L in free carnitine (P < 0.001), 5.2 μmol /L in short-chain acylcarnitine (P < 0.001), 1.0 μmol/L in long chain acylcarnitine (P < 0.001), and 21.8 μmol/L in total carnitine (P < 0.001). CONCLUSION: Low serum levels of carnitine in terminal neoplastic patients are decreased greatly due to the decreased dietary intake and impaired endogenous synthesis of this substance. These low serum carnitine levels also contribute to the progression of cachexia in cancer patients. PMID:16874868

Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

PubMed Central

Rapin, Isabelle; Weidenheim, Karen; Lindenbaum, Yelena; Rosenbaum, Pearl; Merchant, Saumil N.; Krishna, Sindu; Dickson, Dennis W.

2009-01-01

Cockayne syndrome and xeroderma pigmentosum–Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31½ years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum–Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known. PMID:17092472

Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group.

PubMed

Strasser, Florian; Luftner, Diana; Possinger, Kurt; Ernst, Gernot; Ruhstaller, Thomas; Meissner, Winfried; Ko, You-Dschun; Schnelle, Martin; Reif, Marcus; Cerny, Thomas

2006-07-20

To compare the effects of cannabis extract (CE), delta-9-tetrahydrocannabinol (THC), and placebo (PL) on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS). Adult patients with advanced cancer, CACS, weight loss (> or = 5% over 6 months), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 were randomly assigned (2:2:1) to receive CE (standardized for 2.5 mg THC and 1 mg cannabidiol) or THC (2.5 mg) or PL orally, twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily with a visual analog scale (VAS); QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (composite score: questions 29 and 30). Cannabinoid-related toxicity was assessed every 2 weeks. Of 289 patients screened, 243 were randomly assigned and 164 (CE, 66 of 95 patients; THC, 65 of 100 patients; and PL, 33 of 48 patients) completed treatment. At baseline, groups were comparable for age (mean, 61 years), sex (54% men), weight loss (32% > or = 10%), PS (13% ECOG = 2), antineoplastic treatment (50%), appetite (mean VAS score, 31/100 mm), and QOL (mean score, 30/100). Intent-to-treat analysis showed no significant differences between the three arms for appetite, QOL, or cannabinoid-related toxicity. Increased appetite was reported by 73%, 58%, and 69% of patients receiving CE, THC, or PL, respectively. An independent data review board recommended termination of recruitment because of insufficient differences between study arms. CE at the oral dose administered was well tolerated by these patients with CACS. No differences in patients' appetite or QOL were found either between CE, THC, and PL or between CE and THC at the dosages investigated.

Correlation between the international consensus definition of the Cancer Anorexia-Cachexia Syndrome (CACS) and patient-centered outcomes in advanced non-small cell lung cancer.

PubMed

LeBlanc, Thomas W; Nipp, Ryan D; Rushing, Christel N; Samsa, Greg P; Locke, Susan C; Kamal, Arif H; Cella, David F; Abernethy, Amy P

2015-04-01

The cancer anorexia-cachexia syndrome (CACS) is common in patients with advanced solid tumors and is associated with adverse outcomes including poor quality of life (QOL), impaired functioning, and shortened survival. To apply the recently posed weight-based international consensus CACS definition to a population of patients with advanced non-small cell lung cancer (NSCLC) and explore its impact on patient-reported outcomes. Ninety-nine patients participated in up to four study visits over a six-month period. Longitudinal assessments included measures of physical function, QOL, and other clinical variables such as weight and survival. Patients meeting the consensus CACS criteria at Visit 1 had a significantly shorter median survival (239.5 vs. 446 days; hazard ratio, 2.06, P < 0.05). Physical function was worse in the CACS group (mean Karnofsky Performance Status score 68 vs. 77, Eastern Cooperative Oncology Group Performance Status score 1.8 vs. 1.3, P < 0.05 for both), as was QOL (Functional Assessment of Cancer Therapy-General [FACT-G] Lung Cancer subscale of 17.2 vs. 19.9, Anorexia/Cachexia subscale of 31.4 vs. 37.9, P < 0.05 for both). Differences in the FACT-G and the Functional Assessment of Chronic Illness Therapy-Fatigue subscale approached but did not reach statistical significance. Longitudinally, all measures of physical function and QOL worsened regardless of CACS status, but the rate of decline was more rapid in the CACS group. The weight-based component of the recently proposed international consensus CACS definition is useful in identifying patients with advanced NSCLC who are likely to have significantly inferior survival and who will develop more precipitous declines in physical function and QOL. This definition may be useful for clinical screening purposes and identify patients with high palliative care needs. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Rapid differentiation of citrus Hop stunt viroid variants by use of real-time RT-PCR and high resolution melting analysis

USDA-ARS?s Scientific Manuscript database

The RNA genome of Hop stunt viroid (HSVd) contains five to six nucleotides in a variable (V) domain, called the cachexia expression motif, which is associated with pathogenic and non-pathogenic variants in citrus. Current methods to differentiate HSVd variants rely on lengthy greenhouse biological i...

Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human Disease.

PubMed

Go, Kristina L; Delitto, Daniel; Judge, Sarah M; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Judge, Andrew R; Trevino, Jose G

2017-07-01

Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model. The purpose of this study was to evaluate the degree to which an orthotopic PDX model of PC recapitulates these aspects of the human disease. Human PDX-derived PC tumors were implanted directly into the pancreas of NOD.Cg-Prkdc Il2rg/SzJ mice. Tumor growth, metastasis, and muscle wasting were then evaluated. Orthotopically implanted PDX-derived tumors consistently incorporated into the murine pancreatic parenchyma, metastasized to both the liver and lungs and induced muscle wasting directly proportional to the size of the tumor, consistent of the cancer cachexia syndrome. Through the orthotopic implantation technique described, we demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human PC.

Role of Protein Carbonylation in Skeletal Muscle Mass Loss Associated with Chronic Conditions

PubMed Central

Barreiro, Esther

2016-01-01

Muscle dysfunction, characterized by a reductive remodeling of muscle fibers, is a common systemic manifestation in highly prevalent conditions such as chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), cancer cachexia, and critically ill patients. Skeletal muscle dysfunction and impaired muscle mass may predict morbidity and mortality in patients with chronic diseases, regardless of the underlying condition. High levels of oxidants may alter function and structure of key cellular molecules such as proteins, DNA, and lipids, leading to cellular injury and death. Protein oxidation including protein carbonylation was demonstrated to modify enzyme activity and DNA binding of transcription factors, while also rendering proteins more prone to proteolytic degradation. Given the relevance of protein oxidation in the pathophysiology of many chronic conditions and their comorbidities, the current review focuses on the analysis of different studies in which the biological and clinical significance of the modifications induced by reactive carbonyls on proteins have been explored so far in skeletal muscles of patients and animal models of chronic conditions such as COPD, disuse muscle atrophy, cancer cachexia, sepsis, and physiological aging. Future research will elucidate the specific impact and sites of reactive carbonyls on muscle protein content and function in human conditions. PMID:28248228

Antioxidant effects of açaí seed ( Euterpe oleracea ) in anorexia-cachexia syndrome induced by Walker-256 tumor.

PubMed

Nascimento, Vitor Hugo Nunes do; Lima, Carla Dos Santos; Paixão, Jorge Tadeu Campos; Freitas, Jofre Jacob da Silva; Kietzer, Katia Simone

2016-09-01

To assess antioxidant effects of açaí seed extract on anorexia-cachexia induced by Walker-256 tumor. A population of 20 lab rats were distributed into four groups (n=5): Control Group (CG), which only received tumor inoculation. Experimental Group-100 (EG-100), with animals submitted to tumor inoculation and treated with seed extract in a 100 mg / ml concentration through gavage. Experimental Group-200 (EG-200), with animals submitted to tumor inoculation and treated with seed extract in a 200 mg / ml concentration. Placebo Group (GP), which received tumor inoculation and ethanol-water solution. We analyzed proteolysis, lipid peroxidation, tumor diameter and weight. Lipid peroxidation was representative only in the cerebral cortex, where there was more oxidative stress in rats treated with the extract (p = 0.0276). For proteolysis, there was less muscle damage in untreated rats (p = 0.0312). Only tumor diameter in treated rats was significantly lower (p = 0.0200) compared to untreated ones. The açaí seed extract showed no beneficial effect on the general framework of the cachectic syndrome in lab rats. However, some anticarcinogenic effects were observed in the tumor diameter and weight.

Efficacy and Safety of Sipjeondaebo-Tang for Anorexia in Patients with Cancer: A Pilot, Randomized, Double-Blind, Placebo-Controlled Trial.

PubMed

Cheon, Chunhoo; Yoo, Jeong-Eun; Yoo, Hwa-Seung; Cho, Chong-Kwan; Kang, Sohyeon; Kim, Mia; Jang, Bo-Hyoung; Shin, Yong-Cheol; Ko, Seong-Gyu

2017-01-01

Anorexia occurs in about half of cancer patients and is associated with high mortality rate. However, safe and long-term use of anorexia treatment is still an unmet need. The purpose of the present study was to examine the feasibility of Sipjeondaebo-tang (Juzen-taiho-to, Shi-Quan-Da-Bu-Tang) for cancer-related anorexia. A total of 32 participants with cancer anorexia were randomized to either Sipjeondaebo-tang group or placebo group. Participants were given 3 g of Sipjeondaebo-tang or placebo 3 times a day for 4 weeks. The primary outcome was a change in the Anorexia/Cachexia Subscale of Functional Assessment of Anorexia/Cachexia Therapy (FAACT). The secondary outcomes included Visual Analogue Scale (VAS) of anorexia, FAACT scale, and laboratory tests. Anorexia and quality of life measured by FAACT and VAS were improved after 4 weeks of Sipjeondaebo-tang treatment. However, there was no significant difference between changes of Sipjeondaebo-tang group and placebo group. Sipjeondaebo-tang appears to have potential benefit for anorexia management in patients with cancer. Further large-scale studies are needed to ensure the efficacy. This trial is registered with ClinicalTrials.gov NCT02468141.

Nutritional status and nutritional support before and after pancreatectomy for pancreatic cancer and chronic pancreatitis.

PubMed

Karagianni, Vasiliki Th; Papalois, Apostolos E; Triantafillidis, John K

2012-12-01

Cachexia, malnutrition, significant weight loss, and reduction in food intake due to anorexia represent the most important pathophysiological consequences of pancreatic cancer. Pathophysiological consequences result also from pancreatectomy, the type and severity of which differ significantly and depend on the type of the operation performed. Nutritional intervention, either parenteral or enteral, needs to be seen as a method of support in pancreatic cancer patients aiming at the maintenance of the nutritional and functional status and the prevention or attenuation of cachexia. Oral nutrition could reduce complications while restoring quality of life. Enteral nutrition in the post-operative period could also reduce infective complications. The evidence for immune-enhanced feed in patients undergoing pancreaticoduodenectomy for pancreatic cancer is supported by the available clinical data. Nutritional support during the post-operative period on a cyclical basis is preferred because it is associated with low incidence of gastric stasis. Postoperative total parenteral nutrition is indicated only to those patients who are unable to be fed orally or enterally. Thus nutritional deficiency is a relatively widesoread and constant finding suggesting that we must optimise the nutritional status both before and after surgery.

Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC.

PubMed

Zhang, Hongjie; Garcia, Jose M

2015-06-01

Cancer anorexia-cachexia syndrome (CACS) is associated with increased morbidity and mortality. Anamorelin is a novel, orally active ghrelin receptor agonist in clinical development for the treatment of CACS in NSCLC. The aim of this review is to summarize preclinical and clinical studies evaluating anamorelin as a potential promising treatment for CACS in NSCLC. Pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability of anamorelin for the treatment of CACS in NSCLC were reviewed. Anamorelin administration may lead to increases in food intake, body weight and lean body mass, and a stimulatory effect on growth hormone secretion in NSCLC patients. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. Targeting ghrelin receptors presents the advantage of potentially addressing multiple mechanisms of CACS simultaneously including appetite, muscle protein balance, adipose tissue metabolism, energy expenditure and inflammation. Clinical data suggest that anamorelin is well tolerated and it effectively increases appetite, body weight and lean mass in patients with advanced NSCLC. Long-term safety remains unknown at this time. The potential synergistic effects of anamorelin with nutritional support or exercise as well as its efficacy/safety in other tumor types are also unknown.

Pathophysiology of anorexia in the cancer cachexia syndrome

PubMed Central

Ezeoke, Chukwuemeka Charles; Morley, John E

2015-01-01

Anorexia is commonly present in persons with cancer and a major component of cancer cachexia. There are multiple causes of anorexia in cancer. Peripherally, these can be due to (i) substances released from or by the tumour, e.g. pro-inflammatory cytokines, lactate, and parathormone-related peptide; (ii) tumours causing dysphagia or altering gut function; (iii) tumours altering nutrients, e.g. zinc deficiency; (iv) tumours causing hypoxia; (v) increased peripheral tryptophan leading to increased central serotonin; or (vi) alterations of release of peripheral hormones that alter feeding, e.g. peptide tyrosine tyrosine and ghrelin. Central effects include depression and pain, decreasing the desire to eat. Within the central nervous system, tumours create multiple alterations in neurotransmitters, neuropeptides, and prostaglandins that modulate feeding. Many of these neurotransmitters appear to produce their anorectic effects through the adenosine monophosphate kinase/methylmalonyl coenzyme A/fatty acid system in the hypothalamus. Dynamin is a guanosine triphosphatase that is responsible for internalization of melanocortin 4 receptors and prostaglandin receptors. Dynamin is up-regulated in a mouse model of cancer anorexia. A number of drugs, e.g. megestrol acetate, cannabinoids, and ghrelin agonists, have been shown to have some ability to be orexigenic in cancer patients. PMID:26675762

Grape polyphenols and propolis mixture inhibits inflammatory mediator release from human leukocytes and reduces clinical scores in experimental arthritis.

PubMed

Mossalayi, M D; Rambert, J; Renouf, E; Micouleau, M; Mérillon, J M

2014-02-15

Polyphenols from red fruits and bee-derived propolis (PR) are bioactive natural products in various in vitro and in vivo models. The present study shows that hematotoxicity-free doses of grape polyphenols (GPE) and PR differentially decreased the secretion of pro-inflammatory cytokines from activated human peripheral blood leucocytes. While GPE inhibited the monocytes/macrophage response, propolis decreased both monokines and interferon γ (IFNγ) production. When used together, their distinct effects lead to the attenuation of all inflammatory mediators, as supported by a significant modulation of the transcriptomic profile of pro-inflammatory genes in human leukocytes. To enforce in vitro data, GPE+PR were tested for their ability to improve clinical scores and cachexia in chronic rat adjuvant-induced arthritis (AA). Extracts significantly reduced arthritis scores and cachexia, and this effect was more significant in animals receiving continuous low doses compared to those receiving five different high doses. Animals treated daily had significantly better clinical scores than corticoid-treated rats. Together, these findings indicate that the GPE+PR combination induces potent anti-inflammatory activity due to their complementary immune cell modulation. Copyright © 2013 Elsevier GmbH. All rights reserved.

Pathophysiology of anorexia in the cancer cachexia syndrome.

PubMed

Ezeoke, Chukwuemeka Charles; Morley, John E

2015-12-01

Anorexia is commonly present in persons with cancer and a major component of cancer cachexia. There are multiple causes of anorexia in cancer. Peripherally, these can be due to (i) substances released from or by the tumour, e.g. pro-inflammatory cytokines, lactate, and parathormone-related peptide; (ii) tumours causing dysphagia or altering gut function; (iii) tumours altering nutrients, e.g. zinc deficiency; (iv) tumours causing hypoxia; (v) increased peripheral tryptophan leading to increased central serotonin; or (vi) alterations of release of peripheral hormones that alter feeding, e.g. peptide tyrosine tyrosine and ghrelin. Central effects include depression and pain, decreasing the desire to eat. Within the central nervous system, tumours create multiple alterations in neurotransmitters, neuropeptides, and prostaglandins that modulate feeding. Many of these neurotransmitters appear to produce their anorectic effects through the adenosine monophosphate kinase/methylmalonyl coenzyme A/fatty acid system in the hypothalamus. Dynamin is a guanosine triphosphatase that is responsible for internalization of melanocortin 4 receptors and prostaglandin receptors. Dynamin is up-regulated in a mouse model of cancer anorexia. A number of drugs, e.g. megestrol acetate, cannabinoids, and ghrelin agonists, have been shown to have some ability to be orexigenic in cancer patients.

Group I Paks support muscle regeneration and counteract cancer-associated muscle atrophy.

PubMed

Cerquone Perpetuini, Andrea; Re Cecconi, Andrea David; Chiappa, Michela; Martinelli, Giulia Benedetta; Fuoco, Claudia; Desiderio, Giovanni; Castagnoli, Luisa; Gargioli, Cesare; Piccirillo, Rosanna; Cesareni, Gianni

2018-05-21

Skeletal muscle is characterized by an efficient regeneration potential that is often impaired during myopathies. Understanding the molecular players involved in muscle homeostasis and regeneration could help to find new therapies against muscle degenerative disorders. Previous studies revealed that the Ser/Thr kinase p21 protein-activated kinase 1 (Pak1) was specifically down-regulated in the atrophying gastrocnemius of Yoshida hepatoma-bearing rats. In this study, we evaluated the role of group I Paks during cancer-related atrophy and muscle regeneration. We examined Pak1 expression levels in the mouse Tibialis Anterior muscles during cancer cachexia induced by grafting colon adenocarcinoma C26 cells and in vitro by dexamethasone treatment. We investigated whether the overexpression of Pak1 counteracts muscle wasting in C26-bearing mice and in vitro also during interleukin-6 (IL6)-induced or dexamethasone-induced C2C12 atrophy. Moreover, we analysed the involvement of group I Paks on myogenic differentiation in vivo and in vitro using the group I chemical inhibitor IPA-3. We found that Pak1 expression levels are reduced during cancer-induced cachexia in the Tibialis Anterior muscles of colon adenocarcinoma C26-bearing mice and in vitro during dexamethasone-induced myotube atrophy. Electroporation of muscles of C26-bearing mice with plasmids directing the synthesis of PAK1 preserves fiber size in cachectic muscles by restraining the expression of atrogin-1 and MuRF1 and possibly by inducing myogenin expression. Consistently, the overexpression of PAK1 reduces the dexamethasone-induced expression of MuRF1 in myotubes and increases the phospho-FOXO3/FOXO3 ratio. Interestingly, the ectopic expression of PAK1 counteracts atrophy in vitro by restraining the IL6-Stat3 signalling pathway measured in luciferase-based assays and by reducing rates of protein degradation in atrophying myotubes exposed to IL6. On the other hand, we observed that the inhibition of group I Paks has no effect on myotube atrophy in vitro and is associated with impaired muscle regeneration in vivo and in vitro. In fact, we found that mice treated with the group I inhibitor IPA-3 display a delayed recovery from cardiotoxin-induced muscle injury. This is consistent with in vitro experiments showing that IPA-3 impairs myogenin expression and myotube formation in vessel-associated myogenic progenitors, C2C12 myoblasts, and satellite cells. Finally, we observed that IPA-3 reduces p38α/β phosphorylation that is required to proceed through various stages of satellite cells differentiation: activation, asymmetric division, and ultimately myotube formation. Our data provide novel evidence that is consistent with group I Paks playing a central role in the regulation of muscle homeostasis, atrophy and myogenesis. © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Home artificial nutrition in advanced cancer patients.

PubMed

Ruggeri, Enrico; Agostini, Federica; Fettucciari, Luana; Giannantonio, Marilena; Pironi, Loris; Pannuti, Franco

2013-01-01

Malnutrition is over 50% in advanced cancer patients and is related to a decreased survival. Cachexia is the first reason for death in 4-23% of cases. The aim of the study was to estimate the appropriateness of the criteria to select patients for home artificial nutrition and its effectiveness to avoid death from cachexia and to improve quality of life in patients with advanced cancer assisted at home by the National Tumor Association (ANT) Foundation. The criteria for patient selection are: inadequate caloric intake ± malnutrition; life expectancy ≥6 weeks; suitable psycho-physical conditions; informed consent. The measured parameters were sex, age, tumor site, food intake, nutritional status, Karnofsky performance status, indication for home artificial nutrition, type of home artificial nutrition (enteral or parenteral), and survival after starting home artificial nutrition. The ANT Foundation assisted 29,348 patients in Bologna and its province from July 1990 to July 2012. Home artificial nutrition had been submitted to 618 patients (2.1%): enteral to 285/618 (46.1%) and parenteral to 333/618 (53.9%). Access routes for home artificial nutrition were: 39% nasogastric tube, 26% percutaneous endoscopic gastrostomy, 33% digiunostomy, and 2% gastrostomy. The central venous catheters used for home artificial nutrition were: 61% non-tunneled, 13 peripherally inserted, 8% partially tunneled, and 18% totally implanted. By July 2012, all the patients had died. Duration of life ≥6 weeks was 78% (484/618). Karnofsky performance status was related to survival ( P <0.0001): one month after starting home artificial nutrition, it decreased in 73 patients (12%), was unchanged in 414 (67%), and increased in 131 (21%). The low incidence of home artificial nutrition over all the patients assisted by the ANT Foundation and the achievement to avoid death from cachexia in 78% prove the efficacy of the criteria of patient selection in order to prevent its excessive and indiscriminate use. It was effective in maintaining and improving the performance status in 88% of patients. Karnofsky performance status is a reliable prognostic index to start home artificial nutrition.

Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f

PubMed Central

Morimoto, Megumi; Amano, Yuichiro; Oka, Masahiro; Harada, Ayako; Fujita, Hisashi; Hikichi, Yukiko; Tozawa, Ryuichi; Yamaoka, Masuo

2017-01-01

Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia. PMID:29216311

MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.

PubMed

Burgos, Jonathan R; Iresjö, Britt-Marie; Smedh, Ulrika

2016-04-01

The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor per se. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid P component (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation.

Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trial.

PubMed

Calder, Philip C; Laviano, Alessandro; Lonnqvist, Fredrik; Muscaritoli, Maurizio; Öhlander, Maria; Schols, Annemie

2018-02-01

Cachectic patients with chronic obstructive pulmonary disease (COPD) may benefit from nutritional support. This double-blind, randomized, controlled trial evaluated the safety and efficacy of targeted medical nutrition (TMN) vs. an isocaloric comparator in pre-cachectic and cachectic patients with COPD. Patients aged ≥50 years with moderate-to-severe COPD and involuntary weight loss or low body mass index (16-18 kg/m 2 ) were randomized 1:1 to receive TMN (~230 kcal; 2 g omega-3 fatty acids; 10 μg 25-hydroxy-vitamin D3) or isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov Identifier: NCT02442908). Primary safety endpoints comprised adverse events and changes in vital signs, laboratory parameters, and concomitant medications. Secondary efficacy endpoints included changes in weight, body composition, exercise tolerance, metabolic biomarkers, and systemic inflammation. Forty-five patients were randomized to receive TMN (n = 22; mean 69.2 years) or isocaloric comparator (n = 23; mean 69.7 years). TMN was well tolerated. Adverse events were similar in number and type in both groups. Compliance to both products was good (TMN, 79%; comparator, 77%). Both groups gained weight, but the TMN group gained comparatively more fat mass (P = 0.0013). Reductions in systolic blood pressure (P = 0.0418) and secondary endpoints of triglycerides (P = 0.0217) and exercise-induced fatigue (P = 0.0223) and dyspnoea (P = 0.0382), and increases in high-density lipoprotein cholesterol (P = 0.0254), were observed in the TMN vs. the comparator group by week 12. Targeted medical nutrition containing high-dose omega-3 fatty acids, vitamin D, and high-quality protein is well tolerated with a good safety profile and has positive effects on blood pressure and blood lipids and on exercise-induced fatigue and dyspnoea. Therefore, this TMN could be clinically beneficial in the nutritional and metabolic support of pre-cachectic and cachectic patients with COPD. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model

PubMed Central

Sawada, Yumi; Hashimoto, Hirofumi; Yoshimura, Mitsuhiro; Ohbuchi, Katsuya; Sudo, Yuka; Suzuki, Masami; Miyano, Kanako; Shiraishi, Seiji; Higami, Yoshikazu; Yanagihara, Kazuyoshi; Hattori, Tomohisa; Kase, Yoshio; Ueta, Yoichi; Uezono, Yasuhito

2017-01-01

Cancer cachexia (CC) is a multifactorial disease characterized by decreased food intake and loss of body weight due to reduced musculature with or without loss of fat mass. Patients with gastric cancer have a high incidence of cachexia. We previously established a novel CC rat model induced by human gastric cancer-derived 85As2 cells in order to examine the pathophysiology of CC and identify potential therapeutics. In patients with CC, anorexia is often observed, despite elevation of ghrelin, suggesting that ghrelin resistance may develop in these patients. In this study, we aimed to clarify the occurrence of ghrelin resistance in CC rats accompanied by anorexia and we investigated whether rikkunshito (RKT), a traditional Japanese Kampo medicine that potentiates ghrelin signaling, ameliorated CC-related anorexia through alleviation of ghrelin resistance. 85As2-tumor-bearing rats developed severe CC symptoms, including anorexia and loss of body weight/musculature, with the latter symptoms being greater in cachectic rats than in non-tumor-bearing or pair-fed rats. CC rats showed poor responses to intraperitoneal injection of ghrelin. In CC rats, plasma ghrelin levels were elevated and hypothalamic anorexigenic peptide mRNA levels were decreased, whereas hypothalamic growth hormone secretagogue receptor (GHS-R) mRNA was not affected. In vitro, RKT directly enhanced ghrelin-induced GHS-R activation. RKT administrated orally for 7 days partly alleviated the poor response to ghrelin and ameliorated anorexia without affecting the elevation of plasma ghrelin levels in CC rats. The expression of hypothalamic orexigenic neuropeptide Y mRNA but not hypothalamic GHS-R mRNA was increased by RKT. Thus, the 85As2 cell-induced CC rat model developed ghrelin resistance, possibly contributing to anorexia and body weight loss. The mechanism through which RKT ameliorated anorexia in the CC rat model may involve alleviation of ghrelin resistance by enhancement of ghrelin signaling. These findings suggest that RKT may be a promising agent for the treatment of CC. PMID:28249026

Medical use of cannabis in the Netherlands.

PubMed

Gorter, Robert W; Butorac, Mario; Cobian, Eloy Pulido; van der Sluis, Willem

2005-03-08

The authors investigated the indications for cannabis prescription in the Netherlands and assessed its efficacy and side effects. A majority (64.1%) of patients reported a good or excellent effect on their symptoms. Of these patients, approximately 44% used cannabis for >/=5 months. Indications were neurologic disorders, pain, musculoskeletal disorders, and cancer anorexia/cachexia. Inhaled cannabis was perceived as more effective than oral administration. Reported side effects were generally mild.

Latest consensus and update on protein-energy wasting in chronic kidney disease.

PubMed

Obi, Yoshitsugu; Qader, Hemn; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

2015-05-01

Protein-energy wasting (PEW) is a state of metabolic and nutritional derangements in chronic disease states including chronic kidney disease (CKD). Cumulative evidence suggests that PEW, muscle wasting and cachexia are common and strongly associated with mortality in CKD, which is reviewed here. The malnutrition-inflammation score (KALANTAR Score) is among the comprehensive and outcome-predicting nutritional scoring tools. The association of obesity with poor outcomes is attenuated across more advanced CKD stages and eventually reverses in the form of obesity paradox. Frailty is closely associated with PEW, muscle wasting and cachexia. Muscle loss shows stronger associations with unfavorable outcomes than fat loss. Adequate energy supplementation combined with low-protein diet for the management of CKD may prevent the development of PEW and can improve adherence to low-protein diet, but dietary protein requirement may increase with aging and is higher under dialysis therapy. Phosphorus burden may lead to poor outcomes. The target serum bicarbonate concentration is normal range and at least 23 mEq/l for nondialysis-dependent and dialysis-dependent CKD patients, respectively. A benefit of exercise is suggested but not yet conclusively proven. Prevention and treatment of PEW should involve individualized and integrated approaches to modulate identified risk factors and contributing comorbidities.

Quantifying the impact of standardized assessment and symptom management tools on symptoms associated with cancer-induced anorexia cachexia syndrome.

PubMed

Andrew, Inga M; Waterfield, Kerry; Hildreth, Anthony J; Kirkpatrick, Graeme; Hawkins, Colette

2009-12-01

The objective of this study was to quantify the impact of standardized assessment and management tools on patient symptom scores in cancer-induced anorexia cachexia syndrome (ACS) using a within-group study design. Baseline assessments included the Patient Generated Subjective Global Assessment (PG-SGA) tool and an amended Symptoms and Concerns Checklist (SCC). Symptom management strategies, written for this project, were instigated. Follow-up SCC scores were collected at 2 and 4 weeks. Forty out of 79 patients referred were recruited; 29/79 (36.7%) were too unwell or had died prior to consent. At baseline, the PG-SGA tool revealed 250 active symptoms associated with ACS. Total PG-SGA score was above 9 for all patients. Predominant interventions involved simple dietary advice and prescription of artificial saliva, mouthwash and prokinetic antiemetics. Median total SCC score improved sequentially from 11 at baseline, to 7 and 4 at first and second review, respectively (visit 1 to 2, p = 0.001; visit 1 to 3, p < 0.001; and visit 2 to 3, p = 0.02). We conclude that patients with ACS are recognised late in their disease and have a considerable burden of active symptoms. A structured approach to assessment and management has a significant impact on symptom burden.

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

PubMed Central

Breitbart, Astrid; Auger-Messier, Mannix; Molkentin, Jeffery D.

2011-01-01

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future. PMID:21421824

Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study.

PubMed

Muscaritoli, Maurizio; Lucia, Simone; Farcomeni, Alessio; Lorusso, Vito; Saracino, Valeria; Barone, Carlo; Plastino, Francesca; Gori, Stefania; Magarotto, Roberto; Carteni, Giacomo; Chiurazzi, Bruno; Pavese, Ida; Marchetti, Luca; Zagonel, Vittorina; Bergo, Eleonora; Tonini, Giuseppe; Imperatori, Marco; Iacono, Carmelo; Maiorana, Luigi; Pinto, Carmine; Rubino, Daniela; Cavanna, Luigi; Di Cicilia, Roberto; Gamucci, Teresa; Quadrini, Silvia; Palazzo, Salvatore; Minardi, Stefano; Merlano, Marco; Colucci, Giuseppe; Marchetti, Paolo

2017-10-03

In cancer patients, malnutrition is associated with treatment toxicity, complications, reduced physical functioning, and decreased survival. The Prevalence of Malnutrition in Oncology (PreMiO) study identified malnutrition or its risk among cancer patients making their first medical oncology visit. Innovatively, oncologists, not nutritionists, evaluated the nutritional status of the patients in this study. PreMiO was a prospective, observational study conducted at 22 medical oncology centers across Italy. For inclusion, adult patients (>18 years) had a solid tumor diagnosis, were treatment-naive, and had a life expectancy >3 months. Malnutrition was identified by the Mini Nutritional Assessment (MNA), appetite status with a visual analog scale (VAS), and appetite loss with a modified version of Anorexia-Cachexia Subscale (AC/S-12) of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT). Of patients enrolled ( N= 1,952), 51% had nutritional impairment; 9% were overtly malnourished, and 43% were at risk for malnutrition. Severity of malnutrition was positively correlated with the stage of cancer. Over 40% of patients were experiencing anorexia, as reported in the VAS and FAACT questionnaire. During the prior six months, 64% of patients lost weight (1-10 kg). Malnutrition, anorexia, and weight loss are common in cancer patients, even at their first visit to a medical oncology center.

Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice.

PubMed

Bindels, Laure B; Neyrinck, Audrey M; Salazar, Nuria; Taminiau, Bernard; Druart, Céline; Muccioli, Giulio G; François, Emmanuelle; Blecker, Christophe; Richel, Aurore; Daube, Georges; Mahillon, Jacques; de los Reyes-Gavilán, Clara G; Cani, Patrice D; Delzenne, Nathalie M

2015-01-01

We tested the hypothesis that changing the gut microbiota using pectic oligosaccharides (POS) or inulin (INU) differently modulates the progression of leukemia and related metabolic disorders. Mice were transplanted with Bcr-Abl-transfected proB lymphocytes mimicking leukemia and received either POS or INU in their diet (5%) for 2 weeks. Combination of pyrosequencing, PCR-DGGE and qPCR analyses of the 16S rRNA gene revealed that POS decreased microbial diversity and richness of caecal microbiota whereas it increased Bifidobacterium spp., Roseburia spp. and Bacteroides spp. (affecting specifically B. dorei) to a higher extent than INU. INU supplementation increased the portal SCFA propionate and butyrate, and decreased cancer cell invasion in the liver. POS treatment did not affect hepatic cancer cell invasion, but was more efficient than INU to decrease the metabolic alterations. Indeed, POS better than INU delayed anorexia linked to cancer progression. In addition, POS treatment increased acetate in the caecal content, changed the fatty acid profile inside adipose tissue and counteracted the induction of markers controlling β-oxidation, thereby hampering fat mass loss. Non digestible carbohydrates with prebiotic properties may constitute a new nutritional strategy to modulate gut microbiota with positive consequences on cancer progression and associated cachexia.

Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.

PubMed

Prado, C M; Cushen, S J; Orsso, C E; Ryan, A M

2016-05-01

Our understanding of body composition (BC) variability in contemporary populations has significantly increased with the use of imaging techniques. Abnormal BC such as sarcopenia (low muscle mass) and obesity (excess adipose tissue) are predictors of poorer prognosis in a variety of conditions or clinical situations. As a catabolic illness, a defining feature of cancer is muscle loss. Although the conceptual model of wasting in cancer is typically conceived as involuntary weight loss leading to low body weight, recent studies have shown that both sarcopenia and cachexia can be present with obesity. The combination of low muscle and high adipose tissue (sarcopenic obesity) is an emerging abnormal BC phenotype prevalent across the body weight, and hence BMI spectra. Sarcopenia and sarcopenic obesity in cancer are in most instances occult conditions, which have been independently associated with higher incidence of chemotherapy toxicity, shorter time to tumour progression, poorer outcomes of surgery, physical impairment and shorter survival. Although the mechanisms are yet to be fully understood, the associations with poorer clinical outcomes emphasise the value of nutritional assessment as well as the need to develop appropriate interventions to countermeasure abnormal BC. Sarcopenia and sarcopenic obesity create diverse nutritional requirements, highlighting the compelling need for a more comprehensive and differentiated understanding of energy and protein requirements in this heterogeneous population.

Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.

PubMed

Shukla, Surendra K; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V; Yu, Fang; Singh, Pankaj K

2015-12-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.

Lipid mobilising factors specifically associated with cancer cachexia.

PubMed Central

Beck, S. A.; Tisdale, M. J.

1991-01-01

Both urine and plasma from mice and humans with cancer cachexia have been shown to contain higher levels of lipid mobilising activity than normal controls, even after acute starvation. There was no significant increase in the urinary lipid mobilising activity of either mice or humans after acute starvation, suggesting that the material in the cachectic situation was probably not due to an elevation of hormones normally associated with the catabolic state in starvation. Further characterisation of the lipid mobilising activity in the urine of cachectic mice using Sephadex G50 exclusion chromatography showed four distinct peaks of activity of apparent molecular weights of greater than 20, 3, 1.5 and less than 0.7 kDa. No comparable peaks of activity were found in the urine of a non tumour-bearing mouse. The high molecular weight activity was probably formed by aggregation of low molecular weight material, since treatment with 0.5 M NaCl caused dissociation to material with a broad spectrum of molecular weights between 3 and 0.7 kDa. Lipolytic species of similar molecular weights were also found in the urine of cachectic cancer patients, but not in normal urine even after 24 h starvation. The lipid mobilising species may be responsible for catabolism of host adipose tissue in the cachectic state. PMID:2069843