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Sample records for cancer initiation progression

  1. Tobacco Use Initiation | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Reprogramming bladder cancer cells for studying cancer initiation and progression.

    PubMed

    Iskender, Banu; Izgi, Kenan; Canatan, Halit

    2016-10-01

    The induced pluripotent stem cell (iPSC) technology is the forced expression of specific transcription factors in somatic cells resulting in transformation into self-renewing, pluripotent cells which possess the ability to differentiate into any type of cells in the human body. While malignant cells could also be reprogrammed into iPSC-like cells with lower efficiency due to the genetic and epigenetic barriers in cancer cells, only a limited number of cancer cell types could be successfully reprogrammed until today. In the present study, we aimed at reprogramming two bladder cancer cell lines HTB-9 and T24 using a non-integrating Sendai virus (SeV) system. We have generated six sub-clones using distinct combinations of four factors-OCT4, SOX2, KLF4 and c-MYC-in two bladder cancer cell lines. Only a single sub-clone, T24 transduced with 4Fs, gave rise to iPSC-like cells. Bladder cancer cell-derived T24 4F cells represent unique features of pluripotent cells such as epithelial-like morphology, colony-forming ability, expression of pluripotency-associated markers and bearing the ability to differentiate in vitro. This is the first study focusing on the reprogramming susceptibility of two different bladder cancer cell lines to nuclear reprogramming. Further molecular characterisation of T24 4F cells could provide a better insight for biomarker research in bladder carcinogenesis and could offer a valuable tool for the development of novel therapeutic approaches in bladder carcinoma.

  3. Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression

    DTIC Science & Technology

    2016-05-01

    AWARD NUMBER: W81XWH-15-1-0095 TITLE: Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1...pathways in ovarian stem cells and in transformed ovarian cells affected by obesity that lead to ovarian cancer initiation and progression. 15. SUBJECT

  4. Identification and Targeting of Tyrosine Kinase Activity in Prostate Cancer Initiation, Progression, and Metastasis

    DTIC Science & Technology

    2012-10-01

    Tyrosine Kinase Activity in Prostate Cancer Initiation, Progression, and Metastasis PRINCIPAL INVESTIGATOR: Justin Drake CONTRACTING...PROJECT NUMBER Justin Drake and Owen Witte 5e. TASK NUMBER Email: jdrake@mednet.ucla.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S...of tyrosine kinase networks during prostate cancer progression Justin M. Drakea, Nicholas A. Grahamb,c, Tanya Stoyanovaa, Amir Sedghia, Andrew S

  5. Tight Junctions: A Barrier to the Initiation and Progression of Breast Cancer?

    PubMed Central

    Brennan, Kieran; Offiah, Gozie; McSherry, Elaine A.; Hopkins, Ann M.

    2010-01-01

    Breast cancer is a complex and heterogeneous disease that arises from epithelial cells lining the breast ducts and lobules. Correct adhesion between adjacent epithelial cells is important in determining the normal structure and function of epithelial tissues, and there is accumulating evidence that dysregulated cell-cell adhesion is associated with many cancers. This review will focus on one cell-cell adhesion complex, the tight junction (TJ), and summarize recent evidence that TJs may participate in breast cancer development or progression. We will first outline the protein composition of TJs and discuss the functions of the TJ complex. Secondly we will examine how alterations in these functions might facilitate breast cancer initiation or progression; by focussing on the regulatory influence of TJs on cell polarity, cell fate and cell migration. Finally we will outline how pharmacological targeting of TJ proteins may be useful in limiting breast cancer progression. Overall we hope to illustrate that the relationship between TJ alterations and breast cancer is a complex one; but that this area offers promise in uncovering fundamental mechanisms linked to breast cancer progression. PMID:19920867

  6. Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression.

    PubMed

    McConkey, David J; Lee, Sangkyou; Choi, Woonyoung; Tran, Mai; Majewski, Tadeusz; Lee, Sooyong; Siefker-Radtke, Arlene; Dinney, Colin; Czerniak, Bogdan

    2010-01-01

    Urothelial cancer has served as one of the most important sources of information about the mutational events that underlie the development of human solid malignancies. Although "field effects" that affect the entire bladder mucosa appear to initiate disease, tumors develop along 2 distinct biological "tracks" that present vastly different challenges for clinical management. Recent whole genome methodologies have facilitated even more rapid progress in the identification of the molecular mechanisms involved in bladder cancer initiation and progression. Specifically, whole organ mapping combined with high resolution, high throughput SNP analyses have identified a novel class of candidate tumor suppressors ("forerunner genes") that localize near more familiar tumor suppressors but are disrupted at an earlier stage of cancer development. Furthermore, whole genome comparative genomic hybridization (CGH) and mRNA expression profiling have demonstrated that the 2 major subtypes of urothelial cancer (papillary/superficial and non-papillary/muscle-invasive) are truly distinct molecular entities, and in recent work our group has discovered that muscle-invasive tumors express molecular markers characteristic of a developmental process known as "epithelial-to-mesenchymal transition" (EMT). Emerging evidence indicates that urothelial cancers contain subpopulations of tumor-initiating cells ("cancer stem cells") but the phenotypes of these cells in different tumors are heterogeneous, raising questions about whether or not the 2 major subtypes of cancer share a common precursor. This review will provide an overview of these new insights and discuss priorities for future investigation.

  7. The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression.

    PubMed

    Tafani, Marco; Sansone, Luigi; Limana, Federica; Arcangeli, Tania; De Santis, Elena; Polese, Milena; Fini, Massimo; Russo, Matteo A

    2016-01-01

    The presence of ROS is a constant feature in living cells metabolizing O2. ROS concentration and compartmentation determine their physiological or pathological effects. ROS overproduction is a feature of cancer cells and plays several roles during the natural history of malignant tumor. ROS continuously contribute to each step of cancerogenesis, from the initiation to the malignant progression, acting directly or indirectly. In this review, we will (a) underline the role of ROS in the pathway leading a normal cell to tumor transformation and progression, (b) define the multiple roles of ROS during the natural history of a tumor, (c) conciliate many conflicting data about harmful or beneficial effects of ROS, (d) rethink the importance of oncogene and tumor suppressor gene mutations in relation to the malignant progression, and (e) collocate all the cancer hallmarks in a mechanistic sequence which could represent a "physiological" response to the initial growth of a transformed stem/pluripotent cell, defining also the role of ROS in each hallmark. We will provide a simplified sketch about the relationships between ROS and cancer. The attention will be focused on the contribution of ROS to the signaling of HIF, NFκB, and Sirtuins as a leitmotif of cancer initiation and progression.

  8. The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression

    PubMed Central

    Sansone, Luigi; Limana, Federica; Arcangeli, Tania; De Santis, Elena; Polese, Milena; Fini, Massimo; Russo, Matteo A.

    2016-01-01

    The presence of ROS is a constant feature in living cells metabolizing O2. ROS concentration and compartmentation determine their physiological or pathological effects. ROS overproduction is a feature of cancer cells and plays several roles during the natural history of malignant tumor. ROS continuously contribute to each step of cancerogenesis, from the initiation to the malignant progression, acting directly or indirectly. In this review, we will (a) underline the role of ROS in the pathway leading a normal cell to tumor transformation and progression, (b) define the multiple roles of ROS during the natural history of a tumor, (c) conciliate many conflicting data about harmful or beneficial effects of ROS, (d) rethink the importance of oncogene and tumor suppressor gene mutations in relation to the malignant progression, and (e) collocate all the cancer hallmarks in a mechanistic sequence which could represent a “physiological” response to the initial growth of a transformed stem/pluripotent cell, defining also the role of ROS in each hallmark. We will provide a simplified sketch about the relationships between ROS and cancer. The attention will be focused on the contribution of ROS to the signaling of HIF, NFκB, and Sirtuins as a leitmotif of cancer initiation and progression. PMID:26798421

  9. Role of Protein Synthesis Initiation Factors in Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression

    DTIC Science & Technology

    2012-03-01

    Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression. PRINCIPAL INVESTIGATOR: Columba de la Parra Simental CONTRACTING...00935 Role of Protein Synthesis Initiation Factors in Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression Columba de la Parra Simental...Protein Synthesis Initiation Factors in Dietary Soy Isoflavone- Mediated Effects on Breast Cancer Progression. 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S

  10. Effects of Androgen and Estrogen Receptor Signaling Pathways on Bladder Cancer Initiation and Progression

    PubMed Central

    Godoy, Guilherme; Gakis, Georgios; Smith, Carolyn L.; Fahmy, Omar

    2016-01-01

    Epidemiologic studies have long demonstrated clear differences in incidence and progression of bladder cancer between genders suggesting that the mechanisms of development and progression in these tumors have a strong association with steroid hormonal pathways. Such observations led to preclinical studies investigating the role of androgen and estrogen receptors, as well as their cognate hormones in bladder cancer initiation and progression. Using various in vitro cell line assays and in vivo mouse models, studies have elucidated different mechanisms and signaling pathways through which these steroid receptors may participate in this disease. More recently, RNA expression data from multiple studies revealed a luminal subtype of bladder cancer that exhibited an estrogen receptor signaling pathway, making it a strong candidate for further consideration of targeted therapies in the future. Despite the promising preclinical data demonstrating potential roles for both antiandrogen and antiestrogen strategies targeting these pathways in different stages of bladder cancer, only two clinical trials are currently active and accruing patients for such clinical studies. Targeted therapies in bladder cancer are a large unmet need and have the potential to change treatment paradigms and improve oncological outcomes of patients with bladder cancer. PMID:27376135

  11. Targeted Cancer Therapy: Vital Oncogenes and a New Molecular Genetic Paradigm for Cancer Initiation Progression and Treatment

    PubMed Central

    Willis, Rudolph E.

    2016-01-01

    It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis. PMID:27649156

  12. Targeted Cancer Therapy: Vital Oncogenes and a New Molecular Genetic Paradigm for Cancer Initiation Progression and Treatment.

    PubMed

    Willis, Rudolph E

    2016-09-14

    It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis.

  13. Impact of hyperhomocysteinemia on breast cancer initiation and progression: epigenetic perspective.

    PubMed

    Naushad, Shaik Mohammad; Reddy, Cheruku Apoorva; Kumaraswami, Konda; Divyya, Shree; Kotamraju, Srigiridhar; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadha Rao; Kutala, Vijay Kumar

    2014-03-01

    Our recent study showing association of hyperhomocysteinemia and hypomethioninemia in breast cancer and other studies indicating association of hyperhomocysteinemia with metastasis and development of drug resistance in breast cancer cells treated with homocysteine lead us to hypothesize that homocysteine might modulate the expression of certain tumor suppressors, i.e., RASSF1, RARβ1, CNND1, BRCA1, and p21, and might influence prognostic markers such as BNIP3 by inducing epigenetic alteration. To demonstrate this hypothesis, we have treated MCF-7 and MDA-MB-231 cells with different doses of homocysteine and observed dose-dependent inhibition of BRCA1 and RASSF1, respectively. In breast cancer tissues, we observed the following expression pattern: BNIP3 > BRCA1 > RARβ1 > CCND1 > p21 > RASSF1. Hyperhomocysteinemia was positively associated with BRAC1 hypermethylation both in breast cancer tissue and corresponding peripheral blood. Peripheral blood CpG island methylation of BRCA1 in all types of breast cancer and methylation of RASSF1 in ER/PR-negative breast cancers showed positive correlation with total plasma homocysteine. The methylation of RASSF1 and BRCA1 was associated with breast cancer initiation as well as progression, while BRCA1 methylation was associated with DNA damage. Vitamin B12 showed inverse association with the methylation at both the loci. RFC1 G80A and cSHMT C1420T variants showed positive association with methylation at both the loci. Genetic variants influencing remethylation step were associated positively with BRCA1 methylation and inversely with RASSF1 methylation. GCPII C1561T variant showed inverse association with BRCA1 methylation. We found good correlation of BRAC1 (r = 0.90) and RASSF1 (0.92) methylation pattern between the breast cancer tissue and the corresponding peripheral blood. To conclude, elevated homocysteine influences methionine dependency phenotype of breast cancer cells and is associated with breast cancer progression by

  14. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression

    PubMed Central

    Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L.; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R.; Yamada, Hiroshi Y.; Cruz-Monserrate, Zobeida; May, Randal; Houchen, Courtney W.; Steele, Vernon E.; Rao, Chinthalapally V.

    2015-01-01

    Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID:25906749

  15. Radiation Promotes Colorectal Cancer Initiation and Progression by Inducing Senescence-Associated Inflammatory Responses

    PubMed Central

    Kim, Sang Bum; Bozeman, Ronald; Kaisani, Aadil; Kim, Wanil; Zhang, Lu; Richardson, James A.; Wright, Woodring E.; Shay, Jerry W.

    2015-01-01

    Proton radiotherapy is becoming more common since protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared to conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIR) which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence associated gene (P19Arf) are markedly increased. Following these changes loss of Casein kinase Iα (CKIα) and induction of chronic DNA damage and TP53 mutations are increased compared to x-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, CDDO-EA, reduces proton irradiation associated SIR and tumorigenesis. Thus, exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  16. Short-form Ron is a novel determinant of ovarian cancer initiation and progression

    PubMed Central

    Moxley, Katherine M.; Wang, Luyao; Welm, Alana L.; Bieniasz, Magdalena

    2016-01-01

    Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment. PMID:27551332

  17. Exercise in Regulation of Inflammation-Immune Axis Function in Cancer Initiation and Progression

    PubMed Central

    Koelwyn, Graeme J.; Wennerberg, Erik; Demaria, Sandra; Jones, Lee W.

    2016-01-01

    Pharmacologic manipulation of the immune system is emerging as a viable and robust treatment for some cancer patients. Exercise-induced modulation of the immune system may be another adjunctive strategy for inhibiting tumor initiation and progression. In healthy individuals, exercise has been shown to modulate a number of cell subsets involved in innate and adaptive immunity. Here, we provide an overview of the current state of knowledge pertaining to exercise modulation of the inflammation-immune axis in cancer. The current evidence suggests that exercise may be a promising adjunctive strategy that can favorably alter numerous components of the immune system, which, in turn, may modulate tumorigenesis. However, many important knowledge gaps are evident. To this end, we propose a framework to guide future research efforts investigating the immune effects of exercise in cancer. PMID:26676894

  18. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis.

    PubMed

    Reiter, Russel J; Rosales-Corral, Sergio A; Tan, Dun-Xian; Acuna-Castroviejo, Dario; Qin, Lilan; Yang, Shun-Fa; Xu, Kexin

    2017-04-17

    There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even

  19. Spontaneous initiation, promotion and progression of colorectal cancer in the novel A/J Min/+ mouse.

    PubMed

    Sødring, Marianne; Gunnes, Gjermund; Paulsen, Jan Erik

    2016-04-15

    The C57BL/6J multiple intestinal neoplasia (Min/+) mouse is a widely used murine model for familial adenomatous polyposis, a hereditary form of human colorectal cancer. However, it is a questionable model partly because the vast majority of tumors arise in the small intestine, and partly because the fraction of tumors that progress to invasive carcinomas is minuscule. A/J mice are typically more susceptible to carcinogen-induced colorectal cancer than C57BL/6J mice. To investigate whether the novel Min/+ mouse on the A/J genetic background could be a better model for colorectal cancer, we examined the spontaneous intestinal tumorigenesis in 81 A/J Min/+ mice ranging in age from 4 to 60 weeks. The A/J Min/+ mouse exhibited a dramatic increase in number of colonic lesions when compared to what has been reported for the conventional Min/+ mouse; however, an increase in small intestinal lesions did not occur. In addition, this novel mouse model displayed a continual development of colonic lesions highlighted by the transition from early lesions (flat ACF) to tumors over time. In mice older than 40 weeks, 13 colonic (95% CI: 8.7-16.3) and 21 small intestinal (95% CI: 18.6-24.3) tumors were recorded. Notably, a considerable proportion of those lesions progressed to carcinomas in both the colon (21%) and small intestine (51%). These findings more closely reflect aspects of human colorectal carcinogenesis. In conclusion, the novel A/J Min/+ mouse may be a relevant model for initiation, promotion and progression of colorectal cancer.

  20. Biomechanical profile of cancer stem-like/tumor-initiating cells derived from a progressive ovarian cancer model.

    PubMed

    Babahosseini, Hesam; Ketene, Alperen N; Schmelz, Eva M; Roberts, Paul C; Agah, Masoud

    2014-07-01

    We herein report, for the first time, the mechanical properties of ovarian cancer stem-like/tumor-initiating cells (CSC/TICs). The represented model is a spontaneously transformed murine ovarian surface epithelial (MOSE) cell line that mimics the progression of ovarian cancer from early/non-tumorigenic to late/highly aggressive cancer stages. Elastic modulus measurements via atomic force microscopy (AFM) illustrate that the enriched CSC/TICs population (0.32±0.12kPa) are 46%, 61%, and 72% softer (P<0.0001) than their aggressive late-stage, intermediate, and non-malignant early-stage cancer cells, respectively. Exposure to sphingosine, an anti-cancer agent, induced an increase in the elastic moduli of CSC/TICs by more than 46% (0.47±0.14kPa, P<0.0001). Altogether, our data demonstrate that the elastic modulus profile of CSC/TICs is unique and responsive to anti-cancer treatment strategies that impact the cytoskeleton architecture of cells. These findings increase the chance for obtaining distinctive cell biomechanical profiles with the intent of providing a means for effective cancer detection and treatment control. This novel study utilized atomic force microscopy to demonstrate that the elastic modulus profile of cancer stem cell-like tumor initiating cells is unique and responsive to anti-cancer treatment strategies that impact the cytoskeleton of these cells. These findings pave the way to the development of unique means for effective cancer detection and treatment control. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Complex role for the immune system in initiation and progression of pancreatic cancer.

    PubMed

    Inman, Kristin S; Francis, Amanda A; Murray, Nicole R

    2014-08-28

    The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.

  2. Complex role for the immune system in initiation and progression of pancreatic cancer

    PubMed Central

    Inman, Kristin S; Francis, Amanda A; Murray, Nicole R

    2014-01-01

    The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed. PMID:25170202

  3. New advances on critical implications of tumor- and metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence

    PubMed Central

    Mimeault, M.; Batra, S.K.

    2010-01-01

    Summary Accumulating lines of experimental evidence have revealed that the malignant transformation of multipotent tissue-resident adult stem/progenitor cells into cancer stem/progenitor cells endowed with a high self-renewal capacity and aberrant multilineage differentiation potential may be at origin of the most types of human aggressive and recurrent cancers. Based on new cancer stem/progenitor cell concepts of carcinogenesis, it is suggested that a small subpopulation of highly tumorigenic and migrating cancer stem/progenitor cells, also designated as cancer- and metastasis-initiating cells, can provide critical roles for primary tumor growth, metastases at distant tissues and organs, treatment resistance and disease relapse. Particularly, cancer initiation and progression to locally invasive and metastatic stages is often associated with a persistent activation of distinct developmental signaling pathways in these immature cells during epithelial-mesenchymal transition program. The signaling cascades that are often deregulated in cancer stem/progenitor cells include hedgehog, epidermal growth factor receptor (EGFR), Wnt/β-catenin, NOTCH, polycomb gene product BMI-1 and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). Importantly, the results from recent investigations have also indicated that different cancer subtypes may harbor distinct subsets and/or number of cancer-initiating cells during cancer progression as well as before or after therapy initiation and disease recurrence. Therefore, the identification of the molecular transforming events that frequently occur in cancer- and metastasis-initiating cells versus their differentiated progenies is of immense interest to develop new targeting approach for improving current therapies against aggressive, metastatic, recurrent and lethal cancers. PMID:20552555

  4. Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer.

    PubMed

    Qu, Zhaoxia; Sun, Fan; Zhou, Jingjiao; Li, Liwen; Shapiro, Steven D; Xiao, Gutian

    2015-08-15

    Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6-deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6-deficient mice were significantly smaller. Notably, both the lung tumor-suppressing and -promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer.

  5. Interleukin-6 prevents the initiation but enhances the progression of lung cancer

    PubMed Central

    Qu, Zhaoxia; Sun, Fan; Zhou, Jingjiao; Li, Liwen; Shapiro, Steven D.; Xiao, Gutian

    2015-01-01

    Recent studies suggest that high expression of the pro-inflammatory cytokine interleukin-6 (IL-6) is associated with poor survival of lung cancer patients. Accordingly, IL-6 has been a target of great interest for lung cancer therapy. However, the role of IL-6 in lung cancer has not been determined yet. Here, we demonstrate that IL-6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared to wild type mice, IL-6 deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL-6 deficient mice were significantly smaller. Notably, both the lung tumor-suppressing and -promoting functions of IL-6 involve its ability in activating the transcription factor STAT3. IL-6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator Cyclin D1. These studies reveal a previously unexplored role of IL-6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL-6/STAT3-targeted therapies for this deadliest human cancer. PMID:26122841

  6. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy

    PubMed Central

    Sullivan, James P.; Minna, John D.; Shay, Jerry W.

    2010-01-01

    The discovery of rare tumor cells with stem cell features first in leukemia and later in solid tumors has emerged as an important area in cancer research. It has been determined that these stem-like tumor cells, termed cancer stem cells, are the primary cellular component within a tumor that drives disease progression and metastasis. In addition to their stem-like ability to self-renew and differentiate, cancer stem cells are also enriched in cells resistant to conventional radiation therapy and to chemotherapy. The immediate implications of this new tumor growth paradigm not only require a re-evaluation of how tumors are initiated, but also on how tumors should be monitored and treated. However, despite the relatively rapid pace of cancer stem cell research in solid tumors such as breast, brain, and colon cancers, similar progress in lung cancer remains hampered in part due to an incomplete understanding of lung epithelial stem cell hierarchy and the complex heterogeneity of the disease. In this review, we provide a critical summary of what is known about the role of normal and malignant lung stem cells in tumor development, the progress in characterizing lung cancer stem cells and the potential for therapeutically targeting pathways of lung cancer stem cell self-renewal. PMID:20094757

  7. Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

    PubMed Central

    Sharma, Divya Khandige; Bressler, Kamiko; Patel, Harshil; Balasingam, Nirujah

    2016-01-01

    Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation. PMID:28083147

  8. MicroRNA biomarkers predicting risk, initiation and progression of colorectal cancer

    PubMed Central

    Lee, Kyungjin; Ferguson, Lynnette R

    2016-01-01

    Colorectal cancer is a major global cause of morbidity and mortality. Current strategies employed to increase detection of early, curable stages of this disease are contributing to a reduction of the negative health impact from it. While there is a genetic component to the risk of disease, diet and environment are known to have major effects on the risk of an individual for developing the disease. However, there is the potential to reduce the impact of this disease further by preventing disease development. Biomarkers which can either predict the risk for or early stages of colorectal cancer could allow intervention at a time when prospects could be modified by environmental factors, including lifestyle and diet choices. Thus, such biomarkers could be used to identify high risk individuals who would benefit from lifestyle and dietary interventions to prevent this disease. This review will give an overview on one type of biomarker in the form of microRNAs, which have the potential to predict an individual’s risk for colorectal cancer, as well as providing a highly sensitive and non-invasive warning of disease presence and/or progression. MicroRNA biomarkers which have been studied and whose levels look promising for this purpose include MiR-18a, MiR-21, MiR-92a, MiR-135b, MiR-760, MiR-601. Not only have several individual microRNAs appeared promising as biomarkers, but panels of these may be even more useful. Furthermore, understanding dietary sources and ways of dietary modulation of these microRNAs might be fruitful in reducing the incidence and slowing the progression of colorectal cancer. PMID:27672263

  9. Differential Requirement for Src-family Tyrosine Kinases in the Initiation, Progression and Metastasis of Prostate Cancer

    PubMed Central

    Gelman, Irwin H.; Peresie, Jennifer; Eng, Kevin H.; Foster, Barbara A.

    2014-01-01

    Prostate cancer (CaP) recurrence after androgen ablation therapy (ADT) remains a significant cause of mortality in aging men. Malignant progression and metastasis are typically driven by genetic and epigenetic changes controlled by the androgen receptor (AR). However, evidence suggests that activated non-receptor tyrosine kinases, including those of the Src family (SFK), directly phosphorylate AR, thereby activating its transcriptional activity in the absence of serum androgen levels. To ascertain whether CaP progression and metastasis require SFK members an autochthonous transgenic adenocarcinoma (AD) of the mouse prostate (TRAMP) model was crossed into Src-, Lyn- or Fyn-null backgrounds. Primary-site CaP formation was dependent on Src, to a lesser extent, Lyn, but not Fyn. Only Src−/−;TRAMP prostate tumors were marked by reactive stroma. SFK deficiency did not affect progression to neuroendocrine (NE) disease, although there were fewer new cancer cases initiating after 34 weeks in the SFK−/−;TRAMP mice compared to TRAMP controls. Fifteen to 21% of older (>33 weeks) Lyn- or Fyn-null TRAMP mice lacking primary-site tumors suffered from aggressive metastatic AD growths, compared with 3% of TRAMP mice. Taken with the data that TRAMP mice lacking Src or Lyn exhibited fewer macroscopic metastases compared to Fyn−/−;TRAMP and TRAMP controls, this suggests that SFK can either promote or suppress specific parameters of metastatic growth, possibly depending on cross-talk with primary tumors. These data identify critical, yet potentially opposing roles played by various SFKs in the initiation and metastatic potential of CaP using the TRAMP model. Implications: Genetically defined mouse models indicate a critical role for Src tyrosine kinase in prostate cancer initiation and metastatic progression. PMID:25053806

  10. Global cancer research initiative

    PubMed Central

    Love, Richard R

    2010-01-01

    Cancer is an increasing problem for low- and middle-income countries undergoing an epidemiologic transition from dominantly acute communicable disease to more frequent chronic disease with increased public health successes in the former domain. Progress against cancer in high-income countries has been modest and has come at enormous expense. There are several well-conceived global policy and planning initiatives which, with adequate political will, can favorably impact the growing global cancer challenges. Most financial resources for cancer, however, are spent on diagnosis and management of patients with disease in circumstances where specific knowledge about effective approaches is significantly limited, and the majority of interventions, other than surgery, are not cost-effective in resource-limited countries by global standards. In summary, how to intervene effectively on a global scale for the majority of citizens who develop cancer is poorly defined. In contrast to technology-transfer approaches, markedly increased clinical research activities are more likely to benefit cancer sufferers. In these contexts, a global cancer research initiative is proposed, and mechanisms for realizing such an effort are suggested. PMID:21188101

  11. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression

    PubMed Central

    Lee, Jong Hun; Khor, Tin Oo; Shu, Limin; Su, Zheng-Yuan; Fuentes, Francisco; Kong, Ah-Ng Tony

    2013-01-01

    Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinases (e.g., JNK), caspases and the mitochondria damage/cytochrome c pathways. Phytochemicals may also have anti-cancer effects by inhibiting the IKK/NF-κB pathway, inhibiting STAT3, and causing cell cycle arrest. In addition, other mechanisms may include epigenetic alterations (e.g., inhibition of HDACs, miRNAs, and the modification of the CpG methylation of cancer-related genes). In this review, we will discuss: the current advances in the study of Nrf2 signaling; Nrf2-deficient tumor mouse models; the epigenetic control of Nrf2 in tumorigenesis and chemoprevention; Nrf2-mediated cancer chemoprevention by naturally occurring dietary phytochemicals; and the mutation or hyper-expression of the Nrf2–Keap1 signaling pathway in advanced tumor cells. The future development of dietary phytochemicals for chemoprevention must integrate in vitro signaling mechanisms, relevant biomarkers of human diseases, and combinations of different phytochemicals and/or non-toxic therapeutic drugs, including

  12. Role of Lysophospholipids in the Initiation, Progression and Therapy of Breast Cancer

    DTIC Science & Technology

    2005-06-01

    autotaxin levels areincreased approximately 28 fold in breast cancer cells isolated directly from patients.This should result in increased LPA and S1P ...apoptosis in breast cancer cells.We have utilized a novel Si1P antibody to neutralize S1P in vitro and are currentlytreating mice with breast cancer...epithelium. We have obtained a LPP transgenic mouse to determine theeffects of degradation of LPA and S1P on breast function and tumorigenesis by

  13. Progress in Initiator Modeling

    SciTech Connect

    Hrousis, C A; Christensen, J S

    2009-05-04

    There is great interest in applying magnetohydrodynamic (MHD) simulation techniques to the designs of electrical high explosive (HE) initiators, for the purpose of better understanding a design's sensitivities, optimizing its performance, and/or predicting its useful lifetime. Two MHD-capable LLNL codes, CALE and ALE3D, are being used to simulate the process of ohmic heating, vaporization, and plasma formation in the bridge of an initiator, be it an exploding bridgewire (EBW), exploding bridgefoil (EBF) or slapper type initiator. The initiation of the HE is simulated using Tarver Ignition & Growth reactive flow models. 1-D, 2-D and 3-D models have been constructed and studied. The models provide some intuitive explanation of the initiation process and are useful for evaluating the potential impact of identified aging mechanisms (such as the growth of intermetallic compounds or powder sintering). The end product of this work is a simulation capability for evaluating margin in proposed, modified or aged initiation system designs.

  14. X Chromosome Inactivation and Breast Cancer: Epigenetic Alteration in Tumor Initiation and Progression

    DTIC Science & Technology

    2007-09-01

    types of mammary tumors, but not others. For instance, X chromosomal abnormalities appear to be associated with basal -like human breast cancer (BLC...with the Xi (Richardson et al., 2006). Seventeen of thirty-eight BRCA1WT basal -like (BLC) and non-BLC tumor samples lacked detectable XIST RNA...chromosome, suggesting loss of the XIST-expressing Xi in these cells. Twelve of the sporadic, basal -like tumor samples also showed a loss of heterozygous X

  15. The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

    PubMed Central

    2012-01-01

    Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long

  16. Molecular Mechanisms of Gastric Cancer Initiation and Progression by Helicobacter pylori

    PubMed Central

    Servetas, Stephanie L.; Bridge, Dacie R.; Merrell, D. Scott

    2016-01-01

    Purpose of Review Infection with the Gram-negative, microaerophilic pathogen Helicobacter pylori results in gastric cancer (GC) in a subset of infected individuals. As such, H. pylori is the only World Health Organization classified bacterial class I carcinogen. Numerous studies have identified mechanisms by which H. pylori alters host cell signaling pathways to cause disease. The purpose of this review is to highlight recent studies that explore mechanisms associated with induction of GC. Recent Findings Over the last year and a half, new mechanisms contributing to the etiology of H. pylori associated GC development have been discovered. In addition to utilizing the oncogenic CagA toxin to alter host cell signaling pathways, H. pylori also induces host DNA damage and alters DNA methylation to perturb downstream signaling. Furthermore, H. pylori activates numerous host cell pathways and proteins that result in epithelial-to-mesenchymal transition (EMT) and induction of cell survival and proliferation. Summary Mounting evidence suggests that H. pylori promotes gastric carcinogenesis using a multifactorial approach. Intriguingly, many of the targeted pathways and mechanism show commonality with diverse forms of cancer. PMID:26779778

  17. Initiators and promoters for the occurrence of screen-detected breast cancer and the progression to clinically-detected interval breast cancer.

    PubMed

    Yen, Amy Ming-Fang; Wu, Wendy Yi-Ying; Tabar, Laszlo; Duffy, Stephen W; Smith, Robert A; Chen, Hsiu-Hsi

    2017-03-01

    The risk factors responsible for breast cancer have been well documented, but the roles of risk factors as initiators, causing the occurrence of screen-detected breast cancer, or promoters, responsible for the progression of the screen-detected to the clinically-detected breast cancer, have been scarcely evaluated. We used data from women in a cohort in Kopparberg (Dalarna), Sweden between 1977 and 2010. Conventional risk factors, breast density, and tumor-specific biomarkers are superimposed to the temporal course of the natural history of the disease. The results show that older age at first full-term pregnancy, dense breast, and a family history of breast cancer increased the risk of entering the preclinical screen-detectable phase of breast cancer by 23%, 41%, and 89%, respectively. Overweight/obesity (body mass index ≥25 kg/m(2)) was a significant initiator (adjusted relative risk [aRR] 1.15; 95% confidence interval [CI], 0.99-1.33), but was inversely associated with the role of promoter (aRR 0.65; 95% CI, 0.51-0.82). Dense breast (aRR 1.46; 95% CI, 1.12-1.91), triple-negative (aRR 2.07; 95% CI, 1.37-3.15), and Ki-67 positivity (aRR 1.66; 95% CI, 1.19-2.30) were statistically significant promoters. When the molecular biomarkers were considered collectively as one classification, the basal-like subtype was the most influential subtype on promoters (aRR 4.24; 95% CI, 2.56-7.02) compared with the Luminal A subtype. We ascertained state-dependent covariates of initiators and promoters to classify the risk of the two-step progression of breast cancer. The results of the current study are useful for individually-tailored screening and personalized clinical surveillance of patients with breast cancer that was detected at an early stage. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  18. Metastasis initiating cells in primary prostate cancer tissues from transurethral resection of the prostate (TURP) predicts castration-resistant progression and survival of prostate cancer patients.

    PubMed

    Li, Qinlong; Li, Quanlin; Nuccio, Jill; Liu, Chunyan; Duan, Peng; Wang, Ruoxiang; Jones, Lawrence W; Chung, Leland W K; Zhau, Haiyen E

    2015-09-01

    We previously reported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naïve patients can predict the progression to castration resistance and the overall survival of PC patients. © 2015 Wiley Periodicals, Inc.

  19. Metastasis Initiating Cells in Primary Prostate Cancer Tissues From Transurethral Resection of the Prostate (TURP) Predicts Castration-Resistant Progression and Survival of Prostate Cancer Patients

    PubMed Central

    Li, Qinlong; Li, Quanlin; Nuccio, Jill; Liu, Chunyan; Duan, Peng; Wang, Ruoxiang; Jones, Lawrence W.; Chung, Leland W. K.; Zhau, Haiyen E.

    2016-01-01

    BACKGROUND We previouslyreported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. METHODS We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. RESULTS PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. CONCLUSIONS The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naïve patients can predict the progression to castration resistance and the overall survival of PC patients. PMID:25990623

  20. Roles of Caloric Restriction, Ketogenic Diet and Intermittent Fasting during Initiation, Progression and Metastasis of Cancer in Animal Models: A Systematic Review and Meta-Analysis

    PubMed Central

    Wang, Hao; Wang, Feng; Guan, Wenxian

    2014-01-01

    Background The role of dietary restriction regimens such as caloric restriction, ketogenic diet and intermittent fasting in development of cancers has been detected via abundant preclinical experiments. However, the conclusions are controversial. We aim to review the relevant animal studies systematically and provide assistance for further clinical studies. Methods Literatures on associations between dietary restriction and cancer published in PubMed in recent twenty years were comprehensively searched. Animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer were extracted from each eligible study. We analyzed the tumor incidence rates from 21 studies about caloric restriction. Results Fifty-nine studies were involved in our system review. The involved studies explored roles of dietary restriction during initiation, progression and metastasis of cancer. About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role, with the pooled OR (95%CI) of 0.20 (0.12, 0.34) relative to controls. Ketogenic diet was also positively associated with cancer, which was indicated by eight of the nine studies. However, 37.5% of the related studies obtained a negative conclusion that intermittent fasting was not significantly preventive against cancer. Conclusions Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated. PMID:25502434

  1. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis.

    PubMed

    Lv, Mengmeng; Zhu, Xingya; Wang, Hao; Wang, Feng; Guan, Wenxian

    2014-01-01

    The role of dietary restriction regimens such as caloric restriction, ketogenic diet and intermittent fasting in development of cancers has been detected via abundant preclinical experiments. However, the conclusions are controversial. We aim to review the relevant animal studies systematically and provide assistance for further clinical studies. Literatures on associations between dietary restriction and cancer published in PubMed in recent twenty years were comprehensively searched. Animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer were extracted from each eligible study. We analyzed the tumor incidence rates from 21 studies about caloric restriction. Fifty-nine studies were involved in our system review. The involved studies explored roles of dietary restriction during initiation, progression and metastasis of cancer. About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role, with the pooled OR (95%CI) of 0.20 (0.12, 0.34) relative to controls. Ketogenic diet was also positively associated with cancer, which was indicated by eight of the nine studies. However, 37.5% of the related studies obtained a negative conclusion that intermittent fasting was not significantly preventive against cancer. Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated.

  2. A new role of the Rac-GAP β2-chimaerin in cell adhesion reveals opposite functions in breast cancer initiation and tumor progression

    PubMed Central

    Casado-Medrano, Victoria; Barrio-Real, Laura; García-Rostán, Ginesa; Baumann, Matti; Rocks, Oliver; Caloca, María J.

    2016-01-01

    β2-chimaerin is a Rac1-specific negative regulator and a candidate tumor suppressor in breast cancer but its precise function in mammary tumorigenesis in vivo is unknown. Here, we study for the first time the role of β2-chimaerin in breast cancer using a mouse model and describe an unforeseen role for this protein in epithelial cell-cell adhesion. We demonstrate that expression of β2-chimaerin in breast cancer epithelial cells reduces E-cadherin protein levels, thus loosening cell-cell contacts. In vivo, genetic ablation of β2-chimaerin in the MMTV-Neu/ErbB2 mice accelerates tumor onset, but delays tumor progression. Finally, analysis of clinical databases revealed an inverse correlation between β2-chimaerin and E-cadherin gene expressions in Her2+ breast tumors. Furthermore, breast cancer patients with low β2-chimaerin expression have reduced relapse free survival but develop metastasis at similar times. Overall, our data redefine the role of β2-chimaerin as tumor suppressor and provide the first in vivo evidence of a dual function in breast cancer, suppressing tumor initiation but favoring tumor progression. PMID:27058424

  3. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    PubMed

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  4. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

    PubMed Central

    Saloman, Jami L.; Albers, Kathryn M.; Li, Dongjun; Hartman, Douglas J.; Crawford, Howard C.; Muha, Emily A.; Rhim, Andrew D.; Davis, Brian M.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations. PMID:26929329

  5. Initial Study of Radiological and Clinical Efficacy Radioembolization Using 188Re-Human Serum Albumin (HSA) Microspheres in Patients with Progressive, Unresectable Primary or Secondary Liver Cancers

    PubMed Central

    Nowicki, Mirosław L.; Ćwikła, Jarosław B.; Sankowski, Artur J.; Shcherbinin, Sergey; Grimes, Josh; Celler, Anna; Buscombe, John R.; Bator, Andrzej; Pech, Maciej; Mikołajczak, Renata; Pawlak, Dariusz

    2014-01-01

    Background The aim of this initial study was to evaluate the clinical and radiological effectiveness of radioembolization (RE) using 188Re-Human Serum Albumin (HSA) microspheres in patients with advanced, progressive, unresectable primary or secondary liver cancers, not suitable to any other form of therapy. Material/Methods Overall, we included 13 patients with 20 therapy sessions. Clinical and radiological responses were assessed at 6 weeks after therapy, and then every 3 months. The objective radiological response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 by sequential MRI. Adverse events were evaluated using NCI CTCAE v.4.03. Results There were 4 patients with hepatocellular carcinoma (HCC), 6 with metastatic colorectal cancer (mCRC), 2 with neuroendocrine carcinoma (NEC), and 1 patient with ovarian carcinoma. Mean administered activity of 188Re HSA was 7.24 GBq (range 3.8–12.4) A high microspheres labeling efficacy of over 97±2.1% and low urinary excretion of 188Re (6.5±2.3%) during first 48-h follow-up. Median overall survival (OS) for all patients was 7.1 months (CI 6.2–13.3) and progression-free survival (PFS) was 5.1 months (CI 2.4–9.9). In those patients who had a clinical partial response (PR), stable disease (SD), and disease progression (DP) as assessed 6 weeks after therapy, the median OS was 9/5/4 months, respectively, and PFS was 5/2/0 months, respectively. The treatment adverse events (toxicity) were at an acceptable level. Initially and after 6 weeks, the CTC AE was grade 2, while after 3 months it increased to grade 3 in 4 subjects. This effect was mostly related to rapid cancer progression in this patient subgroup. Conclusions The results of this preliminary study indicate that RE using 188Re HSA is feasible and a viable option for palliative therapy in patients with extensive progressive liver cancer. It was well tolerated by most patients, with a low level of toxicity during the 3 months of

  6. Sphingosylphosphorylcholine in cancer progress

    PubMed Central

    Yue, Hong-Wei; Jing, Qing-Chuan; Liu, Ping-Ping; Liu, Jing; Li, Wen-Jing; Zhao, Jing

    2015-01-01

    Sphingosylphosphorylcholine (SPC) is a naturally occurring bioactive sphingolipid in blood plasma, metabolizing from the hydrolysis of the membrane sphingolipid. It has been shown to exert multifunctional role in cell physiological regulation either as an intracellular second messenger or as an extracellular agent through G protein coupled receptors (GPCRs). Because of elevated levels of SPC in malicious ascites of patients with cancer, the role of SPC in tumor progression has prompted wide interest. The factor was reported to affect the proliferation and/or migration of many cancer cells, including pancreatic cancer cells, epithelial ovarian carcinoma cells, rat C6 glioma cells, neuroblastoma cells, melanoma cells, and human leukemia cells. This review covers current knowledge of the role of SPC in tumor. PMID:26550104

  7. Arsenic | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Prevention | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Home | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Preventing Breast Cancer: Making Progress

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... 000 women will have been diagnosed with invasive breast cancer, and nearly 41,000 women will die from ...

  11. Acknowledgements | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Sunburn | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. Survival | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Incidence | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Cadmium | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Diagnosis | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Benzene | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Radon | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Nitrate | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Mortality | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Weight | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Introduction | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Mortality | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Acknowledgements | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Survival | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Benzene | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Prostate Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Cervical Cancer Screening | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Prostate Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Ovarian Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Breast Cancer Screening | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. Life After Cancer | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Colorectal Cancer Screening | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Bladder Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Breast Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Colorectal Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Lung Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Kidney Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Lung Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Kidney Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Targeting ECM Disrupts Cancer Progression

    PubMed Central

    Venning, Freja A.; Wullkopf, Lena; Erler, Janine T.

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression. PMID:26539408

  3. Targeting ECM Disrupts Cancer Progression.

    PubMed

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.

  4. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.

    PubMed

    Connolly, Nina P; Stokum, Jesse A; Schneider, Craig S; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J; Kim, Anthony J; Simard, J Marc; Winkles, Jeffrey A; Holland, Eric C; Woodworth, Graeme F

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  5. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

    PubMed Central

    Stokum, Jesse A.; Schneider, Craig S.; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J.; Kim, Anthony J.; Simard, J. Marc; Winkles, Jeffrey A.; Holland, Eric C.; Woodworth, Graeme F.

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  6. Accelerating Progress Against Cancer

    Cancer.gov

    Investment in cancer research is making a difference, but we still must overcome disparities in cancer incidence and mortality, and expand research to detect cancers earlier and develop more effective, less-toxic treatments. NCI supports research studies and programs across the country that are working to further advance cancer, research, and clinical care.

  7. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.

    PubMed

    Hermann, Patrick C; Sancho, Patricia; Cañamero, Marta; Martinelli, Paola; Madriles, Francesc; Michl, Patrick; Gress, Thomas; de Pascual, Ricardo; Gandia, Luis; Guerra, Carmen; Barbacid, Mariano; Wagner, Martin; Vieira, Catarina R; Aicher, Alexandra; Real, Francisco X; Sainz, Bruno; Heeschen, Christopher

    2014-11-01

    Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC. We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting

  8. Connected Health and Progress against Cancer

    Cancer.gov

    An NCI Cancer Currents blog post about a new report from President’s Cancer Panel outlining how connective technologies can promote cancer prevention, enhance patients’ treatment experience, and accelerate progress in cancer research.

  9. Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis.

    PubMed

    Harrison, Sean; Lennon, Rosie; Holly, Jeff; Higgins, Julian P T; Gardner, Mike; Perks, Claire; Gaunt, Tom; Tan, Vanessa; Borwick, Cath; Emmet, Pauline; Jeffreys, Mona; Northstone, Kate; Rinaldi, Sabina; Thomas, Stephen; Turner, Suzanne D; Pease, Anna; Vilenchick, Vicky; Martin, Richard M; Lewis, Sarah J

    2017-06-01

    To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF-prostate cancer relationship in humans; and 10 animal studies examining the IGF-prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. IGF-I is a potential mechanism underlying the

  10. Hyaluronan, Inflammation, and Breast Cancer Progression

    PubMed Central

    Schwertfeger, Kathryn L.; Cowman, Mary K.; Telmer, Patrick G.; Turley, Eva A.; McCarthy, James B.

    2015-01-01

    Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory “cancerized” or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression. PMID:26106384

  11. Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor initiating cells

    PubMed Central

    Xie, Han; Hanai, Jun-ichi; Ren, Jian-Guo; Kats, Lev; Burgess, Kerri; Bhargava, Parul; Signoretti, Sabina; Billiard, Julia; Duffy, Kevin J.; Grant, Aaron; Wang, Xiaoen; Lorkiewicz, Pawel K.; Schatzman, Sabrina; Bousamra, Michael; Lane, Andrew N.; Higashi, Richard M.; Fan, Teresa W.M.; Pandolfi, Pier Paolo; Sukhatme, Vikas P.; Seth, Pankaj

    2014-01-01

    Summary The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the inter-conversion of pyruvate and lactate, is upregulated in human cancers and is associated with aggressive tumor outcomes. Here we use a novel inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by re-activation of mitochondrial function in vitro but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC including cancer stem cell-dependent drug resistant tumors. PMID:24726384

  12. Progress in breast cancer: overview.

    PubMed

    Arteaga, Carlos L

    2013-12-01

    This edition of CCR Focus titled Research in Breast Cancer: Frontiers in Genomics, Biology, and Clinical Investigation reviews six topics that cover areas of translational research of high impact in breast cancer. These topics represent areas of breast cancer research where significant progress has occurred but also where very important challenges remain. The papers in this CCR Focus section are contributed by experts in the respective areas of investigation. Herein, key aspects of these contributions and the research directions they propose are reviewed. ©2013 AACR.

  13. Health information technology: strategic initiatives, real progress.

    PubMed

    Kolodner, Robert M; Cohn, Simon P; Friedman, Charles P

    2008-01-01

    We fully agree with Carol Diamond and Clay Shirky that deployment of health information technology (IT) is necessary but not sufficient for transforming U.S. health care. However, the recent work to advance health IT is far from an exercise in "magical thinking." It has been strategic thinking. To illustrate this, we highlight recent initiatives and progress under four focus areas: adoption, governance, privacy and security, and interoperability. In addition, solutions exist for health IT to advance rapidly without adversely affecting future policy choices. A broad national consensus is emerging in support of advancing health IT to enable the transformation of health and care.

  14. Roles for Growth Factors in Cancer Progression

    PubMed Central

    Witsch, Esther; Sela, Michael; Yarden, Yosef

    2011-01-01

    Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy. PMID:20430953

  15. Management of progressive metastatic prostate cancer.

    PubMed

    Waselenko, J K; Dawson, N A

    1997-10-01

    Metastatic prostate cancer is a growing health problem and is the second leading cause of cancer death in men. While the response of patients with metastatic prostate cancer to initial hormonal manipulation is excellent, the majority of patients eventually progress. As a result, a growing number of patients and their physicians need-to-find acceptable therapeutic alternatives. Fortunately, the number of therapies in the management armamentarium is growing and includes: alternative hormonal therapies, chemotherapy, radioisotopes, and investigational agents. The major focus of treatment has shifted to palliation and quality of life. The decline of prostate-specific antigen (PSA) has become another important end point as evidence supporting a correlation with prolonged survival mounts. Enrolling eligible patients in clinical trials is critical to the development of new treatment strategies for this difficult disease.

  16. Nuclear morphometry, nucleomics and prostate cancer progression

    PubMed Central

    Veltri, Robert W; Christudass, Christhunesa S; Isharwal, Sumit

    2012-01-01

    Prostate cancer (PCa) results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults (such as chronic infection, inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks), followed by a multistep process of progression. These steps include several genetic and epigenetic alterations, as well as alterations to the chromatin structure, which occur in response to the carcinogenic stress-related events that sustain proliferative signaling. Events such as evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are readily observed. In addition, in conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of PCa, involving energy metabolism and evasion of the immune surveillance system, appear to be involved. In addition, when cancer spread and metastasis occur, the ‘tumor microenvironment' in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a ‘seed and soil' site where PCa proliferation and growth may occur over time. When PCa is initiated and progression ensues, significant alterations in nuclear size, shape and heterochromatin (DNA transcription) organization are found, and key nuclear transcriptional and structural proteins, as well as multiple nuclear bodies can lead to precancerous and malignant changes. These series of cellular and tissue-related malignancy-associated events can be quantified to assess disease progression and management. PMID:22504875

  17. [Initiation, promotion, initiation experiments with radon and cigarette smoke: Lung tumors in rats]. Progress report

    SciTech Connect

    Moolgavkar, S.H.

    1994-10-01

    During the past several years, the authors have made considerable progress in modeling carcinogenesis in general, and in modeling radiation carcinogenesis, in particular. They present an overview of their progress in developing stochastic carcinogenesis models and applying them to experimental and epidemiologic data sets. Traditionally, cancer models have been used for the analysis of incidence (or prevalence) data in epidemiology and time to tumor data in experimental studies. The relevant quantities for the analysis of these data are the hazard function and the probability of tumor. The derivation of these quantities is briefly described here. More recently, the authors began to use these models for the analysis of data on intermediate lesions on the pathway to cancer. Such data are available in experimental carcinogenesis studies, in particular in initiation and promotion studies on the mouse skin and the rat liver. If however, quantitative information on intermediate lesions on the pathway to lung cancer were to be come available at some future date, the methods that they have developed for the analysis of initiation-promotion experiments could easily be applied to the analysis of these lesions. The mathematical derivations here are couched in terms of a particular two-mutation model of carcinogenesis. Extension to models postulating more than two mutations is not always straightforward.

  18. Spatial Moran models, II: cancer initiation in spatially structured tissue

    PubMed Central

    Foo, J; Leder, K

    2016-01-01

    We study the accumulation and spread of advantageous mutations in a spatial stochastic model of cancer initiation on a lattice. The parameters of this general model can be tuned to study a variety of cancer types and genetic progression pathways. This investigation contributes to an understanding of how the selective advantage of cancer cells together with the rates of mutations driving cancer, impact the process and timing of carcinogenesis. These results can be used to give insights into tumor heterogeneity and the “cancer field effect,” the observation that a malignancy is often surrounded by cells that have undergone premalignant transformation. PMID:26126947

  19. NCI Dictionary | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Secondhand Smoke | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Fat Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Custom Report | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. About the Report | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Stage at Diagnosis | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Chemical Exposures | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Early Detection | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Youth Tobacco Use | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Alcohol Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Director's Message | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Data Sources | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Basic Research and Progress against Cancer

    Cancer.gov

    An infographic about the importance of basic research for making progress against cancer. The graphic shows the research milestones that led to the development and approval of crizotinib (Xalkori®) to treat certain non-small cell lung cancers.

  12. Indoor Tanning | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. Physical Activity | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Tobacco Use | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. End of Life | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Report Highlights | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Contact Us | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Adult Tobacco Use | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Frequently Asked Questions | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Quitting Smoking | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. HPV Immunization | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Smoking Cessation | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Prevention Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Treatment Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Data Resources | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Secondhand Smoke Exposure | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Contact Us | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Red Meat Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Indoor Tanning | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Secondhand Smoke | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Basic Research and Progress against Pediatric Cancer

    Cancer.gov

    An infographic about the importance of basic research for making progress against childhood cancers. Shows the milestones that led to development and approval of dinutuximab (Unituxin®) to treat neuroblastoma, a cancer seen mainly in children.

  13. Heme oxygenase-1 in macrophages controls prostate cancer progression.

    PubMed

    Nemeth, Zsuzsanna; Li, Mailin; Csizmadia, Eva; Döme, Balazs; Johansson, Martin; Persson, Jenny Liao; Seth, Pankaj; Otterbein, Leo; Wegiel, Barbara

    2015-10-20

    Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.

  14. Metastasis: an early event in cancer progression.

    PubMed

    Hu, Yijun; Yu, Xiya; Xu, Guixia; Liu, Shanrong

    2017-05-01

    Metastasis is the leading cause of death for a majority of cancer patients, and thus the need to understand the biology of metastasis becomes increasingly acute. When metastasis is initiated in tumor progression remains obscure. Better understanding of mechanisms regulating acquisition of metastatic ability in tumor cells will provide novel therapeutic targets and prevention of metastasis in clinics accompanied with the treatment of the primary tumor might be helpful in reducing metastasis-related mortality. A literature search was performed in multiple electronic databases. Research papers from clinical reports to experimental studies on metastasis were analyzed. The article discusses tumor heterogeneity and genomic instability in the context of metastasis and tumor cell dissemination. And then we review biological mechanism of metastasis at an early stage in both intracellular (CSCs and CTCs) and extracellular (microenvironment) context. Finally, current development of anti-metastatic therapies is summarized. Metastasis could be initiated at an early point of tumor progression. Therefore, early intervention on metastasis should be applied among cancer patients in clinical settings.

  15. Sulindac and Celecoxib regulate cell cycle progression by p53/p21 up regulation to induce apoptosis during initial stages of experimental colorectal cancer.

    PubMed

    Vaish, Vivek; Rana, Chandan; Piplani, Honit; Vaiphei, Kim; Sanyal, Sankar Nath

    2014-03-01

    In the present study we have elaborated the putative mechanisms could be followed by the non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib in the regulation of cell cycle checkpoints along with tumor suppressor proteins to achieve their chemopreventive effects in the initial stages of experimental colorectal cancer. Male Sprague-Dawley rats were administered with 1,2-dimethylhydrazine dihydrochloride (DMH) to produce early stages of colorectal carcinogenesis. The mRNA expression profiles of various target genes were analyzed by RT-PCR and validated by quantitative real-time PCR, whereas protein expression was analyzed by Western blotting. Nuclear localization of transcription factors or other nuclear proteins was analyzed by electrophoretic mobility shift assay and immunofluorescence. Flowcytometry was performed to analyze the differential apoptotic events and cell cycle regulation. Molecular docking studies with different target proteins were also performed to deduce the various putative mechanisms of action followed by Sulindac and Celecoxib. We observed that DMH administration has abruptly increased the proliferation of colonic cells which is macroscopically visible in the form of multiple plaque lesions and co-relates with the disturbed molecular mechanisms of cell cycle regulation. However, co-administration of NSAIDs has shown regulatory effects on cell cycle checkpoints via induction of various tumor suppressor proteins. We may conclude that Sulindac and Celecoxib could possibly follow p53/p21 mediated regulation of cell proliferation, where down regulation of NF-κB signaling and activation of PPARγ might serve as important additional events in vivo.

  16. Cancer stem cells: progress and challenges in lung cancer

    PubMed Central

    Templeton, Amanda K.; Miyamoto, Shinya; Babu, Anish; Munshi, Anupama

    2014-01-01

    The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called “cancer stem cells” (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs. PMID:27358855

  17. Tumour progression and the nature of cancer.

    PubMed Central

    Clark, W. H.

    1991-01-01

    The nature of neoplasia and its sometime end result, cancer, has been studied by exposition and explanation of the sequential lesions of tumour progression. Neoplastic lesions were divided into four classes on the basis of growth characteristics and whether lesional growth is confined to one or more tissue compartments. Class IA, the initial lesion, an orderly, probably clonal growth, usually differentiates and disappears. Class IB: Failure to differentiate accompanied by disorderly growth. Class IC: Randomly dispersed atypical cells, constituting a precursor state. Class II, intermediate lesions, apparently arising from the atypical cells, show temporally unrestricted growth within the tissue compartment of origin. Class III lesions, primary invasive cancers, show temporally unrestricted growth in two or more tissue compartments and metastasise along different paths, a property associated with extracellular matrix interaction. The metastatic pathways may result from different subsets of cells in the primary cancer. Class IV lesions are the metastases. It was concluded that, all neoplasms develop in the same way, have the same general behavioural characteristics, and, when malignant, all interact with the extracellular matrix of the primary and the secondary sites. The origins and development of cancer are considered to be pluralistic and not due to a discrete change in a cell, whose progeny, as a result of that discrete change, carries all of the information required to explain the almost limitless events of a neoplastic system. Images Figure 4 PMID:1911211

  18. Fibroblasts—a key host cell type in tumor initiation, progression, and metastasis

    PubMed Central

    Strell, Carina; Rundqvist, Helene

    2012-01-01

    Tumor initiation, growth, invasion, and metastasis occur as a consequence of a complex interplay between the host environment and cancer cells. Fibroblasts are now recognized as a key host cell type involved in host–cancer signaling. This review discusses some recent studies that highlight the roles of fibroblasts in tumor initiation, early progression, invasion, and metastasis. Some clinical studies describing the prognostic significance of fibroblast-derived markers and signatures are also discussed. PMID:22509805

  19. MicroRNA and Breast Cancer Progression

    DTIC Science & Technology

    2007-08-01

    AD_________________ Award Number: W81XWH-05-1-0428 TITLE: MicroRNA and Breast Cancer Progression...3. DATES COVERED (From - To) 15 JUL 2005 - 14 JUL 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER MicroRNA and Breast Cancer Progression 5b...We hypothesized that certain miRNA species are differentially expressed in the normal breast epithelium and breast cancer cells. Our concept was that

  20. Life After Cancer Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Cancer Survivors and Obesity | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Cancer Survivors and Physical Activity | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Financial Burden of Cancer Care | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Cancer Survivors and Smoking | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Progress Report 2013. Turnaround Arts Initiative

    ERIC Educational Resources Information Center

    Stoelinga, Sara Ray; Joyce, Katie; Silk, Yael

    2013-01-01

    This interim progress report provides a look at Turnaround Arts schools in their first year, including: (1) a summary of the evaluation design and research questions; (2) a preliminary description of strategies used to introduce the arts in Turnaround Arts schools; and (3) a summary of school reform indicators and student achievement data at…

  6. Role of mitochondrial dysfunction in cancer progression

    PubMed Central

    Hsu, Chia-Chi; Tseng, Ling-Ming

    2016-01-01

    Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca2+, or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy. PMID:27022139

  7. Liver cancer stem cell markers: Progression and therapeutic implications.

    PubMed

    Sun, Jing-Hui; Luo, Qing; Liu, Ling-Ling; Song, Guan-Bin

    2016-04-07

    Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.

  8. HRD Initiatives Contributing to Women's Career Progress.

    ERIC Educational Resources Information Center

    McDonald, Kimberly S.; Hite, Linda M.

    1999-01-01

    Highlights findings from the literature on management development experiences that influence women's advancement. Discusses results of a study of 27 female managers about their participation in management development. Describes four human resource development (HRD) initiatives with the potential to enhance women's management development: training,…

  9. Inflammation in prostate cancer progression and therapeutic targeting

    PubMed Central

    Stark, Timothy; Livas, Lydia

    2015-01-01

    Chronic inflammation contributes to the onset and progression of human cancer, via modifications in the tumor microenvironment by remodeling the extracellular matrix (ECM) and initiating epithelial mesenchymal transition (EMT). At the biological level, chronically inflamed cells release cytokines that are functionally dictating a constitutively active stroma, promoting tumor growth and metastasis. In prostate cancer, inflammation correlates with increased development of “risk factor” lesions or proliferative inflammatory atrophy (PIA). Chronic inflammation in benign prostate biopsy specimens can be associated with high-grade prostate tumors in adjacent areas. In this article, we discuss the current understanding of the incidence of inflammation in prostate cancer progression and the significance of the process in therapeutic targeting of specific inflammatory signaling pathways and critical effectors during tumor progression. Further understanding of the process of chronic inflammation in prostate tumor progression to metastasis will enable development and optimization of novel therapeutic modalities for the treatment of high-risk patients with advanced disease. PMID:26816843

  10. SOX4 is essential for prostate tumorigenesis initiated by PTEN ablation | Office of Cancer Genomics

    Cancer.gov

    Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten.

  11. Studying the Role of Eukaryotic Translation Initiation Factor 4E (eIF4E) Phosphorylation by MNK1/2 Kinases in Prostate Cancer Development and Progression

    DTIC Science & Technology

    2013-06-01

    Krop,  I.  E.,  Rousseau ,  C.,  Cocolakis,  E.,  Borden,  K.  L.,  Benz,  C.  C.,  and Miller, W.  H.,  Jr.  (2011) Clin Cancer Res 17, 2874‐2884  7...S., Long, J. C., and Caceres, J. F. (2006) Mol Cell Biol 26, 5744‐5758  15.  Buxade, M., Parra, J. L.,  Rousseau , S., Shpiro, N., Marquez, R

  12. Regulation of Prostate Cancer Progression by the Tumor Microenvironment

    PubMed Central

    Shiao, Stephen L.; Chu, Gina Chia-Yi; Chung, Leland W. K.

    2016-01-01

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease . Experimental data has uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  13. Regulation of prostate cancer progression by the tumor microenvironment.

    PubMed

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Correlation between Oxidative Stress, Nutrition, and Cancer Initiation

    PubMed Central

    Saha, Subbroto Kumar; Lee, Soo Bin; Won, Jihye; Choi, Hye Yeon; Kim, Kyeongseok; Yang, Gwang-Mo; Abdal Dayem, Ahmed

    2017-01-01

    Inadequate or excessive nutrient consumption leads to oxidative stress, which may disrupt oxidative homeostasis, activate a cascade of molecular pathways, and alter the metabolic status of various tissues. Several foods and consumption patterns have been associated with various cancers and approximately 30–35% of the cancer cases are correlated with overnutrition or malnutrition. However, several contradictory studies are available regarding the association between diet and cancer risk, which remains to be elucidated. Concurrently, oxidative stress is a crucial factor for cancer progression and therapy. Nutritional oxidative stress may be induced by an imbalance between antioxidant defense and pro-oxidant load due to inadequate or excess nutrient supply. Oxidative stress is a physiological state where high levels of reactive oxygen species (ROS) and free radicals are generated. Several signaling pathways associated with carcinogenesis can additionally control ROS generation and regulate ROS downstream mechanisms, which could have potential implications in anticancer research. Cancer initiation may be modulated by the nutrition-mediated elevation in ROS levels, which can stimulate cancer initiation by triggering DNA mutations, damage, and pro-oncogenic signaling. Therefore, in this review, we have provided an overview of the relationship between nutrition, oxidative stress, and cancer initiation, and evaluated the impact of nutrient-mediated regulation of antioxidant capability against cancer therapy. PMID:28714931

  15. [Cancer initiating cell theory: popularity and controversies].

    PubMed

    Chen, Hua; Huang, Qiang; Dong, Jun; Lan, Qing

    2006-06-01

    The cancer stem cell model proposes that most tumors are derived from a single cell that is transformed into a cancer-initiating cell (cancer stem cell). Cancer stem cells have the capacity to proliferate, differentiate, and form tumors in vivo. However, the origin of cancer stem cells remains controversial. Normal stem cells are regarded as an ideal candidate for the origin of cancer stem cells when take similar characters and signaling pathways between them into consideration. In addition,cell fusion is an important physiologic process during development and tissue repair,and is closely related to several fundamental features of tumors,and thus could be involved in the development of cancer stem cells.

  16. Linking obesogenic dysregulation to prostate cancer progression

    PubMed Central

    Taylor, Renea A; Lo, Jennifer; Ascui, Natasha; Watt, Matthew J

    2015-01-01

    The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies. PMID:26581226

  17. Baseline genetic associations in the Parkinson's Progression Markers Initiative (PPMI).

    PubMed

    Nalls, Mike A; Keller, Margaux F; Hernandez, Dena G; Chen, Lan; Stone, David J; Singleton, Andrew B

    2016-01-01

    The Parkinson's Progression Marker Initiative is an international multicenter study whose main goal is investigating markers for Parkinson's disease (PD) progression as part of a path to a treatment for the disease. This manuscript describes the baseline genetic architecture of this study, providing not only a catalog of disease-linked variants and mutations, but also quantitative measures with which to adjust for population structure. Three hundred eighty-three newly diagnosed typical PD cases, 65 atypical PD and 178 healthy controls, from the Parkinson's Progression Marker Initiative study have been genotyped on the NeuroX or Immunochip arrays. These data are freely available to all researchers interested in pursuing PD research within the Parkinson's Progression Marker Initiative. The Parkinson's Progression Marker Initiative represents a study population with low genetic heterogeneity. We recapitulate known PD associations from large-scale genome-wide association studies and refine genetic risk score models for PD predictability (area under the curve, ∼0.74). We show the presence of six LRRK2 p.G2019S and nine GBA p.N370S mutation carriers. The Parkinson's Progression Marker Initiative study and its genetic data are useful in studies of PD biomarkers. The genetic architecture described here will be useful in the analysis of myriad biological and clinical traits within this study. © 2015 International Parkinson and Movement Disorder Society.

  18. Recent Progress in Pancreatic Cancer

    PubMed Central

    Wolfgang, Christopher L.; Herman, Joseph M.; Laheru, Daniel A.; Klein, Alison P.; Erdek, Michael A.; Fishman, Elliot K.; Hruban, Ralph H.

    2013-01-01

    Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer. PMID:23856911

  19. The Cancer Genome Anatomy Project: EST Sequencing and the Genetics of Cancer Progression1

    PubMed Central

    Krizman, David B; Wagner, Lukas; Lash, Alex; Strausberg, Robert L; Emmert-Buck, Michael R

    1999-01-01

    Abstract As the process of tumor progression proceeds from the normal cellular state to a preneoplastic condition and finally to the fully invasive form, the molecular characteristics of the cell change as well. These characteristics can be considered a molecular fingerprint of the cell at each stage of progression and, analogous to fingerprinting a criminal, can be used as markers of the progression process. Based on this premise, the Cancer Genome Anatomy Project was initiated with the broad goal of determining the comprehensive molecular characterization of normal, premalignant, and malignant tumor cells, thus making a reality the identification of all major cellular mechanisms leading to tumor initiation and progression ([Strausberg, R.L., Dahl, C.A., and Klausner, R.D. (1997). “New opportunities for uncovering the molecular basis of cancer.” Nat. Genet., 16: 415–516.], www.ncbi.nlm.nih.gov/ncicgap/). The expectation of determining the genetic fingerprints of cancer progression will allow for 1) correlation of disease progression with therapeutic outcome; 2) improved evaluation of disease treatment; 3) stimulation of novel approaches to prevention, detection, and therapy; and 4) enhanced diagnostic tools for clinical applications. Whereas acquiring the comprehensive molecular analysis of cancer progression may take years, results from initial, short-term goals are currently being realized and are proving very fruitful. PMID:10933042

  20. The Cancer Genome Anatomy Project: EST sequencing and the genetics of cancer progression.

    PubMed

    Krizman, D B; Wagner, L; Lash, A; Strausberg, R L; Emmert-Buck, M R

    1999-06-01

    As the process of tumor progression proceeds from the normal cellular state to a preneoplastic condition and finally to the fully invasive form, the molecular characteristics of the cell change as well. These characteristics can be considered a molecular fingerprint of the cell at each stage of progression and, analogous to fingerprinting a criminal, can be used as markers of the progression process. Based on this premise, the Cancer Genome Anatomy Project was initiated with the broad goal of determining the comprehensive molecular characterization of normal, premalignant, and malignant tumor cells, thus making a reality the identification of all major cellular mechanisms leading to tumor initiation and progression ([Strausberg, R.L., Dahl, C.A., and Klausner, R.D. (1997). "New opportunities for uncovering the molecular basis of cancer." Nat. Genet., 16: 415-516.], www.ncbi.nlm.nih.gov/ncicgap/). The expectation of determining the genetic fingerprints of cancer progression will allow for 1) correlation of disease progression with therapeutic outcome; 2) improved evaluation of disease treatment; 3) stimulation of novel approaches to prevention, detection, and therapy; and 4) enhanced diagnostic tools for clinical applications. Whereas acquiring the comprehensive molecular analysis of cancer progression may take years, results from initial, short-term goals are currently being realized and are proving very fruitful.

  1. Algorithmic methods to infer the evolutionary trajectories in cancer progression

    PubMed Central

    Graudenzi, Alex; Ramazzotti, Daniele; Sanz-Pamplona, Rebeca; De Sano, Luca; Mauri, Giancarlo; Moreno, Victor; Antoniotti, Marco; Mishra, Bud

    2016-01-01

    The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next-generation sequencing data and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent work on the “selective advantage” relation among driver mutations in cancer progression and investigate its applicability to the modeling problem at the population level. Here, we introduce PiCnIc (Pipeline for Cancer Inference), a versatile, modular, and customizable pipeline to extract ensemble-level progression models from cross-sectional sequenced cancer genomes. The pipeline has many translational implications because it combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations, and progression model inference. We demonstrate PiCnIc’s ability to reproduce much of the current knowledge on colorectal cancer progression as well as to suggest novel experimentally verifiable hypotheses. PMID:27357673

  2. The significance of the senescence pathway in breast cancer progression.

    PubMed

    Pare, Rahmawati; Yang, Tao; Shin, Joo-Shik; Lee, Cheok Soon

    2013-06-01

    Invasive breast cancer develops through prolonged accumulation of multiple genetic changes. The progression to a malignant phenotype requires overriding of growth inhibition. It is evident that some breast cancers have an inherited basis, and both hereditary and sporadic cancers appear to involve molecular mechanisms that are linked to the cell cycle. Frequently, changes in the molecular pathways with gene deletions, point mutations and/or overexpression of growth factors can be seen in these cancers. Recent evidence also implicates the senescence pathway in breast carcinogenesis. It has a barrier effect towards excessive cellular growth, acting as the regulator of tumour initiation and progression. Later in carcinogenesis, acquisition of the senescence associated secretory phenotype may instead promote tumour progression by stimulating growth and transformation in adjacent cells. This two-edge role of senescence in cancer directs more investigations into the effects of the senescence pathway in the development of malignancy. This review presents the current evidence on the roles of senescence molecular pathways in breast cancer and its progression.

  3. DISCOIDIN DOMAIN RECEPTOR TYROSINE KINASES: NEW PLAYERS IN CANCER PROGRESSION

    PubMed Central

    Valiathan, Rajeshwari R.; Marco, Marta; Leitinger, Birgit; Kleer, Celina G.; Fridman, Rafael

    2012-01-01

    Almost all human cancers display dysregulated expression and/or function of one or more receptor tyrosine kinases (RTKs). The strong causative association between altered RTK function and cancer progression has translated into novel therapeutic strategies that target these cell surface receptors in the treatment of cancer. Yet, the full spectrum of RTKs that may alter the oncogenic process is not completely understood. Accumulating evidence suggests that a unique set of RTKs known as the Discoidin Domain Receptors (DDRs) play a role in cancer progression by regulating the interactions of tumor cells with their surrounding collagen matrix. The DDRs are the only RTKs that specifically bind to, and are activated by collagen. Hence, the DDRs are part of the signaling networks that translate information from the extracellular matrix thereby acting as key regulators of cell-matrix interactions. Under physiological conditions, DDRs control cell and tissue homeostasis by acting as collagen sensors, transducing signals that regulate cell polarity, tissue morphogenesis, and cell differentiation. In cancer, DDRs are hijacked by tumor cells to disrupt normal cell-matrix communication and initiate pro-migratory and pro-invasive programs. Importantly, several cancer types exhibit DDR mutations, which are thought to alter receptor function and contribute to cancer progression. Other evidence suggests that the actions of DDRs in cancer are complex, either promoting or suppressing tumor cell behavior in a DDR type/isoform specific and context dependent manner. Thus, there is still a considerable gap in our knowledge of DDR actions in cancer tissues. This review summarizes the current knowledge on DDR expression and function in cancer and discusses the potential implications of DDRs in cancer biology. It is hoped that this effort will encourage more research into these poorly understood but unique RTKs, which have the potential of becoming novel therapeutics targets in cancer. PMID

  4. Progress on Simulating the Initiation of Vacuum Insulator Flashover

    DTIC Science & Technology

    2009-06-01

    of a +45° angled insulator as well as pictures demonstrating anode and cathode initiated flashover events [2]. In order to focus our attention on...Progress on Simulating the Initiation of Vacuum Insulator Flashover M.P. Perkins, T.L. Houck, J.B. Javedani, G.E. Vogtlin, D.A. Goerz Lawrence...In this article we will discuss physics models that have been implemented in a PIC code to better understand the initiation of flashover . The PIC

  5. Metabolic imbalance and prostate cancer progression

    PubMed Central

    Burton, Anya J; Tilling, Kate M; Holly, Jeff M; Hamdy, Freddie C; Rowlands, Mari-Anne E; Donovan, Jenny L; Martin, Richard M

    2010-01-01

    There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of ω-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made. PMID:21532839

  6. Timing of multikinase inhibitor initiation in differentiated thyroid cancer.

    PubMed

    Brose, Marcia S; Smit, Jan Wa; Lin, Chia-Chi; Pitoia, Fabian; Fellous, Marc; DeSanctis, Yoriko; Schlumberger, Martin; Tori, Masayuki; Sugitani, Iwao

    2017-03-07

    There are limited treatment options for patients with radioactive iodine-refractory, progressive differentiated thyroid cancer. Although there is consensus that multikinase inhibitor therapy should be considered in patients with progressive disease with considerable tumor load or symptomatic disease, uncertainty exists on the optimal timing to treat with a multikinase inhibitor, especially for asymptomatic patients. RIFTOS MKI is an international, prospective, open-label, multicenter, noninterventional study with the primary objective to compare the time to symptomatic progression from study entry in asymptomatic patients with radioactive iodine -refractory, progressive differentiated thyroid cancer for whom there is a decision to initiate multikinase inhibitors at study entry (cohort 1) with those for whom there is a decision to not initiate multikinase inhibitors at study entry (cohort 2). Secondary endpoints are overall survival and progression-free survival, which will be compared between cohorts 1 and 2. Additional secondary endpoints are postprogression survival from time of symptomatic progression, duration of and response to each systemic treatment regimen, and dosing of sorafenib throughout the treatment period. Asymptomatic, multikinase inhibitor-naive patients aged ≥18 years with histologically/cytologically documented differentiated thyroid cancer that is radioactive iodine-refractory are eligible. Patients may receive any therapy for differentiated thyroid cancer, including sorafenib or other multikinase inhibitors if indicated and decided on by the treating physician. In total, 700 patients are estimated to be enrolled from >20 countries. Final analysis will be performed once the last enrolled patient has been followed up with for 24 months. (ClinicalTrials.gov identifier: NCT02303444).

  7. National Cancer Moonshot Initiative platform | Office of Cancer Genomics

    Cancer.gov

    As part of the Vice President’s National Cancer Moonshot Initiative, the National Cancer Institute has launched an online engagement platform to enable the research community and the public to submit cancer research ideas to a Blue Ribbon Panel of scientific experts. Any member of the public is encouraged to submit his or her ideas for reducing the incidence of cancer and developing better ways to prevent, treat, and cure all types of cancer. Research ideas may be submitted in the following areas:

  8. Connexins in Prostate Cancer Initiation and Progression

    DTIC Science & Technology

    2012-09-01

    2006) Capacity of the Golgi Apparatus for Cargo Transport Prior to Complete Assembly. Mol.Biol.Cell, 17, 4105-4117. Parmender P. Mehta, Ph.D... Golgi -resident protein [31], Giantin, a Golgi -associated structural protein [32] and Caveolin 2 (Cav-2) [30], which are the makers for the secretory...endocytic itinerary of this mutant? We wished to investigate whether or not it traffics to the cell surface via endoplasmic reticulum and Golgi and

  9. Connexins in Prostate Cancer Initiation and Progression

    DTIC Science & Technology

    2013-11-01

    as underlined, were designed to contain XhoI and BamHI sites, respectively. The PCR products were first purified using QIAquick PCR purification kit...purified PCR products were cloned into EcoRI/BamHI- digested pEYFP-NI. The entire coding sequences of EYFP- tagged full-length and truncated Cx43 andCx32...freshmedium 8 h post-transfection. Retrovirus Production and Infection of Cells—Control and recombinant retroviruses harboring full-length and mutant Cxs

  10. Reprogramming cancer cells: overview & current progress.

    PubMed

    Lim, Kian Lam; Teoh, Hoon Koon; Choong, Pei Feng; Teh, Hui Xin; Cheong, Soon Keng; Kamarul, Tunku

    2016-07-01

    Cancer is a disease with genetic and epigenetic origins, and the possible effects of reprogramming cancer cells using the defined sets of transcription factors remain largely uninvestigated. In the handful of publications available so far, findings have shown that reprogramming cancer cells changed the characteristics of the cells to differ from the parental cancer cells. These findings indicated the possibility of utilizing reprogramming technology to create a disease model in the laboratory to be used in studying the molecular pathogenesis or for drug screening of a particular cancer model. Despite numerous methods employed in generating induced pluripotent stem cells (iPSCs) from cancer cells only a few studies have successfully reprogrammed malignant human cells. In this review we will provide an overview on i) methods to reprogram cancer cells, ii) characterization of the reprogrammed cancer cells, and iii) the differential effects of reprogramming on malignancy, epigenetics and response of the cancer cells to chemotherapeutic agents. Continued technical progress in cancer cell reprogramming technology will be instrumental for more refined in vitro disease models and ultimately for the development of directed and personalized therapy for cancer patients in the future.

  11. Cancer nanomedicine: progress, challenges and opportunities.

    PubMed

    Shi, Jinjun; Kantoff, Philip W; Wooster, Richard; Farokhzad, Omid C

    2017-01-01

    The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

  12. Multifunctional nanoparticles: recent progress in cancer therapeutics.

    PubMed

    Seeta Rama Raju, G; Benton, Leah; Pavitra, E; Yu, Jae Su

    2015-09-04

    Although much progress has been made in treating cancers, cancer death rates in and around the United States are still high. Current treatments are either ineffective against some cancers or detrimental to patients, which decreases their quality of life. The use of nanotechnology in cancer therapy can potentially increase patient survival, reduce side effects, and reduce mortality rates because nanoparticles (NPs) have the potential to target only tumors and bypass healthy cells. NPs possess many features, including size, shape, charge, and composition, which allow them to carry chemotherapeutics to cancer cells. NPs can also be used in radiotherapy as radiosensitizers and in imaging as contrast agents. Many studies have performed in vitro and/or in vivo experiments on these particles in human and animal cell lines. This review discusses recent studies on different NPs and their potential use in cancer therapy.

  13. Cancer nanomedicine: progress, challenges and opportunities

    PubMed Central

    Shi, Jinjun; Kantoff, Philip W.; Wooster, Richard; Farokhzad, Omid C.

    2017-01-01

    The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano–bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano–bio interactions to develop more effective nanotherapeutics for cancer patients. PMID:27834398

  14. Gene Expression Analysis of Breast Cancer Progression

    DTIC Science & Technology

    2005-07-01

    representation of the retroviral vectors SFG-tdRFP-cmvFLuc, constitutively expressing tdRFP and firefly luciferase; and Cis-TGFD1-Smads- HSV1 - tk/GFP...AD Award Number: DAMD 17-02-1-0484 TITLE: Gene Expression Analysis of Breast Cancer Progression PRINCIPAL INVESTIGATOR: William L. Gerald, M.D., Ph.D...CONTRACT NUMBER Gene Expression Analysis of Breast Cancer Progression 5b. GRANT NUMBER DAMD17-02-1-0484 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 6d

  15. The Reactive Stroma Microenvironment and Prostate Cancer Progression

    PubMed Central

    Barron, David A.; Rowley, David R.

    2013-01-01

    Reactive stroma initiates during early prostate cancer development and co-evolves with prostate cancer progression. Previous studies have defined the key markers of reactive stroma and have established that reactive stroma biology influences prostate tumorigenesis and progression. The stem/progenitor cells of origin and the mechanisms that regulate their recruitment and activation to myofibroblasts or carcinoma-associated fibroblasts are essentially unknown. Key regulatory factors have been identified, including transforming growth factor beta, interleukin-8, fibroblast growth factors, connective tissue growth factor, wingless homologs-Wnts, and stromal cell-derived factor-1, among others. The biology of reactive stroma in cancer is similar to the more predictable biology of the stroma compartment during wound repair at sites where the epithelial barrier function is breached and a stromal response is generated. The co-evolution of reactive stroma and the biology of how reactive stroma - carcinoma interactions regulate cancer progression and metastasis are targets for new therapeutic approaches. Such approaches are strategically designed to inhibit cancer progression by uncoupling the reactive stroma niche. PMID:22930558

  16. Host Factors and Cancer Progression: Biobehavioral Signaling Pathways and Interventions

    PubMed Central

    Lutgendorf, Susan K.; Sood, Anil K.; Antoni, Michael H.

    2010-01-01

    Whereas evidence for the role of psychosocial factors in cancer initiation has been equivocal, support continues to grow for links between psychological factors such as stress, depression, and social isolation and progression of cancer. In vitro, in vivo, and clinical studies show that stress- related processes can impact pathways implicated in cancer progression, including immuno-regulation, angiogenesis, and invasion. Contributions of systemic factors, such as stress hormones to the crosstalk between tumor and stromal cells, appear to be critical in modulating downstream signaling pathways with important implications for disease progression. Inflammatory pathways may also be implicated in fatigue and other factors related to quality of life. Although substantial evidence supports a positive effect of psychosocial interventions on quality of life in cancer, the clinical evidence for efficacy of stress-modulating psychosocial interventions in slowing cancer progression remains inconclusive, and the biobehavioral mechanisms that might explain such effects are still being established. This article reviews research findings to date and outlines future avenues of research in this area. PMID:20644093

  17. Human Cancer Models Initiative | Office of Cancer Genomics

    Cancer.gov

    The Human Cancer Models Initiative (HCMI) is an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data. In an effort to advance cancer research and more fully understand how in vitro findings are related to clinical biology, HCMI-developed models and related data will be available as a community resource for cancer research.

  18. Current progress in immunotherapy for pancreatic cancer.

    PubMed

    Foley, Kelly; Kim, Victoria; Jaffee, Elizabeth; Zheng, Lei

    2016-10-10

    Pancreatic cancer remains one of the most lethal cancers with few treatment options. Immune-based strategies to treat pancreatic cancer, such as immune checkpoint inhibitors, therapeutic vaccines, and combination immunotherapies, are showing promise where other approaches have failed. Immune checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, are effective as single agents in immune sensitive cancers like melanoma, but lack efficacy in immune insensitive cancers including pancreatic cancer. However, these inhibitors are showing clinical activity, even in traditionally non-immunogenic cancers, when combined with other interventions, including chemotherapy, radiation therapy, and therapeutic vaccines. Therapeutic vaccines given together with immune modulating agents are of particular interest because vaccines are the most efficient way to induce effective anti-tumor T cell responses, which is required for immunotherapies to be effective. In pancreatic cancer, early studies suggest that vaccines can induce T cells that have the potential to recognize and kill pancreatic cancer cells, but the tumor microenvironment inhibits effective T cell trafficking and function. While progress has been made in the development of immunotherapies for pancreatic cancer over the last several years, additional trials are needed to better understand the signals within the tumor microenvironment that are formidable barriers to T cell infiltration and function. Additionally, as more pancreatic specific antigens are identified, immunotherapies will continue to be refined to provide the most significant clinical benefit. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Catalog of genetic progression of human cancers: breast cancer.

    PubMed

    Desmedt, Christine; Yates, Lucy; Kulka, Janina

    2016-03-01

    With the rapid development of next-generation sequencing, deeper insights are being gained into the molecular evolution that underlies the development and clinical progression of breast cancer. It is apparent that during evolution, breast cancers acquire thousands of mutations including single base pair substitutions, insertions, deletions, copy number aberrations, and structural rearrangements. As a consequence, at the whole genome level, no two cancers are identical and few cancers even share the same complement of "driver" mutations. Indeed, two samples from the same cancer may also exhibit extensive differences due to constant remodeling of the genome over time. In this review, we summarize recent studies that extend our understanding of the genomic basis of cancer progression. Key biological insights include the following: subclonal diversification begins early in cancer evolution, being detectable even in in situ lesions; geographical stratification of subclonal structure is frequent in primary tumors and can include therapeutically targetable alterations; multiple distant metastases typically arise from a common metastatic ancestor following a "metastatic cascade" model; systemic therapy can unmask preexisting resistant subclones or influence further treatment sensitivity and disease progression. We conclude the review by describing novel approaches such as the analysis of circulating DNA and patient-derived xenografts that promise to further our understanding of the genomic changes occurring during cancer evolution and guide treatment decision making.

  20. Progress in Rectal Cancer Treatment

    PubMed Central

    Ceelen, Wim P.

    2012-01-01

    The dramatic improvement in local control of rectal cancer observed during the last decades is to be attributed to attention to surgical technique and to the introduction of neoadjuvant therapy regimens. Nevertheless, systemic relapse remains frequent and is currently insufficiently addressed. Intensification of neoadjuvant therapy by incorporating chemotherapy with or without targeted agents before the start of (chemo)radiation or during the waiting period to surgery may present an opportunity to improve overall survival. An increasing number of patients can nowadays undergo sphincter preserving surgery. In selected patients, local excision or even a “wait and see” approach may be feasible following active neoadjuvant therapy. Molecular and genetic biomarkers as well as innovative imaging techniques may in the future allow better selection of patients for this treatment option. Controversy persists concerning the selection of patients for adjuvant chemotherapy and/or targeted therapy after neoadjuvant regimens. The currently available evidence suggests that in complete pathological responders long-term outcome is excellent and adjuvant therapy may be omitted. The results of ongoing trials will help to establish the ideal tailored approach in resectable rectal cancer. PMID:22970381

  1. Biobehavioral Approaches to Cancer Progression and Survival

    PubMed Central

    Lutgendorf, Susan K.; Andersen, Barbara L.

    2014-01-01

    Over the last decade, there have been groundbreaking strides in our understanding of the multiple biological pathways by which psychosocial and behavioral factors can affect cancer progression. It is now clear that biobehavioral factors not only affect cellular immunity but both directly and indirectly modulate fundamental processes in cancer growth, including inflammation, angiogenesis, invasion, and metastasis. There is also an emerging understanding of how psychological and behavioral factors used in interventions can impact these physiological processes. This review outlines our current understanding of the physiological mechanisms by which psychological, social, and behavioral processes can affect cancer progression. The intervention literature is discussed, along with recommendations for future research to move the field of biobehavioral oncology forward. PMID:25730724

  2. Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.

    PubMed

    Feng, Shu; Dakhova, Olga; Creighton, Chad J; Ittmann, Michael

    2013-04-15

    Prostate cancer is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that fibroblast growth factor (FGF) receptors are important in prostate cancer initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21, and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require α-Klotho (KL) and/or β-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as coreceptors along with classic FGF receptors (FGFR) to mediate potent biologic activity. Here we show that FGF19 is expressed in primary and metastatic prostate cancer tissues, where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion, and colony formation of prostate cancer cells at low ligand concentrations. FGF19 silencing in prostate cancer cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in prostate cancer cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biologic effects in prostate cancer. Our findings support the concept that therapies targeting FGFR signaling may have efficacy in prostate cancer and highlight FGF19 as a relevant endocrine FGF in this setting.

  3. Caveolin-1 and prostate cancer progression.

    PubMed

    Freeman, Michael R; Yang, Wei; Di Vizio, Dolores

    2012-01-01

    Caveolin-1 was identified in the 1990s as a marker of aggressive prostate cancer. The caveolin-1 protein localizes to vesicular structures called caveolae and has been shown to bind and regulate many signaling proteins involved in oncogenesis. Caveolin-1 also has lipid binding properties and mediates aspects of cholesterol and fatty acid metabolism and can elicit biological responses in a paracrine manner when secreted. Caveolin-1 is also present in the serum of prostate cancer patients and circulating levels correlate with extent of disease. Current evidence indicates that increased expression of caveolin-1 in prostate adenocarcinoma cells and commensurate downregulation of the protein in prostate stroma, mediate progression to the castration-resistant phase of prostate cancer through diverse pathways. This chapter summarizes the current state of our understanding of the cellular and physiologic mechanisms in which caveolin-1 participates in the evolution of prostate cancer cell phenotypes.

  4. Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

    PubMed Central

    Ma, Jie; Frank, Markus H.

    2010-01-01

    Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment. PMID:20184545

  5. Tumor initiation in human malignant melanoma and potential cancer therapies.

    PubMed

    Ma, Jie; Frank, Markus H

    2010-02-01

    Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment.

  6. Eukaryotic translation initiation factors and cancer.

    PubMed

    Ali, Muhammad Umar; Ur Rahman, Muhammad Saif; Jia, Zhenyu; Jiang, Cao

    2017-06-01

    Recent technological advancements have shown tremendous mechanistic accomplishments in our understanding of the mechanism of messenger RNA translation in eukaryotic cells. Eukaryotic messenger RNA translation is very complex process that includes four phases (initiation, elongation, termination, and ribosome recycling) and diverse mechanisms involving protein and non-protein molecules. Translation regulation is principally achieved during initiation step of translation, which is organized by multiple eukaryotic translation initiation factors. Eukaryotic translation initiation factor proteins help in stabilizing the formation of the functional ribosome around the start codon and provide regulatory mechanisms in translation initiation. Dysregulated messenger RNA translation is a common feature of tumorigenesis. Various oncogenic and tumor suppressive genes affect/are affected by the translation machinery, making the components of the translation apparatus promising therapeutic targets for the novel anticancer drug. This review provides details on the role of eukaryotic translation initiation factors in messenger RNA translation initiation, their contribution to onset and progression of tumor, and how dysregulated eukaryotic translation initiation factors can be used as a target to treat carcinogenesis.

  7. Pancreatic Cancer: Progress and Challenges in a Rapidly Moving Field.

    PubMed

    Collisson, Eric A; Olive, Kenneth P

    2017-03-01

    "Pancreatic Cancer: Advances in Science and Clinical Care," a Special Conference of the American Association for Cancer Research, was held in Orlando, FL, on May 12 to 15, bringing together more than 450 basic, translational, clinical, and epidemiologic pancreatic cancer researchers as well as pancreatic cancer patients, survivors, and advocates. Pancreatic cancer remains one of the great challenges in medicine, but the accelerating pace of research and early hints of clinical successes to come were palpable throughout the meeting. Prominent meeting themes included immunology and the tumor microenvironment, heterogeneity of both the epithelial and stromal compartments, personalized medicine efforts to integrate molecular information into clinical practice, new approaches to early detection, and clinical trials using a host of novel targeted therapies. Adding to the vibrant atmosphere of the meeting, a coalition of pancreatic cancer research and support foundations participated, with several innovative initiatives announced by individual organizations. We present here a summary of meeting highlights, a series of "success factors" that will benchmark the progress of the field over the next 2 years, and three challenges to the pancreatic cancer research community as it moves toward to the goal of extending patient survival. Cancer Res; 77(5); 1060-2. ©2017 AACR.

  8. Progress Against Prostate Cancer | NIH MedlinePlus the Magazine

    MedlinePlus

    ... of this page please turn Javascript on. Feature: Prostate Cancer Progress Against Prostate Cancer Past Issues / Winter 2010 Table of Contents Click ... This can narrow the urethra, decreasing urine flow. Prostate cancer is made up of cells the body does ...

  9. Chk1 promotes replication fork progression by controlling replication initiation.

    PubMed

    Petermann, Eva; Woodcock, Mick; Helleday, Thomas

    2010-09-14

    DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.

  10. PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

    PubMed Central

    Li, Jiarong; Karaplis, Andrew C.; Huang, Dao C.; Siegel, Peter M.; Camirand, Anne; Yang, Xian Fang; Muller, William J.; Kremer, Richard

    2011-01-01

    Parathyroid hormone–related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer — it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention. PMID:22056386

  11. Financial Burden of Cancer Care - Life After Cancer Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Noncoding RNAs in gastric cancer: Research progress and prospects

    PubMed Central

    Zhang, Meng; Du, Xiang

    2016-01-01

    Noncoding RNAs (ncRNAs) have attracted much attention in cancer research field. They are involved in cellular development, proliferation, differentiation and apoptosis. The dysregulation of ncRNAs has been reported in tumor initiation, progression, invasion and metastasis in various cancers, including gastric cancer (GC). In the past few years, an accumulating body of evidence has deepened our understanding of ncRNAs, and several emerging ncRNAs have been identified, such as PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs). The competing endogenous RNA (ceRNA) networks include mRNAs, microRNAs, long ncRNAs (lncRNAs) and circRNAs, which play critical roles in the tumorigenesis of GC. This review summarizes the recent hotspots of ncRNAs involved in GC pathobiology and their potential applications in GC. Finally, we briefly discuss the advances in the ceRNA network in GC. PMID:27547004

  13. Therapeutic implications of Cancer Initiating Cells.

    PubMed

    Scopelliti, Alessandro; Cammareri, Patrizia; Catalano, Veronica; Saladino, Vitanna; Todaro, Matilde; Stassi, Giorgio

    2009-08-01

    Until few years ago, all neoplastic cells within a tumour were suggested to have tumorigenic capacity, but recent evidences hint to the possibility that such feature is confined to a subset of Cancer Initiating Cells (CICs), also called Cancer Stem Cells (CSCs). These cells are the reservoir of the heterogeneous populations of differentiated cancer cells constituting the tumour bulk. Mechanisms shared with somatic stem cells, such as quiescence, self-renewal ability, asymmetric division and multidrug resistance, allow to these cells to drive tumour growth and to evade conventional therapy. Here, we give a brief overview on the origin of CICs, the mechanisms involved in chemoresistance and therapeutic implications. Current cancer treatments, based on the assumption that tumour cell population responds homogeneously, have been developed to eradicate proliferating cells. The new model of tumorigenesis entails significant therapeutic implications, in fact if a small fraction of CICs survives conventional therapy it may lead to recurrence after month or years of apparent remission. Selective targeting of CICs could eliminate the tumour from the root, overcoming the emergence of clones capable of evading traditional therapy and increasing overall disease free survival.

  14. Cell Polarity Proteins in Breast Cancer Progression.

    PubMed

    Rejon, Carlis; Al-Masri, Maia; McCaffrey, Luke

    2016-10-01

    Breast cancer, one of the leading causes of cancer related death in women worldwide, is a heterogeneous disease with diverse subtypes that have different properties and prognoses. The developing mammary gland is a highly proliferative and invasive tissue, and some of the developmental programs may be aberrantly activated to promote breast cancer progression. In the breast, luminal epithelial cells exhibit apical-basal polarity, and the failure to maintain this organizational structure, due to disruption of polarity complexes, is implicated in promoting hyperplasia and tumors. Therefore, understanding the mechanisms underlying loss of polarity will contribute to our knowledge of the early stages leading to the pathogenesis of the disease. In this review, we will discuss recent findings that support the idea that loss of apical-basal cell polarity is a crucial step in the acquisition of the malignant phenotype. Oncogene induced loss of tissue organization shares a conserved cellular mechanism with developmental process, we will further describe the role of the individual polarity complexes, the Par, Crumbs, and Scribble, to couple cell division orientation and cell growth. We will examine symmetric or asymmetric cell divisions in mammary stem cell and their contribution to the development of breast cancer subtypes and cancer stem cells. Finally, we will highlight some of the recent advances in our understanding of the molecular mechanisms by which changes in epithelial polarity programs promote invasion and metastasis through single cell and collective cell modes. J. Cell. Biochem. 117: 2215-2223, 2016. © 2016 Wiley Periodicals, Inc.

  15. Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity

    PubMed Central

    Zhang, Lisa J.; Xiong, Yin; Nilubol, Naris; He, Mei; Bommareddi, Swaroop; Zhu, Xuguang; Jia, Li; Xiao, Zhen; Park, Jeong-Won; Xu, Xia; Patel, Dhaval; Willingham, Mark C.; Cheng, Sheue-yann; Kebebew, Electron

    2015-01-01

    Cancer gender disparity has been observed for a variety of human malignancies. Thyroid cancer is one such cancer with a higher incidence in women, but more aggressive disease in men. There is scant evidence on the role of sex hormones on cancer initiation/progression. Using a transgenic mouse model of follicular thyroid cancer (FTC), we found castration led to lower rates of cancer in females and less advanced cancer in males. Mechanistically, less advanced cancer in castrated males was due to increased expression of tumor suppressor (Glipr1, Sfrp1) and immune-regulatory genes and higher tumor infiltration with M1 macrophages and CD8 cells. Functional study showed that GLIPR1 reduced cell growth and increased chemokine secretion (Ccl5) that activates immune cells. Our data demonstrate that testosterone regulates thyroid cancer progression by reducing tumor suppressor gene expression and tumor immunity. PMID:25576159

  16. Post-Newtonian Initial Data with Waves: Progress in Evolution

    NASA Technical Reports Server (NTRS)

    Kelly, Bernard J.; Tichy, Wolfgang; Zlochower, Yosef; Campanelli, Manuela; Whiting, Bernard

    2010-01-01

    "In Kelly \\et al [Phys. Rev. D, 76:024008, (2007)], we presented new binary black-hole initial data adapted to puncture evolutions in numerical relativity. This data satisfies the constraint equations to 2.5 post-Newtonian order, and contains a transverse-traceless "wavy" metric contribution, violating the standard assumption of conformal flatness. We report on progress in evolving this data with a modem moving-puncture implementation of the BSSN equations in several numerical codes. We discuss the effect of the new metric terms on junk radiation and continuity of physical radiation extracted."

  17. Multiscale Models of Breast Cancer Progression

    PubMed Central

    Chakrabarti, Anirikh; Verbridge, Scott; Stroock, Abraham D.; Fischbach, Claudia; Varner, Jeffrey D.

    2013-01-01

    Breast cancer initiation, invasion and metastasis span multiple length and time scales. Molecular events at short length scales lead to an initial tumorigenic population, which left unchecked by immune action, acts at increasingly longer length scales until eventually the cancer cells escape from the primary tumor site. This series of events is highly complex, involving multiple cell types interacting with (and shaping) the microenvironment. Multiscale mathematical models have emerged as a powerful tool to quantitatively integrate the convective-diffusion-reaction processes occurring on the systemic scale, with the molecular signaling processes occurring on the cellular and subcellular scales. In this study, we reviewed the current state of the art in cancer modeling across multiple length scales, with an emphasis on the integration of intracellular signal transduction models with pro-tumorigenic chemical and mechanical microenvironmental cues. First, we reviewed the underlying biomolecular origin of breast cancer, with a special emphasis on angiogenesis. Then, we summarized the development of tissue engineering platforms which could provide highfidelity ex vivo experimental models to identify and validate multiscale simulations. Lastly, we reviewed top-down and bottom-up multiscale strategies that integrate subcellular networks with the microenvironment. We present models of a variety of cancers, in addition to breast cancer specific models. Taken together, we expect as the sophistication of the simulations increase, that multiscale modeling and bottom-up agent-based models in particular will become an increasingly important platform technology for basic scientific discovery, as well as the identification and validation of potentially novel therapeutic targets. PMID:23008097

  18. Obesity and cancer--mechanisms underlying tumour progression and recurrence.

    PubMed

    Park, Jiyoung; Morley, Thomas S; Kim, Min; Clegg, Deborah J; Scherer, Philipp E

    2014-08-01

    Over the past several years, the field of cancer research has directed increased interest towards subsets of obesity-associated tumours, which include mammary, renal, oesophageal, gastrointestinal and reproductive cancers in both men and women. The increased risk of breast cancer that is associated with obesity has been widely reported; this has drawn much attention and as such, warrants investigation of the key mechanisms that link the obese state with cancer aetiology. For instance, the obese setting provides a unique adipose tissue microenvironment with concomitant systemic endocrine alterations that favour both tumour initiation and progression. Major metabolic differences exist within tumours that distinguish them from non-transformed healthy tissues. Importantly, considerable metabolic differences are induced by tumour cells in the stromal vascular fraction that surrounds them. The precise mechanisms that underlie the association of obesity with cancer and the accompanying metabolic changes that occur in the surrounding microenvironment remain elusive. Nonetheless, specific therapeutic agents designed for patients with obesity who develop tumours are clearly needed. This Review discusses recent advances in understanding the contributions of obesity to cancer and their implications for tumour treatment.

  19. NFAT Proteins: Emerging Roles in Cancer Progression

    PubMed Central

    Mancini, Maria; Toker, Alex

    2010-01-01

    Preface The roles of nuclear factor of activated T cells (NFAT) transcription factors have been extensively studied in the immune system. However, ubiquitous expression of NFAT isoforms in mammalian tissues has been recently observed, as well as an emerging role for these transcription factors in human cancer. Various NFAT isoforms are functional in tumor cells and multiple compartments in the tumor microenvironment including fibroblasts, endothelial cells and infiltrating immune cells. How do NFAT isoforms regulate the complex interplay between these compartments during carcinoma progression? The answers lie with the multiple functions attributed to NFAT including cell growth, survival, invasion and angiogenesis. In addition to sorting out the complex role of NFAT in cancer we face the challenge of targeting this pathway therapeutically. PMID:19851316

  20. Rapidly progressive glomerulonephritis after immunotherapy for cancer.

    PubMed

    Parker, M G; Atkins, M B; Ucci, A A; Levey, A S

    1995-04-01

    Cytokines have been used in experimental and standard protocols for immune enhancement for cancer. The combination of interleukin-2 and interferon-alpha 2 beta has been used in experimental protocols for metastatic renal cell carcinoma. A man who developed rapidly progressive renal failure after receiving this combination therapy is reported. A renal biopsy revealed a pauci-immune crescentic glomerulonephritis. Antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were absent. The spectrum of renal disease and potentially related extrarenal manifestations associated with interleukin-2 and inteferon-alpha are reviewed. A pathogenesis of altered cell-mediated immunity, consistent with abnormalities in extrarenal organs after immune enhancement, is proposed.

  1. RNA editing, epitranscriptomics, and processing in cancer progression.

    PubMed

    Witkin, Keren L; Hanlon, Sean E; Strasburger, Jennifer A; Coffin, John M; Jaffrey, Samie R; Howcroft, T Kevin; Dedon, Peter C; Steitz, Joan A; Daschner, Phil J; Read-Connole, Elizabeth

    2015-01-01

    The transcriptome is extensively and dynamically regulated by a network of RNA modifying factors. RNA editing enzymes APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and ADAR (adenosine deaminase, RNA-specific) irreversibly recode primary RNA sequences, whereas newly described methylases (writers) and de-methylases (erasers) dynamically alter RNA molecules in response to environmental conditions. RNA modifications can affect RNA splicing, nuclear-cytoplasmic transport, translation, and regulation of gene expression by RNA interference. In addition, tRNA base modifications, processing, and regulated cleavage have been shown to alter global patterns of mRNA translation in response to cellular stress pathways. Recent studies, some of which were discussed at this workshop, have rekindled interest in the emerging roles of RNA modifications in health and disease. On September 10th, 2014, the Division of Cancer Biology, NCI sponsored a workshop to explore the role of epitranscriptomic RNA modifications and tRNA processing in cancer progression. The workshop attendees spanned a scientific range including chemists, virologists, and RNA and cancer biologists. The goal of the workshop was to explore the interrelationships between RNA editing, epitranscriptomics, and RNA processing and the enzymatic pathways that regulate these activities in cancer initiation and progression. At the conclusion of the workshop, a general discussion focused on defining the major challenges and opportunities in this field, as well as identifying the tools, technologies, resources and community efforts required to accelerate research in this emerging area.

  2. Analysis of Dachsous2 in Breast Cancer Progression and Recurrence

    DTIC Science & Technology

    2010-10-01

    definitive conclusion. pg. 4 0.000 0.005 0.010 0.015 0.020 0.025 0.030 0.035 MCF7 MDA-MB- 231 Hs 578T MCF-10A MCF-12A SKOV3 MOLT - 4 RPMI 8226 SW 872...2010 4 . TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-08-1-0631 Analysis of Dachsous2 in Breast Cancer Progression and Recurrence 5b. GRANT...Ds2 that could be used in paraffin section analysis of tumour samples from ANN patients. We initially generated 4 antisera to the entire

  3. The Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer

    PubMed Central

    Krogan, Nevan J.; Lippman, Scott; Agard, David A.; Ashworth, Alan; Ideker, Trey

    2017-01-01

    Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, called The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these Cancer Cell Maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. PMID:26000852

  4. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

  5. High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation

    PubMed Central

    Zasadil, Lauren M.; Britigan, Eric M. C.; Ryan, Sean D.; Kaur, Charanjeet; Guckenberger, David J.; Beebe, David J.; Moser, Amy R.; Weaver, Beth A.

    2016-01-01

    Aneuploidy, an abnormal chromosome number that deviates from a multiple of the haploid, has been recognized as a common feature of cancers for >100 yr. Previously, we showed that the rate of chromosome missegregation/chromosomal instability (CIN) determines the effect of aneuploidy on tumors; whereas low rates of CIN are weakly tumor promoting, higher rates of CIN cause cell death and tumor suppression. However, whether high CIN inhibits tumor initiation or suppresses the growth and progression of already initiated tumors remained unclear. We tested this using the ApcMin/+ mouse intestinal tumor model, in which effects on tumor initiation versus progression can be discriminated. ApcMin/+ cells exhibit low CIN, and we generated high CIN by reducing expression of the kinesin-like mitotic motor protein CENP-E. CENP-E+/−;ApcMin/+ doubly heterozygous cells had higher rates of chromosome missegregation than singly heterozygous cells, resulting in increased cell death and a substantial reduction in tumor progression compared with ApcMin/+ animals. Intestinal organoid studies confirmed that high CIN does not inhibit tumor cell initiation but does inhibit subsequent cell growth. These findings support the conclusion that increasing the rate of chromosome missegregation could serve as a successful chemotherapeutic strategy. PMID:27146113

  6. HPV Immunization - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Tobacco Policy/Regulatory Factors | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. UV Exposure and Sun Protective Practices | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Diet, Physical Activity, and Weight | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Chemical Exposures - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Medicaid Coverage of Tobacco Dependency Treatments | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Person-Years of Life Lost | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. Sun-Protective Behavior | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Recent Updates and Archive | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Trends at a Glance | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Smoking Cessation - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Secondhand Smoke - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. HPV Immunization - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Smoking Cessation - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Methodology for Characterizing Trends | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Recent Updates and Archive | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Clinicians' Advice to Quit Smoking | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Diet - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Smoke-free Home Rules | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Fruit and Vegetable Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Tobacco Company Marketing Expenditures | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Smoke-free Home Rules | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Secondhand Smoke - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Tobacco Use - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Incidence and Mortality Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Genes Involved in Oxidation and Prostate Cancer Progression

    DTIC Science & Technology

    2007-01-01

    Kimmel Comprehensive Cancer Center at Johns Hopkins , Baltimore, Maryland3 Corresponding author: Elizabeth A. Platz...Prostate Cancer Progression PRINCIPAL INVESTIGATOR: Elizabeth A. Platz, ScD, MPH CONTRACTING ORGANIZATION: Johns Hopkins University... Cancer Prevention and Control Program at the Sidney Kimmel Comprehensive Cancer Center . o With Dr. James Herman and other Sidney Kimmel

  12. Cancer stem cell targeted therapy: progress amid controversies.

    PubMed

    Wang, Tao; Shigdar, Sarah; Gantier, Michael P; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; Zhou, Shu-Feng; Zhao, Xinhan; Duan, Wei

    2015-12-29

    Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.

  13. Cancer stem cell targeted therapy: progress amid controversies

    PubMed Central

    Wang, Tao; Shigdar, Sarah; Gantier, Michael P.; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; Zhou, Shu-Feng; Zhao, Xinhan; Duan, Wei

    2015-01-01

    Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy. PMID:26496035

  14. Making progress: the role of cancer councils in Australia in indigenous cancer control

    PubMed Central

    2014-01-01

    Background Indigenous Australians have poorer outcomes from cancer for a variety of reasons including poorer participation in screening programs, later diagnosis, higher rates of cancer with poor prognosis and poorer uptake and completion of treatment. Cancer prevention and support for people with cancer is part of the core business of the State and Territory Cancer Councils. To support sharing of lessons learned, this paper reports an environmental scan undertaken in 2010 in cancer councils (CCs) nationwide that aimed to support Indigenous cancer control. Methods The methods replicated the approach used in a 2006 environmental scan of Indigenous related activity in CCs. The Chief Executive Officer of each CC nominated individuals for interview. Interviews explored staffing, projects, programs and activities to progress cancer control issues for Indigenous Australians, through phone or face-to-face interviews. Reported initiatives were tabulated using predetermined categories of activity and summaries were returned to interviewees, the Aboriginal and Torres Strait Islander Subcommittee and Chief Executive Officers for verification. Results All CCs participated and modest increases in activity had occurred in most states since 2006 through different means. Indigenous staff numbers were low and no Indigenous person had yet been employed in smaller CCs; no CC had an Indigenous Board member and efforts at capacity building were often directed outside of the organisation. Developing partnerships with Indigenous organisations were ongoing. Acknowledgement and specific mention of Indigenous people in policy was increasing. Momentum increased following the establishment of a national subcommittee which increased the profile of Indigenous issues and provided collegial and practical support for those committed to reducing Indigenous cancer disparities. Government funding of “Closing the Gap” and research in the larger CCs have been other avenues for increasing knowledge

  15. Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression.

    PubMed

    Sridaran, Dhivya; Ramamoorthi, Ganesan; MahaboobKhan, Rasool; Kumpati, Premkumar

    2016-10-01

    During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention. Graphical abstract Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment (TM), and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic

  16. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.

    PubMed

    Goetz, Matthew P; Toi, Masakazu; Campone, Mario; Sohn, Joohyuk; Paluch-Shimon, Shani; Huober, Jens; Park, In Hae; Trédan, Olivier; Chen, Shin-Cheh; Manso, Luis; Freedman, Orit C; Garnica Jaliffe, Georgina; Forrester, Tammy; Frenzel, Martin; Barriga, Susana; Smith, Ian C; Bourayou, Nawel; Di Leo, Angelo

    2017-10-02

    Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

  17. Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach.

    PubMed

    Kim, Eunjung; Rebecca, Vito; Fedorenko, Inna V; Messina, Jane L; Mathew, Rahel; Maria-Engler, Silvya S; Basanta, David; Smalley, Keiran S M; Anderson, Alexander R A

    2013-12-01

    We present an integrated study to understand the key role of senescent fibroblasts in driving melanoma progression. Based on the hybrid cellular automata paradigm, we developed an in silico model of normal skin. The model focuses on key cellular and microenvironmental variables that regulate interactions among keratinocytes, melanocytes, and fibroblasts, key components of the skin. The model recapitulates normal skin structure and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model predicted the important role of the skin microenvironment in melanoma initiation and progression. Our in vitro experiments showed that dermal fibroblasts, which are an important source of growth factors in the skin, adopt a secretory phenotype that facilitates cancer cell growth and invasion when they become senescent. Our coculture experiments showed that the senescent fibroblasts promoted the growth of nontumorigenic melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated by these experimental results, we incorporated senescent fibroblasts into our model and showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes. The interaction between senescent fibroblasts and the early-stage melanoma cells leads to melanoma initiation and progression. Of microenvironmental factors that senescent fibroblasts produce, proteases are shown to be one of the key contributing factors that promoted melanoma development from our simulations. Although not a direct validation, we also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. This leads us to the conclusion that senescent fibroblasts may create a prooncogenic skin microenvironment that cooperates with mutant melanocytes to drive melanoma initiation and progression and should therefore be considered as a

  18. Considerations for initiating and progressing running programs in obese individuals.

    PubMed

    Vincent, Heather K; Vincent, Kevin R

    2013-06-01

    Running has rapidly increased in popularity and elicits numerous health benefits, including weight loss. At present, no practical guidelines are available for obese persons who wish to start a running program. This article is a narrative review of the emerging evidence of the musculoskeletal factors to consider in obese patients who wish to initiate a running program and increase its intensity. Main program goals should include gradual weight loss, avoidance of injury, and enjoyment of the exercise. Pre-emptive strengthening exercises can improve the strength of the foot and ankle, hip abductor, quadriceps, and trunk to help support the joints bearing the loads before starting a running program. Depending on the presence of comorbid joint pain, nonimpact exercise or walking (on a flat surface, on an incline, and at high intensity) can be used to initiate the program. For progression to running, intensity or mileage increases should be slow and consistent to prevent musculoskeletal injury. A stepwise transition to running at a rate not exceeding 5%-10% of weekly mileage or duration is reasonable for this population. Intermittent walk-jog programs are also attractive for persons who are not able to sustain running for a long period. Musculoskeletal pain should neither carry over to the next day nor be increased the day after exercising. Rest days in between running sessions may help prevent overuse injury. Patients who have undergone bariatric surgery and are now lean can also run, but special foci such as hydration and energy replacement must be considered. In summary, obese persons can run for exercise, provided they follow conservative transitions and progression, schedule rest days, and heed onset of pain symptoms. Copyright © 2013 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

  19. A Mathematical-Biological Joint Effort to Investigate the Tumor-Initiating Ability of Cancer Stem Cells

    PubMed Central

    Fornari, Chiara; Beccuti, Marco; Lanzardo, Stefania; Conti, Laura; Balbo, Gianfranco; Cavallo, Federica; Calogero, Raffaele A.; Cordero, Francesca

    2014-01-01

    The involvement of Cancer Stem Cells (CSCs) in tumor progression and tumor recurrence is one of the most studied subjects in current cancer research. The CSC hypothesis states that cancer cell populations are characterized by a hierarchical structure that affects cancer progression. Due to the complex dynamics involving CSCs and the other cancer cell subpopulations, a robust theory explaining their action has not been established yet. Some indications can be obtained by combining mathematical modeling and experimental data to understand tumor dynamics and to generate new experimental hypotheses. Here, we present a model describing the initial phase of ErbB2+ mammary cancer progression, which arises from a joint effort combing mathematical modeling and cancer biology. The proposed model represents a new approach to investigate the CSC-driven tumorigenesis and to analyze the relations among crucial events involving cancer cell subpopulations. Using in vivo and in vitro data we tuned the model to reproduce the initial dynamics of cancer growth, and we used its solution to characterize observed cancer progression with respect to mutual CSC and progenitor cell variation. The model was also used to investigate which association occurs among cell phenotypes when specific cell markers are considered. Finally, we found various correlations among model parameters which cannot be directly inferred from the available biological data and these dependencies were used to characterize the dynamics of cancer subpopulations during the initial phase of ErbB2+ mammary cancer progression. PMID:25184361

  20. CRCHD Launches National Colorectal Cancer Outreach and Screening Initiative

    Cancer.gov

    The NCI CRCHD launches National Screen to Save Colorectal Cancer Outreach and Screening Initiative which aims to increase colorectal cancer screening rates among racially and ethnically diverse and rural communities.

  1. Chemokines in Cancer Development and Progression and Their Potential as Targeting Molecules for Cancer Treatment

    PubMed Central

    Mukaida, Naofumi; Sasaki, So-ichiro; Baba, Tomohisa

    2014-01-01

    Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer. PMID:24966464

  2. Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer

    PubMed Central

    Seeley, Todd W; Sternlicht, Mark D; Klaus, Stephen J; Neff, Thomas B; Liu, David Y

    2017-01-01

    The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neundl-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592). In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors. PMID:28331872

  3. Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer.

    PubMed

    Seeley, Todd W; Sternlicht, Mark D; Klaus, Stephen J; Neff, Thomas B; Liu, David Y

    2017-01-01

    The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neu(ndl)-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592). In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors.

  4. Autophagy in malignant transformation and cancer progression

    PubMed Central

    Galluzzi, Lorenzo; Pietrocola, Federico; Bravo-San Pedro, José Manuel; Amaravadi, Ravi K; Baehrecke, Eric H; Cecconi, Francesco; Codogno, Patrice; Debnath, Jayanta; Gewirtz, David A; Karantza, Vassiliki; Kimmelman, Alec; Kumar, Sharad; Levine, Beth; Maiuri, Maria Chiara; Martin, Seamus J; Penninger, Josef; Piacentini, Mauro; Rubinsztein, David C; Simon, Hans-Uwe; Simonsen, Anne; Thorburn, Andrew M; Velasco, Guillermo; Ryan, Kevin M; Kroemer, Guido

    2015-01-01

    Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy. PMID:25712477

  5. Impact of Tumor Progression on Cancer Incidence Curves

    PubMed Central

    Luebeck, E. Georg; Curtius, Kit; Jeon, Jihyoun; Hazelton, William D.

    2013-01-01

    Cancer arises through a multistage process, but it is not fully clear how this process influences the age-specific incidence curve. Studies of colorectal and pancreatic cancer using the multistage-clonal-expansion (MSCE) model have identified two phases of the incidence curves. One phase is linear beginning about age of 60, suggesting that at least two rare rate-limiting mutations occur prior to clonal expansion of premalignant cells. A second phase is exponential, seen in earlier-onset cancers occurring before the age of 60 that are associated with premalignant clonal expansion. Here we extend the MSCE model to include clonal expansion of malignant cells, an advance that permits study of the effects of tumor growth and extinction on the incidence of colorectal, gastric, pancreatic and esophageal adenocarcinomas in the digestive tract. After adjusting the age-specific incidence for birth-cohort and calendar-year trends, we found that initiating mutations and premalignant cell kinetics can explain the primary features of the incidence curve. However, we also found that the incidence data of these cancers harbored information on the kinetics of malignant clonal expansion prior to clinical detection, including tumor growth rates and extinction probabilities on three characteristic time scales for tumor progression. Additionally, the data harbored information on the mean sojourn times for prema-lignant clones until occurrence of either the first malignant cell or the first persistent (surviving) malignant clone. Lastly, the data also harbored information on the mean sojourn time of persistent malignant clones to the time of diagnosis. In conclusion, cancer incidence curves can harbor significant information about hidden processes of tumor initiation, premalignant clonal expansion and malignant transformation, and even some limited information on tumor growth before clinical detection. PMID:23054397

  6. RhoE is required for contact inhibition and negatively regulates tumor initiation and progression.

    PubMed

    Hernández-Sánchez, Marta; Poch, Enric; Guasch, Rosa M; Ortega, Joaquín; López-Almela, Inmaculada; Palmero, Ignacio; Pérez-Roger, Ignacio

    2015-07-10

    RhoE is a small GTPase involved in the regulation of actin cytoskeleton dynamics, cell cycle and apoptosis. The role of RhoE in cancer is currently controversial, with reports of both oncogenic and tumor-suppressive functions for RhoE. Using RhoE-deficient mice, we show here that the absence of RhoE blunts contact-inhibition of growth by inhibiting p27Kip1 nuclear translocation and cooperates in oncogenic transformation of mouse primary fibroblasts. Heterozygous RhoE+/gt mice are more susceptible to chemically induced skin tumors and RhoE knock-down results in increased metastatic potential of cancer cells. These results indicate that RhoE plays a role in suppressing tumor initiation and progression.

  7. RhoE is required for contact inhibition and negatively regulates tumor initiation and progression

    PubMed Central

    Hernández-Sánchez, Marta; Poch, Enric; Guasch, Rosa M.; Ortega, Joaquín; López-Almela, Inmaculada; Palmero, Ignacio; Pérez-Roger, Ignacio

    2015-01-01

    RhoE is a small GTPase involved in the regulation of actin cytoskeleton dynamics, cell cycle and apoptosis. The role of RhoE in cancer is currently controversial, with reports of both oncogenic and tumor-suppressive functions for RhoE. Using RhoE-deficient mice, we show here that the absence of RhoE blunts contact-inhibition of growth by inhibiting p27Kip1 nuclear translocation and cooperates in oncogenic transformation of mouse primary fibroblasts. Heterozygous RhoE+/gt mice are more susceptible to chemically induced skin tumors and RhoE knock-down results in increased metastatic potential of cancer cells. These results indicate that RhoE plays a role in suppressing tumor initiation and progression. PMID:26036260

  8. Dynamic Testing of Signal Transduction Deregulation During Breast Cancer Initiation

    DTIC Science & Technology

    2012-07-01

    VL. Protein Microarray Analysis of Mammary Epithelial Cells from Obese and Non- Obese Women at High-Risk for Breast Cancer . Cancer Epidemiol...from Obese and Non- Obese Women at High-Risk for Breast Cancer . Cancer Epidemiol Biomarkers Prevention. 20:476-482, 2011 (cover article). PMID...Std. Z39.18 Victoria Seewaldt, M.D. Dynamic Testing of Signal Transduction Deregulation During Breast Cancer Initiation Duke University Durham

  9. Bridging hypoxia, inflammation and estrogen receptors in thyroid cancer progression.

    PubMed

    Tafani, Marco; De Santis, Elena; Coppola, Luigi; Perrone, Giulietta A; Carnevale, Ilaria; Russo, Andrea; Pucci, Bruna; Carpi, Angelo; Bizzarri, Mariano; Russo, Matteo A

    2014-02-01

    Thyroid cancer is a common endocrine-related cancer with a higher incidence in women than in men. Thyroid tumors are classified on the basis of their histopathology as papillary, follicular, medullary, and undifferentiated or anaplastic. Epidemiological and in vitro or in vivo studies have suggested a correlation between incidence of thyroid malignancies and hormones. In particular, growing evidence indicates a role of estrogens and estrogen receptors (ERs) in thyroid tumorigenesis, reprogramming and progression. In this scenario, estrogens are hypothesized to contribute to the observed female predominance of thyroid cancer in reproductive years. However, the precise contribution of estrogens in thyroid proliferative disease initiation and progression is not well understood. HIF-1α and NF-κB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression and resistance to chemotherapy. In fact, HIF-1α and NF-κB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic and differentiation reprogramming, inflammatory-reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement, they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7 and some TLRs are activated by HIF-1α; and that, in turn, alarmin receptors strongly activate NF-κB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these inhibitors are natural compounds or off-label drugs already used to cure other

  10. Impact of deleterious passenger mutations on cancer progression

    PubMed Central

    McFarland, Christopher D.; Korolev, Kirill S.; Kryukov, Gregory V.; Sunyaev, Shamil R.; Mirny, Leonid A.

    2013-01-01

    Cancer progression is driven by the accumulation of a small number of genetic alterations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional mutations termed passengers. Passengers are widely believed to have no role in cancer, yet many passengers fall within protein-coding genes and other functional elements that can have potentially deleterious effects on cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter the course of neoplastic progression. Our approach combines evolutionary simulations of cancer progression with an analysis of cancer sequencing data. From simulations, we find that passengers accumulate and largely evade natural selection during progression. Although individually weak, the collective burden of passengers alters the course of progression, leading to several oncological phenomena that are hard to explain with a traditional driver-centric view. We then tested the predictions of our model using cancer genomics data and confirmed that many passengers are likely damaging and have largely evaded negative selection. Finally, we use our model to explore cancer treatments that exploit the load of passengers by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Though both approaches lead to cancer regression, the latter is a more effective therapy. Our results suggest a unique framework for understanding cancer progression as a balance of driver and passenger mutations. PMID:23388632

  11. Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

    PubMed Central

    Lorger, Mihaela; Felding-Habermann, Brunhilde

    2010-01-01

    Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Up-regulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might codetermine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases. PMID:20382702

  12. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis.

    PubMed

    Lorger, Mihaela; Felding-Habermann, Brunhilde

    2010-06-01

    Brain metastases are difficult to treat and mostly develop late during progressive metastatic disease. Patients at risk would benefit from the development of prevention and improved treatments. This requires knowledge of the initial events that lead to brain metastasis. The present study reveals cellular events during the initiation of brain metastasis by breast cancer cells and documents the earliest host responses to incoming cancer cells after carotid artery injection in immunodeficient and immunocompetent mouse models. Our findings capture and characterize heterogeneous astrocytic and microglial reactions to the arrest and extravasation of cancer cells in the brain, showing immediate and drastic changes in the brain microenvironment on arrival of individual cancer cells. We identified reactive astrocytes as the most active host cell population that immediately localizes to individual invading tumor cells and continuously associates with growing metastatic lesions. Up-regulation of matrix metalloproteinase-9 associated with astrocyte activation in the immediate vicinity of extravasating cancer cells might support their progression. Early involvement of different host cell types indicates environmental clues that might codetermine whether a single cancer cell progresses to macrometastasis or remains dormant. Thus, information on the initial interplay between brain homing tumor cells and reactive host cells may help develop strategies for prevention and treatment of symptomatic breast cancer brain metastases.

  13. VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation.

    PubMed

    Fantozzi, Anna; Gruber, Dorothea C; Pisarsky, Laura; Heck, Chantal; Kunita, Akiko; Yilmaz, Mahmut; Meyer-Schaller, Nathalie; Cornille, Karen; Hopfer, Ulrike; Bentires-Alj, Mohamed; Christofori, Gerhard

    2014-03-01

    An epithelial-mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the upregulated expression of the proangiogenic factor VEGF-A and by increased tumor angiogenesis. On the basis of these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A-mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation.

  14. Role of MicroRNA Genes in Breast Cancer Progression

    DTIC Science & Technology

    2006-08-01

    AD_________________ Award Number: W81XWH-05-1-0483 TITLE: Role of microRNA Genes in Breast Cancer ...proposal, we asked if miRNA expression is altered as cells progress through the different stages of cancer . Through our microarray experiments, we have...shown that many miRNAs are differentially regulated as cells progress through cancer stages. A general trend in miRNA expression emerges from this work

  15. Role of Reactive Stroma in Prostate Cancer Progression

    DTIC Science & Technology

    2008-02-01

    AD_________________ Award Number: W81XWH-04-1-0189 TITLE: Role of Reactive Stroma in Prostate Cancer Progression PRINCIPAL INVESTIGATOR: David R...REPORT TYPE Final 3. DATES COVERED 12 JAN 2004 - 11 JAN 2008 4. TITLE AND SUBTITLE Role of Reactive Stroma in Prostate Cancer Progression 5a. CONTRACT...the reactive stroma of experimental prostate cancer . Using a modified approach, we are placing an inducible Cre recombinase behind the FAP gene

  16. Alzheimer's Disease Neuroimaging Initiative 2 Clinical Core: Progress and plans.

    PubMed

    Aisen, Paul S; Petersen, Ronald C; Donohue, Michael; Weiner, Michael W

    2015-07-01

    This article reviews the current status of the Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and summarizes planning for the next stage of the project. Clinical Core activities and plans were synthesized based on discussions among the Core leaders and external advisors. The longitudinal data in ADNI-2 provide natural history data on a clinical trials population and continue to inform refinement and standardization of assessments, models of trajectories, and clinical trial methods that have been extended into sporadic preclinical Alzheimer's disease (AD). Plans for the next phase of the ADNI project include maintaining longitudinal follow-up of the normal and mild cognitive impairment cohorts, augmenting specific clinical cohorts, and incorporating novel computerized cognitive assessments and patient-reported outcomes. A major hypothesis is that AD represents a gradually progressive disease that can be identified precisely in its long presymptomatic phase, during which intervention with potentially disease-modifying agents may be most useful. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  17. [Research progress on mechanisms of modern medicine in cancer metastasis].

    PubMed

    Chen, Hui; Qu, Jing-Lian; Gong, Jie-Ning

    2014-08-01

    Cancer metastasis is the most dangerous stage of tumorigenesis and evolution, the primary cause of death in cancer patients. Clinically, more than 60% of cancer patients have found metastasis at the time of examination. Modern medicine has made significant progress on the mechanisms of cancer metastasis in recent years, from the simple "anatomy and machinery" theory forward to the "seed and soil" theory, then to the "microenvironmental" theory and the "cancer stem cell" theory. The emerging "cancer stem cell" theory successfully explains phenomenon such as tumor genetic heterogeneity, anoikis resistance, tumor dormancy, providing more new targets and ideas for the diagnosis and treatment of cancer metastasis.

  18. Activation of blood coagulation in cancer: implications for tumour progression

    PubMed Central

    Lima, Luize G.; Monteiro, Robson Q.

    2013-01-01

    Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies. PMID:23889169

  19. Activation of blood coagulation in cancer: implications for tumour progression.

    PubMed

    Lima, Luize G; Monteiro, Robson Q

    2013-09-04

    Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies.

  20. Solitary Fibrous Tumor of the Prostate Which Was Initially Misdiagnosed as Prostate Cancer

    PubMed Central

    Osamu, Soma; Murasawa, Hiromi; Yoneyama, Takahiro; Koie, Takuya; Ohyama, Chikara

    2017-01-01

    Solitary fibrous tumor (SFT) of the prostate is a very rare tumor. We report a case of 65-year-old man with SFT of the prostate which was initially misdiagnosed as prostate cancer. Finally, we performed total prostatectomy and the tumor was histologically diagnosed as SFT of the prostate. The patient's clinical course has progressed favorably with no obvious recurrence 18 months postoperatively.

  1. Initial surgical management of thyroid cancer.

    PubMed

    Witt, Robert L

    2008-01-01

    The rapid increase in the rate of papillary thyroid cancer is likely caused by improved surveillance. A significant trend toward total thyroidectomy for low-risk differentiated thyroid cancer is present in the United States after a paradigm shift from treatment of macroscopic disease to the treatment of macroscopic and microscopic disease by increasingly sensitive tests. Compelling arguments for thyroid lobectomy and total thyroidectomy for low-risk thyroid cancer remain. The relatively small number of deaths from thyroid cancer, the small number of clinical thyroid cancers, and the huge number of incidental thyroid cancers are indicative of how little we understand the biology of this disease. Clinical medicine awaits biologic markers to refine treatment recommendations.

  2. Initiation of Breast Cancer: Activated Catechol Estrogens

    DTIC Science & Technology

    1999-06-01

    cancer. The CE are identified and quantified by HPLC with multichannel electrochemical detection after extraction from tissue. We have obtained...cancer by mutating critical genes [1]. Depurinating adducts are lost from DNA by hydrolysis of the glycosidic bond, leaving apurinic sites, which if...women with and without breast cancer. CE were to be quantified by gas chromatography/mass spectrometry (GC/MS) analysis after extraction from tissue

  3. Regulated lysosomal exocytosis mediates cancer progression

    PubMed Central

    Machado, Eda; White-Gilbertson, Shai; van de Vlekkert, Diantha; Janke, Laura; Moshiach, Simon; Campos, Yvan; Finkelstein, David; Gomero, Elida; Mosca, Rosario; Qiu, Xiaohui; Morton, Christopher L.; Annunziata, Ida; d’Azzo, Alessandra

    2015-01-01

    Understanding how tumor cells transition to an invasive and drug-resistant phenotype is central to cancer biology, but the mechanisms underlying this transition remain unclear. We show that sarcomas gain these malignant traits by inducing lysosomal exocytosis, a ubiquitous physiological process. During lysosomal exocytosis, the movement of exocytic lysosomes along the cytoskeleton and their docking at the plasma membrane involve LAMP1, a sialylated membrane glycoprotein and target of the sialidase NEU1. Cleavage of LAMP1 sialic acids by NEU1 limits the extent of lysosomal exocytosis. We found that by down-regulation of NEU1 and accumulation of oversialylated LAMP1, tumor cells exacerbate lysosomal exocytosis of soluble hydrolases and exosomes. This facilitates matrix invasion and propagation of invasive signals, and purging of lysosomotropic chemotherapeutics. In Arf−⁄− mice, Neu1 haploinsufficiency fostered the development of invasive, pleomorphic sarcomas, expressing epithelial and mesenchymal markers, and lysosomal exocytosis effectors, LAMP1 and Myosin-11. These features are analogous to those of metastatic, pleomorphic human sarcomas, where low NEU1 levels correlate with high expression of lysosomal exocytosis markers. In a therapeutic proof of principle, we demonstrate that inhibiting lysosomal exocytosis reversed invasiveness and chemoresistance in aggressive sarcoma cells. Thus, we reveal that this unconventional, lysosome-regulated pathway plays a primary role in tumor progression and chemoresistance. PMID:26824057

  4. Mouse Models of Follicular and Papillary Thyroid Cancer Progression

    PubMed Central

    Russo, Marika A.; Arciuch, Valeria G. Antico; Di Cristofano, Antonio

    2011-01-01

    A significant number of well-differentiated thyroid cancers progress or recur, becoming resistant to current therapeutic options. Mouse models recapitulating the genetic and histological features of advanced thyroid cancer have been an invaluable tool to dissect the mechanisms involved in the progression from indolent, well differentiated tumors to aggressive, poorly differentiated carcinomas, and to identify novel therapeutic targets. In this review, we focus on the lessons learned from models of epithelial cell-derived thyroid cancer showing progression from hyperplastic lesions to locally invasive and metastatic carcinomas. PMID:22654848

  5. Non-muscle myosins in tumor progression, cancer cell invasion and metastasis

    PubMed Central

    Ouderkirk, J. L.; Krendel, M.

    2014-01-01

    The actin cytoskeleton, which regulates cell polarity, adhesion, and migration, can influence cancer progression, including initial acquisition of malignant properties by normal cells, invasion of adjacent tissues, and metastasis to distant sites. Actin-dependent molecular motors, myosins, play key roles in regulating tumor progression and metastasis. In this review, we examine how non-muscle myosins regulate neoplastic transformation and cancer cell migration and invasion. Members of the myosin superfamily can act as either enhancers or suppressors of tumor progression. This review summarizes the current state of knowledge on how mutations or epigenetic changes in myosin genes and changes in myosin expression may affect tumor progression and patient outcomes and discusses the proposed mechanisms linking myosin inactivation or upregulation to malignant phenotype, cancer cell migration, and metastasis. PMID:25087729

  6. Initiation of Massive Landsliding through Progressive Strength Reduction in Volcanoes

    NASA Astrophysics Data System (ADS)

    Reid, M. E.; Keith, T. C.; Kayen, R. E.; Iverson, N. R.; Iverson, R. M.; Brien, D. L.

    2011-12-01

    Landslides that sculpt deeply into volcano edifices can be extremely large. For example, the 1980 collapse of Mount St. Helens (MSH) volcano generated a 2.8 km3 debris-avalanche deposit from a series of massive retrogressive failures. Rock shear strength plays a fundamental role in such landsliding, yet pertinent data from modern volcano collapse surfaces are rare. The collapse crater at MSH affords access to rocks directly from the failure surface of the1980 massive landslide. We used a combination of field observations, laboratory strength tests designed to mimic conditions in the pre-collapse edifice, and quasi-3D slope-stability analyses to investigate the effects of progressive strength reduction, caused by pre-collapse deformation, on the instability of the volcano's edifice. Within the MSH crater, we observed that the basal shear zone from the outermost initial landslide block (Block I) of the 1980 failure formed primarily in pervasively shattered older dacitic dome rocks; shearing was not localized in sloping volcanic strata or in weak, hydrothermally altered rocks. We collected relatively undisturbed tube samples and disturbed bulk samples of the shattered dacite from near the slip surface of Block I. Using a triaxial testing device, equipped with high-pressure components to mimic overburden stresses in the pre-collapse edifice, we determined the quasi-static drained shear strength of the undisturbed samples. These tests indicated a peak angle of internal friction, φ, of 35° and a residual φ (after undergoing axial strain up to 20%) of 29°. We also determined residual shear strength using a specially constructed large-volume ring-shear apparatus that imposed large quasi-static shear strains exceeding 100%. These tests yielded a similar residual strength, with φ of 27°. Prior to its catastrophic collapse in 1980, the MSH edifice was deformed northward tens of meters by an intruding cryptodome, which likely caused shearing along a summit fault and

  7. Cancer and birth defects surveillance system for communities around the Savannah River Site. Annual progress report

    SciTech Connect

    Dunbar, J.B.

    1994-05-01

    The US DOE funded this grant to the Medical University of South Carolina for a cancer and birth defects registry for an initial three year period which was completed as of April 29, 1994. While this Technical Progress Report is prepared principally to document the activities of year 03, it also summarizes the accomplishments of the first two years in order to put into perspective the energy and progress of the program over the entire three year funding cycle.

  8. Attenuated Transforming Growth Factor Beta Signaling as a Therapeutic for Prostate Cancer Progression

    DTIC Science & Technology

    2008-04-01

    beta 1: comparative immunohistochemical localization in human primary and metastatic prostate cancer. Lab Invest 1995;73:628-35. 3. Brogi E, Wu T...regulated. Hence, focal overexpression of TGF-b at sites of early cancer might be expected to initiate a local reactive stroma, typified by matrix...depending on many local variables. Regardless, co-evolution of a reactive stroma does seem to correlate with tumor progression. Hence, it has been

  9. The AURORA initiative for metastatic breast cancer.

    PubMed

    Zardavas, D; Maetens, M; Irrthum, A; Goulioti, T; Engelen, K; Fumagalli, D; Salgado, R; Aftimos, P; Saini, K S; Sotiriou, C; Campbell, P; Dinh, P; von Minckwitz, G; Gelber, R D; Dowsett, M; Di Leo, A; Cameron, D; Baselga, J; Gnant, M; Goldhirsch, A; Norton, L; Piccart, M

    2014-11-11

    Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients.

  10. Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

    PubMed Central

    Federico, Lorenzo; Jeong, Kang Jin; Vellano, Christopher P.; Mills, Gordon B.

    2016-01-01

    The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, inflammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. PMID:25977291

  11. Neither Saints nor Sinners: Initial Reporting of the "Progressive" Case.

    ERIC Educational Resources Information Center

    Swain, Bruce M.

    1980-01-01

    Examines the circumstances of the 1979 "Progressive" case, in which the federal government quashed an article about hydrogen bomb production. Notes reportorial lapses that prevented a full and balanced account of the situation. (RL)

  12. Neither Saints nor Sinners: Initial Reporting of the "Progressive" Case.

    ERIC Educational Resources Information Center

    Swain, Bruce M.

    1980-01-01

    Examines the circumstances of the 1979 "Progressive" case, in which the federal government quashed an article about hydrogen bomb production. Notes reportorial lapses that prevented a full and balanced account of the situation. (RL)

  13. Fibroblasts, an inconspicuous but essential player in colon cancer development and progression

    PubMed Central

    Mukaida, Naofumi; Sasaki, Soichiro

    2016-01-01

    Tumor microenvironments have a crucial role in cancer initiation and progression, and share many molecular and pathological features with wound healing process. Unless treated, tumors, however, do not heal in contrast to wounds that heal within a limited time framework. Wounds heal in coordination of a myriad of types of cells, particularly endothelial cells, leukocytes, and fibroblasts. Similar sets of cells also contribute to cancer initiation and progression, and as a consequence, anti-cancer treatment strategies have been proposed and tested by targeting endothelial cells and/or leukocytes. Compared with endothelial cells and leukocytes, less attention has been paid to the roles of cancer-associated fibroblasts (CAFs), fibroblasts present in tumor tissues, because their heterogeneity hinders the elucidation on them at cellular and molecular levels. Here, we will discuss the origin of CAFs and their crucial roles in cancer initiation and progression, and the possibility to develop a novel type of anti-cancer treatment by manipulating the migration and functions of CAFs. PMID:27340347

  14. Tumor Suppressor Genes in Early Breast Cancer and its Progression

    DTIC Science & Technology

    1997-09-01

    Yamakawa K., Akiyama F., Kasumi F., Sakamoto G. and Nakamura Y. Allelotype of breast cancer: cumulative allele losses promote tumor progression in...and Cancer 4:113-121,1992. 18. Sato T., Akiyama F., Sakamoto G., Kasumi F. and Nakamura Y. Accumulation of genetic alterations and progression of...identified Proc. Natl. Acad. USA 87; 7737-7741, 1990. 23. Saito H., Inazawa J., Saito S., Kasumi F., Koi S., Sagae S., Kudo R., Saito J., Noda K. and

  15. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome

    PubMed Central

    Zhang, Qunyuan; Ye, Jian; Wang, Fang; Zhang, Yanping; Hunborg, Pamela; Varvares, Mark A.; Hoft, Daniel F.; Hsueh, Eddy C.; Peng, Guangyong

    2015-01-01

    The Cancer Immunoediting concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4+ and CD8+ T cells in the pathogenesis of breast cancer remain unclear. Here we utilized two murine breast cancer models (4T1 and E0771) and demonstrated that both CD4+ and CD8+ T cells were increased and involved in immune responses, but with distinct dynamic trends in breast cancer development. In addition to cell number increases, CD4+ T cells changed their dominant subsets from Th1 in the early stages to Treg and Th17 cells in the late stages of the cancer progression. We also analyzed CD4+ and CD8+ T cell infiltration in primary breast cancer tissues from cancer patients. We observed that CD8+ T cells are the key effector cell population mediating effective anti-tumor immunity resulting in better clinical outcomes. In contrast, intra-tumoral CD4+ T cells have negative prognostic effects on breast cancer patient outcomes. These studies indicate that CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches. PMID:25968569

  16. A dietary restriction influences the progression but not the initiation of MSG-Induced nonalcoholic steatohepatitis.

    PubMed

    Fujimoto, Makoto; Tsuneyama, Koichi; Nakanishi, Yuko; Salunga, Thucydides L; Nomoto, Kazuhiro; Sasaki, Yoshiyuki; Iizuka, Seiichi; Nagata, Mitsunobu; Suzuki, Wataru; Shimada, Tsutomu; Aburada, Masaki; Shimada, Yutaka; Gershwin, M Eric; Selmi, Carlo

    2014-03-01

    The metabolic syndrome is a major worldwide health care issue and a dominant risk factor for cardiovascular disease. The liver manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). Although significant research has been performed, the basic pathogenesis of NAFLD/NASH remains controversial and effective treatments are still unavailable. We have previously reported on a murine model of NASH induced by the neonatal injection of monosodium glutamate (MSG), which includes the clinical manifestations of central obesity, diabetes, hyperlipidemia, and ultimately liver inflammation, fibrosis, and cancer. Although MSG is considered a safe food additive, its administration to pregnant rats increases the voracity and growth hormone levels in the offspring. To further understand the biology of this model, we have investigated the influence of the calorie intake on these clinical manifestations by feeding animals a restrictive diet. MSG-treated animals fed a restrictive diet continue to manifest obesity and early stage NASH but have improvements in serum lipid profiles. At 12 months of age, mice had manifestations of obesity, whether animals were fed a restricted or control diet, but animals fed a restrictive diet had a reduction in the progression of NASH. In conclusion, MSG appears to be a critical factor in the initiation of obesity, whereas calorie intake may modulate the progression of disease.

  17. Kidney, Lung, Ovarian, and Prostate Cancer - Treatment Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Breast, Cervical, and Colorectal Cancers - Early Detection Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Bladder, Breast, and Colorectal Cancer- Treatment Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Survival, Smoking, Physical Activity, and Obesity - Life After Cancer Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Androgen deprivation modulates gene expression profile along prostate cancer progression.

    PubMed

    Volante, Marco; Tota, Daniele; Giorcelli, Jessica; Bollito, Enrico; Napoli, Francesca; Vatrano, Simona; Buttigliero, Consuelo; Molinaro, Luca; Gontero, Paolo; Porpiglia, Francesco; Tucci, Marcello; Papotti, Mauro; Berruti, Alfredo; Rapa, Ida

    2016-10-01

    Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and initially induces tumor regression, but invariably results in castration-resistant prostate cancer through various mechanisms, incompletely discovered. Our aim was to analyze the dynamic modulation, determined by ADT, of the expression of selected genes involved in the pathogenesis and progression of prostate cancer (TMPRSS2:ERG, WNT11, SPINK1, CHGA, AR, and SPDEF) using real-time polymerase chain reaction in a series of 59 surgical samples of prostate carcinomas, including 37 cases preoperatively treated with ADT and 22 untreated cases, and in 43 corresponding biopsies. The same genes were analyzed in androgen-deprived and control LNCaP cells. Three genes were significantly up-modulated (WNT11 and AR) or down-modulated (SPDEF) in patients treated with ADT versus untreated cases, as well as in androgen-deprived LNCaP cells. The effect of ADT on CHGA gene up-modulation was almost exclusively detected in cases positive for the TMPRSS2:ERG fusion. The correlation between biopsy and surgical samples was poor for most of the tested genes. Gene expression analysis of separate tumor areas from the same patient showed an extremely heterogeneous profile in the 6 tested cases (all untreated). In conclusion, our results strengthened the implication of ADT in promoting a prostate cancer aggressive phenotype and identified potential biomarkers, with special reference to the TMPRSS2:ERG fusion, which might favor the development of neuroendocrine differentiation in hormone-treated patients. However, intratumoral heterogeneity limits the use of gene expression analysis as a potential prognostic or predictive biomarker in patients treated with ADT.

  2. Progress in neutron capture therapy for cancer

    SciTech Connect

    Allen, B.J.; Harrington, B.V.; Moore, D.E.

    1992-09-01

    Prognosis for some cancers is good, but for others, few patients will survive 12 months. This latter group of cancers is characterised by a proclivity to disseminate malignant cells in the host organ. In some cases systemic metastases occur, but in other cases, failure to achieve local control results in death. First among these cancers are the high grade brain tumours, astrocytoma 3,4 and glioblastoma multiforme. Local control of these tumors should lead to cure. Other cancers melanoma metastatic to the brain, for which a useful palliative therapy is not yet available, and pancreatic cancer for which localised control at an early stage could bring about improved prognosis. Patients with these cancers have little grounds for hope. Our primary objective is to reverse this situation with Neutron Capture Therapy (NCT). The purpose of this fourth symposium is to hasten the day whereby patients with these cancers can reasonably hope for substantial remissions.

  3. Progress in neutron capture therapy for cancer

    SciTech Connect

    Allen, B.J.; Harrington, B.V. ); Moore, D.E. )

    1992-01-01

    Prognosis for some cancers is good, but for others, few patients will survive 12 months. This latter group of cancers is characterised by a proclivity to disseminate malignant cells in the host organ. In some cases systemic metastases occur, but in other cases, failure to achieve local control results in death. First among these cancers are the high grade brain tumours, astrocytoma 3,4 and glioblastoma multiforme. Local control of these tumors should lead to cure. Other cancers melanoma metastatic to the brain, for which a useful palliative therapy is not yet available, and pancreatic cancer for which localised control at an early stage could bring about improved prognosis. Patients with these cancers have little grounds for hope. Our primary objective is to reverse this situation with Neutron Capture Therapy (NCT). The purpose of this fourth symposium is to hasten the day whereby patients with these cancers can reasonably hope for substantial remissions.

  4. Differential roles of STAT3 in the initiation and growth of lung cancer.

    PubMed

    Zhou, J; Qu, Z; Yan, S; Sun, F; Whitsett, J A; Shapiro, S D; Xiao, G

    2015-07-01

    Signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including pulmonary adenocarcinoma. However, the role of STAT3 in lung cancer pathogenesis has not been determined. Using lung epithelial-specific inducible knockout strategies, we demonstrate that STAT3 has contrasting roles in the initiation and growth of both chemically and genetically induced lung cancers. Selective deletion of lung epithelial STAT3 in mice before cancer induction by the smoke carcinogen, urethane, resulted in increased lung tissue damage and inflammation, K-Ras oncogenic mutations and tumorigenesis. Deletion of lung epithelial STAT3 after establishment of lung cancer inhibited cancer cell proliferation. Simultaneous deletion of STAT3 and expression of oncogenic K-Ras in mouse lung elevated pulmonary injury, inflammation and tumorigenesis, but reduced tumor growth. These studies indicate that STAT3 prevents lung cancer initiation by maintaining pulmonary homeostasis under oncogenic stress, whereas it facilitates lung cancer progression by promoting cancer cell growth. These studies also provide a mechanistic basis for targeting STAT3 to lung cancer therapy.

  5. MicroRNA in Development and in the Progression of Cancer | Center for Cancer Research

    Cancer.gov

    MicroRNA in Development and in the Progression of Cancer is divided into three parts. It provides a more complete understanding of miRNA function, summarizes the recent progress, and provides insights by which miRNAs regulate normal development and diseases (including cancers) and the fate of stem cells. It also presents the prospect of the great potential of miRNAs in cancer stem cells and therapeutic advances for cancer treatment.

  6. Carcinoma Initiation via Rb Tumor Suppressor Inactivation: A Versatile Approach to Epithelial Subtype-Dependent Cancer Initiation in Diverse Tissues

    PubMed Central

    Song, Yurong; Gilbert, Debra; O’Sullivan, T. Norene; Yang, Chunyu; Pan, Wenqi; Fathalizadeh, Alisan; Lu, Lucy; Haines, Diana C.; Martin, Philip L.; Van Dyke, Terry

    2013-01-01

    Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages surrounded by a variety of stromal cell types. Understanding cancer etiologies requires evaluating the relationship among cell types during disease initiation and through progression. Genetically engineered mouse (GEM) models facilitate the prospective examination of early oncogenic events, which is not possible in humans. Since most solid tumors harbor aberrations in the RB network, we developed an inducible GEM approach for the establishment and assessment of carcinoma initiation in a diverse range of epithelial tissues and subtypes upon inactivation of RB-mediated tumor suppression (RB-TS). The system allows independent assessment of epithelial subtypes that express either cytokeratins (K) 18 or 19. By Cre-dependent expression of a protein that dominantly inactivates RB and functionally redundant proteins p107 and p130, neoplasia could be initiated in either K18 or K19 expressing cells of numerous tissues. By design, because only a single pathway aberration was engineered, carcinomas developed stochastically only after long latency. Hence, this system, which allows for directed cell type-specific carcinoma initiation, facilitates further definition of events that can progress neoplasms to aggressive cancers via engineered, carcinogen-induced and/or spontaneous evolution. PMID:24312475

  7. Small-molecule targeting of translation initiation for cancer therapy

    PubMed Central

    Aktas, Bertal H.; Qiao, Yuan; Ozdelen, Esra; Schubert, Roland; Sevinc, Sema; Harbinski, Fred; Grubissich, Luciano; Singer, Samuel; Halperin, Jose A.

    2013-01-01

    Translation initiation plays a critical role in the regulation of cell growth and tumorigenesis. We report here that inhibiting translation initiation through induction of eIF2α phosphorylation by small-molecular-weight compounds restricts the availability of the eIF2·GTP·Met-tRNAi ternary complex and abrogates the proliferation of cancer cells in vitro and tumor growth in vivo. Restricting the availability of the ternary complex preferentially down-regulates the expression of growth-promoting proteins and up-regulates the expression of ER stress response genes in cancer cells as well as in tumors excised from either animal models of human cancer or cancer patients. These findings provide the first direct evidence for translational control of gene-specific expression by small molecules in vivo and indicate that translation initiation factors are bona fide targets for development of mechanism-specific anti-cancer agents. PMID:24091475

  8. A Genetic Interaction Screen for Breast Cancer Progression Driver Genes

    DTIC Science & Technology

    2013-06-01

    AD_________________ Award Number: W81XWH-12-1-0082 TITLE: A Genetic Interaction Screen for Breast...COVERED 1 2012 - 3 2013 4. TITLE AND SUBTITLE A Genetic Interaction Screen for Breast Cancer Progression Driver Genes 5a. CONTRACT NUMBER...analysis of genetic alterations in human breast cancers has revealed that individual tumors accumulate mutations in approximately ninety different genes

  9. RGS-GAIP-interacting protein controls breast cancer progression.

    PubMed

    Wang, Ling; Lau, Julie S; Patra, Chitta Ranjan; Cao, Ying; Bhattacharya, Santanu; Dutta, Shamit; Nandy, Debashis; Wang, Enfeng; Rupasinghe, Chamila N; Vohra, Pawan; Spaller, Mark R; Mukhopadhyay, Debabrata

    2010-12-01

    Although the importance of RGS-GAIP-interacting protein (GIPC) in the biology of malignant cells is well known, the molecular mechanism of GIPC in the inhibition of tumor progression has not been identified. This study focused on elucidating the molecular role of GIPC in breast cancer progression. By using a human breast tumor specimen, an in vivo mouse model, and breast cancer cell lines, we showed for the first time that GIPC is involved in breast cancer progression through regulation of breast cancer cell proliferation, survival, and invasion. Furthermore, we found that the Akt/Mdm2/p53 axis, insulin-like growth factor-1 receptor, matrix metalloproteinase-9, and Cdc42 were downstream of GIPC signaling in breast cancer cells. Moreover, we showed that wild-type p53 reduced GIPC-induced breast cancer cell survival, whereas mutant p53 inhibited GIPC-induced cell invasion. Finally, we demonstrated that an N-myristoylated GIPC peptide (CR1023, N-myristoyl-PSQSSSEA) capable of blocking the PDZ domain of GIPC successfully inhibited MDA-MB-231 cell proliferation, survival, and further in vivo tumor growth. Taken together, these findings demonstrate the importance of GIPC in breast tumor progression, which has a potentially significant impact on the development of therapies against many common cancers expressing GIPC, including breast and renal cancer. ©2010 AACR.

  10. RGS-GAIP–interacting protein controls breast cancer progression

    PubMed Central

    Wang, Ling; Lau, Julie S.; Patra, Chitta Ranjan; Cao, Ying; Bhattacharya, Shantanu; Dutta, Shamit; Nandy, Debashis; Wang, Enfeng; Rupasinghe, Chamila N.; Vohra, Pawan; Spaller, Mark R.; Mukhopadhyay, Debabrata

    2013-01-01

    While the importance of RGS-GAIP–interacting protein (GIPC) in the biology of malignant cells is well known, the molecular mechanism of GIPC in the inhibition of tumor progression has not been identified. This study focused on elucidating the molecular role of GIPC in breast cancer progression. By using a human breast tumor specimen, an in vivo mouse model, and breast cancer cell lines, we showed for the first time that GIPC is involved in breast cancer progression through regulation of breast cancer cell proliferation, survival, and invasion. Furthermore, we found that the Akt/Mdm2/p53 axis, insulin-like growth factor-1 receptor (IGF-1R), matrix metalloproteinase-9 (MMP-9), and Cdc42 were downstream of GIPC signaling in breast cancer cells. Moreover, we showed that wild-type p53 reduced GIPC-induced breast cancer cell survival, whereas mutant p53 inhibited GIPC-induced cell invasion. Finally, we demonstrated that a myristylated GIPC peptide (CR1023, Myristoyl-PSQSSSEA) capable of blocking the PDZ domain of GIPC successfully inhibited MDA-MB-231 cell proliferation, survival, and further in vivo tumor growth. Taken together, these findings demonstrate the importance of GIPC in breast tumor progression, which has a potentially significant impact on the development of therapies against many common cancers expressing GIPC, including breast and renal cancer. PMID:21047775

  11. Optimizing initial chemotherapy for metastatic pancreatic cancer.

    PubMed

    Mantripragada, Kalyan C; Safran, Howard

    2016-05-01

    The two combination chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel represent major breakthroughs in the management of metastatic pancreatic cancer. Both regimens showed unprecedented survival advantage in the setting of front-line therapy. However, their application for treatment of patients in the community is challenging because of significant toxicities, thus limiting potential benefits to a narrow population of patients. Modifications to the dose intensity or schedule of those regimens improve their tolerability, while likely retaining survival advantage over single-agent chemotherapy. Newer strategies to optimize these two active regimens in advanced pancreatic cancer are being explored that can help personalize treatment to individual patients.

  12. Ovarian cancer immunotherapy: opportunities, progresses and challenges

    PubMed Central

    2010-01-01

    Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer. PMID:20146807

  13. AR Alternative Splicing and Prostate Cancer Progression

    DTIC Science & Technology

    2013-07-01

    receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 2001; 61: 2892 - 2898. Supplementary...cells were maintained in RMPI 1640 (Invitrogen) with 10% fetal bovine serum (FBS), 100 units/ml penicillin , and 100g/ml streptomy- cin in a 5% CO2... hypersensitivity to low androgen. Cancer Res 2001;61: 2892–8. 15. Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. Splicing of a novel androgen

  14. Genes Involved in Oxidation and Prostate Cancer Progression

    DTIC Science & Technology

    2008-01-01

    association of genes and prostate cancer progression from these simulated nested case - control studies to what would be observed if the entire...Control Sampling: Methods for Nested Case - Control Studies of Candidate Genes and Prostate Cancer Progression”. This work forms one aim of MS Wang’s...prostate cancer risk: results from two large nested case - control studies . Carcinogenesis. 2007 Nov 13; [Epub ahead of print] PMID: 17999989 Dr

  15. Immunological Targeting of Tumor Initiating Prostate Cancer Cells

    DTIC Science & Technology

    2014-10-01

    clinically using well-accepted immuno-competent animal models. 2) Keywords: Prostate Cancer , Lymphocyte, Vaccine , Antibody 3) Overall Project Summary...generating a novel prostate cancer vaccine aimed at targeting the castration resistant epithelial cells left behind after initial androgen ablation. 6...of origin for prostate cancer . Nature 461:495-500. 2. Drake,C.G., E.J.Lipson, and J.R.Brahmer. 2014. Breathing new life into immunotherapy

  16. Research progress in the treatment of small cell lung cancer

    PubMed Central

    Qiu, Yan-fang; Liu, Zhi-gang; Yang, Wen-juan; Zhao, Yu; Tang, Jiao; Tang, Wei-zhi; Jin, Yi; Li, Fang; Zhong, Rui; Wang, Hui

    2017-01-01

    Small cell lung cancer (SCLC) accounts for approximately 10-15% of all lung cancers. No significant improvement has been made for patients with SCLC in the past several decades. The main progresses were the thoracic radiation and prophylactic cranial irradiation (PCI) that improved the patient survival rate. For patients with limited disease and good performance status (PS), concurrent chemoradiotherapy (CCRT) followed by PCI should be considered. For extensive disease, the combination of etoposide and platinum-based chemotherapy remains the standard treatment and consolidative thoracic radiotherapy is beneficial for patients who have a significant respond to initial chemotherapy. However, the prognosis still remains poor. Recently, efforts have been focused on molecular targets and immunotherapy. But numerous molecular targets methods have failed to show a significant clinical benefit in patients with SCLC. It is anticipated that further development of research will depend on the on-going trials for molecular targeted therapy and immunotherapy which are promising and may improve the outcomes for SCLC in the next decade. PMID:28123595

  17. GPR56 Plays Varying Roles in Endogenous Cancer Progression

    PubMed Central

    Xu, Lei; Begum, Shahinoor; Barry, Marc; Crowley, Denise; Yang, Liquan; Bronson, Roderick T.; Hynes, Richard O.

    2011-01-01

    GPR56, a non-classical adhesion receptor, was previously reported to suppress tumor growth and metastasis in xenograft models using human melanoma cell lines. To understand whether GPR56 plays similar roles in the development of endogenous tumors, we analyzed cancer progression in Gpr56−/− mice using a variety of transgenic cancer models. Our results showed that GPR56 suppressed prostate cancer progression in the TRAMP model on a mixed genetic background, similar to its roles in progression of melanoma xenografts. However, its roles in other cancer types appeared to be complex. It had marginal effects on tumor onset of mammary tumors in the MMTV-PyMT model, but had no effects on subsequent tumor progression in either the MMTV-PyMT mice or the melanoma model, Ink4a/Arf−/− tyr-Hras. These results indicate diverse roles of GPR56 in cancer progression and provide the first genetic evidence for the involvement of an adhesion GPCR in endogenous cancer development. PMID:20333450

  18. Extensions to the modeling of initiation and progression: applications to substance use and abuse.

    PubMed

    Neale, Michael C; Harvey, Eric; Maes, Hermine H M; Sullivan, Patrick F; Kendler, Kenneth S

    2006-07-01

    Twin data can provide valuable insight into the relationship between the stages of phenomena such as disease or substance abuse. Initiation of substance use may be caused by factors that are the same as, partially shared with, or completely independent of those that cause progression from use to abuse. Comparison of rates of progression among the cotwins of twins who do vs. do not initiate provides indirect information about the relationship between initiation and progression. Existing models for this relationship have been difficult to extend because they are usually expressed in terms of explicit integrals. In this paper, the problem is overcome by regarding the analysis of twin data on initiation and progression as a special case of missing data, in which individuals who do not initiate are regarded as having missing data on progression measures. Using the general framework for the analysis of ordinal data with missing values available in Mx makes extensions that include other variables much easier. The effects of continuous covariates such as age on initiation and progression becomes simple. Also facilitated are the examination of initiation and progression in two or more substances, and transition models with two or more steps. The methods are illustrated with data on the effects of cohort on liability to cannabis use and abuse, bivariate analysis of tobacco use and dependence and cannabis use and abuse, and the relationships between initiation of smoking, regular smoking and nicotine dependence. Other suitable applications include the relationship between symptoms and diagnosis, such as fears and the progression to phobia.

  19. GPR56 in cancer progression: current status and future perspective.

    PubMed

    Yang, Liquan; Xu, Lei

    2012-04-01

    Cell adhesion is a critical process during cancer progression and is mediated by transmembrane receptors. Recently, GPR56, a member of the adhesion family of G protein-coupled receptors, was established as a new type of adhesion receptor that binds to extracellular matrix proteins and shown to play inhibitory roles in melanoma progression. Further studies revealed that the extracellular portion and the seven transmembrane domains of GPR56 function antagonistically to regulate VEGF production and angiogenesis via a signaling pathway mediated by PKCα. Tissue transglutaminase was identified as the first extracellular matrix protein that binds to GPR56. It is a crosslinking enzyme in the extracellular matrix but is also expressed in the cytosol. Tissue transglutaminase plays pleiotropic roles in cancer progression. Whether and how it might mediate GPR56-regulated cancer progression awaits further investigation.

  20. Role of Aquaporin 1 Signalling in Cancer Development and Progression

    PubMed Central

    Tomita, Yoko; Dorward, Hilary; Yool, Andrea J.; Smith, Eric; Townsend, Amanda R.; Price, Timothy J.; Hardingham, Jennifer E.

    2017-01-01

    Cancer is a major health burden worldwide. Despite the advances in our understanding of its pathogenesis and continued improvement in cancer management and outcomes, there remains a strong clinical demand for more accurate and reliable biomarkers of metastatic progression and novel therapeutic targets to abrogate angiogenesis and tumour progression. Aquaporin 1 (AQP1) is a small hydrophobic integral transmembrane protein with a predominant role in trans-cellular water transport. Recently, over-expression of AQP1 has been associated with many types of cancer as a distinctive clinical prognostic factor. This has prompted researchers to evaluate the link between AQP1 and cancer biological functions. Available literature implicates the role of AQP1 in tumour cell migration, invasion and angiogenesis. This article reviews the current understanding of AQP1-facilitated tumour development and progression with a focus on regulatory mechanisms and downstream signalling pathways. PMID:28146084

  1. Is human cytomegalovirus associated with breast cancer progression?

    PubMed Central

    2013-01-01

    Background It has been hypothesized that human cytomegalovirus (HCMV) may be associated with breast cancer progression. However, the role of HCMV infection in breast cancer remains controversial. We aimed to assess whether HCMV genes (UL122 and UL83) could be detected in breast carcinomas and reinvestigated their possible association with breast cancer progression. DNA from paraffin-embedded tissues was analyzed by real-time PCR. We investigated 20 fibroadenomas and 27 primary breast carcinomas (stages II, III, and IV). Findings Two carcinomas were positive for HCMV, one was positive for two TaqMan viral detection probes, and one was positive for a sole TaqMan viral detection probe (UL83), whereas the remainder of the samples was negative. Conclusions Samples studied showed no association between HCMV infection and breast cancer progression. PMID:23557440

  2. Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene

    SciTech Connect

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; Hung, Ming -Szu; Hsieh, David; Au, Alfred; Jablons, David M.; You, Liang

    2015-06-08

    Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Methods: Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. Results: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. Conclusion: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

  3. Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene

    DOE PAGES

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; ...

    2015-06-08

    Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Methods:more » Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. Results: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. Conclusion: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.« less

  4. Genetic Abnormalities in Oral Leukoplakia and Oral Cancer Progression.

    PubMed

    Kil, Tae Jun; Kim, Hyun Sil; Kim, Hyung Jun; Nam, Woong; Cha, In-Ho

    2016-01-01

    The cancer progression of oral leukoplakia is an important watchpoint in the follow-up observation of the patients. However, potential malignancies of oral leukoplakia cannot be estimated by histopathologic assessment alone. We evaluated genetic abnormalities at the level of copy number variation (CNV) to investigate the risk for developing cancer in oral leukoplakias. The current study used 27 oral leukoplakias with histological evidence of dysplasia. The first group (progressing dysplasia) consisted of 7 oral lesions from patients with later progression to cancer at the same site. The other group (non- progressing dysplasia) consisted of 20 lesions from patients with no occurrence of oral cancer and longitudinal follow up (>7 years). We extracted DNA from Formalin-Fixed Paraffin-Embedded (FFPE) samples and examined chromosomal loci and frequencies of CNVs using Taqman copy number assays. CNV frequently occurred at 3p, 9p, and 13q loci in progressing dysplasia. Our results also indicate that CNV at multiple loci-in contrast to single locus occurrences-is characteristic of progressing dysplasia. This study suggests that genetic abnormalities of the true precancer demonstrate the progression risk which cannot be delineated by current histopathologic diagnosis.

  5. Alterations in Cell-Extracellular Matrix Interactions during Progression of Cancers

    PubMed Central

    Jinka, Rajeswari; Kapoor, Renu; Sistla, Pavana Goury; Raj, T. Avinash; Pande, Gopal

    2012-01-01

    Cancer progression is a multistep process during which normal cells exhibit molecular changes that culminate into the highly malignant and metastatic phenotype, observed in cancerous tissues. The initiation of cell transformation is generally associated with genetic alterations in normal cells that lead to the loss of intercellular- and/or extracellular-matrix- (ECM-) mediated cell adhesion. Transformed cells undergo rapid multiplication and generate more modifications in adhesion and motility-related molecules which allow them to escape from the original site and acquire invasive characteristics. Integrins, which are multifunctional adhesion receptors, and are present, on normal as well as transformed cells, assist the cells undergoing tumor progression in creating the appropriate environment for their survival, growth, and invasion. In this paper, we have briefly discussed the role of ECM proteins and integrins during cancer progression and described some unique conditions where adhesion-related changes could induce genetic mutations in anchorage-independent tumor model systems. PMID:22262973

  6. Targeted Radiation Therapy for Cancer Initiative

    DTIC Science & Technology

    2013-09-01

    system, 3) whether Beacon® Transponder is of benefit in pelvic radiation therapy following prostatectomy, 4) whether hypofractionated treatment plans...enroll a combined total of up to 40 subjects from both centers. Task 4. Hypofractionated Radiotherapy in Patients with Favorable Risk Prostate...Cancer Using the Calypso® 4D Localization System. . The original hypofractionated trial listed under this task has been removed and replaced

  7. Targeted Radiation Therapy for Cancer Initiative

    DTIC Science & Technology

    2010-09-01

    Transponder is of benefit in pelvic radiation therapy following prostatectomy, 4) whether hypofractionated treatment plans which are more beam on...centers. Task 4. A Hypofractionated IMRT Therapy in Patients with Favorable Risk Prostate Cancer Using the Calypso® 4D Localization System: A...Feasibility Study. We are awaiting the preliminary results from the RTOG 0415, which is a similar hypofractionated study (not using the Calypso

  8. Targeted Radiation Therapy for Cancer Initiative

    DTIC Science & Technology

    2011-09-01

    whether Beacon® Transponder is of benefit in pelvic radiation therapy following prostatectomy, 4) whether hypofractionated treatment plans which...both centers. Task 4. A Hypofractionated IMRT Therapy in Patients with Favorable Risk Prostate Cancer Using the Calypso® 4D Localization System...A Feasibility Study. We are awaiting the preliminary results from the RTOG 0415, which is a similar hypofractionated study (not using the

  9. Targeted Radiation Therapy for Cancer Initiative

    DTIC Science & Technology

    2016-09-01

    continence during radiation therapy for prostate cancer. * *Waggoner A, Brown M, Tinnel B, Halligan J, Brand T, Brooks J, Ninneman S, Hughs G...Gossweiler M, Waggoner A, Huang R, Ninneman S, Hughs G, Wendt S, Brown M, Tinnel B, Macdonald D. (8-9 February 2013). Anorectal angle is associated...Therapy Symposium, Orlando, FL. * Gossweiler M, Waggoner A, Huang R, Ninneman S, Hughs G, Wendt S, Brown M, Tinnel B, Macdonald D. (2013, April

  10. Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

    PubMed Central

    Bernstein, Carol; Bernstein, Harris

    2015-01-01

    Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy. PMID:25987950

  11. Epigenetic reduction of DNA repair in progression to gastrointestinal cancer.

    PubMed

    Bernstein, Carol; Bernstein, Harris

    2015-05-15

    Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.

  12. The European initiative for quality management in lung cancer care.

    PubMed

    Blum, Torsten G; Rich, Anna; Baldwin, David; Beckett, Paul; De Ruysscher, Dirk; Faivre-Finn, Corinne; Gaga, Mina; Gamarra, Fernando; Grigoriu, Bogdan; Hansen, Niels C G; Hubbard, Richard; Huber, Rudolf Maria; Jakobsen, Erik; Jovanovic, Dragana; Konsoulova, Assia; Kollmeier, Jens; Massard, Gilbert; McPhelim, John; Meert, Anne-Pascale; Milroy, Robert; Paesmans, Marianne; Peake, Mick; Putora, Paul-Martin; Scherpereel, Arnaud; Schönfeld, Nicolas; Sitter, Helmut; Skaug, Knut; Spiro, Stephen; Strand, Trond-Eirik; Taright, Samya; Thomas, Michael; van Schil, Paul E; Vansteenkiste, Johan F; Wiewrodt, Rainer; Sculier, Jean-Paul

    2014-05-01

    Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.

  13. Obesity is associated with risk of progression for low-risk prostate cancers managed expectantly.

    PubMed

    Bhindi, Bimal; Kulkarni, Girish S; Finelli, Antonio; Alibhai, Shabbir M H; Hamilton, Robert J; Toi, Ants; van der Kwast, Theodorus H; Evans, Andrew; Hersey, Karen; Jewett, Michael A S; Zlotta, Alexandre R; Trachtenberg, John; Fleshner, Neil E

    2014-11-01

    Active surveillance (AS) is an expectant management strategy for prostate cancer (PCa). The impact of obesity on progression is not well characterized in this population. To determine if obesity is associated with progression in men on AS for low-risk PCa. Men undergoing AS for low-risk PCa (no Gleason pattern ≥4, three or fewer cores involved or one-third or less of the total number of cores involved, and no core with >50% cancer involvement) were identified at our institution. The outcomes were pathologic progression (defined as no longer meeting low-risk criteria on follow-up biopsy) and therapeutic progression (defined as intent to initiate active treatment). Kaplan-Meier curves and multivariable logistic regression and Cox proportional hazards models were used, with separate models for reclassification at confirmatory biopsy (first biopsy after diagnostic biopsy) and progression beyond confirmatory biopsy. In this cohort of 565 men (median follow-up: 48 mo), 124 (22%) were obese (body mass index [BMI] ≥30kg/m(2)). Pathologic and therapeutic progression occurred in 168 men (30%) and 172 men (30%), respectively. No association was noted between obesity and risk of progression at the confirmatory biopsy. However, beyond confirmatory biopsy, obesity was associated with a greater probability of pathologic progression (p=0.007) and therapeutic progression (p=0.007) in Kaplan-Meier analyses. In adjusted Cox models, each 5-unit increase in BMI was associated with an increased risk of pathologic progression (hazard ratio [HR]: 1.5; 95% confidence interval [CI], 1.1-2.1; p=0.02) and therapeutic progression (HR: 1.4; 95% CI, 1.0-1.9; p=0.05). The main limitation is the retrospective design, limiting the ability to assess BMI changes over time. Obesity was associated with a significantly increased risk of progression beyond the confirmatory biopsy. This suggests an increased risk of long-term biologic progression rather than solely misclassification. As opposed to

  14. miR-221/222 induces pancreatic cancer progression through the regulation of matrix metalloproteinases.

    PubMed

    Xu, Qinhong; Li, Pei; Chen, Xin; Zong, Liang; Jiang, Zhengdong; Nan, Ligang; Lei, Jianjun; Duan, Wanxing; Zhang, Dong; Li, Xuqi; Sha, Huanchen; Wu, Zheng; Ma, Qingyong; Wang, Zheng

    2015-06-10

    MicroRNAs are involved in the initiation and progression of pancreatic cancer. In this study, we showed that miR-221/222 is overexpressed in pancreatic cancer. MiR-221/222 overexpression significantly promoted pancreatic cancer cell proliferation and invasion while inhibiting apoptosis. The expression of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 was increased in miR-221/222 mimic-transfected pancreatic cancer cells. Validation experiments identified TIMP-2 as a direct target of miR-221/222. These data indicate that overexpressed miR-221/222 may play an oncogenic role in pancreatic cancer by inducing the expression of MMP-2 and MMP-9, thus leading to cancer cell invasion.

  15. Reprogramming of human cancer cells to pluripotency for models of cancer progression

    PubMed Central

    Kim, Jungsun; Zaret, Kenneth S

    2015-01-01

    The ability to study live cells as they progress through the stages of cancer provides the opportunity to discover dynamic networks underlying pathology, markers of early stages, and ways to assess therapeutics. Genetically engineered animal models of cancer, where it is possible to study the consequences of temporal-specific induction of oncogenes or deletion of tumor suppressors, have yielded major insights into cancer progression. Yet differences exist between animal and human cancers, such as in markers of progression and response to therapeutics. Thus, there is a need for human cell models of cancer progression. Most human cell models of cancer are based on tumor cell lines and xenografts of primary tumor cells that resemble the advanced tumor state, from which the cells were derived, and thus do not recapitulate disease progression. Yet a subset of cancer types have been reprogrammed to pluripotency or near-pluripotency by blastocyst injection, by somatic cell nuclear transfer and by induced pluripotent stem cell (iPS) technology. The reprogrammed cancer cells show that pluripotency can transiently dominate over the cancer phenotype. Diverse studies show that reprogrammed cancer cells can, in some cases, exhibit early-stage phenotypes reflective of only partial expression of the cancer genome. In one case, reprogrammed human pancreatic cancer cells have been shown to recapitulate stages of cancer progression, from early to late stages, thus providing a model for studying pancreatic cancer development in human cells where previously such could only be discerned from mouse models. We discuss these findings, the challenges in developing such models and their current limitations, and ways that iPS reprogramming may be enhanced to develop human cell models of cancer progression. PMID:25712212

  16. [Epigenetic alterations in cervical cancer progression].

    PubMed

    Ríos-Romero, Magdalena; Soto-Valladares, Ana Guadalupe; Piña-Sánchez, Patricia

    2015-01-01

    Despite the use of the screening test, such as Papanicolaou, and the detection of human papillomavirus (HPV), cervical cancer remains as a public health problem in México and it is the second leading cause of death for malignant neoplasias among women. High-risk HPV infection is the main risk factor for the development of premalignant lesions and cervical cancer; however, HPV infection is not the only factor; there are various genetic and epigenetic alterations required for the development of neoplasias; some of them have been described and even in some cases they have been suggested as biomarkers for prognosis. However, in contrast with other cancer types, such as breast cancer, in cervical cancer the use of biomarkers has not been established for clinical applications. Unlike genetic alterations, epigenetic alterations are potentially reversible; in this sense, their characterization is important, since they have not only a potential use as biomarkers, but they also could represent new therapeutic targets for treatment of cervical cancer. This review describes some of the more common epigenetic alterations in cervical cancer and its potential use in routine clinical practice.

  17. Emerging role of cell polarity proteins in breast cancer progression and metastasis

    PubMed Central

    Chatterjee, Sudipa June; McCaffrey, Luke

    2014-01-01

    Breast cancer is a heterogeneous group of diseases that frequently exhibits loss of growth control, and disrupted tissue organization and differentiation. Several recent studies indicate that apical–basal polarity provides a tumor-suppressive function, and that disrupting polarity proteins affects many stages of breast cancer progression from initiation through metastasis. In this review we highlight some of the recent advances in our understanding of the molecular mechanisms by which loss of apical–basal polarity deregulates apoptosis, proliferation, and promotes invasion and metastasis in breast cancer. PMID:24648766

  18. The extracellular matrix: A dynamic niche in cancer progression

    PubMed Central

    Lu, Pengfei; Weaver, Valerie M.

    2012-01-01

    The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche. PMID:22351925

  19. Obesity, rather than diet, drives epigenomics alterations in colonic epithelium resembling cancer progression

    PubMed Central

    Li, Ruifang; Grimm, Sara A.; Chrysovergis, Kaliopi; Kosak, Justin; Wang, Xingya; Du, Ying; Burkholder, Adam; Janardhan, Kyathanahalli; Mav, Deepak; Shah, Ruchir; Eling, Thomas E.; Wade, Paul A.

    2014-01-01

    Summary While obesity represents one of several risk factors for colorectal cancer in humans, the mechanistic underpinnings of this association remain unresolved. Environmental stimuli, including diet, can alter the epigenetic landscape of DNA cis-regulatory elements affecting gene expression and phenotype. Here, we explored the impact of diet and obesity on gene expression and the enhancer landscape in murine colonic epithelium. Obesity led to the accumulation of histone modifications associated with active enhancers at genomic loci downstream of signaling pathways integral to the initiation and progression of colon cancer. Meanwhile, colon-specific enhancers lost the same histone mark, poising cells for loss of differentiation. These alterations reflect a transcriptional program with many features shared with the program driving colon cancer progression. The interrogation of enhancer alterations by diet in colonic epithelium provides insights into the biology underlying high-fat diet and obesity as risk factors for colon cancer. PMID:24703701

  20. Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression.

    PubMed

    Li, Ruifang; Grimm, Sara A; Chrysovergis, Kaliopi; Kosak, Justin; Wang, Xingya; Du, Ying; Burkholder, Adam; Janardhan, Kyathanahalli; Mav, Deepak; Shah, Ruchir; Eling, Thomas E; Wade, Paul A

    2014-04-01

    While obesity represents one of several risk factors for colorectal cancer in humans, the mechanistic underpinnings of this association remain unresolved. Environmental stimuli, including diet, can alter the epigenetic landscape of DNA cis-regulatory elements affecting gene expression and phenotype. Here, we explored the impact of diet and obesity on gene expression and the enhancer landscape in murine colonic epithelium. Obesity led to the accumulation of histone modifications associated with active enhancers at genomic loci downstream of signaling pathways integral to the initiation and progression of colon cancer. Meanwhile, colon-specific enhancers lost the same histone mark, poising cells for loss of differentiation. These alterations reflect a transcriptional program with many features shared with the program driving colon cancer progression. The interrogation of enhancer alterations by diet in colonic epithelium provides insights into the biology underlying high-fat diet and obesity as risk factors for colon cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. PPARgamma, Bioactive Lipids, and Cancer Progression

    PubMed Central

    Robbins, Gregory T.; Nie, Daotai

    2012-01-01

    In this article we review the evolution of cancer research involving PPARgamma, including mechanisms, target genes, and clinical applications. For the last thirteen years, the effects of PPARgamma activity on tumor biology have been studied intensely. Most of this research has focused upon the potential for employing agonists of this nuclear receptor in cancer treatment. As a monotherapy such agonists have shown little success in clinical trials, while they have shown promise as components of combination treatments both in culture and in animal models. Other investigations have explored a possible role for PPARgamma as a tumor suppressor, and as an inducer of differentiation of cancer stem cells. Whereas early studies have yielded variable conclusions regarding the prevalence of PPARgamma mutations in cancer, the protein level of this receptor has been more recently identified as a significant prognostic marker. We predict that indicators of PPARgamma activity may also serve as predictive markers for tailoring treatments. PMID:22201838

  2. Akt isoform specific effects in ovarian cancer progression

    PubMed Central

    Linnerth-Petrik, Nicolle M.; Santry, Lisa A.; Moorehead, Roger; Jücker, Manfred

    2016-01-01

    Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer. PMID:27533079

  3. Education For All (EFA) - Fast Track Initiative Progress Report 30046

    ERIC Educational Resources Information Center

    World Bank Education Advisory Service, 2004

    2004-01-01

    Launched in June 2002, the Education For All-Fast Track Initiative (FTI) is a performance-based program focusing on the implementation of sustainable policies in support of universal primary completion (UPC) and the required resource mobilization. During its twenty months of implementation, FTI has delivered on results, which give reason for…

  4. Progressing from Initially Ambiguous Functional Analyses: Three Case Examples

    ERIC Educational Resources Information Center

    Tiger, Jeffrey H.; Fisher, Wayne W.; Toussaint, Karen A.; Kodak, Tiffany

    2009-01-01

    Most often functional analyses are initiated using a standard set of test conditions, similar to those described by Iwata, Dorsey, Slifer, Bauman, and Richman [Iwata, B. A., Dorsey, M. F., Slifer, K. J., Bauman, K. E., & Richman, G. S. (1994). "Toward a functional analysis of self-injury." "Journal of Applied Behavior Analysis, 27", 197-209…

  5. Hemlock woolly adelgid initiative: progress and future direction

    Treesearch

    Brad Onken; Melody. Keena

    2008-01-01

    In 2001, the USDA Forest Service in cooperation with the National Association of State Foresters and the National Plant Board proposed a five-year program that would accelerate development and implementation of management options to reduce the spread and impact of hemlock woolly adelgid. From 2003-2007, this "Hemlock Woolly Adelgid Initiative" has involved...

  6. Evaluating Complex Systems-Building Initiatives: A Work in Progress

    ERIC Educational Resources Information Center

    Walker, Gary; Kubisch, Anne C.

    2008-01-01

    In April 2007, more than 60 people--practitioners, advocates, funders, and evaluators--met for 2 days in Pittsburgh, Pennsylvania, to discuss the challenges that arise in evaluating systems change or systems-building initiatives and to suggest approaches to resolving those challenges. The symposium was convened by the partners of BUILD, a…

  7. Integrated Proteomic and Metabolic Analysis of Breast Cancer Progression

    PubMed Central

    Shaw, Patrick G.; Chaerkady, Raghothama; Wang, Tao; Vasilatos, Shauna; Huang, Yi; Van Houten, Bennett; Pandey, Akhilesh; Davidson, Nancy E.

    2013-01-01

    One of the most persistent hallmarks of cancer biology is the preference of tumor cells to derive energy through glycolysis as opposed to the more efficient process of oxidative phosphorylation (OXPHOS). However, little is known about the molecular cascades by which oncogenic pathways bring about this metabolic switch. We carried out a quantitative proteomic and metabolic analysis of the MCF10A derived cell line model of breast cancer progression that includes parental cells and derivatives representing three different tumor grades of Ras-driven cancer with a common genetic background. A SILAC (Stable Isotope Labeling by Amino acids in Cell culture) labeling strategy was used to quantify protein expression in conjunction with subcellular fractionation to measure dynamic subcellular localization in the nucleus, cytosol and mitochondria. Protein expression and localization across cell lines were compared to cellular metabolic rates as a measure of oxidative phosphorylation (OXPHOS), glycolysis and cellular ATP. Investigation of the metabolic capacity of the four cell lines revealed that cellular OXPHOS decreased with breast cancer progression independently of mitochondrial copy number or electron transport chain protein expression. Furthermore, glycolytic lactate secretion did not increase in accordance with cancer progression and decreasing OXPHOS capacity. However, the relative expression and subcellular enrichment of enzymes critical to lactate and pyruvate metabolism supported the observed extracellular acidification profiles. This analysis of metabolic dysfunction in cancer progression integrated with global protein expression and subcellular localization is a novel and useful technique for determining organelle-specific roles of proteins in disease. PMID:24086712

  8. Incidence of brain metastasis at initial presentation of lung cancer

    PubMed Central

    Villano, J. Lee; Durbin, Eric B.; Normandeau, Chris; Thakkar, Jigisha P.; Moirangthem, Valentina; Davis, Faith G.

    2015-01-01

    Background No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease. Methods We report the first population-based analysis on BM incidence at cancer diagnosis using the Kentucky Cancer Registry (KCR) and Alberta Cancer Registry (ACR). All cancer cases with BM were identified from KCR and ACR, with subsequent focus on metastases from lung primaries; the annual number of BMs at initial presentation was derived. Comparisons were made between Kentucky and Alberta for the stage and site of organ involvement of lung cancer. Results Low incidence of BM was observed in the United States until mandatory reporting began in 2010. Both the KCR and ACR recorded the highest incidence of BM from lung cancer, with total BM cases at initial presentation occurring at 88% and 77%, respectively. For lung cancer, stage IV was the most common stage at presentation for both registries and ranged from 45.9% to 57.2%. When BM from lung was identified, the most common synchronous organ site of metastasis was osseous, occurring at 28.4%. Conclusion Our analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available. PMID:24891450

  9. Progressing From Initially Ambiguous Functional Analyses: Three Case Examples

    PubMed Central

    Tiger, Jeffrey H.; Fisher, Wayne W.; Toussaint, Karen A.; Kodak, Tiffany

    2009-01-01

    Most often functional analyses are initiated using a standard set of test conditions, similar to those described by Iwata, Dorsey, Slifer, Bauman, and Richman (1982/1994). These test conditions involve the careful manipulation of motivating operations, discriminative stimuli, and reinforcement contingencies to determine the events related to the occurrence and maintenance of problem behavior. Some individuals display problem behavior that is occasioned and reinforced by idiosyncratic or otherwise unique combinations of environmental antecedents and consequences of behavior, which are unlikely to be detected using these standard assessment conditions. For these individuals, modifications to the standard test conditions or the inclusion of novel test conditions may result in clearer assessment outcomes. The current study provides three case examples of individuals whose functional analyses were initially undifferentiated; however, modifications to the standard conditions resulted in the identification of behavioral functions and the implementation of effective function-based treatments. PMID:19233611

  10. Proteomic analysis of mitochondria: biological and clinical progresses in cancer.

    PubMed

    Wang, Yang; Zhang, Jing; Li, Bin; He, Qing-Yu

    2017-10-01

    Mitochondria play important roles in regulating multiple biological processes and signalling pathways in eukaryotic cells, and mitochondrial dysfunction may result in a wide range of serious diseases, including cancer. With improvements in the identification of mitochondrial proteins, mitochondrial proteomics has made great achievements. In particular, this approach has been widely used to compare tumour cells at different stages of malignancy. Therefore, there is an urgent need to identify and characterize the function of mitochondrial proteins in cancer progression and to determine the involved mechanisms. Areas covered: We provide an overview of recent progress related to mitochondrial proteomics in cancer and the application of comparative mitochondrial proteomics in various biological processes, including apoptosis, necroptosis, autophagy and metastasis, as well as clinical progress in cancer. Proteomics-related reports were found using PubMed and Google Scholar databases. Expert commentary: Understanding both post-translational modification and post-translational processing is important in the comprehensive characterization of protein function. The application of comparative mitochondrial proteomics to investigate clinical samples and cancer cells will contribute to our understanding of the molecular interplay of mitochondrial proteins in the development of cancer. This approach will mine more biomarkers for diagnosis and prognosis and improve therapeutic outcomes among cancer patients.

  11. Neutrophil extracellular traps in cancer progression.

    PubMed

    Cools-Lartigue, Jonathan; Spicer, Jonathan; Najmeh, Sara; Ferri, Lorenzo

    2014-11-01

    Neutrophils are being increasingly recognized as an important element in tumor progression. They have been shown to exert important effects at nearly every stage of tumor progression with a number of studies demonstrating that their presence is critical to tumor development. Novel aspects of neutrophil biology have recently been elucidated and its contribution to tumorigenesis is only beginning to be appreciated. Neutrophil extracellular traps (NETs) are neutrophil-derived structures composed of DNA decorated with antimicrobial peptides. They have been shown to trap and kill microorganisms, playing a critical role in host defense. However, their contribution to tumor development and metastasis has recently been demonstrated in a number of studies highlighting NETs as a potentially important therapeutic target. Here, studies implicating NETs as facilitators of tumor progression and metastasis are reviewed. In addition, potential mechanisms by which NETs may exert these effects are explored. Finally, the ability to target NETs therapeutically in human neoplastic disease is highlighted.

  12. Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

    PubMed

    Patel, Jyoti D; Krilov, Lada; Adams, Sylvia; Aghajanian, Carol; Basch, Ethan; Brose, Marcia S; Carroll, William L; de Lima, Marcos; Gilbert, Mark R; Kris, Mark G; Marshall, John L; Masters, Gregory A; O'Day, Steven J; Polite, Blasé; Schwartz, Gary K; Sharma, Sunil; Thompson, Ian; Vogelzang, Nicholas J; Roth, Bruce J

    2014-01-10

    extremely challenging economic environment, we continue to make progress. Maintaining and accelerating that progress require that we keep our eyes on the future and pursue a path that builds on the stunning successes of the past. We must continue to show our policymakers the successes in cancer survival and quality of life (QOL) they have enabled, emphasizing the need to sustain our national investment in the remarkably productive US cancer research enterprise. We must also look to innovative methods for transforming how we care for-and learn from-patients with cancer. Consider, for example, that fewer than 5% of adult patients with cancer currently participate in clinical trials. What if we were able to draw lessons from the other 95%? This possibility led ASCO this year to launch CancerLinQ, a groundbreaking health information technology initiative that will provide physicians with access to vast quantities of clinical data about real-world patients and help achieve higher quality, higher value cancer care. As you read the following pages, I hope our collective progress against cancer over the past year inspires you. More importantly, I hope the pride you feel motivates you to help us accelerate the pace of scientific advancement. Clifford A. Hudis, MD, FACP President American Society of Clinical Oncology.

  13. Cerium chloride reduces enamel lesion initiation and progression in vitro.

    PubMed

    Wegehaupt, F J; Buchalla, W; Sener, B; Attin, T; Schmidlin, P R

    2014-01-01

    Determination of the potential of cerium chloride to reduce artificial carious mineral loss and lesion depth progression. A total of 160 enamel samples were prepared from 40 bovine lower central incisors. Crowns were sectioned into four pieces, embedded in acrylic resin, ground flat and allocated to eight groups (S1-S4 and D1-D4; n = 20). Specimens of groups D1-D4 were stored (for 7 days) in a demineralizing buffer solution to induce caries-like lesions. Afterwards, samples were treated for 30 s with one of the following solutions: placebo (S1 and D1), amine fluoride (S2 and D2), cerium chloride (S3 and D3) and a combination of fluoride and cerium chloride (S4 and D4). After another 7 (D1-D4) or 14 (S1-S4) days in demineralizing buffer solution, integrated mineral loss and lesion depth were determined by transversal microradiography and compared by Scheffé's post hoc tests. In groups S1-S4, the highest values for integrated mineral loss and lesion depth were observed for group S1 (placebo), the lowest values for group S4. The results in groups S2-S4 were not significantly different. In groups D1-D4, the highest values for integrated mineral loss and lesion depth were observed for group D1 (placebo), the lowest values in groups D3 and D4. In group D2, integrated mineral loss and lesion depth were significantly lower as compared to D1, but significantly higher compared to groups D3 and D4. Cerium chloride and its combination with fluoride are able to significantly reduce carious mineral loss and the progression of lesion depth.

  14. Beyond the cancer cell: progression-level determinants highlight the multiscale nature of carcinogenesis risk.

    PubMed

    Hlatky, Lynn; Hahnfeldt, Philip

    2014-02-01

    Over the last several decades, improved awareness of the prevalence of carcinogens in the environment, along with a growing appreciation of the complexity of the carcinogenesis process, has shifted policy on cancer risk from one of strict avoidance of carcinogens to one of adherence to exposure limits deemed "safe" based on quantitative risk estimation. Meanwhile, given the mutagenic nature of most carcinogens, attention has gravitated to developing a genetic rationale for measuring and comparing risks. This focus has culminated in the now well-established multistage mutational paradigm, which holds that a stepwise sequence of mutations drives cell "initiation" and the subsequent "transformation" of an initiated cell into a cancer cell, and that, once created, a cancer cell will inevitably undergo "progression" to become overt disease. Unanticipated by this paradigm is the effect progression-phase population- and tissue-level bottleneck events may have on this process. Attesting to this is the prevalence of tumor dormancy, a state of arrested growth of an otherwise fully malignant, often microscopic cancer mass, maintained by interactions among cancer cells and between cancer and host cells. The proper inclusion of such progression-modifying influences would clearly behoove risk estimation and improve our understanding of the natural history of cancer by accounting for the less-than-certain risk of eventual cancer disease even when cancer cells are present. Such an improved understanding, in turn, stands to better inform policy-making and influence such clinical practice decisions as whether to treat the increasingly smaller tumors detectable with advancing technologies.

  15. Cancer stem cells as the engine of unstable tumor progression.

    PubMed

    Solé, Ricard V; Rodríguez-Caso, Carlos; Deisboeck, Thomas S; Saldaña, Joan

    2008-08-21

    Genomic instability is considered by many authors the key engine of tumorigenesis. However, mounting evidence indicates that a small population of drug resistant cancer cells can also be a key component of tumor progression. Such cancer stem cells would define a compartment effectively acting as the source of most tumor cells. Here we study the interplay between these two conflicting components of cancer dynamics using two types of tissue architecture. Both mean field and multicompartment models are studied. It is shown that tissue architecture affects the pattern of cancer dynamics and that unstable cancers spontaneously organize into a heterogeneous population of highly unstable cells. This dominant population is in fact separated from the low-mutation compartment by an instability gap, where almost no cancer cells are observed. The possible implications of this prediction are discussed.

  16. The role of gelatinases in colorectal cancer progression and metastasis.

    PubMed

    Mook, Olaf R F; Frederiks, Wilma M; Van Noorden, Cornelis J F

    2004-12-17

    Various proteases are involved in cancer progression and metastasis. In particular, gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, have been implicated to play a role in colon cancer progression and metastasis in animal models and patients. In the present review, the clinical relevance and the prognostic value of messenger ribonucleic acid (mRNA) and protein expression and proenzyme activation of MMP-2 and MMP-9 are evaluated in relation to colorectal cancer. Expression of tissue inhibitors of MMPs (TIMPs) in relation with MMP expression in cancer tissues and the relevance of detection of plasma or serum levels of MMP-2 and/or MMP-9 and TIMPs for prognosis are also discussed. Furthermore, involvement of MMP-2 and MMP-9 in experimental models of colorectal cancer is reviewed. In vitro studies have suggested that gelatinase is expressed in cancer cells but animal models indicated that gelatinase expression in non-cancer cells in tumors contributes to cancer progression. In fact, interactions between cancer cells and host tissues have been shown to modulate gelatinase expression in host cells. Inhibition of gelatinases by synthetic MMP inhibitors has been considered to be an attractive approach to block cancer progression. However, despite promising results in animal models, clinical trials with MMP inhibitors have been disappointing so far. To obtain more insight in the (patho)physiological functions of gelatinases, regulation of MMP-2 and MMP-9 expression is discussed. Mitogen activated protein kinase (MAPK) signalling has been shown to be involved in regulation of gelatinase expression in both cancer cells and non-cancer cells. Expression can be triggered by a variety of stimuli including growth factors, cytokines and extracellular matrix (ECM) components. On the other hand, MMP-2 and MMP-9 activity regulates bioavailability and activity of growth factors and cytokines, affects the immune response and is involved in angiogenesis. Because of the

  17. Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression.

    PubMed

    Maity, Biswanath; Stewart, Adele; O'Malley, Yunxia; Askeland, Ryan W; Sugg, Sonia L; Fisher, Rory A

    2013-08-01

    Breast cancer is a large global health burden and the most frequently diagnosed malignancy in women worldwide. Here, we utilize RGS6(-/-) mice to interrogate the role of regulator of G protein signaling 6 (RGS6), localized to the ductal epithelium in mouse and human breast, as a novel tumor suppressor in vivo. RGS6(-/-) mice exhibit accelerated 7,12-dimethylbenza[α]anthracene (DMBA)-induced tumor initiation and progression, as well as decreased overall survival. Analysis of carcinogenic aberrations in the mammary glands of DMBA-treated mice revealed a failure of the DNA damage response concurrent with augmented oncogenesis in RGS6(-/-) animals. Furthermore, RGS6 suppressed cell growth induced by either human epidermal growth factor receptor 2 or estrogen receptor activation in both MCF-7 breast cancer cells and mammary epithelial cells (MECs). MECs isolated from RGS6(-/-) mice also showed a deficit in DMBA-induced ATM/p53 activation, reactive oxygen species generation and apoptosis confirming that RGS6 is required for effective activation of the DNA damage response in these cells, a critical countermeasure against carcinogen-mediated genotoxic stress. The ability of RGS6 to simultaneously enhance DNA-damage-induced apoptotic signaling and suppress oncogenic cell growth likely underlie the accelerated tumorigenesis and cellular transformation observed in DMBA-treated RGS6(-/-) mice and isolated MECs, respectively. Unsurprisingly, spontaneous tumor formation was also seen in old female RGS6(-/-) but not in wild-type mice. Our finding that RGS6 is downregulated in all human breast cancer subtypes independent of their molecular classification indicates that obtaining a means to restore the growth suppressive and pro-apoptotic actions of RGS6 in breast might be a viable means to treat a large spectrum of breast tumors.

  18. Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression

    PubMed Central

    Fisher, Rory A.

    2013-01-01

    Breast cancer is a large global health burden and the most frequently diagnosed malignancy in women worldwide. Here, we utilize RGS6− /− mice to interrogate the role of regulator of G protein signaling 6 (RGS6), localized to the ductal epithelium in mouse and human breast, as a novel tumor suppressor in vivo. RGS6− /− mice exhibit accelerated 7,12-dimethylbenza[α]anthracene (DMBA)-induced tumor initiation and progression, as well as decreased overall survival. Analysis of carcinogenic aberrations in the mammary glands of DMBA-treated mice revealed a failure of the DNA damage response concurrent with augmented oncogenesis in RGS6−/− animals. Furthermore, RGS6 suppressed cell growth induced by either human epidermal growth factor receptor 2 or estrogen receptor activation in both MCF-7 breast cancer cells and mammary epithelial cells (MECs). MECs isolated from RGS6−/− mice also showed a deficit in DMBA-induced ATM/p53 activation, reactive oxygen species generation and apoptosis confirming that RGS6 is required for effective activation of the DNA damage response in these cells, a critical countermeasure against carcinogen-mediated genotoxic stress. The ability of RGS6 to simultaneously enhance DNA-damage-induced apoptotic signaling and suppress oncogenic cell growth likely underlie the accelerated tumorigenesis and cellular transformation observed in DMBA-treated RGS6−/− mice and isolated MECs, respectively. Unsurprisingly, spontaneous tumor formation was also seen in old female RGS6−/− but not in wild-type mice. Our finding that RGS6 is downregulated in all human breast cancer subtypes independent of their molecular classification indicates that obtaining a means to restore the growth suppressive and pro-apoptotic actions of RGS6 in breast might be a viable means to treat a large spectrum of breast tumors. PMID:23598467

  19. Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2.

    PubMed

    Mulligan, L M; Gardner, E; Smith, B A; Mathew, C G; Ponder, B A

    1993-03-01

    Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11 (11pter-p13), 17 (17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours.

  20. AR Alternative Splicing and Prostate Cancer Progression

    DTIC Science & Technology

    2012-07-01

    Johnson Jr RT, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low... penicillin , and 100g/ml streptomy- cin in a 5% CO2 incubator at 37 °C. The 293T and Cos-7 cell lines were cultured in DMEM with 10% FBS. For androgen

  1. Progress on Simulating the Initiation of Vacuum Insulator Flashover

    SciTech Connect

    Perkins, M P; Houck, T L; Javedani, J B; Vogtlin, G E; Goerz, D A

    2009-06-26

    Vacuum insulators are critical components in many pulsed power systems. The insulators separate the vacuum and non-vacuum regions, often under great stress due to high electric fields. The insulators will often flashover at the dielectric vacuum interface for electric field values much lower than for the bulk breakdown through the material. Better predictive models and computational tools are needed to enable insulator designs in a timely and inexpensive manner for advanced pulsed power systems. In this article we will discuss physics models that have been implemented in a PIC code to better understand the initiation of flashover. The PIC code VORPAL has been ran on the Linux cluster Hera at LLNL. Some of the important physics modules that have been implemented to this point will be discussed for simple angled insulators. These physics modules include field distortion due to the dielectric, field emission, secondary electron emission, insulator charging, and the effects of magnitude fields. In the future we will incorporate physics modules to investigate the effects of photoemission, electron stimulated desorption, and gas ionization. This work will lead to an improved understanding of flashover initiation and better computational tools for advanced insulator design.

  2. Progressing from initially ambiguous functional analyses: three case examples.

    PubMed

    Tiger, Jeffrey H; Fisher, Wayne W; Toussaint, Karen A; Kodak, Tiffany

    2009-01-01

    Most often functional analyses are initiated using a standard set of test conditions, similar to those described by Iwata, Dorsey, Slifer, Bauman, and Richman [Iwata, B. A., Dorsey, M. F., Slifer, K. J., Bauman, K. E., & Richman, G. S. (1994). Toward a functional analysis of self-injury. Journal of Applied Behavior Analysis, 27, 197-209 (Reprinted from Analysis and Intervention in Developmental Disabilities, 2, 3-20, 1982)]. These test conditions involve the careful manipulation of motivating operations, discriminative stimuli, and reinforcement contingencies to determine the events related to the occurrence and maintenance of problem behavior. Some individuals display problem behavior that is occasioned and reinforced by idiosyncratic or otherwise unique combinations of environmental antecedents and consequences of behavior, which are unlikely to be detected using these standard assessment conditions. For these individuals, modifications to the standard test conditions or the inclusion of novel test conditions may result in clearer assessment outcomes. The current study provides three case examples of individuals whose functional analyses were initially undifferentiated; however, modifications to the standard conditions resulted in the identification of behavioral functions and the implementation of effective function-based treatments.

  3. Chemokines: key players in cancer progression and metastasis

    PubMed Central

    Singh, Rajesh; Lilladr, James W.; Singh, Shailesh

    2013-01-01

    Instructed cell migration is a fundamental component of various biological systems and is critical to the pathogenesis of many diseases including cancer. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. However, functional mechanisms of chemokine are not well implicit, which is crucial for designing new therapeutics to control tumor growth and metastasis. Multiple functions and mode of actions have been advocated for chemokines and their receptors in the progression of primary and secondary tumors. In this review, we have discussed current advances in understanding the role of the chemokines and their corresponding receptor in tumor progression and metastasis. PMID:21622291

  4. SUMOylation-mediated regulation of cell cycle progression and cancer

    PubMed Central

    Eifler, Karolin; Vertegaal, Alfred C.O.

    2016-01-01

    SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. PMID:26601932

  5. Involvement of mesenchymal stem cells in cancer progression and metastases.

    PubMed

    Chang, Astra I; Schwertschkow, Aaron H; Nolta, Jan A; Wu, Jian

    2015-01-01

    Mesenchymal stem/stromal cells (MSCs) are known to be the helpers for the healing of tissue damage, often referred to as ambulatory cells. However, MSCs are also recruited by cancer cells to similarly aid in tumor growth and progression. In this review, some of the key steps in cancer progression and metastases are described including the various steps in which MSCs participate and may play important roles. MSCs aid in cancer cells' ability to evade immune attack, while promoting tumor angiogenesis, even being counter-acting against chemotherapeutics and other drugs used to fight various cancers. Furthermore, MSCs participate in many of the crucial steps in invasion and metastasis, including stimulating the epithelial-mesenchymal transition (EMT) and induction of stem-like properties that allow cancer stem cells to increase their survivability through the circulation. These steps are described in detail. Differences between circulating tumor cells (CTCs) and cancer stem cells (CSCs) are discussed, along with descriptions of the formation of a pre-metastatic niche, the role of exosomes from both cancer cells and MSCs in metastasis and tumor reseeding (self-seeding). More and more, MSCs are being proposed as a promising tumor targeting drug-delivery tool. In order to fulfill this promise, further understanding of the precise roles that MSCs play in the process of cancer metastases must be achieved, in attempting to create remedies that will improve the outcome of available therapeutics.

  6. Transcriptional network of androgen receptor in prostate cancer progression.

    PubMed

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  7. Natural flavonoids targeting deregulated cell cycle progression in cancer cells.

    PubMed

    Singh, Rana Pratap; Agarwal, Rajesh

    2006-03-01

    The prolonged duration requiring alteration of multi-genetic and epigenetic molecular events for cancer development provides a strong rationale for cancer prevention, which is developing as a potential strategy to arrest or reverse carcinogenic changes before the appearance of the malignant disease. Cell cycle progression is an important biological event having controlled regulation in normal cells, which almost universally becomes aberrant or deregulated in transformed and neoplastic cells. In this regard, targeting deregulated cell cycle progression and its modulation by various natural and synthetic agents are gaining widespread attention in recent years to control the unchecked growth and proliferation in cancer cells. In fact, a vast number of experimental studies convincingly show that many phytochemicals halt uncontrolled cell cycle progression in cancer cells. Among these phytochemicals, natural flavonoids have been identified as a one of the major classes of natural anticancer agents exerting antineoplastic activity via cell cycle arrest as a major mechanism in various types of cancer cells. This review is focused at the modulatory effects of natural flavonoids on cell cycle regulators including cyclin-dependent kinases and their inhibitors, cyclins, p53, retinoblastoma family of proteins, E2Fs, check-point kinases, ATM/ATR and survivin controlling G1/S and G2/M check-point transitions in cell cycle progression, and discusses how these molecular changes could contribute to the antineoplastic effects of natural flavonoids.

  8. Rectal prolapse as initial clinical manifestation of colon cancer.

    PubMed

    Chen, C-W; Hsiao, C-W; Wu, C-C; Jao, S-W

    2008-04-01

    Rectal prolapse as the initial clinical manifestation of colorectal cancer is uncommon. We describe the case of a 75-year-old woman who was diagnosed as having adenocarcinoma of the sigmoid colon after presenting with complete rectal prolapse. The tumor caused rectosigmoid intussusception and then it prolapsed out through the anus. She underwent rectosigmoidectomy and rectopexy. The postoperative course was uneventful. The relationship between colorectal cancer and rectal prolapse has not been clearly established. This case report describes an unusual presentation of colorectal cancer. It suggests that rectal prolapse can present as the initial symptom of colorectal cancer and may also be a presenting feature of the occult intra-abdominal pathology. The importance of adequate investigation such as colonoscopy should be emphasized in patients who develop a new onset of rectal prolapse.

  9. PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis.

    PubMed

    Su, Z Z; Goldstein, N I; Jiang, H; Wang, M N; Duigou, G J; Young, C S; Fisher, P B

    1999-12-21

    Cancer is a progressive disease culminating in acquisition of metastatic potential by a subset of evolving tumor cells. Generation of an adequate blood supply in tumors by production of new blood vessels, angiogenesis, is a defining element in this process. Although extensively investigated, the precise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a genetic element, progression elevated gene-3 (PEG-3), whose expression directly correlates with cancer progression and acquisition of oncogenic potential by transformed rodent cells. We presently demonstrate that forced expression of PEG-3 in tumorigenic rodent cells, and in human cancer cells, increases their oncogenic potential in nude mice as reflected by a shorter tumor latency time and the production of larger tumors with increased vascularization. Moreover, inhibiting endogenous PEG-3 expression in progressed rodent cancer cells by stable expression of an antisense expression vector extinguishes the progressed cancer phenotype. Cancer aggressiveness of PEG-3 expressing rodent cells correlates directly with increased RNA transcription, elevated mRNA levels, and augmented secretion of vascular endothelial growth factor (VEGF). Furthermore, transient ectopic expression of PEG-3 transcriptionally activates VEGF in transformed rodent and human cancer cells. Taken together these data demonstrate that PEG-3 is a positive regulator of cancer aggressiveness, a process regulated by augmented VEGF production. These studies also support an association between expression of a single nontransforming cancer progression-inducing gene, PEG-3, and the processes of cancer aggressiveness and angiogenesis. In these contexts, PEG-3 may represent an important target molecule for developing cancer therapeutics and inhibitors of angiogenesis.

  10. HGF-MET in cancer progression and biomarker discovery.

    PubMed

    Matsumoto, Kunio; Umitsu, Masataka; De Silva, Dinuka M; Roy, Arpita; Bottaro, Donald P

    2017-01-08

    Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases respectively for invasion-metastasis and resistance against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in autocrine/paracrine manner are causes for resistance to EGF receptor tyrosine kinase inhibitors and ALK inhibitors. HGF secreted in the tumor microenvironment contributes to the innate and acquired resistance to RAF inhibitors. Changes in serum/plasma HGF, soluble MET, and phosphor-MET have been confirmed to be associated with disease progression, metastasis, therapy response, and survival. Higher serum/plasma HGF levels are associated with therapy resistance and/or metastasis, while lower HGF levels are associated with progression-free survival and overall survival after treatment with targeted drugs in lung cancer, gastric cancer, colon cancer, and malignant melanoma. Urinary soluble MET levels in patients with bladder cancer are higher than those in patients without bladder cancer and associated with disease progression. Some of the multi-kinase inhibitors that target MET have received regulatory approval, whereas none of the selective HGF-MET inhibitors have shown efficacy in phase III clinical trials. Validation of the HGF-MET pathway as a critical driver in cancer development/progression and utilization of appropriate biomarkers are key to development and approval of HGF-MET inhibitors for clinical use. This article is protected by copyright. All rights reserved.

  11. A Critical Review on the Effect of Docosahexaenoic Acid (DHA) on Cancer Cell Cycle Progression.

    PubMed

    Newell, Marnie; Baker, Kristi; Postovit, Lynne M; Field, Catherine J

    2017-08-17

    Globally, there were 14.1 million new cancer diagnoses and 8.2 million cancer deaths in 2012. For many cancers, conventional therapies are limited in their successes and an improved understanding of disease progression is needed in conjunction with exploration of alternative therapies. The long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA), has been shown to enhance many cellular responses that reduce cancer cell viability and decrease proliferation both in vitro and in vivo. A small number of studies suggest that DHA improves chemotherapy outcomes in cancer patients. It is readily incorporated into cancer cell membranes and, as a result there has been considerable research regarding cell membrane initiated events. For example, DHA has been shown to mediate the induction of apoptosis/reduction of proliferation in vitro and in vivo. However, there is limited research into the effect of DHA on cell cycle regulation in cancer cells and the mechanism(s) by which DHA acts are not fully understood. The purpose of the current review is to provide a critical examination of the literature investigating the ability of DHA to stall progression during different cell cycle phases in cancer cells, as well as the consequences that these changes may have on tumour growth, independently and in conjunction with chemotherapy.

  12. Stanniocalcin-2 (STC2): A potential lung cancer biomarker promotes lung cancer metastasis and progression.

    PubMed

    Na, Sang-su; Aldonza, Mark Borris; Sung, Hye-Jin; Kim, Yong-In; Son, Yeon Sung; Cho, Sukki; Cho, Je-Yoel

    2015-06-01

    The homodimeric glycoprotein, stanniocalcin 2 (STC2) is previously known to be involved in the regulation of calcium and phosphate transport in the kidney and also reported to play multiple roles in several cancers. However, its function and clinical significance in lung cancer have never been reported and still remain uncertain. Here, we investigated the possibility of STC2 as a lung cancer biomarker and identified its potential role in lung cancer cell growth, metastasis and progression. Proteomic analysis of secretome of primary cultured lung cancer cells revealed higher expression of STC2 in cancers compared to that of adjacent normal cells. RT-PCR and Western blot analyses showed higher mRNA and protein expressions of STC2 in lung cancer tissues compared to the adjacent normal tissues. Knockdown of STC2 in H460 lung cancer cells slowed down cell growth progression and colony formation. Further analysis revealed suppression of migration, invasion and delayed G0/G1 cell cycle progression in the STC2 knockdown cells. STC2 knockdown also attenuated the H202-induced oxidative stress on H460 cell viability with a subsequent increase in intracellular ROS levels, which suggest a protective role of STC2 in redox regulatory system of lung cancer. These findings suggest that STC2 can be a potential lung cancer biomarker and plays a positive role in lung cancer metastasis and progression. This article is part of a Special Issue entitled: Medical Proteomics. Copyright © 2015. Published by Elsevier B.V.

  13. Recent Progress on Nutraceutical Research in Prostate Cancer

    PubMed Central

    Li, Yiwei; Ahmad, Aamir; Kong, Dejuan; Bao, Bin; Sarkar, Fazlul H.

    2014-01-01

    Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy. Prostate Cancer (PCa) is most frequently diagnosed cancer and second leading cause of cancer-related death in men in US. Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa. Several nutraceuticals including isoflavone, indole-3-carbinol, 3,3’-diindolylmethane, lycopene, (-)-epigallocatechin-3-gallate, and curcumin are known to down-regulate the signal transductions in AR, Akt, NF-κB, and other signal transduction pathways which are vital for the development of PCa and the progression of PCa from androgen-sensitive to castrate-resistant PCa. Therefore, nutraceutical treatment in combination with conventional therapeutics could achieve better treatment outcome in prostate cancer therapy. Interestingly, some nutraceuticals could regulate the function of cancer stem cell (CSC) related miRNAs and associated molecules, leading to the inhibition of prostatic CSCs which are responsible for drug-resistance, tumor progression, and recurrence of PCa. Hence, nutraceuticals may serve as powerful agents for the prevention of PCa progression and they could also be useful in combination with chemotherapeutics or radiotherapy. Such strategy could become a promising newer approach for the treatment of metastatic PCa with better treatment outcome by improving overall survival. PMID:24375392

  14. Targeting Tumor Initiating Cells through Inhibition of Cancer Testis Antigens and Notch Signaling: A Hypothesis.

    PubMed

    Colombo, Michela; Mirandola, Leonardo; Reidy, Adair; Suvorava, Natallia; Konala, Venu; Chiaramonte, Raffaella; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Nugyen, Diane D; Dalhbeck, Scott; Cobos, Everardo; Figueroa, Jose A; Chiriva-Internati, Maurizio

    2015-03-01

    Tumor initiating cells (TICs) differ from normal stem cells (SCs) in their ability to initiate tumorigenesis, invasive growth, metastasis and the acquisition of chemo and/or radio-resistance. Over the past years, several studies have indicated the potential role of the Notch system as a key regulator of cellular stemness and tumor development. Furthermore, the expression of cancer testis antigens (CTA) in TICs, and their role in SC differentiation and biology, has become an important area of investigation. Here, we propose a model in which CTA expression and Notch signaling interacts to maintain the sustainability of self-replicating tumor populations, ultimately leading to the development of metastasis, drug resistance and cancer progression. We hypothesize that Notch-CTA interactions in TICs offer a novel opportunity for meaningful therapeutic interventions in cancer.

  15. Milk and the risk and progression of cancer.

    PubMed

    Rock, Cheryl L

    2011-01-01

    Observational evidence suggests that nutritional factors contribute to a substantial proportion of cancer cases, and milk contains numerous bioactive substances that could affect risk and progression of cancer. Cancer results from multiple genetic and epigenetic events over time, so demonstrating a specific effect of nutrients or other bioactive food components in human cancer is challenging. Epidemiological evidence consistently suggests that milk intake is protective against colorectal cancer. Calcium supplements have been shown to reduce risk for recurrence of adenomatous polyps. Calcium supplementation has not been observed to reduce risk for colon cancer, although long latency and baseline calcium intake affect interpretation of these results. High calcium intake from both food and supplements is associated with increased risk for advanced or fatal prostate cancer. Results from epidemiological studies examining the relationship between intake of dairy foods and breast or ovarian cancer risk are not consistent. Animal studies have suggested that galactose may be toxic to ovarian cells, but results from epidemiological studies that have examined ovarian cancer risk and milk and/or lactose intakes are mixed. Dietary guidelines for cancer prevention encourage meeting recommended levels of calcium intake primarily through food choices rather than supplements, and choosing low-fat or nonfat dairy foods. Copyright © 2011 S. Karger AG, Basel.

  16. Recent progress in nanotechnology for cancer therapy.

    PubMed

    Tang, Mu-Fei; Lei, Lei; Guo, Sheng-Rong; Huang, Wen-Lin

    2010-09-01

    The application of nanotechnology significantly benefits clinical practice in cancer diagnosis, treatment, and management. Especially, nanotechnology offers a promise for the targeted delivery of drugs, genes, and proteins to tumor tissues and therefore alleviating the toxicity of anticancer agents in healthy tissues. This article reviews current nanotechnology platforms for anticancer drug delivery, including polymeric nanoparticles, liposomes, dendrimers, nanoshells, carbon nanotubes, superparamagnetic nanoparticles, and nucleic acid-based nanoparticles [DNA, RNA interference (RNAi), and antisense oligonucleotide (ASO)] as well as nanotechnologies for combination therapeutic strategies, for example, nanotechnologies combined with multidrug-resistance modulator, ultrasound, hyperthermia, or photodynamic therapy. This review raises awareness of the advantages and challenges for the application of these therapeutic nanotechnologies, in light of some recent advances in nanotechnologic drug delivery and cancer therapy.

  17. Clinical Cancer Advances 2017: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

    PubMed

    Burstein, Harold J; Krilov, Lada; Aragon-Ching, Jeanny B; Baxter, Nancy N; Chiorean, E Gabriela; Chow, Warren Allen; De Groot, John Frederick; Devine, Steven Michael; DuBois, Steven G; El-Deiry, Wafik S; Epstein, Andrew S; Heymach, John; Jones, Joshua Adam; Mayer, Deborah K; Miksad, Rebecca A; Pennell, Nathan A; Sabel, Michael S; Schilsky, Richard L; Schuchter, Lynn Mara; Tung, Nadine; Winkfield, Karen Marie; Wirth, Lori J; Dizon, Don S

    2017-02-01

    . Importantly, the advances described in this report would not have been possible without the individuals who volunteered to participate in clinical trials as part of their treatment. To turn the promising vision of a cancer moonshot into meaningful advances, we need sustained, robust federal funding for continued research and innovation. Approximately 30% of the research highlighted in this report was funded, at least in part, through federal dollars appropriated to the National Institutes of Health or the National Cancer Institute. Without this federal investment-unique internationally in scale, duration, and impact for decades-I fear we may lose the forward momentum needed to further the progress we see highlighted in this report. Federal lawmakers can further fuel progress by advancing initiatives that facilitate the use of big data to achieve the common good of high-quality care for all patients. Such programs, like ASCO's CancerLinQ, will rapidly increase the pace of progress and dramatically expand the reach of treatment advances to the millions of patients who are living with cancer today or who will do so in the future. This investment will yield medical, scientific, economic, and societal benefits for years to come. Much work still lies ahead. Many questions remain about how cancer develops and spreads and how best to treat it. As you read through Clinical Cancer Advances 2017, I hope you are as inspired as I am by the gains the clinical cancer research community has made over the past year and by the promise of a new era of advances just over the horizon. Daniel F Hayes, MD, FASCO, FACP ASCO President, 2016 to 2017.

  18. ING4 Loss in Prostate Cancer Progression

    DTIC Science & Technology

    2016-10-01

    TMA, mouse model , human model . 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...differentiation, Myc, ING4, chromatin, integrins, Erg, Pten, Miz1, CREB, Notch, p38, prostate cancer oncogenesis, TMA, mouse model , human model 3...of hits in model Months 28-34* Milestone #2: Prepare manuscript for publication Months 35-36 Specific Aim 2: Determine how loss of ING4 impacts

  19. Pancreatic Cancer: Progress in Systemic Therapy.

    PubMed

    Perkhofer, Luka; Ettrich, Thomas J; Seufferlein, Thoma

    2014-05-01

    Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the Western world. Due to lack of specific symptoms and no accessible precursor lesions, primary diagnosis is commonly delayed, resulting in the identification of only 15-20% of patients with potentially curable disease. The major limiting factor is an already locally advanced or metastatic disease at the time of diagnosis. Consequently, systemic therapy forms the backbone of treatment strategy for the majority of patients. A deeper understanding of the molecular characteristics of pancreatic cancer has led to the identification of several potential therapeutic targets. A variety of targeted therapies are currently under clinical evaluation as single agents or in combination with chemotherapy for PDAC. This review highlights the current state of chemotherapy in pancreatic cancer and provides an outlook on its future perspectives. This review focuses on the current chemotherapy regimens for the systemic treatment of PDAC. Various neoadjuvant approaches have been explored, including chemoradiation, chemotherapy followed by chemoradiation or intensified chemotherapy without defining a standard of care so far. The standard of care is gemcitabine or 5-fluorouracil. The oral fluoropyrimidine S-1 may be a promising new agent in this setting. For first-line treatment of metastatic pancreatic cancer, no targeted therapy has yet demonstrated clinical benefit apart from the combination of the tyrosine kinase inhibitor erlotinib plus gemcitabine. Recently, novel chemotherapeutic regimens such as FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound paclitaxel have been introduced. Both combinations have proved to be superior to the standard gemcitabine regimen. For second-line treatment the combination of 5-fluorouracil/leucovorin and oxaliplatin yields improved results compared to best supportive care.

  20. SPANXB2 and Prostate Cancer Progression

    DTIC Science & Technology

    2013-10-01

    that SPANX-B2 may be the key regulator of prostate cancer aggressive cell behavior and metastasis. In this report, for the first time, we illustrate...that regulatory role of SPANXB2 in PC3 cells by using shRNA knockdown technique. Knockdown of SPANXB2 in PC3 cells significantly reduces the cell ...proliferation, migration, and invasion ability compared with the wild type PC3 cells . Additionally, co-culture of these knockdown cells with stromas

  1. Neutrophils support lung colonization of metastasis-initiating breast cancer cells

    PubMed Central

    Wculek, Stefanie K.; Malanchi, Ilaria

    2015-01-01

    Despite progress in the development of drugs efficiently targeting cancer cells, treatments of metastatic tumours are often ineffective. The now well established dependency of cancer cells on their microenvironment1 suggests that targeting the non-cancer cell component of the tumour might form the basis for the development of novel therapeutic approaches. However, the as yet poorly characterised contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumourigenesis is still controversial2-4. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissue by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacologic inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression. PMID:26649828

  2. Neutrophils support lung colonization of metastasis-initiating breast cancer cells.

    PubMed

    Wculek, Stefanie K; Malanchi, Ilaria

    2015-12-17

    Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.

  3. The Thoc1 ribonucleoprotein and prostate cancer progression.

    PubMed

    Chinnam, Meenalakshmi; Wang, Yanqing; Zhang, Xiaojing; Gold, David L; Khoury, Thaer; Nikitin, Alexander Yu; Foster, Barbara A; Li, Yanping; Bshara, Wiam; Morrison, Carl D; Payne Ondracek, Rochelle D; Mohler, James L; Goodrich, David W

    2014-11-01

    The majority of newly diagnosed prostate cancers will remain indolent, but distinguishing between aggressive and indolent disease is imprecise. This has led to the important clinical problem of overtreatment. THOC1 encodes a nuclear ribonucleoprotein whose expression is higher in some cancers than in normal tissue. The hypothesis that THOC1 may be a functionally relevant biomarker that can improve the identification of aggressive prostate cancer has not been tested. THOC1 protein immunostaining was evaluated in a retrospective collection of more than 700 human prostate cancer specimens and the results associated with clinical variables and outcome. Thoc1 was conditionally deleted in an autochthonous mouse model (n = 22 or 23 per genotype) to test whether it is required for prostate cancer progression. All statistical tests were two-sided. THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth. Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment. © The Author 2014. Published by Oxford University Press. All rights reserved. For

  4. c-FOS suppresses ovarian cancer progression by changing adhesion

    PubMed Central

    Oliveira-Ferrer, L; Rößler, K; Haustein, V; Schröder, C; Wicklein, D; Maltseva, D; Khaustova, N; Samatov, T; Tonevitsky, A; Mahner, S; Jänicke, F; Schumacher, U; Milde-Langosch, K

    2014-01-01

    Background: C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown. Methods: Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis. Results: Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis. Conclusion: In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces. PMID:24322891

  5. The role of MTDH/AEG-1 in the progression of cancer

    PubMed Central

    Shi, Xue; Wang, Xin

    2015-01-01

    Cancer progression is driven by an accumulation of numerous genetic and epigenetic alterations in cancer cells themselves as well as constructional changes in their microenvironment. Metadherin (MTDH)/Astrocyte elevated gene-1 (AEG-1) has emerged in recent years as a key contributor to the carcinogenic process in diverse organs and tissues. As a multifunctional mediator of carcinogenesis, MTDH/AEG-1 has been found to be involved in multiple signaling pathways, such as: PI3K/Akt, NF-κB, Wnt/β-catenin and MAPK. Overexpression of MTDH/AEG-1 is observed in a variety of cancers belonging to all biological systems, and has crucial relevance with cancer progression, including initiation, proliferation, invasion, metastasis and chemoresistance. In addition, a plethora of studies have convincingly demonstrated that MTDH/AEG-1 overexpression markedly correlates with poor clinical prognosis. These findings suggest that MTDH/AEG-1 may be used as a potential biomarker for the diagnosis of cancer, monitoring of cancer progression, and target therapies which may simultaneously inhibit tumor growth, block metastasis, and intensify the efficacy of chemotherapeutic treatments. PMID:26131054

  6. Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer

    PubMed Central

    TELANG, NITIN

    2015-01-01

    Cancer-initiating stem cells (CISC) represent a minor subpopulation of heterogeneous breast cancer. CISC are responsible for the acquired resistance to conventional chemoendocrine therapy and eventual relapse observed in patients with breast cancer. Certain molecular subtypes of clinical breast cancer that exhibit differential expression of genes coding for hormone and growth factor receptors differ in their response to conventional chemoendocrine therapy and targeted therapeutic inhibitors. Thus, the development of reliable cell culture models for CISC may provide a valuable experimental approach for the study of stem cell-targeted therapy for the treatment of breast cancer. The present study utilized optimized cell culture systems as experimental models for different molecular subtypes of clinical breast cancer, including luminal A, human epidermal growth factor receptor (HER)-2-enriched and triple negative breast cancer. Biomarker end points, including control of homeostatic growth, cancer risk and drug resistance, were quantitatively analyzed in the selected models. The results of the analyses indicated that, compared with the non-tumorigenic controls, the cell models representing the aforementioned molecular subtypes of clinical breast cancer exhibited aberrant cell cycle progression, downregulated cellular apoptosis and loss of control of homeostatic growth, as evidenced by hyperproliferation. Additionally, these models displayed persistent cancer risk, as indicated by their high incidence and frequency of anchorage-independent (AI) colony formation in vitro and their tumor development capacity in vivo. Furthermore, in the presence of maximum cytostatic drug concentrations, the drug-resistant phenotypes isolated from the parental drug-sensitive cell lines representing luminal A, HER-2-enriched and triple negative breast cancer exhibited an 11.5, 5.0 and 6.2 fold increase in cell growth, and a 5.6, 5.4 and 4.4 fold increase in the number of AI colonies

  7. Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer.

    PubMed

    Telang, Nitin

    2015-12-01

    Cancer-initiating stem cells (CISC) represent a minor subpopulation of heterogeneous breast cancer. CISC are responsible for the acquired resistance to conventional chemoendocrine therapy and eventual relapse observed in patients with breast cancer. Certain molecular subtypes of clinical breast cancer that exhibit differential expression of genes coding for hormone and growth factor receptors differ in their response to conventional chemoendocrine therapy and targeted therapeutic inhibitors. Thus, the development of reliable cell culture models for CISC may provide a valuable experimental approach for the study of stem cell-targeted therapy for the treatment of breast cancer. The present study utilized optimized cell culture systems as experimental models for different molecular subtypes of clinical breast cancer, including luminal A, human epidermal growth factor receptor (HER)-2-enriched and triple negative breast cancer. Biomarker end points, including control of homeostatic growth, cancer risk and drug resistance, were quantitatively analyzed in the selected models. The results of the analyses indicated that, compared with the non-tumorigenic controls, the cell models representing the aforementioned molecular subtypes of clinical breast cancer exhibited aberrant cell cycle progression, downregulated cellular apoptosis and loss of control of homeostatic growth, as evidenced by hyperproliferation. Additionally, these models displayed persistent cancer risk, as indicated by their high incidence and frequency of anchorage-independent (AI) colony formation in vitro and their tumor development capacity in vivo. Furthermore, in the presence of maximum cytostatic drug concentrations, the drug-resistant phenotypes isolated from the parental drug-sensitive cell lines representing luminal A, HER-2-enriched and triple negative breast cancer exhibited an 11.5, 5.0 and 6.2 fold increase in cell growth, and a 5.6, 5.4 and 4.4 fold increase in the number of AI colonies

  8. Focus Meeting 2, ``Astronomical Heritage: Progressing the UNESCO-IAU Initiative'' Introduction and overview

    NASA Astrophysics Data System (ADS)

    Ruggles, Clive; Sidorenko, Anna

    2016-10-01

    Marking seven years of formal cooperation between the IAU and the UNESCO World Heritage Centre to implement UNESCO's ``Astronomy and World Heritage'' Thematic Initiative, this Focus Meeting reviewed achievements, challenges, and progress on particular World Heritage List nomination projects.

  9. CONSTRUCTION PROGRESS PHOTO OF REMOTE ANALYTICAL FACILITY (CPP627) SHOWING INITIAL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    CONSTRUCTION PROGRESS PHOTO OF REMOTE ANALYTICAL FACILITY (CPP-627) SHOWING INITIAL EXCAVATION. INL PHOTO NUMBER NRTS-54-10703. Unknown Photographer, 5/21/1954 - Idaho National Engineering Laboratory, Idaho Chemical Processing Plant, Fuel Reprocessing Complex, Scoville, Butte County, ID

  10. Proteomics Standards Initiative: Fifteen Years of Progress and Future Work.

    PubMed

    Deutsch, Eric W; Orchard, Sandra; Binz, Pierre-Alain; Bittremieux, Wout; Eisenacher, Martin; Hermjakob, Henning; Kawano, Shin; Lam, Henry; Mayer, Gerhard; Menschaert, Gerben; Perez-Riverol, Yasset; Salek, Reza M; Tabb, David L; Tenzer, Stefan; Vizcaíno, Juan Antonio; Walzer, Mathias; Jones, Andrew R

    2017-09-15

    The Proteomics Standards Initiative (PSI) of the Human Proteome Organization (HUPO) has now been developing and promoting open community standards and software tools in the field of proteomics for 15 years. Under the guidance of the chair, cochairs, and other leadership positions, the PSI working groups are tasked with the development and maintenance of community standards via special workshops and ongoing work. Among the existing ratified standards, the PSI working groups continue to update PSI-MI XML, MITAB, mzML, mzIdentML, mzQuantML, mzTab, and the MIAPE (Minimum Information About a Proteomics Experiment) guidelines with the advance of new technologies and techniques. Furthermore, new standards are currently either in the final stages of completion (proBed and proBAM for proteogenomics results as well as PEFF) or in early stages of design (a spectral library standard format, a universal spectrum identifier, the qcML quality control format, and the Protein Expression Interface (PROXI) web services Application Programming Interface). In this work we review the current status of all of these aspects of the PSI, describe synergies with other efforts such as the ProteomeXchange Consortium, the Human Proteome Project, and the metabolomics community, and provide a look at future directions of the PSI.

  11. Global threat reduction initiative Russian nuclear material removal progress

    SciTech Connect

    Cummins, Kelly

    2008-07-15

    In December 1999 representatives from the United States, the Russian Federation, and the International Atomic Energy Agency (IAEA) started discussing a program to return to Russia Soviet- or Russian-supplied highly enriched uranium (HEU) fuel stored at the Russian-designed research reactors outside Russia. Trilateral discussions among the United States, Russian Federation, and the International Atomic Energy Agency (IAEA) have identified more than 20 research reactors in 17 countries that have Soviet- or Russian-supplied HEU fuel. The Global Threat Reduction Initiative's Russian Research Reactor Fuel Return Program is an important aspect of the U.S. Government's commitment to cooperate with the other nations to prevent the proliferation of nuclear weapons and weapons-usable proliferation-attractive nuclear materials. To date, 496 kilograms of Russian-origin HEU have been shipped to Russia from Serbia, Latvia, Libya, Uzbekistan, Romania, Bulgaria, Poland, Germany, and the Czech Republic. The pilot spent fuel shipment from Uzbekistan to Russia was completed in April 2006. (author)

  12. Angiogenesis in prostate cancer: onset, progression and imaging.

    PubMed

    Russo, Giovanna; Mischi, Massimo; Scheepens, Wout; De la Rosette, Jean J; Wijkstra, Hessel

    2012-12-01

    What's known on the subject? and What does the study add? Today, angiogenesis is known to play a key role in cancer growth and development. Emerging cancer treatments are based on the suppression of angiogenesis, and modern imaging techniques investigate changes in the microvasculature that are caused by angiogenesis. As for other forms of cancers, angiogenesis is well recognised as a fundamental process in the development of prostate cancer. The novelty of this extensive report on angiogenesis in cancer, with particular attention on prostate cancer and the imaging techniques able to detect it, is the new prospective to the subject. In contrast with the other available reviews, this report goes from 'theory' to 'practice', establishing a clear link between angiogenesis development and imaged angiogenesis features. Once the key role of angiogenesis in the development of cancer and in particular prostate cancer has been fully described, attention is turned to the current imaging methods with the potential to assess the angiogenesis process and, as a consequence, to detect and localise prostate cancer. • As confirmed by all available statistics, cancer represents a major clinical and societal problem in the developed world. The form of cancer with the highest incidence in men is prostate cancer. For prostate cancer, as well as for most forms of cancer, detection of the disease at an early stage is critical to reduce mortality and morbidity. • Today, it is well known that pathological angiogenesis represents a crucial step in cancer development and progression. Comparable with most forms of cancer, angiogenesis also plays a fundamental role for prostate cancer growth. • As a consequence, angiogenesis is an ideal target not only for novel anti-angiogenic therapies, but also for modern imaging techniques that aim at cancer localisation by detection of angiogenic microvascular changes. • These techniques are mainly based on magnetic resonance, ultrasound, and

  13. Recent Progress in the Diagnosis and Treatment of Ovarian Cancer

    PubMed Central

    Jelovac, Danijela; Armstrong, Deborah K.

    2013-01-01

    Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer. PMID:21521830

  14. American Society of Clinical Oncology Obesity Initiative: Rationale, Progress, and Future Directions.

    PubMed

    Ligibel, Jennifer A; Wollins, Dana

    2016-12-10

    Obesity is increasingly being linked to the risk of developing and dying from cancer. In recognition of the growing contribution of obesity to cancer risk and outcomes, ASCO made obesity and cancer one of its core initiatives in 2014. The goals of this initiative included raising awareness of the relationship between obesity and cancer, providing tools and resources to oncology providers and patients to help encourage conversations regarding weight management in cancer survivors, fostering a robust research agenda, and advocating for access to evidence-based weight management programs for cancer survivors. Efforts to date have included developing patient and provider toolkits focused on weight management and physical activity, publishing a policy statement outlining ASCO's initiatives in this area, and hosting a summit focused on obesity research in cancer populations. As ASCO has defined its priorities in the area of obesity and cancer, it has become increasingly clear that obesity is a problem that extends far beyond its impact on cancer risk and outcomes. Many groups, including those focused on heart disease, diabetes, and endocrinology, have been developing, testing, and implementing obesity prevention and treatment strategies for years. As ASCO moves forward with its obesity initiative, the next steps will focus on forging collaboration with groups working on obesity-related initiatives both within and outside of the field of cancer to learn from their efforts and to partner with them on efforts to increase the education of medical professionals; raising awareness in lay populations regarding the negative health consequences of obesity and effective strategies to foster weight loss; developing collaborative research initiatives; and working together to advocate for the societal changes that will be needed to combat the obesity epidemic in the United States and beyond.

  15. Differential action of glycoprotein hormones: significance in cancer progression.

    PubMed

    Govindaraj, Vijayakumar; Arya, Swathy V; Rao, A J

    2014-02-01

    Growth of multicellular organisms depends on maintenance of proper balance between proliferation and differentiation. Any disturbance in this balance in animal cells can lead to cancer. Experimental evidence is provided to conclude with special reference to the action of follicle-stimulating hormone (FSH) on Sertoli cells, and luteinizing hormone (LH) on Leydig cells that these hormones exert a differential action on their target cells, i.e., stimulate proliferation when the cells are in an undifferentiated state which is the situation with cancer cells and promote only functional parameters when the cell are fully differentiated. Hormones and growth factors play a key role in cell proliferation, differentiation, and apoptosis. There is a growing body of evidence that various tumors express some hormones at high levels as well as their cognate receptors indicating the possibility of a role in progression of cancer. Hormones such as LH, FSH, and thyroid-stimulating hormone have been reported to stimulate cell proliferation and act as tumor promoter in a variety of hormone-dependent cancers including gonads, lung, thyroid, uterus, breast, prostate, etc. This review summarizes evidence to conclude that these hormones are produced by some cancer tissues to promote their own growth. Also an attempt is made to explain the significance of the differential action of hormones in progression of cancer with special reference to prostate cancer.

  16. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo

    SciTech Connect

    Hashimoto, Kae; Morishige, Ken-ichirou . E-mail: mken@gyne.med.osaka-u.ac.jp; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  17. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo.

    PubMed

    Hashimoto, Kae; Morishige, Ken-ichirou; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  18. Prostate cancer progression and metastasis: potential regulatory pathways for therapeutic targeting

    PubMed Central

    Nandana, Srinivas; Chung, Leland WK

    2014-01-01

    Skeletal metastasis in advanced prostate cancer (PCa) patients remains a significant cause of morbidity and mortality. Research utilizing animal models during the past decade has reached a consensus that PCa progression and distant metastasis can be tackled at the molecular level. Although there are a good number of models that have shown to facilitate the study of PCa initiation and progression at the primary site, models that mimic the distant dissemination of cancer cells, particularly bone metastasis, are scarce. Despite this limitation, the field has gleaned valuable knowledge on the underlying molecular mechanisms and pathways of PCa progression, including local invasion and distant metastasis, and has moved forward in developing the concepts of current therapeutic modalities. The purpose of this review is to put together recent work on pathways that are currently being targeted for therapy, as well as other prospective novel therapeutic targets to be developed in the future against metastatic and potentially lethal PCa in patients. PMID:25374910

  19. New Progress of Epigenetic Biomarkers in Urological Cancer

    PubMed Central

    Cao, Ziyi

    2016-01-01

    Urological cancers consist of bladder, kidney, prostate, and testis cancers and they are generally silenced at their early stage, which leads to the loss of the best opportunity for early diagnosis and treatment. Desired biomarkers are scarce for urological cancers and current biomarkers are lack of specificity and sensitivity. Epigenetic alterations are characteristic of nearly all kinds of human malignances including DNA methylation, histone modification, and miRNA regulation. Besides, the detection of these epigenetic conditions is easily accessible especially for urine, best target for monitoring the diseases of urinary system. Here, we summarize some new progress about epigenetic biomarkers in urological cancers, hoping to provide new thoughts for the diagnosis, treatment, and prognosis of urological cancers. PMID:27594736

  20. The physics of cancer: The role of epigenetics and chromosome conformation in cancer progression

    NASA Astrophysics Data System (ADS)

    Naimark, Oleg B.; Nikitiuk, Aleksandr S.; Baudement, Marie-Odile; Forné, Thierry; Lesne, Annick

    2016-08-01

    Cancer progression is generally described in terms of accumulated genetic alterations and ensuing changes in cell properties. However, intermediary modifications are involved in the establishment of cancer cell phenotypes, at different levels of nuclear organization: DNA damages and their structural consequences, epigenetic modifications and their impact on chromatin architecture, changes in chromosome 3D organization. We review some of these alterations with a focus on their physical aspects. The challenge is to understand the multiscale interplay between generic physical mechanisms and specific biological factors in cancer cells. We argue that such an interdisciplinary perspective offers a novel viewpoint on cancer progression, early diagnosis and possibly therapeutic targets.

  1. The physics of cancer: The role of epigenetics and chromosome conformation in cancer progression

    SciTech Connect

    Naimark, Oleg B.; Nikitiuk, Aleksandr S.; Baudement, Marie-Odile; Forné, Thierry; Lesne, Annick

    2016-08-02

    Cancer progression is generally described in terms of accumulated genetic alterations and ensuing changes in cell properties. However, intermediary modifications are involved in the establishment of cancer cell phenotypes, at different levels of nuclear organization: DNA damages and their structural consequences, epigenetic modifications and their impact on chromatin architecture, changes in chromosome 3D organization. We review some of these alterations with a focus on their physical aspects. The challenge is to understand the multiscale interplay between generic physical mechanisms and specific biological factors in cancer cells. We argue that such an interdisciplinary perspective offers a novel viewpoint on cancer progression, early diagnosis and possibly therapeutic targets.

  2. Discovery of Novel Gene Elements Associated with Prostate Cancer Progression

    DTIC Science & Technology

    2012-10-01

    Progression John R. Prensner1,8, Matthew K. Iyer1,8, O. Alejandro Balbin1, Saravana M. Dhanasekaran1,2, Qi Cao1, J. Chad Brenner1, Bharathi Laxman3...association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007; 39:631–637. [PubMed: 17401366] 41. Sotelo J, et

  3. Does Lactation Mitigate Triple Negative/Basal Breast Cancer Progression?

    DTIC Science & Technology

    2012-09-01

    generous gift from Kornelia Polyak ) were cultured as previously described [5] and resuspended in PBS immediately prior to injection. Cells were used...Cancer Cell 2008, 13(5):394-406. 6. Polyak K, Hu M: Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland Biol Neoplasia

  4. Initial Progress in Developing the New ICSU World Data System

    NASA Astrophysics Data System (ADS)

    Minster, J. H.; Capitaine, N.; Clark, D. M.; Mokrane, M.

    2009-12-01

    On October 24, 2008, at the 29th International Council for Science (ICSU) General Assembly in Maputo, Mozambique, a decision to form a new ICSU World Data System (WDS) was taken. The new ICSU World Data System (WDS) will replace the framework within which the current ICSU World Data Centers (WDCs) and services of the Federation of Astronomical and Geophysical data-analysis Services (FAGS) are currently organized. The transition from the old organizations to the new WDS was facilitated by the ICSU ad-hoc WDS Transition Team which developed a white paper with recommendations for the new WDS Scientific Committee (WDS-SC). The WDS-SC was appointed by ICSU and reports to the Executive Board and the General Assembly of ICSU. The WDSSC met for the first time in October 2009. WDS-SC shall be the governing body of WDS with the following tasks: 1) to ensure that the WDS clearly supports ICSU’s mission and objectives by ensuring the long-term stewardship and provision of quality-assessed data and data services to the international science community and other stakeholders; 2) to develop, and keep under continuous review, an implementation plan for the creation of the WDS by incorporating the ICSU WDCs, the Services of FAGS and a wide range of other data centers and services; 3) to define agreed standards, establish and oversee the procedures for the review and accreditation of existing and new facilities; 4) to monitor the geographic and disciplinary scope of the system and to develop strategies for the recruitment and establishment of new WDS facilities as necessary; 5) to consider resource issues and provide guidance on funding mechanisms for facilities within WDS when appropriate; 6) to develop strong cooperative links with the ICSU Strategic Coordinating Committee on Information and Data (SCCID);and 7) to cooperate closely with the ICSU Committee on Data for Science and Technology (CODATA). WDS development will proceed from these initial concepts: history and legacy of

  5. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    PubMed Central

    Wang, Wei-Lin W.; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  6. High-Mannose Glycans are Elevated during Breast Cancer Progression*

    PubMed Central

    de Leoz, Maria Lorna A.; Young, Lawrence J. T.; An, Hyun Joo; Kronewitter, Scott R.; Kim, Jaehan; Miyamoto, Suzanne; Borowsky, Alexander D.; Chew, Helen K.; Lebrilla, Carlito B.

    2011-01-01

    Alteration in glycosylation has been observed in cancer. However, monitoring glycosylation changes during breast cancer progression is difficult in humans. In this study, we used a well-characterized transplantable breast tumor mouse model, the mouse mammary tumor virus-polyoma middle T antigen, to observe early changes in glycosylation. We have previously used the said mouse model to look at O-linked glycosylation changes with breast cancer. In this glycan biomarker discovery study, we examined N-linked glycan variations during breast cancer progression of the mouse model but this time doubling the number of mice and blood draw points. N-glycans from total mouse serum glycoproteins were profiled using matrix-assisted laser desorption/ionization Fourier transform-ion cyclotron resonance mass spectrometry at the onset, progression, and removal of mammary tumors. We observed four N-linked glycans, m/z 1339.480 (Hex3HexNAc), 1485.530 (Hex3HexNAc4Fuc), 1809.639 (Hex5HexNAc4Fuc), and 1905.630 (Man9), change in intensity in the cancer group but not in the control group. In a separate study, N-glycans from total human serum glycoproteins of breast cancer patients and controls were also profiled. Analysis of human sera using an internal standard showed the alteration of the low-abundant high-mannose glycans, m/z 1419.475, 1581.528, 1743.581, 1905.634 (Man6–9), in breast cancer patients. A key observation was the elevation of a high-mannose type glycan containing nine mannoses, Man9, m/z 1905.630 in both mouse and human sera in the presence of breast cancer, suggesting an incompletion of the glycosylation process that normally trims back Man9 to produce complex and hybrid type oligosaccharides. PMID:21097542

  7. Spinning Reserve From Hotel Load Response: Initial Progress

    SciTech Connect

    Kueck, John D; Kirby, Brendan J

    2008-11-01

    This project was motivated by the fundamental match between hotel space conditioning load response capability and power system contingency response needs. As power system costs rise and capacity is strained demand response can provide a significant system reliability benefit at a potentially attractive cost. At ORNL s suggestion, Digital Solutions Inc. adapted its hotel air conditioning control technology to supply power system spinning reserve. This energy saving technology is primarily designed to provide the hotel operator with the ability to control individual room temperature set-points based upon occupancy (25% to 50% energy savings based on an earlier study [Kirby and Ally, 2002]). DSI added instantaneous local load shedding capability in response to power system frequency and centrally dispatched load shedding capability in response to power system operator command. The 162 room Music Road Hotel in Pigeon Forge Tennessee agreed to host the spinning reserve test. The Tennessee Valley Authority supplied real-time metering equipment in the form of an internet connected Dranetz-BMI power quality meter and monitoring expertise to record total hotel load during both normal operations and test results. The Sevier County Electric System installed the metering. Preliminary testing showed that hotel load can be curtailed by 22% to 37% depending on the outdoor temperature and the time of day. These results are prior to implementing control over the common area air conditioning loads. Testing was also not at times of highest system or hotel loading. Full response occurred in 12 to 60 seconds from when the system operator s command to shed load was issued. The load drop was very rapid, essentially as fast as the 2 second metering could detect, with all units responding essentially simultaneously. Load restoration was ramped back in over several minutes. The restoration ramp can be adjusted to the power system needs. Frequency response testing was not completed. Initial

  8. Molecular therapy of colorectal cancer: progress and future directions.

    PubMed

    Weng, Wenhao; Feng, Junlan; Qin, Huanlong; Ma, Yanlei

    2015-02-01

    Colorectal cancer (CRC) remains one of the most common types of cancer and leading causes of cancer death worldwide. Although the introduction of cytotoxic drugs such as oxaliplatin, irinotecan and fluorouracil has improved the treatment of advanced CRC, the individual response to chemoradiotherapy varies tremendously from one patient to another. However, recent progress in CRC molecular therapies may provide new insight into the treatment of this disease. Currently, components of the EGFR, VEGF, Wnt and NF-kB pathways are the most important targets for CRC therapy. This review chronicles the development of molecular CRC therapies over the past few decades. We also provide an update on the current progress of research concerning the molecular pathways leading to CRC and discuss the possible implications for CRC therapy.

  9. Stromal Androgen Receptor in Prostate Cancer Development and Progression

    PubMed Central

    Leach, Damien A.; Buchanan, Grant

    2017-01-01

    Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. PMID:28117763

  10. 76 FR 66932 - The National Cancer Institute (NCI) Announces the Initiation of a Public Private Industry...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... Initiation of a Public Private Industry Partnership on Translation of Nanotechnology in Cancer (TONIC) To Promote Translational Research and Development Opportunities of Nanotechnology-Based Cancer Solutions AGENCY: National Cancer Institute (NCI), Office of Cancer Nanotechnology Research (OCNR), National...

  11. Radiosensitivity of Cancer Initiating Cells and Normal Stem Cells

    PubMed Central

    Woodward, Wendy Ann; Bristow, Robert Glen

    2009-01-01

    Mounting evidence suggests that parallels between normal stem cell biology and cancer biology may provide new targets for cancer therapy. Prospective identification and isolation of cancer initiating cells from solid tumors has promoted the descriptive and functional identification of these cells allowing for characterization of their response to contemporary cancer therapies including chemotherapy and radiation. In clinical radiation therapy, the failure to clinically eradicate all tumor cells (e.g. a lack of response, partial response or non-permanent complete response by imaging) is considered a treatment failure. As such, biologists have explored the characteristics of the small population of clonogenic cancer cells that can survive and are capable of re-populating the tumor after sub-curative therapy. Herein, we discuss the convergence of these clonogenic studies with contemporary radiosensitivity studies that employ cell surface markers to identify cancer initiating cells. Implications for and uncertainties regarding incorporation of these concepts into the practice of modern radiation oncology are discussed. PMID:19249646

  12. Genetic and epigenetic aspects of breast cancer progression and therapy.

    PubMed

    Byler, Shannon; Goldgar, Sarah; Heerboth, Sarah; Leary, Meghan; Housman, Genevieve; Moulton, Kimberly; Sarkar, Sibaji

    2014-03-01

    Although breast cancer is a heterogeneous disease that is challenging to characterize and treat, the recent explosion of genetic and epigenetic research may help improve these endeavors. In the present review, we use genetic diversity to characterize and classify different types of breast cancer. We also discuss genetic and epigenetic changes that are involved in the development of different breast cancer types and examine how these changes affect prognosis. It appears that while a combination of mutations and copy number changes determine the type of breast cancer, epigenetic alterations may be the primary initiators of cancer development. Understanding these critical biomarkers and molecular changes will advance our ability to effectively treat breast cancer. Next, we examine potential drug therapies directed at epigenetic changes, as such epigenetic drug treatments may prove useful for treating patient-specific tumors, breast cancer progenitor cells, and drug-resistant cells. Lastly, we discuss on mechanisms of carcinogenesis, including a novel hypothesis outlining the role of epigenetics in the development of cancer progenitor cells and metastasis. Overall, breast cancer subtypes may have a similar epigenetic signal that promotes cancer development, and treatment may be most effective if both epigenetic and genetic differences are targeted.

  13. Minnesota Colorectal Cancer Initiative: successful development and implementation of a community-based colorectal cancer registry.

    PubMed

    Rothenberger, David A; Dalberg, Deanna L; Leininger, Anna

    2004-10-01

    The aim of the Minnesota Colorectal Cancer Initiative is to implement risk-specific interventions to decrease colorectal cancer morbidity and mortality by 1) assisting clinicians to identify and educate individuals and families at high and increased risk for colorectal cancer; 2) providing professional and community education; 3) maintaining a database to evaluate the effectiveness of preventive intervention strategies; and 4) facilitating colorectal cancer research. Two physician groups and the University Cancer Center founded the Minnesota Colorectal Cancer Initiative as a not-for-profit organization. Health care organizations, pharmaceutical companies, a consulting firm, and other practice groups provide continuing financial and other support. A database registry, risk-assessment survey, and consent document were developed and then were approved by an institutional review board. A trial enrollment was conducted. Minnesota Colorectal Cancer Initiative services are available to the public. Participants are actively recruited through member organizations. Minnesota Colorectal Cancer Initiative assesses hereditary risk and will document family history in the medical record on request. A personally targeted reply letter reviews risk factors and recommends specific screening and surveillance strategies for participants and their family members, and when appropriate, provides information regarding genetic counseling and testing services. Minnesota Colorectal Cancer Initiative services are free to participants. Since 1999, Minnesota Colorectal Cancer Initiative has sent individually tailored reply letters providing risk-specific information about colorectal cancer to 717 participants and more than 3200 of their first-degree and second-degree relatives. More than 200 families, previously unidentified as having histories suggestive of hereditary colorectal cancer (attenuated familial polyposis and hereditary nonpolyposis colorectal cancer), have been identified; genetic

  14. Progression and metastasis of lung cancer.

    PubMed

    Popper, Helmut H

    2016-03-01

    Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the "foreign" stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

  15. Depression in cancer: The many biobehavioral pathways driving tumor progression.

    PubMed

    Bortolato, Beatrice; Hyphantis, Thomas N; Valpione, Sara; Perini, Giulia; Maes, Michael; Morris, Gerwyn; Kubera, Marta; Köhler, Cristiano A; Fernandes, Brisa S; Stubbs, Brendon; Pavlidis, Nicholas; Carvalho, André F

    2017-01-01

    Major Depressive Disorder (MDD) is common among cancer patients, with prevalence rates up to four-times higher than the general population. Depression confers worse outcomes, including non-adherence to treatment and increased mortality in the oncology setting. Advances in the understanding of neurobiological underpinnings of depression have revealed shared biobehavioral mechanisms may contribute to cancer progression. Moreover, psychosocial stressors in cancer promote: (1) inflammation and oxidative/nitrosative stress; (2) a decreased immunosurveillance; and (3) a dysfunctional activation of the autonomic nervous system and of the hypothalamic-pituitaryadrenal axis. Consequently, the prompt recognition of depression among patients with cancer who may benefit of treatment strategies targeting depressive symptoms, cognitive dysfunction, fatigue and sleep disturbances, is a public health priority. Moreover, behavioral strategies aiming at reducing psychological distress and depressive symptoms, including addressing unhealthy diet and life-style choices, as well as physical inactivity and sleep dysfunction, may represent important strategies not only to treat depression, but also to improve wider cancer-related outcomes. Herein, we provide a comprehensive review of the intertwined biobehavioral pathways linking depression to cancer progression. In addition, the clinical implications of these findings are critically reviewed.

  16. Regulation of cancer progression by β-endorphin neuron

    PubMed Central

    Sarkar, Dipak K.; Murugan, Sengottuvelan; Zhang, Changqing; Boyadjieva, Nadka

    2011-01-01

    It is becoming increasingly clear that stressful life events can impact cancer growth and metastasis by modulating nervous, endocrine and immune systems. The purpose of this review is to briefly describe the process by which stress may potentiate carcinogenesis and how reducing body stress may prevent cancer growth and progression. The opioid peptide beta-endorphin (BEP) plays a critical role in brining the stress axis to a state of homeostasis. We have recently shown that enhancement of endogenous levels of BEP in the hypothalamus via BEP neuron transplantation suppresses stress response, promotes immune function and reduces the incidence of cancer in rat models of prostate and breast cancers. The cancer preventive effect of BEP is mediated through the suppression of sympathetic neuronal function that results in an increased peripheral natural killer (NK) cell and macrophage activities, elevated levels of anti-inflammatory cytokines and reduced levels of inflammatory cytokines. BEP inhibition of tumor progression also involves alteration in the tumor microenvironment, possibly due to suppression of catecholamine and inflammatory cytokines production that are known to alter DNA repair, cell-matrix attachments, angiogenic process and epithelial-mesenchymal transition. Thus, BEP cell therapy may offer some therapeutic value in cancer prevention. PMID:22287549

  17. Impact of Disease Progression Date Determination on Progression-free Survival Estimates in Advanced Lung Cancer

    PubMed Central

    Qi, Yingwei; Ziegler, Allen; Katie, L.; Hillman, Shauna L.; Redman, Mary W.; Schild, Steven E.; Gandara, David R.; Adjei, Alex A.; Mandrekar, Sumithra J.

    2012-01-01

    PURPOSE Progression-free survival (PFS) based endpoints are controversial; however in advanced lung cancer, overall survival is largely influenced by the progression status. We thus evaluated the impact of progression date (PD) determination approach on PFS estimates. METHODS Individual patient data from 21 trials (14 NCCTG; 7 SWOG) were used. Reported progression date (RPD) was defined as either the scan date or the clinical deterioration date. PD was determined using 4 methods (M): RPD (M1), one day after last progression-free scan (M2), midpoint between last progression-free scan and RPD (M3), and using an interval censoring approach (M4). PFS was estimated using Kaplan-Meier (M1, M2, M3), and maximum likelihood (M4). Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time to progression (TTP) estimates. RESULTS PFS estimates using RPD were the highest, with M2 being the most conservative. M3 and M4 were similar due to majority of progressions occurring during treatment (i.e., frequent disease assessments). M3 was less influenced by the length of the assessment schedules (%difference from true TTP <1.5%) compared to M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials. CONCLUSION The magnitude of difference in the PFS estimates is large enough to alter trial conclusions in advanced lung cancer. Standards for PD determination, use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS based endpoints. PMID:22434489

  18. Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation.

    PubMed

    Liu, Qiuyan; Tan, Qinchun; Zheng, Yuanyuan; Chen, Kun; Qian, Cheng; Li, Nan; Wang, Qingqing; Cao, Xuetao

    2014-04-18

    Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFκB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.

  19. 78 FR 44136 - Submission for OMB review; 30-day Comment Request: National Cancer Institute (NCI) Cancer...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... Cancer Institute (NCI) Cancer Nanotechnology Platform Partnership Scientific Progress Reports SUMMARY..., Center for Strategic Scientific Initiatives, Office of Cancer Nanotechnology Research, National Cancer... (NCI) Alliance for Nanotechnology in Cancer Platform Partnership Scientific Progress Reports, 0925-NEW...

  20. The Role of Cytokines in Breast Cancer Development and Progression

    PubMed Central

    Esquivel-Velázquez, Marcela; Ostoa-Saloma, Pedro; Palacios-Arreola, Margarita Isabel; Nava-Castro, Karen E.; Castro, Julieta Ivonne

    2015-01-01

    Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders. PMID:25068787

  1. The role of cytokines in breast cancer development and progression.

    PubMed

    Esquivel-Velázquez, Marcela; Ostoa-Saloma, Pedro; Palacios-Arreola, Margarita Isabel; Nava-Castro, Karen E; Castro, Julieta Ivonne; Morales-Montor, Jorge

    2015-01-01

    Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders.

  2. Health initiatives for the prevention of skin cancer.

    PubMed

    Greinert, Rüdiger; Breitbart, Eckhard W; Mohr, Peter; Volkmer, Beate

    2014-01-01

    Skin cancer is the most frequent type of cancer in white population worldwide. However, because the most prominent risk factor-solar UV-radiation and/or artificial UV from sunbeds-is known, skin cancer is highly preventable be primary prevention. This prevention needs, that the public is informed by simple and balanced messages about the possible harms and benefits of UV-exposure and how a person should behave under certain conditions of UV-exposure. For this purpose information and recommendations for the public must be age- and target-group specific to cover all periods of life and to reach all sub-groups of a population, continuously. There is a need that political institutions together with Health Institutions and Societies (e.g., European Commission, WHO, EUROSKIN, ICNIRP, etc.), which are responsible for primary prevention of skin cancer, find a common language to inform the public, in order not to confuse it. This is especially important in connection with the ongoing Vitamin D debate, where possible positive effects of UV have to be balanced with the well known skin cancer risk of UV. A continuously ongoing evaluation of interventions and programs in primary prevention is a pre-requisite to assess the effectiveness of strategies. There is surely no "no message fits all" approach, but balanced information in health initiatives for prevention of skin cancer, which use evidence-base strategies, will further be needed in the future to reduce the incidence, morbidity and mortality skin cancer.

  3. IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression.

    PubMed

    Kimura, Yoshitaka; Nagai, Nao; Tsunekawa, Naoki; Sato-Matsushita, Marimo; Yoshimoto, Takayuki; Cua, Daniel J; Iwakura, Yoichiro; Yagita, Hideo; Okada, Futoshi; Tahara, Hideaki; Saiki, Ikuo; Irimura, Tatsuro; Hayakawa, Yoshihiro

    2016-09-01

    Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL-17A was critical for amplifying such local inflammation, as observed in the production of IL-1β and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23-dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30(+) Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  4. New cancer or carcinoid progression to small cell lung cancer?

    PubMed

    Ie, Susanti; Boyd, Michael

    2015-04-01

    Carcinoids and small cell lung cancer share neuroendocrine cellular origins. Surgery is the definitive treatment in typical carcinoid with few recurrences. For patients considered to be poor surgical candidates, ablative and cryotherapies have been utilized with good results. The long-term consequences of these alternatives approaches are unclear. We report a case of typical carcinoid treated with various alternative approaches over a period of 6 years with either transformation to small cell lung cancer or the development of a new primary in the same location.

  5. NF-κB gene signature predicts prostate cancer progression

    PubMed Central

    Jin, Renjie; Yi, Yajun; Yull, Fiona E.; Blackwell, Timothy S.; Clark, Peter E.; Koyama, Tatsuki; Smith, Joseph A.; Matusik, Robert J.

    2014-01-01

    In many prostate cancer (PCa) patients, the cancer will be recurrent and eventually progress to lethal metastatic disease after primary treatment, such as surgery or radiation therapy. Therefore, it would be beneficial to better predict which patients with early-stage PCa would progress or recur after primary definitive treatment. In addition, many studies indicate that activation of NF-κB signaling correlates with PCa progression; however, the precise underlying mechanism is not fully understood. Our studies show that activation of NF-κB signaling via deletion of one allele of its inhibitor, IκBα, did not induce prostatic tumorigenesis in our mouse model. However, activation of NF-κB signaling did increase the rate of tumor progression in the Hi-Myc mouse PCa model when compared to Hi-Myc alone. Using the non-malignant NF-κB activated androgen depleted mouse prostate, a NF-κB Activated Recurrence Predictor 21 (NARP21) gene signature was generated. The NARP21 signature successfully predicted disease-specific survival and distant metastases-free survival in patients with PCa. This transgenic mouse model derived gene signature provides a useful and unique molecular profile for human PCa prognosis, which could be used on a prostatic biopsy to predict indolent versus aggressive behavior of the cancer after surgery. PMID:24686169

  6. Inferring Tree Causal Models of Cancer Progression with Probability Raising

    PubMed Central

    Mauri, Giancarlo; Antoniotti, Marco; Mishra, Bud

    2014-01-01

    Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges) to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models. PMID:25299648

  7. Inferring tree causal models of cancer progression with probability raising.

    PubMed

    Olde Loohuis, Loes; Loohuis, Loes Olde; Caravagna, Giulio; Graudenzi, Alex; Ramazzotti, Daniele; Mauri, Giancarlo; Antoniotti, Marco; Mishra, Bud

    2014-01-01

    Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges) to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models.

  8. The role of MT2-MMP in cancer progression

    SciTech Connect

    Ito, Emiko; Yana, Ikuo; Fujita, Chisato; Irifune, Aiko; Takeda, Maki; Madachi, Ayako; Mori, Seiji; Hamada, Yoshinosuke; Kawaguchi, Naomasa; Matsuura, Nariaki

    2010-03-05

    The role of MT2-MMP in cancer progression remains to be elucidated in spite of many reports on MT1-MMP. Using a human fibrosarcoma cell, HT1080 and a human gastric cancer cell, TMK-1, endogenous expression of MT1-MMP or MT2-MMP was suppressed by siRNA induction to examine the influence of cancer progression in vitro and in vivo. In HT1080 cells, positive both in MT1-MMP and MT2-MMP, the migration as well as the invasion was impaired by MT1-MMP or MT2-MMP suppression. Also cell proliferation in three dimensional (3D) condition was inhibited by MT1-MMP or MT2-MMP suppression and tumor growth in the nude mice transplanted with tumor cells were reduced either MT1-MMP or MT2-MMP suppression with a prolongation of survival time in vivo. MT2-MMP suppression induces more inhibitory effects on 3D proliferation and in vivo tumor growth than MT1-MMP. On the other hand, TMK-1 cells, negative in MT1-MMP and MMP-2 but positive in MT2-MMP, all the migratory, invasive, and 3D proliferative activities in TMK-1 are decreased only by MT2-MMP suppression. These results indicate MT2-MMP might be involved in the cancer progression more than or equal to MT1-MMP independently of MMP-2 and MT1-MMP.

  9. Spectral biopsy for skin cancer diagnosis: initial clinical results

    NASA Astrophysics Data System (ADS)

    Moy, Austin J.; Feng, Xu; Nguyen, Hieu T. M.; Zhang, Yao; Sebastian, Katherine R.; Reichenberg, Jason S.; Tunnell, James W.

    2017-02-01

    Skin cancer is the most common form of cancer in the United States and is a recognized public health issue. Diagnosis of skin cancer involves biopsy of the suspicious lesion followed by histopathology. Biopsies, which involve excision of the lesion, are invasive, at times unnecessary, and are costly procedures ( $2.8B/year in the US). An unmet critical need exists to develop a non-invasive and inexpensive screening method that can eliminate the need for unnecessary biopsies. To address this need, our group has reported on the continued development of a noninvasive method that utilizes multimodal spectroscopy towards the goal of a "spectral biopsy" of skin. Our approach combines Raman spectroscopy, fluorescence spectroscopy, and diffuse reflectance spectroscopy to collect comprehensive optical property information from suspicious skin lesions. We previously described an updated spectral biopsy system that allows acquisition of all three forms of spectroscopy through a single fiber optic probe and is composed of off-the-shelf OEM components that are smaller, cheaper, and enable a more clinic-friendly system. We present initial patient data acquired with the spectral biopsy system, the first from an extensive clinical study (n = 250) to characterize its performance in identifying skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma). We also present our first attempts at analyzing this initial set of clinical data using statistical-based models, and with models currently being developed to extract biophysical information from the collected spectra, all towards the goal of noninvasive skin cancer diagnosis.

  10. Clinical cancer advances 2011: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

    PubMed

    Vogelzang, Nicholas J; Benowitz, Steven I; Adams, Sylvia; Aghajanian, Carol; Chang, Susan Marina; Dreyer, Zoann Eckert; Janne, Pasi A; Ko, Andrew H; Masters, Greg A; Odenike, Olatoyosi; Patel, Jyoti D; Roth, Bruce J; Samlowski, Wolfram E; Seidman, Andrew D; Tap, William D; Temel, Jennifer S; Von Roenn, Jamie H; Kris, Mark G

    2012-01-01

    A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real

  11. Trends in initial management of prostate cancer in New Hampshire.

    PubMed

    Ingimarsson, Johann P; Celaya, Maria O; Laviolette, Michael; Rees, Judy R; Hyams, Elias S

    2015-06-01

    Prostate cancer management strategies are evolving with increased understanding of the disease. Specifically, there is emerging evidence that "low-risk" cancer is best treated with observation, while localized "high-risk" cancer requires aggressive curative therapy. In this study, we evaluated trends in management of prostate cancer in New Hampshire to determine adherence to evidence-based practice. From the New Hampshire State Cancer Registry, cases of clinically localized prostate cancer diagnosed in 2004-2011 were identified and classified according to D'Amico criteria. Initial treatment modality was recorded as surgery, radiation therapy, expectant management, or hormone therapy. Temporal trends were assessed by Chi-square for trend. Of 6,203 clinically localized prostate cancers meeting inclusion criteria, 34, 30, and 28% were low-, intermediate-, and high-risk disease, respectively. For low-risk disease, use of expectant management (17-42%, p < 0.001) and surgery (29-39%, p < 0.001) increased, while use of radiation therapy decreased (49-19 %, p < 0.001). For intermediate-risk disease, use of surgery increased (24-50%, p < 0.001), while radiation decreased (58-34%, p < 0.001). Hormonal therapy alone was rarely used for low- and intermediate-risk disease. For high-risk patients, surgery increased (38-47%, p = 0.003) and radiation decreased (41-38%, p = 0.026), while hormonal therapy and expectant management remained stable. There are encouraging trends in the management of clinically localized prostate cancer in New Hampshire, including less aggressive treatment of low-risk cancer and increasing surgical treatment of high-risk disease.

  12. Impact of S100A8 expression on kidney cancer progression and molecular docking studies for kidney cancer therapeutics.

    PubMed

    Mirza, Zeenat; Schulten, Hans-Juergen; Farsi, Hasan Ma; Al-Maghrabi, Jaudah A; Gari, Mamdooh A; Chaudhary, Adeel Ga; Abuzenadah, Adel M; Al-Qahtani, Mohammed H; Karim, Sajjad

    2014-04-01

    ) signaling. We identified S100A8 as a prospective biomarker for kidney cancer and in silico analysis showed that aspirin, celecoxib, dexamethasone and diclofenac binds to S100A8 and may inhibit downstream signaling in kidney cancer. The present study provides an initial overview of differentially expressed genes in kidney cancer of Saudi Arabian patients using whole-transcript, high-density expression arrays. Our analysis suggests distinct transcriptomic signatures, with significantly high levels of S100A8, and underlying molecular mechanisms contributing to kidney cancer progression. Our docking-based findings shed insight into S100A8 protein as an attractive anticancer target for therapeutic intervention in kidney cancer. To our knowledge, this is the first structure-based docking study for the selected protein targets using the chosen ligands.

  13. Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

    PubMed Central

    Bogaerts, Jan; Sydes, Matthew R.; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M.; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J.; Law, Kate; Trimble, Ted; Seymour, Matthew

    2015-01-01

    Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. PMID:25542058

  14. Early Prediction of Cancer Progression by Depth-Resolved Nanoscale Mapping of Nuclear Architecture from Unstained Tissue Specimens.

    PubMed

    Uttam, Shikhar; Pham, Hoa V; LaFace, Justin; Leibowitz, Brian; Yu, Jian; Brand, Randall E; Hartman, Douglas J; Liu, Yang

    2015-11-15

    Early cancer detection currently relies on screening the entire at-risk population, as with colonoscopy and mammography. Therefore, frequent, invasive surveillance of patients at risk for developing cancer carries financial, physical, and emotional burdens because clinicians lack tools to accurately predict which patients will actually progress into malignancy. Here, we present a new method to predict cancer progression risk via nanoscale nuclear architecture mapping (nanoNAM) of unstained tissue sections based on the intrinsic density alteration of nuclear structure rather than the amount of stain uptake. We demonstrate that nanoNAM detects a gradual increase in the density alteration of nuclear architecture during malignant transformation in animal models of colon carcinogenesis and in human patients with ulcerative colitis, even in tissue that appears histologically normal according to pathologists. We evaluated the ability of nanoNAM to predict "future" cancer progression in patients with ulcerative colitis who did and did not develop colon cancer up to 13 years after their initial colonoscopy. NanoNAM of the initial biopsies correctly classified 12 of 15 patients who eventually developed colon cancer and 15 of 18 who did not, with an overall accuracy of 85%. Taken together, our findings demonstrate great potential for nanoNAM in predicting cancer progression risk and suggest that further validation in a multicenter study with larger cohorts may eventually advance this method to become a routine clinical test.

  15. Vertebral Metastasis as the Initial Manifestation of Colon Cancer.

    PubMed

    Jain, Tushina; Williams, Renee; Liechty, Benjamin; Ann Chen, Lea

    2016-08-01

    Oncology guidelines currently recommend against performing colonoscopies in the workup of adenocarcinoma of unknown primary unless colonic malignancy is otherwise suggested by clinical signs or symptoms. We present 2 cases of metastatic colonic adenocarcinoma that presented only with neurologic symptoms from vertebral metastasis. Although bony metastases are a rare presentation of colon cancer and colonoscopy is not warranted in the initial workup of adenocarcinoma of unknown primary, we describe these cases as a reminder that bony metastases do not rule out a colon cancer diagnosis.

  16. Vertebral Metastasis as the Initial Manifestation of Colon Cancer

    PubMed Central

    Jain, Tushina; Williams, Renee; Liechty, Benjamin

    2016-01-01

    Oncology guidelines currently recommend against performing colonoscopies in the workup of adenocarcinoma of unknown primary unless colonic malignancy is otherwise suggested by clinical signs or symptoms. We present 2 cases of metastatic colonic adenocarcinoma that presented only with neurologic symptoms from vertebral metastasis. Although bony metastases are a rare presentation of colon cancer and colonoscopy is not warranted in the initial workup of adenocarcinoma of unknown primary, we describe these cases as a reminder that bony metastases do not rule out a colon cancer diagnosis. PMID:27807574

  17. Interlinking of hypoxia and estrogen in thyroid cancer progression.

    PubMed

    Rajoria, S; Hanly, E; Nicolini, A; George, A L; Geliebter, J; Shin, E J; Suriano, R; Carpi, A; Tiwari, R K

    2014-01-01

    Estrogen aids in neo-vascularization of various tumors during hypoxic conditions, however the role of estrogen within the hypoxic environment of thyroid cancer is not known. In a series of experimentations, using human thyroid cancer cells, we observed that estrogen and hypoxia modulate the hypoxia inducible factor-1 (HIF-1) signaling which is abrogated by the anti-estrogen fulvestrant and the HIF-1 inhibitor YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole). Furthermore, we found that the conditioned medium from estrogen treated thyroid cancer cells lead to enhanced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs) which is abrogated by HIF-1 inhibitor. These findings, in addition to our previous and other scientific literature data, lead us to conclude that estrogen and hypoxia are interlinked in thyroid cancer and can equally modulate epithelial-endothelial cell interactions by mediating key cellular, metabolic and molecular processes of thyroid cancer progression. We believe that the hormonal component and cellular adaptation to oxygen tension of cancer cells are functionally equivalent with a cellular transition that can be exploited clinically for a combinational approach for thyroid cancer treatment involving antiestrogens as well as anti-hypoxic agents.

  18. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression.

    PubMed

    Cheung, Otto K-W; Cheng, Alfred S-L

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.

  19. CMTM8 inhibits the carcinogenesis and progression of bladder cancer

    PubMed Central

    GAO, DENGHUI; HU, HAO; WANG, YING; YU, WEIDONG; ZHOU, JIANHUA; WANG, XIAOFENG; WANG, WEIPING; ZHOU, CHUNYAN; XU, KEXIN

    2015-01-01

    Bladder cancer is the most common tumor of the urinary tract. The incidence of bladder cancer has increased in the last few decades, thus novel molecular markers for early diagnosis and more efficacious treatment are urgently needed. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 8 (CMTM8) is downregulated in several types of cancers and is associated with tumor progression. However, CMTM8 expression has been unexplored in bladder cancer to date. Our results revealed that the expression of CMTM8 was negative in 46 of 74 (62.2%) bladder cancer samples via immunohistochemistry assay. CMTM8 downregulation was associated with advancing tumor stage and tumor grade. CMTM8 was successfully overexpressed by lentivirus in EJ and T24 cells, and the CCK-8 and Transwell assays showed that CMTM8 overexpression decreased cell proliferation, migration and invasion in vitro. In tumor xenografts upregulation of CMTM8 inhibited tumor growth and lymph node metastasis in vivo. In conclusion, overexpression of CMTM8 in bladder cancer results in reduced malignant cell growth, migration and invasion, which could make it a potential therapeutic target in the treatment of bladder cancer. PMID:26503336

  20. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression

    PubMed Central

    Cheung, Otto K.-W.; Cheng, Alfred S.-L.

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management. PMID:27703473

  1. Does Lactation Mitigate Triple Negative/Basal Breast Cancer Progression

    DTIC Science & Technology

    2013-11-01

    1E). Cell Culture DCIS.com cells and GFP-labeled DCIS.com cells (a generous gift from Kornelia Polyak ) were cultured as previously described [8...transition. Cancer Cell 2008, 13(5):394-406. 9. Polyak K, Hu M: Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland...and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 2005, 7(4):363-373. 57. Hu M, Polyak K: Molecular

  2. [Laparoscopic distal gastrectomy for gastric cancer: initial experience].

    PubMed

    Berrospi, Francisco; Celis, Juan; Ruíz, Eloy; Payet, Eduardo; Chávez, Iván; Young, Frank

    2008-01-01

    To report the initial experience with the laparoscopy-assisted distal gastrectomy (LADG) with D2 lymphadenectomy for gastric cancer. Between May 2006 and May 2007, 29 consecutive GC patients with gastric cancer underwent LADG with D2 lymphadenectomy. The operation consisted in a laparoscopic time to perform lymphadenectomy and mobilization of the distal stomach, followed by a minilaparotomy for exteriorization of the specimen and construction of a hand sewn anastomosis. Twenty-nine patients underwent LADG with D2 lymphadenectomy for gastric cancer. Mean age was 58.2 years. Mean operative time was 287.4 min. Mean number of lymph nodes resected was 42.6. Twelve patients were early gastric cancer, and seventeen were advanced gastric cancer. Mean proximal and distal resection margin were 5.8 cm and 3.5 cm, respectively. Resection margins were negative in all cases. Mean number of lymph nodes resected was 42.6. Thirty-day morbidity rate was 10.3 %. There were no postoperative deaths.CONCLUSION. The short-term results of our LADG with D2 lymphadenectomy for the treatment of gastric cancer shows that a radical surgery, in terms of resection margins and lymphadenectomy, can be done with low morbidity.

  3. Deciphering the Translational Determinants of Prostate Cancer Initiation and Progression

    DTIC Science & Technology

    2012-07-01

    growth, controlled by the 4E-BPs. Science (New York, N.Y 328, 1172-1176, doi :328/5982/1172 [pii]10.1126/science.1187532. 22 Wang, S . et al. Prostate...opinions and/or findings contained in this report are those of the author( s ) and should not be construed as an official Department of the Army...ELEMENT NUMBER 6. AUTHOR( S ) Andrew C. Hsieh Betty Diamond 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: Andrew.hsieh@ucsf.edu 5f

  4. Progress and remaining challenges for cancer control in Latin America and the Caribbean.

    PubMed

    Strasser-Weippl, Kathrin; Chavarri-Guerra, Yanin; Villarreal-Garza, Cynthia; Bychkovsky, Brittany L; Debiasi, Marcio; Liedke, Pedro E R; Soto-Perez-de-Celis, Enrique; Dizon, Don; Cazap, Eduardo; de Lima Lopes, Gilberto; Touya, Diego; Nunes, Joāo Soares; St Louis, Jessica; Vail, Caroline; Bukowski, Alexandra; Ramos-Elias, Pier; Unger-Saldaña, Karla; Brandao, Denise Froes; Ferreyra, Mayra E; Luciani, Silvana; Nogueira-Rodrigues, Angelica; de Carvalho Calabrich, Aknar Freire; Del Carmen, Marcela G; Rauh-Hain, Jose Alejandro; Schmeler, Kathleen; Sala, Raúl; Goss, Paul E

    2015-10-01

    Cancer is one of the leading causes of mortality worldwide, and an increasing threat in low-income and middle-income countries. Our findings in the 2013 Commission in The Lancet Oncology showed several discrepancies between the cancer landscape in Latin America and more developed countries. We reported that funding for health care was a small percentage of national gross domestic product and the percentage of health-care funds diverted to cancer care was even lower. Funds, insurance coverage, doctors, health-care workers, resources, and equipment were also very inequitably distributed between and within countries. We reported that a scarcity of cancer registries hampered the design of credible cancer plans, including initiatives for primary prevention. When we were commissioned by The Lancet Oncology to write an update to our report, we were sceptical that we would uncover much change. To our surprise and gratification much progress has been made in this short time. We are pleased to highlight structural reforms in health-care systems, new programmes for disenfranchised populations, expansion of cancer registries and cancer plans, and implementation of policies to improve primary cancer prevention. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Neoisoliquiritigenin inhibits tumor progression by targeting GRP78-β-catenin signaling in breast cancer.

    PubMed

    Tang, Hailin; Peng, Fu; Huang, Xiaojia; Xie, Xinhua; Chen, Bo; Shen, Jiangang; Gao, Fei; You, Jieshu; Xie, Xiaoming; Chen, Jianping

    2017-09-14

    Although breast cancer mortality has been stable or decreasing in the world, its incidence and recurrence rates have sharply risen worldwide in recent years. Identification of novel preventative biomarkers and drugs for breast cancer has become an urgent issue worldwide. Recently, GRP78 demonstrated a critical role in mediating tumorigenesis, metastasis and angiogenesis. However, the impact of GRP78 in breast cancer and clinical characteristics remains unclear. In this study, we found that GRP78 could promote breast cancer initiation and progression, and higher expression of GRP78 indicated poorer state of breast cancer patients, suggesting that GRP78 was a significant oncogene with the potential to be a novel biomarker and target in clinical investigation. Also, according to the analysis of molecular docking, we found a derivative of Isoliquiritigenin, Neoisoliquiritigenin (NISL), showed a vital inhibitory effect on breast cancer through direct binding to GRP78 to regulate β-catenin pathway. Taken together, this study not only highlight the significance of GRP78 in breast cancer development via β-catenin signaling but also suggest NISL as a natural candidate to inhibit breast cancer by targeting GRP78. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Immune responses to human cancer stem-like cells/cancer-initiating cells.

    PubMed

    Hirohashi, Yoshihiko; Torigoe, Toshihiko; Tsukahara, Tomohide; Kanaseki, Takayuki; Kochin, Vitaly; Sato, Noriyuki

    2016-01-01

    Cancer stem-like cells (CSC)/cancer-initiating cells (CIC) are defined as minor subpopulations of cancer cells that are endowed with properties of higher tumor-initiating ability, self-renewal ability and differentiation ability. Accumulating results of recent studies have revealed that CSC/CIC are resistant to standard cancer therapies, including chemotherapy, radiotherapy and molecular targeting therapy, and eradiation of CSC/CIC is, thus, critical to cure cancer. Cancer immunotherapy is expected to become the "fourth" cancer therapy. Cytotoxic T lymphocytes (CTL) play an essential role in immune responses to cancers, and CTL can recognize CSC/CIC in an antigen-specific manner. CSC/CIC express several tumor-associated antigens (TAA), and cancer testis (CT) antigens are reasonable sources for CSC/CIC-targeting immunotherapy. In this review article, we discuss CSC/CIC recognition by CTL, regulation of immune systems by CSC/CIC, TAA expression in CSC/CIC, and the advantages of CSC/CIC-targeting immunotherapy. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  7. ADAM10: a new player in breast cancer progression?

    PubMed Central

    Mullooly, Maeve; McGowan, Patricia M; Kennedy, Susan A; Madden, Stephen F; Crown, John; O' Donovan, Norma; Duffy, Michael J

    2015-01-01

    Background: The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. As cleavage of several of these proteins has been implicated in cancer formation and progression, we hypothesised that ADAM10 is also involved in these processes. Methods: ADAM10 expression was decreased by RNA interference and the effects of this on cell numbers, invasion and migration were determined. We also examined the effect of ADAM10 inhibition on breast cancer cell line invasion and migration. Results: Using the triple-negative (TN) breast cancer cell lines, BT20, MDA-MB-231 and the non-TN cell line MDA-MB-453, knockdown of ADAM10 expression significantly decreased in vitro migration (P<0.01; for each cell line). Similarly, treatment with the ADAM10-selective inhibitor GI254023X reduced migration in the three cell lines (for BT20, P<0.001; for MDA-MB-231, P=0.005; for MDA-MB-453, P=0.023). In contrast, neither knockdown of ADAM10 nor treatment with the ADAM10-selective inhibitor GI254023X significantly affected cell numbers. Using extracts of primary breast cancers, higher levels of ADAM10 were found more frequently in high-grade vs low-grade tumours (P<0.001) and in oestrogen receptor (ER)-negative compared with ER-positive tumours (P=0.005). Analysis of pooled publicly available data sets found that high levels of ADAM10 mRNA were associated with adverse outcome in patients with the basal subtype of breast cancer. Conclusions: Based on our combined cell line and breast cancer extract data, we conclude that ADAM10 is likely to be involved in breast cancer progression, especially in the basal subtype. PMID:26284334

  8. The lived experience of people with progressive advanced cancer.

    PubMed

    Esteves, Amélia; Roxo, José; Saraiva, Maria da Conceição

    Cancer is a long-term, life-limiting condition, and its end-of-life stage is complex. This study aimed to understand the lived experience of patients with progressive advanced oncological disease. Seven women in an acute hospital in Portugal were interviewed and the results analysed using a phenomenological approach to understand their lived experience. The analysis indicated that lived experience of these patients has six essential constituents: information about one's own health; perception of the disease; emotional reactions; aid strategies by nurses; imitations imposed by the disease; and changes in life perspective. The experience of advanced progressive cancer is very powerful and complex. The authors believe that this study has contributed to the understanding of this situation, particularly in terms of helping to improve palliative care practices.

  9. The wound healing, chronic fibrosis, and cancer progression triad

    PubMed Central

    Rybinski, Brad; Franco-Barraza, Janusz

    2014-01-01

    For decades tumors have been recognized as “wounds that do not heal.” Besides the commonalities that tumors and wounded tissues share, the process of wound healing also portrays similar characteristics with chronic fibrosis. In this review, we suggest a tight interrelationship, which is governed as a concurrence of cellular and microenvironmental reactivity among wound healing, chronic fibrosis, and cancer development/progression (i.e., the WHFC triad). It is clear that the same cell types, as well as soluble and matrix elements that drive wound healing (including regeneration) via distinct signaling pathways, also fuel chronic fibrosis and tumor progression. Hence, here we review the relationship between fibrosis and cancer through the lens of wound healing. PMID:24520152

  10. The molecular biology of medullary thyroid carcinoma: A model for cancer development and progression

    SciTech Connect

    Nelkin, B.D.; de Bustros, A.C.; Mabry, M.; Baylin, S.B. )

    1989-06-02

    Medullary thyroid carcinoma (MTC) is an important human cancer for the study of molecular abnormalities that underlie initiation of neoplasia and subsequent cellular changes during tumor progression. Thus tumor can occur in different inherited forms, each mediated by autosomal dominant genetic events. Germline abnormalities on chromosome 10 are linked to at least one type of genetic MTC, multiple endocrine neoplasia type II. These studies of chromosome 10 in DNA from MTC tumors failed to detect frequent loss of polymorphic DNA markers, suggesting that the genetic mechanisms involved in MTC development may be different from those for other inherited cancers such as retinoblastoma. During tumor progression of MTC, abnormalities develop in expression of the mature phenotype of the endocrine cell from which the tumor arises. In cell culture, chemical modulation or gene insertion can lead to partial correction of these defects in differentiation capacity by activating cellular signaling processes. These studies offer opportunities to dissect the molecular events that regulate endocrine cell differentiation, to determine the precise abnormalities that may underlie the initiation and tumor progression events in MTC and related cancers, and, thereby, to identify new targets for therapeutic intervention.

  11. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel?

    PubMed Central

    Sabharwal, Simran S.; Schumacker, Paul T.

    2015-01-01

    Mitochondria cooperate with their host cells by contributing to bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy. PMID:25342630

  12. Gastric cancer progression associated with local humoral immune responses.

    PubMed

    Yolanda, López-Vidal; Sergio, Ponce-de-León; Hugo, Esquivel-Solís; Isabel, Amieva-Fernández Rosa; Rafael, Barreto-Zúñiga; Aldo, Torre-Delgadillo; Gonzalo, Castillo-Rojas

    2015-11-21

    Although the association between H. pylori and gastric cancer has been well described, the alterations studies are scarce in the humoral immune response in specific anatomical areas of stomach and during the stages of gastric cancer. The aim in this study was to determine the influence of humoral immune responses against H. pylori infection on gastric carcinoma. We selected 16 gastric cancer cases and approximately one matched control per case at the National Institute of Medical Sciences and Nutrition Salvador Zubirán (INCMNSZ); all the cases met the inclusion criteria for the study. We obtained three biopsies from each patient and from each of the predetermined regions of the stomach: antrum, angular portion, corpus, and fundus. From the patients with gastric cancer, additional biopsy specimens were obtained from tumor mid-lesion and tumor margin, and additional specimens were collected at least 2 and 5 cm from the tumor margin. We compared IgA levels against H. pylori in each area of stomach between cases and controls as well as between early and advanced stages of gastric cancer. IgA values were strikingly elevated in cancer cases compared with control subjects; a value that was even higher in the distant periphery of tumor but was remarkably decreased toward the carcinoma lesion. The advanced stages of gastric cancer demonstrated the relapse of the humoral immune response in the mid-lesion region of the tumor compared with the tumor margins and adjacent non-tumor tissue. Gastric cancer is characterized by progressive accumulation of a concentrated, specific IgA response against H. pylori, beginning with an abnormal increase in the entire stomach but particularly in the adjacent non-tumor tissue. Thus, it is possible that this strong immune response also participates in some degree in the damage and in the development of gastric cancer to some extent.

  13. Graphene as Cancer Theranostic Tool: Progress and Future Challenges

    PubMed Central

    Orecchioni, Marco; Cabizza, Roberto; Bianco, Alberto; Delogu, Lucia Gemma

    2015-01-01

    Nowadays cancer remains one of the main causes of death in the world. Current diagnostic techniques need to be improved to provide earlier diagnosis and treatment. Traditional therapy approaches to cancer are limited by lack of specificity and systemic toxicity. In this scenario nanomaterials could be good allies to give more specific cancer treatment effectively reducing undesired side effects and giving at the same time accurate diagnosis and successful therapy. In this context, thanks to its unique physical and chemical properties, graphene, graphene oxide (GO) and reduced graphene (rGO) have recently attracted tremendous interest in biomedicine including cancer therapy. Herein we analyzed all studies presented in literature related to cancer fight using graphene and graphene-based conjugates. In this context, we aimed at the full picture of the state of the art providing new inputs for future strategies in the cancer theranostic by using of graphene. We found an impressive increasing interest in the material for cancer therapy and/or diagnosis. The majority of the works (73%) have been carried out on drug and gene delivery applications, following by photothermal therapy (32%), imaging (31%) and photodynamic therapy (10%). A 27% of the studies focused on theranostic applications. Part of the works here discussed contribute to the growth of the theranostic field covering the use of imaging (i.e. ultrasonography, positron electron tomography, and fluorescent imaging) combined to one or more therapeutic modalities. We found that the use of graphene in cancer theranostics is still in an early but rapidly growing stage of investigation. Any technology based on nanomaterials can significantly enhance their possibility to became the real revolution in medicine if combines diagnosis and therapy at the same time. We performed a comprehensive summary of the latest progress of graphene cancer fight and highlighted the future challenges and the innovative possible

  14. Yin and Yang of Heparanase in Breast Cancer Initiation

    DTIC Science & Technology

    2012-04-01

    less effective in stimulating breast tumor initiation and progression. Experimental procedures and results Sulodexide treatment accelerates PyMT...mediated tumorigenesis. Sulodexide is a mixture of dermatan sulfate (20%) and low-molecular-weight heparin (80%) (Keryx Biopharmaceuticals, Inc...New York). We examined the ability of sulodexide to inhibit HPR1 activity by using a novel ELISA method developed in my laboratory (3-7). As shown

  15. Metabolic Syndrome and Aggressive Prostate Cancer at Initial Diagnosis.

    PubMed

    Di Francesco, Simona; Tenaglia, Raffaele L

    2017-07-01

    Links between metabolic syndrome and prostate cancer after androgen deprivation therapy are emerging. The aim of the research was to investigate the association of metabolic syndrome and aggressive prostate malignancy, at initial diagnosis, without the influence of hormonal treatment. Retrospective analysis of 133 patients with prostate tumor diagnosis between 2007 and 2009 was conducted. Patients with prostate cancer were subdivided in 2 groups according to Gleason score: Gleason score≥7 as high-grade prostate tumor (Group 1) and <7 (Group 2) as low-grade prostate tumor. Metabolic syndrome was defined according to International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute definition. Metabolic syndrome was significantly associated with aggressive prostate cancer (OR 1.87, p<0.05) and a reduced risk of low-grade prostate cancer (OR 0.53, p<0.05) at initial diagnosis, without the influence of endocrine therapy. In our study, patients with metabolic syndrome were more likely to present with more aggressive prostate carcinoma vs. patients without metabolic syndrome. Further research should elucidate these relations in larger samples to confirm these associations and to stabilize future prevention and therapeutic strategies. © Georg Thieme Verlag KG Stuttgart · New York.

  16. LINE-1 Hypomethylation During Primary Colon Cancer Progression

    PubMed Central

    Vu, Anna; Turner, Roderick R.; Hoon, Dave S. B.

    2011-01-01

    Background Methylation levels of genomic repeats such as long interspersed nucleotide elements (LINE-1) are representative of global methylation status and play an important role in maintenance of genomic stability. The objective of the study was to assess LINE-1 methylation status in colorectal cancer (CRC) in relation to adenomatous and malignant progression, tissue heterogeneity, and TNM-stage. Methodology/Principal Findings DNA was collected by laser-capture microdissection (LCM) from normal, adenoma, and cancer tissue from 25 patients with TisN0M0 and from 92 primary CRC patients of various TNM-stages. The paraffin-embedded tissue sections were treated by in-situ DNA sodium bisulfite modification (SBM). LINE-1 hypomethylation index (LHI) was measured by absolute quantitative analysis of methylated alleles (AQAMA) realtime PCR; a greater index indicated enhanced hypomethylation. LHI in normal, cancer mesenchymal, adenoma, and CRC tissue was 0.38 (SD 0.07), 0.37 (SD 0.09), 0.49 (SD 0.10) and 0.53 (SD 0.08), respectively. LHI was significantly greater in adenoma tissue compared to its contiguous normal epithelium (P = 0.0003) and cancer mesenchymal tissue (P<0.0001). LHI did not differ significantly between adenoma and early cancer tissue of Tis stage (P = 0.20). LHI elevated with higher T-stage (P<0.04), was significantly greater in node-positive than node-negative CRC patients (P = 0.03), and was significantly greater in stage IV than all other disease stages (P<0.05). Conclusion/Significance By using in-situ SBM and LCM cell selection we demonstrated early onset of LINE-1 demethylation during adenomatous change of colorectal epithelial cells and demonstrated that LINE-1 demethylation progression is linear in relation to TNM-stage progression. PMID:21533144

  17. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.

    PubMed

    Hattori, Ayuna; Tsunoda, Makoto; Konuma, Takaaki; Kobayashi, Masayuki; Nagy, Tamas; Glushka, John; Tayyari, Fariba; McSkimming, Daniel; Kannan, Natarajan; Tojo, Arinobu; Edison, Arthur S; Ito, Takahiro

    2017-05-25

    Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.

  18. Progress with palbociclib in breast cancer: latest evidence and clinical considerations.

    PubMed

    Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

    2017-02-01

    Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

  19. Progress with palbociclib in breast cancer: latest evidence and clinical considerations

    PubMed Central

    Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

    2016-01-01

    Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer. PMID:28203301

  20. A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression

    PubMed Central

    Simons, Brian W; Durham, Nicholas M; Bruno, Tullia C; Grosso, Joseph F; Schaeffer, Anthony J; Ross, Ashley E; Hurley, Paula J; Berman, David M; Drake, Charles G; Thumbikat, Praveen; Schaeffer, Edward M

    2015-01-01

    Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression. PMID:25348195

  1. MicroRNA-17~92 inhibits colorectal cancer progression by targeting angiogenesis.

    PubMed

    Ma, Huabin; Pan, Jin-Shui; Jin, Li-Xin; Wu, Jianfeng; Ren, Yan-Dan; Chen, Pengda; Xiao, Changchun; Han, Jiahuai

    2016-07-01

    The miR-17~92 microRNA (miRNA) cluster host gene is upregulated in a broad spectrum of human cancers including colorectal cancer (CRC). Previous studies have shown that miR-17~92 promotes tumorigenesis and cancer angiogenesis in some tumor models. However, its role in the initiation and progression of CRC remains unknown. In this study, we found that transgenic mice overexpressing miR-17~92 specifically in epithelial cells of the small and large intestines exhibited decreased tumor size and tumor angiogenesis in azoxymethane and dextran sulfate sodium salt (AOM-DSS)-induced CRC model as compared to their littermates control. Further study showed that miR-17~92 inhibited the progression of CRC via suppressing tumor angiogenesis through targeting multiple tumor angiogenesis-inducing genes, TGFBR2, HIF1α, and VEGFA in vivo and in vitro. Collectively, we demonstrated that miR-17~92 suppressed tumor progression by inhibiting tumor angiogenesis in a genetically engineered mouse model, indicating the presence of cellular context-dependent pro- and anti-cancer effects of miR-17~92.

  2. The dual role of asporin in breast cancer progression

    PubMed Central

    Simkova, Dana; Kharaishvili, Gvantsa; Korinkova, Gabriela; Ozdian, Tomas; Suchánková-Kleplová, Tereza; Soukup, Tomas; Krupka, Michal; Galandakova, Adela; Dzubak, Petr; Janikova, Maria; Navratil, Jiri; Kahounova, Zuzana; Soucek, Karel; Bouchal, Jan

    2016-01-01

    Asporin has been reported as a tumor suppressor in breast cancer, while asporin-activated invasion has been described in gastric cancer. According to our in silico search, high asporin expresion associates with significantly better relapse free survival (RFS) in patients with low-grade tumors but RFS is significantly worse in patients with grade 3 tumors. In line with other studies, we have confirmed asporin expression by RNA scope in situ hybridization in cancer associated fibroblasts. We have also found asporin expression in the Hs578T breast cancer cell line which we confirmed by quantitative RT-PCR and western blotting. From multiple testing, we found that asporin can be downregulated by bone morphogenetic protein 4 while upregulation may be facilited by serum-free cultivation or by three dimensional growth in stiff Alvetex scaffold. Downregulation by shRNA inhibited invasion of Hs578T as well as of CAFs and T47D cells. Invasion of asporin-negative MDA-MB-231 and BT549 breast cancer cells through collagen type I was enhanced by recombinant asporin. Besides other investigations, large scale analysis of aspartic acid repeat polymorphism will be needed for clarification of the asporin dual role in progression of breast cancer. PMID:27409832

  3. Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression.

    PubMed

    Karagiannis, George S; Musrap, Natasha; Saraon, Punit; Treacy, Ann; Schaeffer, David F; Kirsch, Richard; Riddell, Robert H; Diamandis, Eleftherios P

    2015-02-01

    Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

  4. Clinical implications of epithelial cell plasticity in cancer progression.

    PubMed

    Aparicio, Luis A; Blanco, Moisés; Castosa, Raquel; Concha, Ángel; Valladares, Manuel; Calvo, Lourdes; Figueroa, Angélica

    2015-09-28

    In the last few years, the role of epithelial cell plasticity in cancer biology research has gained increasing attention. This concept refers to the ability of the epithelial cells to dynamically switch between different phenotypic cellular states. This programme is particularly relevant during the epithelial-to-mesenchymal transition (EMT) in cancer progression. During colonization, epithelial cells first activate the EMT programme to disseminate from a primary tumour to reach a distant tissue site. During this process, cells are transported into the circulation and are able to escape the immune system of the host. Then, a reverse process called mesenchymal-to-epithelial transition (MET) occurs on cells that settle in the distant organs. Although epithelial cell plasticity has an important impact on tumour biology, the clinical relevance of this concept remains to be recapitulated. In this review, we will update the current state of epithelial cell plasticity in cancer progression and its clinical implications for the design of therapeutic strategies, the acquisition of multidrug resistance, and future perspectives for the management of cancer patients.

  5. [Preoperative intra-arterial chemotherapy for progressive lower rectal cancer].

    PubMed

    Tang, Yun-qiang; Tan, Zhi-ming; Wang, Jia-kang; Tang, Ri-jie; Wang, Jun; Zhao, Hong-yu; Mai, Cong; Zhang, Xiang-liang; Cui, Shu-zhong

    2008-07-01

    To evaluate the therapeutic effect of preoperative regional intra-arterial chemotherapy (PRAC) on progressive lower rectal cancer. Forty-five patients with progressive lower rectal cancer were divided into groups A (23 cases) and B (22 cases) for treatment with PRAC 1 to 2 weeks prior to surgical tumor resection or with surgical resection only, respectively. PRAC caused obvious tissue degeneration and necrosis of rectal cancer with a total effective rate of 95.65%. The rates of radical resection in groups A and B were 91.3% and 72.27%, respectively. The 1-year postoperative survival rates of the two groups were 95.65% and 86.36%, with 3-year survival of 89.96% and 68.18%, and 3-year postoperative recurrence rates of 8.69% and 27.27%, respectively. The anal preservation rates of the two groups were 78.26% and 59.09%. PRAC can increase radical resection rates, promote the postoperative survival and anal preservation rate, and lower the recurrence rate in patients with lower rectal cancer.

  6. The Receptor Tyrosine Kinase AXL in Cancer Progression

    PubMed Central

    Rankin, Erinn B.; Giaccia, Amato J.

    2016-01-01

    The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy. PMID:27834845

  7. Molecular mechanisms by which selenoproteins affect cancer risk and progression.

    PubMed

    Zhuo, Pin; Diamond, Alan M

    2009-11-01

    Selenoproteins comprise a unique class of proteins that contain selenium in the form of selenocysteine. Several selenoproteins have been implicated in the risk or development of cancers in humans by genetic data. These include Selenoprotein P, 3 members of the glutathione peroxidase family of anti-oxidant enzymes and Sep15. At-risk alleles in the germline indicate a likely role in determining susceptibility to cancer, while loss of heterozygosity or chromosomal epigenetic silencing indicate that the reduction in the levels of the corresponding proteins contribute to malignant progression. Lower levels of these proteins are likely to be detrimental due to the resulting cellular stress and perturbations in important regulatory signaling pathways. The genetic data indicating the involvement of these selenoproteins in cancer etiology are discussed, as are the possible mechanisms by which these genes might promote carcinogenesis.

  8. Relating Single Cell Heterogeneity To Genotype During Cancer Progression

    NASA Astrophysics Data System (ADS)

    Rajaram, Satwik

    2013-03-01

    Progression of normal cells towards cancer is driven by a series of genetic changes. Traditional population-averaged measurements have found that cell signalling activities are increasingly altered during this progression. Despite the fact that cancer cells are known to be highly heterogeneous, the response of individual pathways to specific genetic changes remains poorly characterized at a single cell level. Do signalling alterations in a pathway reflect a shift of the whole population, or changes to specific subpopulations? Are alterations to pathways independent, or are cells with alterations in one pathway more likely to be abnormal in another due to crosstalk? We are building a computational framework that analyzes immunofluorescence microscopy images of cells to identify alterations in individual pathways at a single-cell level. A primary novelty of our approach is a ``change of basis'' that allows us to understand signalling in cancer cells in terms of the much better understood patterns of signalling in normal cells. This allows us to model heterogeneous populations of cancer cells as a mixture of distinct subpopulations, each with a specific combination of signalling pathways altered beyond the normal baseline. We used this framework to analyze human bronchial epithelial cell lines containing a series of genetic modifications commonly seen in lung cancer. We confirmed expected trends (such as a population-wide epithelial mesenchymal transition following the last of our series of modifications) and are presently studying the relation between the mutational profiles of cancer cells and pathway crosstalk. Our framework will help establish a more natural basis for future investigations into the phenotype-genotype relationship in heterogeneous populations.

  9. Macrophages promote the progression of premalignant mammary lesions to invasive cancer.

    PubMed

    Carron, Emily C; Homra, Samuel; Rosenberg, Jillian; Coffelt, Seth B; Kittrell, Frances; Zhang, Yiqun; Creighton, Chad J; Fuqua, Suzanne A; Medina, Daniel; Machado, Heather L

    2017-01-31

    Breast cancer initiation, progression and metastasis rely on a complex interplay between tumor cells and their surrounding microenvironment. Infiltrating immune cells, including macrophages, promote mammary tumor progression and metastasis; however, less is known about the role of macrophages in early stage lesions. In this study, we utilized a transplantable p53-null model of early progression to characterize the immune cell components of early stage lesions. We show that macrophages are recruited to ductal hyperplasias with a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These macrophages are a unique subset of macrophages, characterized by pro-inflammatory, anti-inflammatory and immunosuppressive factors. Macrophage ablation studies showed that macrophages are required for both early stage progression and primary tumor formation. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention.

  10. Novel Therapies Against Aggressive and Recurrent Epithelial Cancers by Molecular Targeting Tumor- and Metastasis-Initiating Cells and Their Progenies

    PubMed Central

    Mimeault, Murielle; Batra, Surinder K.

    2010-01-01

    A growing body of experimental evidence has revealed that the highly tumorigenic cancer stem/progenitor cells endowed with stem cell-like properties might be responsible for initiation and progression of numerous aggressive epithelial cancers into locally invasive, metastatic and incurable disease states. The malignant transformation of tissue-resident adult stem/progenitor cells or their progenies into tumorigenic and migrating cancer stem/progenitor cells and their resistance to current cancer therapies have been associated with their high expression levels of specific oncogenic products and drug resistance-associated molecules. In this regard, we describe the tumorigenic cascades that are frequently activated in cancer stem/progenitor cells versus their differentiated progenies during the early and late stages of the epithelial cancer progression. The emphasis is on the growth factor signaling pathways involved in the malignant behavior of prostate and pancreatic cancer stem/progenitor cells and their progenies. Of clinical interest, the potential molecular therapeutic targets to eradicate the tumor- and metastasis-initiating cells and their progenies and develop new effective combination therapies against locally advanced and metastatic epithelial cancers are also described. PMID:20184544

  11. Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis.

    PubMed

    Eyre, Rachel; Alférez, Denis G; Spence, Kath; Kamal, Mohamed; Shaw, Frances L; Simões, Bruno M; Santiago-Gómez, Angélica; Sarmiento-Castro, Aida; Bramley, Maria; Absar, Mohammed; Saad, Zahida; Chatterjee, Sumohan; Kirwan, Cliona; Gandhi, Ashu; Armstrong, Anne C; Wardley, Andrew M; O'Brien, Ciara S; Farnie, Gillian; Howell, Sacha J; Clarke, Robert B

    2016-12-01

    Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease.

  12. Role of cytokines in genesis, progression and prognosis of cervical cancer.

    PubMed

    Paradkar, Prajakta Hemant; Joshi, Jayashree Vinay; Mertia, Priyanka Nirmalsingh; Agashe, Shubhada Vidyadhar; Vaidya, Rama Ashok

    2014-01-01

    Cytokine research is currently at the forefront in cancer research. Deciphering the functions of these multiple small molecules, discovered within the cell and in intercellular spaces, with their abundance and pleotrophism, was initially a great challenge. Advances in analytical chemistry and molecular biology have made it possible to unravel the pathophysiological functions of these polypeptides/proteins which are called interleukins, chemokines, monokines, lymphokines and growth factors. With more than 5 million women contracting cervical cancer every year this cancer is a major cause of mortality and morbidity the world over, particularly in the developing countries. In more than 95% of cases it is associated with human papilloma virus (HPV) infection which is persistent, particularly in those with a defective immune system. Although preventable, the mere magnitude of prevalence of HPV in the world population makes it a dominating current health hazard. The discovery of cytokine dysregulation in cervical cancer has spurted investigation into the possibility of using them as biomarkers in the early diagnosis of cases at high risk of developing cancer. Their critical role in carcinogenesis and progression of cervical cancer is now being revealed to a great extent. From diagnostics to prognosis, and now with a possible role in therapeutics and prevention of cervical cancer, the cytokines are being evaluated in all anticancer approaches. This review endeavours to capture the essence of the astonishing journey of cytokine research in cervical neoplasia.

  13. Glycans and cancer: role of N-glycans in cancer biomarker, progression and metastasis, and therapeutics.

    PubMed

    Taniguchi, Naoyuki; Kizuka, Yasuhiko

    2015-01-01

    Glycosylation is catalyzed by various glycosyltransferase enzymes which are mostly located in the Golgi apparatus in cells. These enzymes glycosylate various complex carbohydrates such as glycoproteins, glycolipids, and proteoglycans. The enzyme activity of glycosyltransferases and their gene expression are altered in various pathophysiological situations including cancer. Furthermore, the activity of glycosyltransferases is controlled by various factors such as the levels of nucleotide sugars, acceptor substrates, nucleotide sugar transporters, chaperons, and endogenous lectin in cancer cells. The glycosylation results in various functional changes of glycoproteins including cell surface receptors and adhesion molecules such as E-cadherin and integrins. These changes confer the unique characteristic phenotypes associated with cancer cells. Therefore, glycans play key roles in cancer progression and treatment. This review focuses on glycan structures, their biosynthetic glycosyltransferases, and their genes in relation to their biological significance and involvement in cancer, especially cancer biomarkers, epithelial-mesenchymal transition, cancer progression and metastasis, and therapeutics. Major N-glycan branching structures which are directly related to cancer are β1,6-GlcNAc branching, bisecting GlcNAc, and core fucose. These structures are enzymatic products of glycosyltransferases, GnT-V, GnT-III, and Fut8, respectively. The genes encoding these enzymes are designated as MGAT5 (Mgat5), MGAT3 (Mgat3), and FUT8 (Fut8) in humans (mice in parenthesis), respectively. GnT-V is highly associated with cancer metastasis, whereas GnT-III is associated with cancer suppression. Fut8 is involved in expression of cancer biomarker as well as in the treatment of cancer. In addition to these enzymes, GnT-IV and GnT-IX (GnT-Vb) will be also discussed in relation to cancer. © 2015 Elsevier Inc. All rights reserved.

  14. High mitochondria content is associated with prostate cancer disease progression

    PubMed Central

    2013-01-01

    Background Mitochondria are suggested to be important organelles for cancer initiation and promotion. This study was designed to evaluate the prognostic value of MTC02, a marker for mitochondrial content, in prostate cancer. Methods Immunohistochemistry of using an antibody against MTC02 was performed on a tissue microarray (TMA) containing 11,152 prostate cancer specimens. Results were compared to histological phenotype, biochemical recurrence, ERG status and other genomic deletions by using our TMA attached molecular information. Results Tumor cells showed stronger MTC02 expression than normal prostate epithelium. MTC02 immunostaining was found in 96.5% of 8,412 analyzable prostate cancers, including 15.4% tumors with weak, 34.6% with moderate, and 46.5% with strong expression. MTC02 expression was associated with advanced pathological tumor stage, high Gleason score, nodal metastases (p < 0.0001 each), positive surgical margins (p = 0.0005), and early PSA recurrence (p < 0.0001) if all cancers were jointly analyzed. Tumors harboring ERG fusion showed higher expression levels than those without (p < 0.0001). In ERG negative prostate cancers, strong MTC02 immunostaining was linked to deletions of PTEN, 6q15, 5q21, and early biochemical recurrence (p < 0.0001 each). Moreover, multiple scenarios of multivariate analyses suggested an independent association of MTC02 with prognosis in preoperative settings. Conclusions Our study demonstrates high-level MTC02 expression in ERG negative prostate cancers harboring deletions of PTEN, 6q15, and 5q21. Additionally, increased MTC02 expression is a strong predictor of poor clinical outcome in ERG negative cancers, highlighting a potentially important role of elevated mitochondrial content for prostate cancer cell biology. PMID:24261794

  15. A Validated Risk Score for Venous Thromboembolism Is Predictive of Cancer Progression and Mortality.

    PubMed

    Kuderer, Nicole M; Culakova, Eva; Lyman, Gary H; Francis, Charles; Falanga, Anna; Khorana, Alok A

    2016-07-01

    Retrospective studies have suggested an association between cancer-associated venous thromboembolism (VTE) and patient survival. We evaluated a previously validated VTE Clinical Risk Score in also predicting early mortality and cancer progression. A large, nationwide, prospective cohort study of adults with solid tumors or lymphoma initiating chemotherapy was conducted from 2002 to 2006 at 115 U.S. practice sites. Survival and cancer progression were estimated by the method of Kaplan and Meier. Multivariate analysis was based on Cox regression analysis adjusted for major prognostic factors including VTE itself. Of 4,405 patients, 134 (3.0%) died and 330 (7.5%) experienced disease progression during the first 4 months of therapy (median follow-up 75 days). Patients deemed high risk (n = 540, 12.3%) by the Clinical Risk Score had a 120-day mortality rate of 12.7% (adjusted hazard ratio [aHR] 3.00, 95% confidence interval [CI] 1.4-6.3), and intermediate-risk patients (n = 2,665, 60.5%) had a mortality rate of 5.9% (aHR 2.3, 95% CI 1.2-4.4) compared with only 1.4% for low-risk patients (n = 1,200, 27.2%). At 120 days of follow-up, cancer progression occurred in 27.2% of high-risk patients (aHR 2.2, 95% CI 1.4-3.5) and 16.4% of intermediate-risk patients (aHR 1.9, 95% CI 1.3-2.7) compared with only 8.5% of low-risk patients (p < .0001). The Clinical Risk Score, originally developed to predict the occurrence of VTE, is also predictive of early mortality and cancer progression during the first four cycles of outpatient chemotherapy, independent from other major prognostic factors including VTE itself. Ongoing and future studies will help determine the impact of VTE prophylaxis on survival. The risk of venous thromboembolism (VTE) is increased in patients receiving cancer chemotherapy. In this article, the authors demonstrate that a popular risk score for VTE in patients with cancer is also associated with the risk of early mortality in this setting. It is important that

  16. SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression

    PubMed Central

    Tiwari, R; Pandey, S K; Goel, S; Bhatia, V; Shukla, S; Jing, X; Dhanasekaran, S M; Ateeq, B

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer in the world, and second leading cause of cancer deaths in the US. Although, anti-EGFR therapy is commonly prescribed for CRC, patients harboring mutations in KRAS or BRAF show poor treatment response, indicating an ardent demand for new therapeutic targets discovery. SPINK1 (serine peptidase inhibitor, Kazal type 1) overexpression has been identified in many cancers including the colon, lung, breast and prostate. Our study demonstrates the functional significance of SPINK1 in CRC progression and metastases. Stable knockdown of SPINK1 significantly decreases cell proliferation, invasion and soft agar colony formation in the colon adenocarcinoma WiDr cells. Conversely, an increase in these oncogenic phenotypes was observed on stimulation with SPINK1-enriched conditioned media (CM) in multiple benign models such as murine colonic epithelial cell lines, MSIE and YAMC (SPINK3-negative). Mechanistically, SPINK1 promotes tumorigenic phenotype by activating phosphatidylinositol 3-kinase (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways, and the SPINK1-positive WiDr cells are sensitive to AKT and MEK inhibitors. Importantly, SPINK1 silencing mediated upregulation of various Metallothionein isoforms, considered as tumor suppressors in CRC, confer sensitivity to doxorubicin, which strengthens the rationale for using the combinatorial treatment approach for the SPINK1-positive CRC patients. Furthermore, in vivo studies using chicken chorioallantoic membrane assay, murine xenograft studies and metastasis models further suggest a pivotal role of SPINK1 in CRC progression and metastasis. Taken together, our study demonstrates an important role for the overexpressed SPINK1 in CRC disease progression, a phenomenon that needs careful evaluation towards effective therapeutic target development. PMID:26258891

  17. Leptin, obesity and breast cancer: progress to understanding the molecular connections.

    PubMed

    Barone, Ines; Giordano, Cinzia; Bonofiglio, Daniela; Andò, Sebastiano; Catalano, Stefania

    2016-12-01

    Obesity has a complicated connection to both breast cancer risk and the clinical behaviour of the established disease. The obese setting provides a unique adipose tissue microenvironment that, in association with systemic endocrine modifications, promotes tumor initiation, primary growth, invasion, and metastatic progression. This review presents an overview of the clinical and experimental evidences highlighting the adipokine leptin as the most important molecular mediator of obesity-breast cancer axis. The research of leptin network operating in this context could launch a new field not only in the knowledge of risk factors for breast cancer but also in the development of leptin targeting drugs as promising anticancer agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Implementation of a performance improvement initiative in colorectal cancer care.

    PubMed

    Marshall, John L; Cartwright, Thomas H; Berry, Carolyn A; Stowell, Stephanie A; Miller, Sara C

    2012-09-01

    In the United States, colorectal cancer (CRC) is the third leading cause of cancer after breast and prostate cancer. Numerous improvement programs have been implemented to increase CRC screening rates, but few have focused on improving the care and management of patients with a diagnosis of this malignancy. As national medical organizations focus on quality of care, efforts are necessary to provide clinicians the opportunity for self-assessment and methods for practice improvement. With this goal in mind, a national continuing medical education-certified performance improvement initiative was conceived. THE INITIATIVE CONSISTED OF THREE STAGES: First, participants self-assessed their performance of predetermined topic measures through a review of patient charts. The topic areas included patient safety and supportive care, evidence-based surveillance, and evidenced-based treatment and were derived from current guidelines and other successful quality-improvement initiatives. Second, an actionable plan for practice improvement was developed in at least one of the three topic areas. Third, after a period of self-improvement, participants reassessed their performance of the same topic measures to determine tangible changes in patient care. A total of 540 patient charts were reviewed by 27 clinicians. Notable results showed large gains in areas of supportive care, such as quantitative pain assessments and emotional well-being evaluations, which traditionally have been a minor focus of other quality-improvement initiatives. Participants also showed tangible improvements in the performance of leading measures of quality care. These findings support the need for continued efforts toward performance improvement in both established and emerging areas of CRC patient care.

  19. Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

    SciTech Connect

    Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

    2011-02-01

    Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

  20. Involvement of human papillomavirus infections in prostate cancer progression.

    PubMed

    Al Moustafa, Ala-Eddin

    2008-08-01

    High-risk human papillomaviruses (HPVs) are sexually transmitted and have been associated with several human carcinomas especially cervical and colorectal. On the other hand, a small number of studies have examined the presence of high-risk HPV in human prostate cancer tissues. Currently, the presence and role of high-risk HPV infections in prostate carcinogenesis remain unclear because of the limited number of investigations. This raises the question whether high-risk HPV infections play any role in human prostate cancer development. However, other investigators and our group were able to immortalize normal and cancer prostate epithelial cells in vitro by E6/E7 of HPV type 16. In this paper, we propose the hypothesis that normal and cancer prostate epithelial cells are susceptible to persistent HPV infections; therefore, high-risk HPV infections play an important role in the progression of prostate cancer. We believe that an international collaboration of epidemiological studies and more molecular biology investigations are necessary to answer these important questions.

  1. Interaction of tumor cells and lymphatic vessels in cancer progression.

    PubMed

    Alitalo, A; Detmar, M

    2012-10-18

    Metastatic spread of cancer through the lymphatic system affects hundreds of thousands of patients yearly. Growth of new lymphatic vessels, lymphangiogenesis, is activated in cancer and inflammation, but is largely inactive in normal physiology, and therefore offers therapeutic potential. Key mediators of lymphangiogenesis have been identified in developmental studies. During embryonic development, lymphatic endothelial cells derive from the blood vascular endothelium and differentiate under the guidance of lymphatic-specific regulators, such as the prospero homeobox 1 transcription factor. Vascular endothelial growth factor-C (VEGF-C) and VEGF receptor 3 signaling are essential for the further development of lymphatic vessels and therefore they provide a promising target for inhibition of tumor lymphangiogenesis. Lymphangiogenesis is important for the progression of solid tumors as shown for melanoma and breast cancer. Tumor cells may use chemokine gradients as guidance cues and enter lymphatic vessels through intercellular openings between endothelial cell junctions or, possibly, by inducing larger discontinuities in the endothelial cell layer. Tumor-draining sentinel lymph nodes show enhanced lymphangiogenesis even before cancer metastasis and they may function as a permissive 'lymphovascular niche' for the survival of metastatic cells. Although our current knowledge indicates that the development of anti-lymphangiogenic therapies may be beneficial for the treatment of cancer patients, several open questions remain with regard to the frequency, mechanisms and biological importance of lymphatic metastases.

  2. Tumor-derived exosomes and their role in cancer progression

    PubMed Central

    Whiteside, Theresa L

    2017-01-01

    Tumor cells actively produce, release and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon the contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as non-invasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation. PMID:27117662

  3. Tumor-Derived Exosomes and Their Role in Cancer Progression.

    PubMed

    Whiteside, Theresa L

    2016-01-01

    Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation.

  4. Initial Progress of Children Identified with Disabilities in Michigan's Reading First Schools

    ERIC Educational Resources Information Center

    Katz, Lauren A.; Stone, C. Addison; Carlisle, Joanne F.; Corey, Douglas Lyman; Zeng, Ji

    2008-01-01

    This 2-year longitudinal study examined initial evidence of progress in reading for 1,512 children with and without identified speech-language and/or learning disabilities (LD-SLD) in the context of the explicit literacy instruction provided in Michigan's Reading First (RF)schools. The findings suggested that children with LD-SLD labels…

  5. 48 CFR 32.503-3 - Initiation of progress payments and review of accounting system.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... payments and review of accounting system. 32.503-3 Section 32.503-3 Federal Acquisition Regulations System... on Costs 32.503-3 Initiation of progress payments and review of accounting system. (a) For..., (2) possessed of an adequate accounting system and controls, and (3) in sound financial condition...

  6. Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy

    PubMed Central

    Poillet-Perez, Laura; Despouy, Gilles; Delage-Mourroux, Régis; Boyer-Guittaut, Michaël

    2014-01-01

    Cancer formation is a complex and highly regulated multi-step process which is highly dependent of its environment, from the tissue to the patient. This complexity implies the development of specific treatments adapted to each type of tumor. The initial step of cancer formation requires the transformation of a healthy cell to a cancer cell, a process regulated by multiple intracellular and extracellular stimuli. The further steps, from the anarchic proliferation of cancer cells to form a primary tumor to the migration of cancer cells to distant organs to form metastasis, are also highly dependent of the tumor environment but of intracellular molecules and pathways as well. In this review, we will focus on the regulatory role of reactive oxygen species (ROS) and autophagy levels during the course of cancer development, from cellular transformation to the formation of metastasis. These data will allow us to discuss the potential of this molecule or pathway as putative future therapeutic targets. PMID:25590798

  7. Cyr61 promotes breast tumorigenesis and cancer progression

    SciTech Connect

    Tsai, Miaw-Sheue; Bogart, Daphne F.; Castaneda, Jessica M.; Li, Patricia; Lupu, Ruth

    2002-01-16

    Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the ''normal'' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and anti-E2 resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.

  8. STAT1 drives tumor progression in serous papillary endometrial cancer.

    PubMed

    Kharma, Budiman; Baba, Tsukasa; Matsumura, Noriomi; Kang, Hyun Sook; Hamanishi, Junzo; Murakami, Ryusuke; McConechy, Melissa M; Leung, Samuel; Yamaguchi, Ken; Hosoe, Yuko; Yoshioka, Yumiko; Murphy, Susan K; Mandai, Masaki; Hunstman, David G; Konishi, Ikuo

    2014-11-15

    Recent studies of the interferon-induced transcription factor STAT1 have associated its dysregulation with poor prognosis in some cancers, but its mechanistic contributions are not well defined. In this study, we report that the STAT1 pathway is constitutively upregulated in type II endometrial cancers. STAT1 pathway alteration was especially prominent in serous papillary endometrial cancers (SPEC) that are refractive to therapy. Our results defined a "SPEC signature" as a molecular definition of its malignant features and poor prognosis. Specifically, we found that STAT1 regulated MYC as well as ICAM1, PD-L1, and SMAD7, as well as the capacity for proliferation, adhesion, migration, invasion, and in vivo tumorigenecity in cells with a high SPEC signature. Together, our results define STAT1 as a driver oncogene in SPEC that modulates disease progression. We propose that STAT1 functions as a prosurvival gene in SPEC, in a manner important to tumor progression, and that STAT1 may be a novel target for molecular therapy in this disease.

  9. Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer

    PubMed Central

    Hallett, Robin M.; Girgis-Gabardo, Adele; Gwynne, William D.; Giacomelli, Andrew O.; Bisson, Jennifer N.P.; Jensen, Jeremy E.; Dvorkin-Gheva, Anna; Hassell, John A.

    2016-01-01

    Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions. PMID:27447971

  10. Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis

    PubMed Central

    Tong, Dali; Liu, Gaolei; Lan, Weihua; Zhang, Dianzheng; Xiao, Hualiang; Zhang, Yao; Huang, Zaoming; Yang, Junjie; Zhang, Jun; Jiang, Jun

    2016-01-01

    Cancer stem cells (CSCs) are a sub-population of tumor cells playing essential roles in initiation, differentiation, recurrence, metastasis and development of drug resistance of various cancers, including bladder cancer. Although multiple lines of evidence suggest that metformin is capable of repressing CSC repopulation in different cancers, the effect of metformin on bladder cancer CSCs remains largely unknown. Using the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model, we demonstrated that metformin is capable of repressing bladder cancer progression from both mild to moderate/severe dysplasia lesions and from carcinoma in situ (CIS) to invasive lesions. Metformin also can arrest bladder cancer cells in G1/S phases, which subsequently leads to apoptosis. And also metformin represses bladder cancer CSC repopulation evidenced by reducing cytokeratin 14 (CK14+) and octamer-binding transcription factor 3/4 (OCT3/4+) cells in both animal and cellular models. More importantly, we found that metformin exerts these anticancer effects by inhibiting COX2, subsequently PGE2 as well as the activation of STAT3. In conclusion, we are the first to systemically demonstrate in both animal and cell models that metformin inhibits bladder cancer progression by inhibiting stem cell repopulation through the COX2/PGE2/STAT3 axis. PMID:27058422

  11. Androgen Receptor Promotes Ligand-Independent Prostate Cancer Progression through c-Myc Upregulation

    PubMed Central

    Gao, Lina; Schwartzman, Jacob; Gibbs, Angela; Lisac, Robert; Kleinschmidt, Richard; Wilmot, Beth; Bottomly, Daniel; Coleman, Ilsa; Nelson, Peter; McWeeney, Shannon; Alumkal, Joshi

    2013-01-01

    The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer – AR and c-Myc – and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control. PMID:23704919

  12. Immunological network signatures of cancer progression and survival

    PubMed Central

    2011-01-01

    Background The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. Methods To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. Results The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. Conclusions The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in

  13. SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer.

    PubMed

    Eifler, Karolin; Vertegaal, Alfred C O

    2015-12-01

    Protein conjugation with Small ubiquitin-like modifier (SUMOylation) has critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancer were recently shown to be dependent on a functioning SUMOylation system, a finding that could be exploited in anticancer therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Macrophages as Key Drivers of Cancer Progression and Metastasis

    PubMed Central

    Nielsen, Sebastian R.

    2017-01-01

    Macrophages are one of the most abundant immune cells in the tumour microenvironment of solid tumours and their presence correlates with reduced survival in most cancers. Macrophages are present at all stages of tumour progression and stimulate angiogenesis, tumour cell invasion, and intravasation at the primary site. At the metastatic site, macrophages and monocytes prepare for the arrival of disseminated tumour cells and promote their extravasation and survival by inhibiting immune-mediated clearance or by directly engaging with tumour cells to activate prosurvival signalling pathways. In addition, macrophages promote the growth of disseminated tumour cells at the metastatic site by organising the formation of a supportive metastatic niche. The development of agents inhibiting the recruitment or the protumorigenic effector functions of macrophages in both the primary tumour and at the metastatic site is a promising strategy to improve cancer survival in the future. PMID:28210073

  15. Effects of Progressive Muscle Relaxation Therapy in Colorectal Cancer Patients.

    PubMed

    Kim, Kyeng Jin; Na, Yeon Kyung; Hong, Hae Sook

    2016-08-01

    This study aimed to examine the effect of progressive muscle relaxation therapy (PMRT) on cortisol level, the Stress Arousal Checklist (SACL) score, blood pressure, and heart rate in colorectal cancer patients undergoing laparoscopic surgery. Forty-six patients were divided into control and experimental groups. Cortisol levels, blood pressure, and heart rate were measured before surgery and between 8:00 and 11:00 a.m. on the first, third, and fifth days after surgery. SACL score was measured before surgery and on the fifth day after surgery at the same time points. PMRT was performed twice a day for 5 days. Analyses of covariance with advanced covariate levels and t tests showed that PMRT helps colorectal cancer patients achieve a lower stress response and provides an important basis for stress control.

  16. Tumor-derived exosomes in oncogenic reprogramming and cancer progression.

    PubMed

    Saleem, Sarmad N; Abdel-Mageed, Asim B

    2015-01-01

    In multicellular organisms, effective communication between cells is a crucial part of cellular and tissue homeostasis. This communication mainly involves direct cell-cell contact as well as the secretion of molecules that bind to receptors at the recipient cells. However, a more recently characterized mode of intercellular communication-the release of membrane vesicles known as exosomes-has been the subject of increasing interest and intensive research over the past decade. Following the discovery of the exosome-mediated immune activation, the pathophysiological roles of exosomes have been recognized in different diseases, including cancer. In this review, we describe the biogenesis and main physical characteristics that define exosomes as a specific population of secreted vesicles, with a special focus on their role in oncogenic transformation and cancer progression.

  17. Tumor-Derived Exosomes in Oncogenic Reprogramming and Cancer Progression

    PubMed Central

    Saleem, Sarmad N; Abdel-Mageed, Asim B

    2014-01-01

    In multicellular organisms, effective communication between cells is a crucial part of cellular and tissue homeostasis. This communication mainly involves direct cell–cell contact as well as the secretion of molecules that bind to receptors at the recipient cells. However, a more recently characterized mode of intercellular communication — the release of membrane vesicles known as exosomes — has been the subject of increasing interest and intensive research over the past decade. Following the discovery of the exosome-mediated immune activation, the pathophysiological roles of exosomes have been recognized in different diseases, including cancer. In this review, we describe the biogenesis and main physical characteristics that define exosomes as a specific population of secreted vesicles, with a special focus on their role in oncogenic transformation and cancer progression. PMID:25156068

  18. Progress in the detection of neoplastic progress and cancer by Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Bakker Schut, Tom C.; Stone, Nicholas; Kendall, Catherine A.; Barr, Hugh; Bruining, Hajo A.; Puppels, Gerwin J.

    2000-05-01

    Early detection of cancer is important because of the improved survival rates when the cancer is treated early. We study the application of NIR Raman spectroscopy for detection of dysplasia because this technique is sensitive to the small changes in molecular invasive in vivo detection using fiber-optic probes. The result of an in vitro study to detect neoplastic progress of esophageal Barrett's esophageal tissue will be presented. Using multivariate statistics, we developed three different linear discriminant analysis classification models to predict tissue type on the basis of the measured spectrum. Spectra of normal, metaplastic and dysplasia tissue could be discriminated with an accuracy of up to 88 percent. Therefore Raman spectroscopy seems to be a very suitable technique to detect dysplasia in Barrett's esophageal tissue.

  19. Impact of intracellular ion channels on cancer development and progression.

    PubMed

    Peruzzo, Roberta; Biasutto, Lucia; Szabò, Ildikò; Leanza, Luigi

    2016-10-01

    Cancer research is nowadays focused on the identification of possible new targets in order to try to develop new drugs for curing untreatable tumors. Ion channels have emerged as "oncogenic" proteins, since they have an aberrant expression in cancers compared to normal tissues and contribute to several hallmarks of cancer, such as metabolic re-programming, limitless proliferative potential, apoptosis-resistance, stimulation of neo-angiogenesis as well as cell migration and invasiveness. In recent years, not only the plasma membrane but also intracellular channels and transporters have arisen as oncological targets and were proposed to be associated with tumorigenesis. Therefore, the research is currently focusing on understanding the possible role of intracellular ion channels in cancer development and progression on one hand and, on the other, on developing new possible drugs able to modulate the expression and/or activity of these channels. In a few cases, the efficacy of channel-targeting drugs in reducing tumors has already been demonstrated in vivo in preclinical mouse models.

  20. Identifying Molecular Culprits of Cervical Cancer Progression | Center for Cancer Research

    Cancer.gov

    Human papillomavirus (HPV) DNA is found in 99.7% of invasive cervical carcinomas, providing strong evidence that the virus is a causative agent in the development of this disease. However, most women who become infected with HPV do not develop invasive cervical lesions, indicating that additional exogenous or genetic factors may determine whether HPV preclinical lesions will progress to cancer. Identification of these factors would be facilitated by a deeper understanding of the cellular and molecular changes that accompany progression to malignancy. In addition, knowledge of which women are at greatest risk for disease progression would be a significant clinical advancement in the management of patients with premalignant cervical lesions.

  1. Prolonged time to progression with fulvestrant for metastatic breast cancer.

    PubMed

    Mello, Celso A L; Chinen, Ludmilla T D; da Silva, Samantha Cabral Severino; do Nascimento Matias, Carolina; Benevides, Carlos Frederico; Gimenes, Daniel Luiz; Fanelli, Marcello F

    2011-06-01

    Although the incidence of breast cancer has been declining in recent years, the disease is still one of the leading causes of cancer deaths in women. Recently, breast cancer has been treated with innovative approaches that use hormone-sensitive therapies. This is because in at least one-third of breast cancers, estrogens mediated via the estrogen receptor pathway act as endocrine growth factors. Fulvestrant has been studied as both first- and second-line therapy for locally advanced and metastatic breast cancer, but few studies have shown its effect as third-line therapy alone. To observe the disease time to progression (TTP) obtained with fulvestrant when used on metastatic breast cancer as first-, second-, and also third-line therapy. We also aimed to correlate the TTP obtained with fulvestrant with hormone receptor, HER2 expression, and metastatic site. This was a cohort study that retrospectively examined medical records of 73 postmenopausal women with advanced breast cancer who were treated with fulvestrant (250 mg/month i.m. injection) and followed at the Department of Medical Oncology at Hospital do Cancer A. C. Camargo in São Paulo, Brazil from August 2003 to December 2006. The median TTP with fulvestrant was about 11 months. When used as the first-line therapy, TTP was about 13 months; when used as second-line, TTP was about 6 months; and when used as third-line, it was about 12 months. No statistically significant difference was observed regarding the therapy line. In patients with positive ER tumors, TTP was 11 months. No significant difference in TTP was observed in negative ER tumors (TTP = 10 months). In patients with positive PgR tumors, TTP was 13 months and for negative PgR, TTP was 6 months (P = 0.008). According to the HER2 status, the TTP was 5 months for HER2+ and 10 months for HER2-. Our findings indicate that fulvestrant is an effective alternative for treatment of metastatic breast cancer.

  2. Nuclear iASPP may facilitate prostate cancer progression

    PubMed Central

    Morris, E V; Cerundolo, L; Lu, M; Verrill, C; Fritzsche, F; White, M J; Thalmann, G N; ten Donkelaar, C S; Ratnayaka, I; Salter, V; Hamdy, F C; Lu, X; Bryant, R J

    2014-01-01

    One of the major challenges in prostate cancer (PCa) research is the identification of key players that control the progression of primary cancers to invasive and metastatic disease. The majority of metastatic PCa express wild-type p53, whereas loss of p63 expression, a p53 family member, is a common event. Here we identify inhibitor of apoptosis-stimulating protein of p53 (iASPP), a common cellular regulator of p53 and p63, as an important player of PCa progression. Detailed analysis of the prostate epithelium of iASPP transgenic mice, iASPPΔ8/Δ8 mice, revealed that iASPP deficiency resulted in a reduction in the number of p63 expressing basal epithelial cells compared with that seen in wild-type mice. Nuclear and cytoplasmic iASPP expression was greater in PCa samples compared with benign epithelium. Importantly nuclear iASPP associated with p53 accumulation in vitro and in vivo. A pair of isogenic primary and metastatic PCa cell lines revealed that nuclear iASPP is enriched in the highly metastatic PCa cells. Nuclear iASPP is often detected in PCa cells located at the invasive leading edge in vivo. Increased iASPP expression associated with metastatic disease and PCa-specific death in a clinical cohort with long-term follow-up. These results suggest that iASPP function is required to maintain the expression of p63 in normal basal prostate epithelium, and nuclear iASPP may inactivate p53 function and facilitate PCa progression. Thus iASPP expression may act as a predictive marker of PCa progression. PMID:25341046

  3. Role of the tumor microenvironment in regulating apoptosis and cancer progression.

    PubMed

    Yaacoub, Katherine; Pedeux, Remy; Tarte, Karin; Guillaudeux, Thierry

    2016-08-10

    Apoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non-malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumor-microenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Progressive osteoblastic bone metastases in breast cancer negative on FDG-PET.

    PubMed

    Huyge, Valérie; Garcia, Camilo; Vanderstappen, Anja; Alexiou, Jean; Gil, Thierry; Flamen, Patrick

    2009-07-01

    Positron emission tomography using F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used in breast cancer. The new generation cameras integrate PET and CT within the same camera, allowing the simultaneous assessment of the structural and metabolic aspects of disease. There is presently a controversy on the clinical significance of osteoblastic bone metastases in breast cancer which are not detected on FDG-PET. It has been suggested that these radiologically dense lesions represent the result of successful treatment of initially osteolytic lesions. We report a case of a 65-year-old woman with a suspicion of recurrent breast cancer based on an increasing serum tumor marker. Serial PET/CT showed progressive blastic bone metastases on the CT without FDG uptake. These lesions were confirmed by bone single photon emission computed tomography. This case report shows: first, that progressive osteoblastic lesions can lack FDG-avidity, leading to a false-negative PET; and secondly, that bone scintigraphy should not be replaced by FDG-PET/CT for the detection of bone metastases in breast cancer.

  5. Towards a Quantitative Endogenous Network Theory of Cancer Genesis and Progression: beyond ``cancer as diseases of genome''

    NASA Astrophysics Data System (ADS)

    Ao, Ping

    2011-03-01

    There has been a tremendous progress in cancer research. However, it appears the current dominant cancer research framework of regarding cancer as diseases of genome leads impasse. Naturally questions have been asked that whether it is possible to develop alternative frameworks such that they can connect both to mutations and other genetic/genomic effects and to environmental factors. Furthermore, such framework can be made quantitative and with predictions experimentally testable. In this talk, I will present a positive answer to this calling. I will explain on our construction of endogenous network theory based on molecular-cellular agencies as dynamical variable. Such cancer theory explicitly demonstrates a profound connection to many fundamental concepts in physics, as such stochastic non-equilibrium processes, ``energy'' landscape, metastability, etc. It suggests that neneath cancer's daunting complexity may lie a simplicity that gives grounds for hope. The rationales behind such theory, its predictions, and its initial experimental verifications will be presented. Supported by USA NIH and China NSF.

  6. Defining the radiobiology of prostate cancer progression: An important question in translational prostate cancer research

    PubMed Central

    Vourganti, Srinivas; Donaldson, Jeffrey; Johnson, Linda; Turkbey, Baris; Bratslavsky, Gennady; Kotula, Leszek

    2015-01-01

    Prostate cancer is one of the most common malignancies affecting men worldwide. High mortality rates from advanced and metastatic prostate cancer in the United States are contrasted by a relatively indolent course in the majority of cases. This gives hope for finding methods that could direct personalized diagnostic, preventative, and treatment approaches to patients with prostate cancer. Recent advances in multiparametric magnetic resonance imaging (MP-MRI) offer a noninvasive diagnostic intervention which allows correlation of prostate tumor image characteristics with underlying biologic evidence of tumor progression. The power of MP-MRI includes examination of both local invasion and nodal disease and might overcome the challenges of analyzing the multifocal nature of prostate cancer. Future directions include a careful analysis of the genomic signature of individual prostatic lesions utilizing image-guided biopsies. This review examines the diagnostic potential of MRI in prostate cancer. PMID:24879423

  7. Weight change, obesity and risk of prostate cancer progression among men with clinically localized prostate cancer.

    PubMed

    Dickerman, Barbra A; Ahearn, Thomas U; Giovannucci, Edward; Stampfer, Meir J; Nguyen, Paul L; Mucci, Lorelei A; Wilson, Kathryn M

    2017-09-01

    Obesity is associated with an increased risk of fatal prostate cancer. We aimed to elucidate the importance and relevant timing of obesity and weight change for prostate cancer progression. We identified 5,158 men diagnosed with localized prostate cancer (clinical stage T1/T2) from 1986 to 2012 in the Health Professionals Follow-up Study. Men were followed for biochemical recurrence and lethal prostate cancer (development of distant metastasis or prostate cancer-specific mortality) until 2012. Cox regression estimated hazard ratios (HRs) for body mass index (BMI) at age 21, BMI at diagnosis, "long-term" weight change from age 21 to diagnosis and "short-term" weight change over spans of 4 and 8 years preceding diagnosis. Because weight, weight change and mortality are strongly associated with smoking, we repeated analyses among never smokers only (N = 2,559). Among all patients, neither weight change nor BMI (at age 21 or at diagnosis) was associated with lethal prostate cancer. Among never smokers, long-term weight gain was associated with an increased risk of lethal disease (HR for gaining >30 pounds vs. stable weight [±10 pounds] 1.59, 95% CI, 1.01-2.50, p-trend = 0.06). Associations between weight change, BMI and lethal prostate cancer were stronger for men with BMI ≥ 25 at age 21 compared to those with BMI < 25. Weight change and obesity were not associated with an increased risk of biochemical recurrence. Our findings among never smoker men diagnosed with localized prostate cancer suggest a positive association between long-term weight gain and risk of lethal prostate cancer. Metabolic changes associated with weight gain may promote prostate cancer progression. © 2017 UICC.

  8. [Autophagy contributes to the initiation of pancreatic cancer].

    PubMed

    Iovanna, Juan L

    2017-03-01

    The pancreatic adenocarcinoma initiation results from the interaction of genetic events combined with multiple other factors. Among the genetic alterations that contribute to the pathogenesis of this disease, the mutation of the KRAS oncogene is required but not sufficient to trigger this cancer. Pancreatitis, an inflammatory disease, facilitates and accelerates the transformation of pancreatic cells when the KRAS oncogene is mutated. Of note, the repertoire of molecular mediators of pancreatitis which are responsible of the promotion of KRAS-mediated transformation is not completely defined. Importantly, autophagy has been proposed as one of the cellular mechanisms contributing to pancreatic carcinogenesis, especially in the initial phases, in which the oncogene KRAS appears to play its leading role. In addition, autophagy is strongly induced during pancreatitis. Although some aspects of autophagy in pancreatic cancer development are not completely established, we can affirm that overexpression of VMP1, an inducer of autophagy which is specifically activated in pancreas during pancreatitis, improves the development of pancreatic precancerous lesions PanINs when the oncogene KRAS is mutated. In addition, inhibition of the autophagic flux with chloroquine inhibits the KRAS pro-tumor effect in the pancreas. In conclusion, activation of expression of VMP1 improves the pro-tumor role of KRAS in pancreas.

  9. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression.

    PubMed

    Cirri, Paolo; Chiarugi, Paola

    2012-06-01

    Several recent papers have now provided compelling experimental evidence that the progression of tumours towards a malignant phenotype does not depend exclusively on the cell-autonomous properties of cancer cells themselves but is also deeply influenced by tumour stroma reactivity, thereby undergoing a strict environmental control. Tumour microenvironmental elements include structural components such as the extracellular matrix or hypoxia as well as stromal cells, either resident cells or recruited from circulating precursors, as macrophages and other inflammatory cells, endothelial cells and cancer-associated fibroblasts (CAFs). All these elements synergistically play a specific role in cancer progression. This review summarizes our current knowledge on the role of CAFs in tumour progression, with a particular focus on the biunivocal interplay between CAFs and cancer cells leading to the activation of the epithelial-mesenchymal transition programme and the achievement of stem cell traits, as well as to the metabolic reprogramming of both stromal and cancer cells. Recent advances on the role of CAFs in the preparation of metastatic niche, as well as the controversial origin of CAFs, are discussed in light of the new emerging therapeutic implications of targeting CAFs.

  10. Depressive symptoms and structural disease progression in knee osteoarthritis: data from the Osteoarthritis Initiative.

    PubMed

    Rathbun, Alan M; Yau, Michelle S; Shardell, Michelle; Stuart, Elizabeth A; Hochberg, Marc C

    2017-01-01

    Depressive symptoms are associated with increases in pain and functional limitations in knee osteoarthritis (OA). The aim was to determine whether depressive symptoms are also associated with greater structural knee OA progression. Four years of annual radiographic and clinical assessments from the Osteoarthritis Initiative were analyzed. The Center for Epidemiological Studies Depression Scale was used to identify depressive symptoms (threshold = ≥16) at the baseline visit. Propensity scores were used to match participants with and without baseline depressive symptoms on multiple potential confounders. Assessment of radiographic knee OA was based on changes in individual radiographic features, which included osteophyte (OST) grade and joint space narrowing (JSN) grade. Mixed effect models were used to examine structural progression between depressed and non-depressed participants with definitive radiographic knee OA. Depressive symptoms were significantly associated with a higher risk of OST progression (odds ratio [OR] = 1.74; 95% confidence interval [CI]: 1.01, 3.00) and a non-significant lower risk of JSN progression (OR = 0.40; 95% CI: 0.14, 1.15) 1 year after baseline. Conversely, there was a non-significant lower risk of OST progression (OR = 0.71; 95% CI: 0.28, 1.79) and higher risk of JSN progression (OR = 1.89; 95% CI: 0.71, 5.06) from year 3 to year 4 of follow-up. However, the patterns of OST progression and JSN progression were not significantly different between the depressed and non-depressed (P = 0.25 and 0.15, respectively). The findings provide no evidence that depressive symptoms have a detectable effect on changes in radiographic disease severity in knee OA.

  11. Chromothripsis and progression-free survival in metastatic colorectal cancer

    PubMed Central

    Skuja, Elina; Kalniete, Dagnija; Nakazawa-Miklasevica, Miki; Daneberga, Zanda; Abolins, Arnis; Purkalne, Gunta; Miklasevics, Edvins

    2017-01-01

    Metastatic dissemination of the primary tumor is the major cause of death in colorectal cancer (CRC) patients. Multiple chromosomal breaks and chromothripsis, a phenomenon involving multiple chromosomal fragmentations occurring in a single catastrophic event, are associated with cancer genesis, progression and developing of metastases. The aim of this study was to evaluate the effect of chromothripsis and total breakpoint count (breakpoint instability index) on progression-free survival (PFS). A total of 19 patients with metastatic CRC (mCRC) receiving FOLFOX first-line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study. The results indicated that the highest breakpoint count was observed in chromosomes 1, 2 and 6. Chromothripsis was detected in 52.6% of the study patients. Furthermore, chromothripsis was associated with an increased median PFS (mPFS; 14 vs. 8 months, respectively; P=0.03), but an association with overall survival was not identified. The present study demonstrated that chromothripsis affected CRC patient survival, suggesting a role for this event as a prognostic and predictive marker in mCRC treatment. PMID:28357089

  12. Mitotic abnormalities leading to cancer predisposition and progression.

    PubMed

    Cavenee, W K

    1989-01-01

    The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one, and so on. That is to say a dissection of the pathway from a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events, we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. A similar mechanism involving the distal short arm of chromosome 17 is apparent in astrocytic tumors and the event is shared by cells in each malignancy stage. This is distinct from a loss of heterozygosity for loci on chromosome 10 which is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and means for determining the genomic locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.

  13. Role of p53 in the progression of gastric cancer.

    PubMed

    Busuttil, Rita A; Zapparoli, Giada V; Haupt, Sue; Fennell, Christina; Wong, Stephen Q; Pang, Jia-Min B; Takeno, Elena A; Mitchell, Catherine; Di Costanzo, Natasha; Fox, Stephen; Haupt, Ygal; Dobrovic, Alexander; Boussioutas, Alex

    2014-12-15

    Intestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer (GC) but is poorly described in terms of molecular changes. Here, we explored the role of TP53, a commonly mutated gene in GC, to determine if p53 protein expression and/or the presence of somatic mutations in TP53 can be used as a predictive marker for patients at risk of progressing to GC from IM. Immunohistochemistry and high resolution melting were used to determine p53 protein expression and TP53 mutation status respectively in normal gastric mucosa, IM without concurrent GC (IM-GC), IM with concurrent GC (IM+GC) and GC. This comparative study revealed an incremental increase in p53 expression levels with progression of disease from normal mucosa, via an IM intermediate to GC. TP53 mutations however, were not detected in IM but occurred frequently in GC. Further, we identified increased protein expression of Mdm2/x, both powerful regulators of p53, in 100% of the IM+GC cohort with these samples also exhibiting high levels of wild-type p53 protein. Our data suggests that TP53 mutations occur late in gastric carcinogenesis contributing to the final transition to cancer. We also demonstrated involvement of Mdmx in GC.

  14. Establishing the colitis-associated cancer progression mouse models.

    PubMed

    Zheng, Haiming; Lu, Zhanjun; Wang, Ruhua; Chen, Niwei; Zheng, Ping

    2016-12-01

    Inflammatory bowel disease (IBD) has been reported as an important inducer of colorectal cancer (CRC). The most malignant IBD-associated CRC type has been highlighted as colitis-associated cancer (CAC). However, lack of CAC cases and difficulties of the long follow-up research have challenged researchers in molecular mechanism probing. Here, we established pre-CAC mouse models (dextran sulfate sodium [DSS] group and azoxymethane [AOM] group) and CAC mouse model (DSS/AOM group) to mimic human CAC development through singly or combinational treatment with DSS and AOM followed by disease activity index analysis. We found that these CAC mice showed much more severe disease phenotype, including serious diarrhea, body weight loss, rectal prolapse and bleeding, bloody stool, tumor burden, and bad survival. By detecting expression patterns of several therapeutic targets-Apc, p53, Kras, and TNF-α-in these mouse models through western blot, histology analysis, qRT-PCR, and ELISA methods, we found that the oncogene Kras expression remained unchanged, while the tumor suppressors-Apc and p53 expression were both significantly downregulated with malignancy progression from pre-CAC to CAC, and TNF-α level was elevated the most in CAC mice blood which is of potential clinical use. These data indicated the successful establishment of CAC development mouse models, which mimics human CAC well both in disease phenotype and molecular level, and highlighted the promoting role of inflammation in CAC progression. This useful tool will facilitate the further study in CAC molecular mechanism.

  15. Progress in systemic chemotherapy of primary breast cancer: an overview.

    PubMed

    Hortobagyi, G N

    2001-01-01

    Substantial progress has been made in the multidisciplinary management of primary breast cancer during the last 30 years. Adjuvant chemotherapy has been shown to significantly reduce the annual risk of cancer recurrence and mortality, and these effects persist even 15 years after diagnosis. Combination chemotherapy is superior to single-agent therapy and anthracycline-containing regimens. Those that combine an anthracycline with 5-fluorouracil and cyclophosphamide are more effective than regimens without an anthracycline. Six cycles of a single regimen appear to provide optimal benefit. Dose reductions below the standard range are associated with inferior results. Dose increases that require growth factor or hematopoietic stem cell support are under investigation; at this time, the existing results provide no compelling reason to use this strategy outside a clinical trial. Regimens using fixed crossover designs with two non-cross-resistant regimens are being evaluated. The addition of a taxane to anthracycline-containing regimens is currently under intense scrutiny, and preliminary analysis of the first three clinical trials has shown encouraging, albeit not compelling, results. For patients with estrogen receptor-positive breast cancer, the sequential administration of chemotherapy and 5 years of tamoxifen therapy provides additive benefits. No compelling evidence exists to combine ovarian ablation with chemotherapy. Most side effects and toxic effects are self-limited, although premature menopause requires monitoring and preventive interventions to preserve bone mineral density. The small risk of acute leukemia is of concern, and additional research to develop safer regimens is clearly indicated. The overall effect of optimal local/regional treatment combined with an anthracycline-containing adjuvant chemotherapy and a taxane (and, for patients with estrogen receptor-positive tumors, 5 years of tamoxifen therapy) is a greater than 50% reduction in annual risks of

  16. Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer.

    PubMed

    Berridge, Michael V; Dong, Lanfeng; Neuzil, Jiri

    2015-08-15

    Mitochondrial DNA (mtDNA), encoding 13 out of more than 1,000 proteins of the mitochondrial proteome, is of paramount importance for the bioenergetic machinery of oxidative phosphorylation that is required for tumor initiation, propagation, and metastasis. In stark contrast to the widely held view that mitochondria and mtDNA are retained and propagated within somatic cells of higher organisms, recent in vitro and in vivo evidence demonstrates that mitochondria move between mammalian cells. This is particularly evident in cancer where defective mitochondrial respiration can be restored and tumor-forming ability regained by mitochondrial acquisition. This paradigm shift in cancer cell biology and mitochondrial genetics, concerning mitochondrial movement between cells to meet bioenergetic needs, not only adds another layer of plasticity to the armory of cancer cells to correct damaged mitochondria, but also points to potentially new therapeutic approaches.

  17. Total RNA Sequencing Analysis of DCIS Progressing to Invasive Breast Cancer

    DTIC Science & Technology

    2016-09-01

    AWARD NUMBER: W81XWH-14-1-0080 TITLE: Total RNA Sequencing Analysis of DCIS Progressing to Invasive Breast Cancer . PRINCIPAL INVESTIGATOR...SUBTITLE Total RNA Sequencing Analysis of DCIS Progressing to Invasive Breast Cancer . 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0080 GRANT11489...funded study of genetic and epigenetic alterations of pre-invasive DCIS that did or did not progress to invasive breast cancer , with an in-depth

  18. Weight and Physical Activity - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Incidence and Stage at Diagnosis - Diagnosis Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Navigating the Trends and Most Recent Estimates Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.