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Sample records for cancer initiation progression

  1. Metabolic, autophagic, and mitophagic activities in cancer initiation and progression.

    PubMed

    Hjelmeland, Anita; Zhang, Jianhua

    2016-04-01

    Cancer is a complex disease marked by uncontrolled cell growth and invasion. These processes are driven by the accumulation of genetic and epigenetic alterations that promote cancer initiation and progression. Contributing to genome changes are the regulation of oxidative stress and reactive species-induced damage to molecules and organelles. Redox regulation, metabolic plasticity, autophagy, and mitophagy play important and interactive roles in cancer hallmarks including sustained proliferation, activated invasion, and replicative immortality. However, the impact of these processes can differ depending on the signaling pathways altered in cancer, tumor type, tumor stage, and/or the differentiation state. Here, we highlight some of the representative studies on the impact of oxidative and nitrosative activities, mitochondrial bioenergetics, metabolism, and autophagy and mitophagy in the context of tumorigenesis. We discuss the implications of these processes for cellular activities in cancer for anti-cancer-based therapeutics. PMID:27372165

  2. Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis.

    PubMed

    McCubrey, James A; Abrams, Stephen L; Fitzgerald, Timothy L; Cocco, Lucio; Martelli, Alberto M; Montalto, Giuseppe; Cervello, Melchiorre; Scalisi, Aurora; Candido, Saverio; Libra, Massimo; Steelman, Linda S

    2015-01-01

    The EGFR/PI3K/PTEN/Akt/mTORC pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, cancer initiating cells (CICs) and metastasis. The expression of this pathway is frequently altered in breast and other cancers due to mutations at or aberrant expression of: HER2, EGFR1, PIK3CA, and PTEN as well as other oncogenes and tumor suppressor genes. miRs and epigenetic mechanisms of gene regulation are also important events which regulate this pathway. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway has been associated with CICs and in some cases resistance to therapeutics. We will review the effects of activation of the EGFR/PI3K/PTEN/Akt/mTORC pathway primarily in breast cancer and development of drug resistance. The targeting of this pathway and other interacting pathways will be discussed as well as clinical trials with novel small molecule inhibitors as well as established drugs that are used to treat other diseases. In this manuscript, we will discuss an inducible EGFR model (v-ERB-B:ER) and its effects on cell growth, cell cycle progression, activation of signal transduction pathways, prevention of apoptosis in hematopoietic, breast and prostate cancer models. PMID:25453219

  3. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications.

    PubMed

    Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Zhang, Xinmin; Fu, Li

    2016-03-01

    Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer. PMID:26791754

  4. 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. PMID:20610280

  5. 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

  6. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.

    PubMed

    Harris, Isaac S; Treloar, Aislinn E; Inoue, Satoshi; Sasaki, Masato; Gorrini, Chiara; Lee, Kim Chung; Yung, Ka Yi; Brenner, Dirk; Knobbe-Thomsen, Christiane B; Cox, Maureen A; Elia, Andrew; Berger, Thorsten; Cescon, David W; Adeoye, Adewunmi; Brüstle, Anne; Molyneux, Sam D; Mason, Jacqueline M; Li, Wanda Y; Yamamoto, Kazuo; Wakeham, Andrew; Berman, Hal K; Khokha, Rama; Done, Susan J; Kavanagh, Terrance J; Lam, Ching-Wan; Mak, Tak W

    2015-02-01

    Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention. PMID:25620030

  7. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

    PubMed Central

    He, Chunbo; Lv, Xiangmin; Hua, Guohua; Lele, Subodh M; Remmenga, Steven; Dong, Jixin; Davis, John S; Wang, Cheng

    2014-01-01

    Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces expression of EGF receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, while knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression. PMID:25798835

  8. 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

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

    PubMed

    Mohammed, Altaf; Janakiram, Naveena B; 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

    2015-06-20

    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

  10. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

    PubMed

    Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

    2016-06-30

    Proton radiotherapy is becoming more common as 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 with 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 (SIRs), 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 and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (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

  11. 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

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

    PubMed

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

    2016-05-01

    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

  13. 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

  14. 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

  15. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    PubMed Central

    Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

    2015-01-01

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer. PMID:26264026

  16. 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. PMID:26566853

  17. Secretome of human bone marrow mesenchymal stem cells: an emerging player in lung cancer progression and mechanisms of translation initiation.

    PubMed

    Attar-Schneider, Oshrat; Zismanov, Victoria; Drucker, Liat; Gottfried, Maya

    2016-04-01

    Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Patients presenting with advanced-stage NSCLC have poor prognosis, while metastatic spread accounts for >70 % of patient's deaths. The major advances in the treatment of lung cancer have brought only minor improvements in survival; therefore, novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of bone marrow MSCs (BM-MSCs) from normal donors on NSCLC cell lines with special emphasis on translation initiation mechanism in the crosstalk. We cultured NSCLC cell lines with BM-MSC conditioned media (i.e., secretome) and showed deleterious effects on the cells' proliferation, viability, death, and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression [eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic translation initiation factor 4GI (eIF4GI)], their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's mitogen-activated protein kinase (MAPK) signaling pathway, downregulated the cell migration, and diminished translation initiation factors' levels. Taken together, our study demonstrates that there is direct dialogue between the BM-MSCs' secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We suggest that therapeutic approach that will sabotage this dialogue, especially in the BM microenvironment, may diminish lung cancer metastatic spread and morbidity and improve the patient

  18. 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

  19. Multiple roles of COUP-TFII in cancer initiation and progression

    PubMed Central

    Litchfield, Lacey M.; Klinge, Carolyn M.

    2012-01-01

    COUP-TFII is an orphan nuclear receptor that acts as a transcriptional activator or repressor in a cell type-dependent manner. Best characterized for its role in the regulation of angiogenesis during mouse development, COUP-TFII also plays important roles in glucose metabolism and cancer. Expression of COUP-TFII is altered in various endocrine conditions. Cell type-specific functions and the regulation of COUP-TFII expression result in its varying physiological and pathological actions in diverse systems. Evidence will be reviewed for oncogenic and tumor suppressive functions of COUP-TFII, with roles in angiogenesis, metastasis, steroidogenesis, and endocrine sensitivity of breast cancer described. The applicability of current data to our understanding of the role of COUP-TFII in cancer will be discussed. PMID:22966133

  20. THE CANCER PROGRESS REPORT

    EPA Science Inventory

    The Cancer Progress Report 2001 is about our Nation's progress against cancer. The information was gathered through a collaborative effort with other key agencies and groups, such as the Centers for Disease Control and Prevention and the American Cancer Society. Data on this site...

  1. 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.

  2. 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

  3. Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression

    PubMed Central

    Riondino, Silvia; Roselli, Mario; Palmirotta, Raffaele; Della-Morte, David; Ferroni, Patrizia; Guadagni, Fiorella

    2014-01-01

    Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of “adiposopathy”, defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC. PMID:24833848

  4. Stochastic dynamics of cancer initiation

    NASA Astrophysics Data System (ADS)

    Foo, Jasmine; Leder, Kevin; Michor, Franziska

    2011-02-01

    Most human cancer types result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Once the first change (or changes) have arisen, tumorigenesis is initiated and the subsequent emergence of additional alterations drives progression to more aggressive and ultimately invasive phenotypes. Elucidation of the dynamics of cancer initiation is of importance for an understanding of tumor evolution and cancer incidence data. In this paper, we develop a novel mathematical framework to study the processes of cancer initiation. Cells at risk of accumulating oncogenic mutations are organized into small compartments of cells and proliferate according to a stochastic process. During each cell division, an (epi)genetic alteration may arise which leads to a random fitness change, drawn from a probability distribution. Cancer is initiated when a cell gains a fitness sufficiently high to escape from the homeostatic mechanisms of the cell compartment. To investigate cancer initiation during a human lifetime, a 'race' between this fitness process and the aging process of the patient is considered; the latter is modeled as a second stochastic Markov process in an aging dimension. This model allows us to investigate the dynamics of cancer initiation and its dependence on the mutational fitness distribution. Our framework also provides a methodology to assess the effects of different life expectancy distributions on lifetime cancer incidence. We apply this methodology to colorectal tumorigenesis while considering life expectancy data of the US population to inform the dynamics of the aging process. We study how the probability of cancer initiation prior to death, the time until cancer initiation, and the mutational profile of the cancer-initiating cell depends on the shape of the mutational fitness distribution and life expectancy of the population.

  5. Translation initiation in colorectal cancer.

    PubMed

    Parsyan, Armen; Hernández, Greco; Meterissian, Sarkis

    2012-06-01

    Colorectal cancers (CRC) are one of the most common causes of morbidity and mortality in high-income countries. Targeted screening programs have resulted in early treatment and a substantial decrease in mortality. However, treatment strategies for CRC still require improvement. Understanding the etiology and pathogenesis of CRC would provide tools for improving treatment of patients with this disease. It is only recently that deregulation of the protein synthesis apparatus has begun to gain attention as a major player in cancer development and progression. Among the numerous steps of protein synthesis, deregulation of the process of translation initiation appears to play a key role in cancer growth and proliferation. This manuscript discusses a fascinating and rapidly growing field exploring translation initiation as a fundamental component in CRC development and progression and summarizing CRC treatment perspectives based on agents targeting translation initiation. PMID:22418835

  6. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression

    PubMed Central

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

  7. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression.

    PubMed

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

  8. EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression

    PubMed Central

    Carethers, John M.; Koi, Minoru; Tseng-Rogenski, Stephanie S.

    2015-01-01

    DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among

  9. 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

  10. 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. PMID:26929329

  11. 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

  12. 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

  13. Preventing Breast Cancer: Making Progress

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... inhibitor, can do an even better job of preventing breast cancer than the SERMs. Aromatase inhibitors stop an enzyme ...

  14. 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

  15. Biobehavioral Influences on Cancer Progression

    PubMed Central

    Costanzo, Erin S.; Sood, Anil K.; Lutgendorf, Susan K.

    2010-01-01

    Synopsis This review focuses on the contributions of stress-related behavioral factors to cancer growth and metastasis and the biobehavioral mechanisms underlying these relationships. We describe behavioral factors that are important in modulation of the stress response and the pivotal role of neuroendocrine regulation in the downstream alteration of physiological pathways relevant to cancer control, including the cellular immune response, inflammation, and tumor angiogenesis, invasion, and cell-signaling pathways. Consequences for cancer progression and metastasis, as well as quality of life, are delineated. Finally, behavioral and pharmacological interventions for cancer patients with the potential to alter these biobehavioral pathways are discussed. PMID:21094927

  16. 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

  17. Progress on the childhood immunization initiative.

    PubMed Central

    Robinson, C A; Evans, W B; Mahanes, J A; Sepe, S J

    1994-01-01

    President Clinton submitted the Comprehensive Childhood Immunization Initiative Act to Congress in April 1993. The objective of the legislation is to protect all children in the United States by their second birthday against nine vaccine-preventable infectious diseases. As originally introduced in the Congress the initiative called for (a) Federal purchase and distribution of recommended childhood vaccines for all children, (b) improving the public health capacity to deliver vaccine, (c) establishing a State-based national immunization information and tracking system, and (d) expanding immunization education and mobilization efforts directed to health care providers and parents. The authors review the progress and current status of the initiative, updating a previous progress report. The President's legislative proposal, modified by Congress, was enacted August 10, 1993. Several key provisions of the original legislation, deferred by Congress, may be incorporated in subsequent legislation or implemented through existing authorities. Therefore, the evolving framework for the initiative derives not from a single legislative mandate, but expands current immunization program activities and adds important new and complementary activities. As mentioned in the original title of the legislation, this is a "comprehensive" effort to address the problem of under-immunization in U.S. preschool children. PMID:7938378

  18. Ursolic Acid Inhibits the Initiation, Progression of Prostate Cancer and Prolongs the Survival of TRAMP Mice by Modulating Pro-Inflammatory Pathways

    PubMed Central

    Shanmugam, Muthu K.; Ong, Tina H.; Kumar, Alan Prem; Lun, Chang K.; Ho, Paul C.; Wong, Peter T. H.; Hui, Kam M.; Sethi, Gautam

    2012-01-01

    Prostate cancer is one of the leading causes of cancer death among men worldwide. In this study, using transgenic adenocarcinoma of mouse prostate (TRAMP) mice, the effect of diet enriched with 1% w/w ursolic acid (UA) was investigated to evaluate the stage specific chemopreventive activity against prostate cancer. We found that TRAMP mice fed with UA diet for 8 weeks (weeks 4 to 12) delayed formation of prostate intraepithelial neoplasia (PIN). Similarly, mice fed with UA diet for 6 weeks (weeks 12 to 18) inhibited progression of PIN to adenocarcinoma as determined by hematoxylin and eosin staining. Finally, TRAMP mice fed with UA diet for 12 weeks (weeks 24 to 36) demonstrated markedly reduced tumor growth without any significant effects on total body weight and prolonged overall survival. With respect to the molecular mechanism, we found that UA down-regulated activation of various pro-inflammatory mediators including, NF-κB, STAT3, AKT and IKKα/β phosphorylation in the dorsolateral prostate (DLP) tissues that correlated with the reduction in serum levels of TNF-α and IL-6. In addition, UA significantly down-regulated the expression levels of cyclin D1 and COX-2 but up-regulated the levels of caspase-3 as revealed by immunohistochemical analysis of tumor tissue sections. Finally, UA was detected in serum samples obtained from various mice groups fed with enriched diet in nanogram quantity indicating that it is well absorbed in the GI tract. Overall, our findings provide strong evidence that UA can be an excellent agent for both the prevention and treatment of prostate cancer. PMID:22427843

  19. 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

  20. An evolutionary model for initiation, promotion, and progression in carcinogenesis.

    PubMed

    Vincent, T L; Gatenby, R A

    2008-04-01

    Human carcinogenesis is a multistep process in which epithelial cells progress through a series of premalignant phenotypes until an invasive cancer emerges. Extensive experimental observations in carcinogenesis have demonstrated this process can be divided into three general eras: initiation, promotion, and progression. However, this empirically derived, tissue-level explanation of carcinogenesis has not been reconciled with the step-wise genotypic and phenotypic changes encompassed in evolutionary paradigms such as the Feoron-Vogelstein diagram. Here, we analyze an evolutionary model of cellular dynamics that defines mutual interactions of cellular and subcellular events and tissue level changes in tumor growth and morphology. Results are expressed using an adaptive landscape that illustrates the evolutionary potential of cells that allow them to adapt to specific microenvironmental selection forces. It is shown that normal epithelial cells have a novel adaptive landscape that permits coexistence of normal cellular populations but also allows invasion by mutant phenotypes. Subsequent cancer evolution is possible due to a relaxation of tissue growth constraints (as mediated by cell-cell and cell-extracellular matrix interactions) and adaptations in response to perturbations in microenvironmental substrate concentrations (due to separation of evolving tumor cells from their blood supply by an intact basement membrane). Simulations, based on the dynamic model, produce three distinct stages of carcinogenesis that are consistent with the initiation, promotion, and progression stages observed experimentally. The simulations provide insight into the underlying cellular and microenvironmental dynamics that govern these empirical observations and suggest novel prevention strategies that may be tested experimentally. PMID:18360700

  1. 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

  2. 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

  3. Basic Research and Progress against Pediatric Cancer

    Cancer.gov

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

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

    PubMed Central

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

    2015-01-01

    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. PMID:26418896

  5. 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. PMID:26418896

  6. 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.

  7. Insidious Changes in Stromal Matrix Fuel Cancer Progression

    PubMed Central

    Miles, Fayth L.

    2014-01-01

    Reciprocal interactions between tumor and stromal cells propel cancer progression and metastasis. An understanding of the complex contributions of the tumor stroma to cancer progression necessitates a careful examination of the extracellular matrix (ECM), which is largely synthesized and modulated by Cancer Associated Fibroblasts (CAFs). This structurally supportive meshwork serves as a signaling scaffold for a myriad of biological processes and responses favoring tumor progression. The ECM is a repository for growth factors and cytokines that promote tumor growth, proliferation, and metastasis through diverse interactions with soluble and insoluble ECM components. Growth factors activated by proteases are involved in the initiation of cell signaling pathways essential to invasion and survival. Various transmembrane proteins produced by the cancer stroma bind the collagen and fibronectin-rich matrix to induce proliferation, adhesion and migration of cancer cells, as well as protease activation. Integrins are critical liaisons between tumor cells and the surrounding stroma, and with their mechano-sensing ability induce cell signaling pathways associated with contractility and migration. Proteoglycans also bind and interact with various matrix proteins in the tumor microenvironment to promote cancer progression. Together, these components function to mediate crosstalk between tumor cells and fibroblasts ultimately to promote tumor survival and metastasis. These stromal factors, which may be expressed differentially according to cancer stage, have prognostic utility and potential. In this review, we examine changes in the ECM of cancer associated fibroblasts induced through carcinogenesis, and the implications of these changes on cancer progression. PMID:24452359

  8. [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.

  9. Microgravity alters cancer growth and progression.

    PubMed

    Jhala, Dhwani V; Kale, Raosaheb K; Singh, Rana P

    2014-01-01

    Study of the process of cancer initiation, growth and progression in altered gravity is of utmost importance considering the health status of researchers visiting in space and future scope of space tourism. Microgravity affects various cells in the body differently; however, the mechanisms of such effects are not understood completely. Therefore, it is imperative to explore various physiological and biochemical processes, particularly those which can influence the process of carcinogenesis. If the changes in physiological or biochemical processes do not revert back to normalcy even after returning from the space to earth, it may lead to various aberrations and morphological changes during the life span. Such changes could lead to pathological conditions including cancer. For example, microgravity is observed to suppress the activity of immune cells, which itself increases the risk of cancer development. It is little known how the microgravity affects cellular and molecular events that determine physiological and biological responses. There is also a possibility of changes in epigenetic signatures during microgravity exposure which remains unexplored. Herein, we have reviewed the effect of microgravity on relevant molecular and biological processes, and how it could influence the course of cancer development. In this regard, we have also highlighted the areas of research that require more attention to bridge the gap of understanding for such biological processes. PMID:24720362

  10. Role of mitochondrial dysfunction in cancer progression.

    PubMed

    Hsu, Chia-Chi; Tseng, Ling-Ming; Lee, Hsin-Chen

    2016-06-01

    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, Ca(2+), 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

  11. Chromosome 6p amplification and cancer progression

    PubMed Central

    Santos, Gda C; Zielenska, M; Prasad, M; Squire, J A

    2007-01-01

    Chromosomal imbalances represent an important mechanism in cancer progression. A clear association between DNA copy‐number aberrations and prognosis has been found in a variety of tumours. Comparative genomic hybridisation studies have detected copy‐number increases affecting chromosome 6p in several types of cancer. A systematic analysis of large tumour cohorts is required to identify genomic imbalances of 6p that correlate with a distinct clinical feature of disease progression. Recent findings suggest that a central part of the short arm of chromosome 6p harbours one or more oncogenes directly involved in tumour progression. Gains at 6p have been associated with advanced or metastatic disease, poor prognosis, venous invasion in bladder, colorectal, ovarian and hepatocellular carcinomas. Copy number gains of 6p DNA have been described in a series of patients who presented initially with follicle centre lymphoma, which subsequently transformed to diffuse large B cell lymphoma. Melanoma cytogenetics has consistently identified aberrations of chromosome 6, and a correlation with lower overall survival has been described. Most of the changes observed in tumours to date map to the 6p21–p23 region, which encompasses approximately half of the genes on all of chromosome 6 and one third of the number of CpG islands in this chromosome. Analyses of the genes that cluster to the commonly amplified regions of chromosome 6p have helped to identify a small number of molecular pathways that become deregulated during tumour progression in diverse tumour types. Such pathways offer promise for new treatments in the future. PMID:16790693

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

    PubMed Central

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

    2016-01-01

    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. PMID:27053846

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

    PubMed

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

    2016-04-01

    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. PMID:27053846

  14. 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

  15. 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.

  16. Quantifying Collective Cell Migration during Cancer Progression

    NASA Astrophysics Data System (ADS)

    Lee, Rachel; Stuelten, Christina; Nordstrom, Kerstin; Parent, Carole; Losert, Wolfgang

    2014-03-01

    As tumors become more malignant, cells invade the surrounding tissue and migrate throughout the body to form secondary, metastatic tumors. This metastatic process is initiated when cells leave the primary tumor, either individually or as groups of collectively migrating cells. The mechanisms regulating how groups of cells collectively migrate are not well characterized. Here we study the migration dynamics of epithelial sheets composed of many cells using quantitative image analysis techniques. By extracting motion information from time-lapse images of cell lines of varying malignancy, we are able to measure how migration dynamics change during cancer progression. We further investigate the role that cell-cell adhesion plays in these collective dynamics by analyzing the migration of cell lines with varying levels of E-cadherin (a cell-cell adhesion protein) expression.

  17. 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. PMID:26828013

  18. Specialized Initiatives - Cancer Imaging Program

    Cancer.gov

    CIP has sponsored a number of programs for specific purposes, using set-aside funds. Among these are Phase 2 N01 ProgramIn-Vivo Cellular & Molecular Imaging Centers (ICMICs) Quantitative Imaging for Evaluation of Responses to Cancer Therapies (QIN) Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms Small Animal Imaging Resource Program (SAIRP) Development of Preclinical Drugs and Enhancers (DCIDE) program.

  19. Progress with the PUB Initiative in Canada

    NASA Astrophysics Data System (ADS)

    Spence, C.; Whitfield, P.; Ouarda, T.; Metcalfe, R.; Pomeroy, J.; Pietroniro, A.

    2008-12-01

    Practicing hydrologists continually face the challenge of prediction in ungauged basins. They are well aware of the difficulties and risks inherent in making predictions and forecasts of the state of water resources. They are cognizant of the climate and landscape change that is forcing our community to address some of the long held assumptions in our methodologies - notably that of stationarity. Furthermore, as resources have become scarcer due to availability or quality limitations, decision makers' demands not only include reports of mere abundance or state but also change. Interactions among hydrological, biochemical and ecological processes now need to be understood and incorporated into new predictive tools. In Canada, progress has been slow but steady. Priorities were identified, including improving prediction in small basins, incorporating process algorithms into deterministic models, implementing new information generating methods, and expanding outreach of new knowledge and techniques. Individual successes are reflective of the needs of each segment of the community. Large utilities and operational forecast offices, with their larger infrastructure, have made progress incorporating new algorithms into deterministic models and applying advanced regionalization tools. The majority of consulting engineers remain constrained by time, budgets and access to data. They remain comfortable reducing uncertainty and building confidence with calibration and reproduction of past conditions. Conservative assumptions are a mainstay for reducing risk. Progress in reducing uncertainty for this segment is made by developing relationships and exchanging information so that practicing hydrologists are aware of the new tools and knowledge they need to ensure wise water management decisions.

  20. Progress of molecular targeted therapies for prostate cancers

    PubMed Central

    Fu, Weihua; Madan, Elena; Yee, Marla; Zhang, Hongtao

    2011-01-01

    Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients. PMID:22146293

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

    PubMed

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

    2016-07-12

    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. 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

  3. 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:

  4. Preventing Breast Cancer: Making Progress

    MedlinePlus

    ... medical literature, the Study of Tamoxifen and Raloxifene (STAR) trial was started in 1998. That study enrolled ... in the BCPT. Studies, such as BCPT and STAR, involve women who have not had breast cancer, ...

  5. rs712 polymorphism within let-7 microRNA-binding site might be involved in the initiation and progression of colorectal cancer in Chinese population

    PubMed Central

    Jiang, Qiang-Hua; Peng, Hong-Xin; Zhang, Yi; Tian, Peng; Xi, Zu-Lian; Chen, Hao

    2015-01-01

    rs712 within 3′-untranslated region of KRAS can affect the specific binding between the mRNA and its targeted microRNAs, leading to the activation of KRAS oncogene. However, the possible association between the locus and susceptibility to colorectal cancer (CRC) remains unclear. We investigated genotypes of the locus in 586 cases and 476 controls to explore the possible association between them. Results of our case–control study showed that genotypes TT (6.5% vs 2.5%, P=0.002, adjusted odds ratio [OR] =2.810, 95% confidence interval [CI] =1.342–5.488) and GT/TT (36.5% vs 30.5%, P=0.038, adjusted OR =1.342, 95% CI =1.030–1.712) and allele T (21.5% vs 6.5%, P=0.004, adjusted OR =1.328, 95% CI =1.105–1.722) of rs712 were significantly associated with an increased risk of CRC, and the significant association was also observed in the recessive model (TT vs GG/GT, 6.5% vs 2.5%, P=0.003, adjusted OR =0.372, 95% CI =0.191–0.725). However, there was no association between genotype GT and risk of CRC (30.0% vs 28.0%, P=0.235, adjusted OR =1.210, 95% CI =0.903–1.548). Furthermore, genotype GT (P=0.003) and allele T (P=0.003) were significantly associated with poor differentiation, and genotypes GT and TT and allele T were significantly associated with tumor-node-metastases stage III (P=0.001 for GT vs GG, P<0.001 for TT vs GG, and P<0.001 for T vs G) and node metastasis (P<0.001 for GT vs GG, P=0.001 for TT vs GG, and P<0.001 for T vs G), respectively. These findings indicated that allele T and genotypes TT and GT/TT of rs712 might be susceptible factors for CRC, and mutated allele and genotypes of the locus might predict a poor clinical outcome in Chinese population. PMID:26543374

  6. Membrane potential and cancer progression

    PubMed Central

    Yang, Ming; Brackenbury, William J.

    2013-01-01

    Membrane potential (Vm), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm is a key biophysical signal in non-excitable cells, modulating important cellular activities, such as proliferation and differentiation. Therefore, the multiplicities of various ion channels/transporters expressed on different cells are finely tuned in order to regulate the Vm. It is well-established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm has functional roles in cancer cell migration. In addition, hyperpolarization is necessary for stem cell differentiation. For example, both osteogenesis and adipogenesis are hindered in human mesenchymal stem cells (hMSCs) under depolarizing conditions. Therefore, in the context of cancer, membrane depolarization might be important for the emergence and maintenance of cancer stem cells (CSCs), giving rise to sustained tumor growth. This review aims to provide a broad understanding of the Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed. In the long term, Vm might be a valuable clinical marker for tumor detection with prognostic value, and could even be artificially modified in order to inhibit tumor growth and metastasis. PMID:23882223

  7. Multifunctional nanoparticles: recent progress in cancer therapeutics.

    PubMed

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

    2015-09-01

    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. PMID:26234539

  8. Progress in immunoconjugate cancer therapeutics.

    PubMed

    Payne, Gillian

    2003-03-01

    Advances in immunoconjugate technology have revitalized the "magic bullet" concept of immunotherapeutics for the treatment of cancer. The growing availability of "human" antibodies, the increased epitope repertoire due to genomics and proteomics efforts, and advances in the means of identification and production of tumor-specific antibodies have greatly increased the potential for cancer therapeutic opportunities. Furthermore, the realization that effector molecule potency must be sufficiently high to be effective at concentrations that might realistically be delivered to the tumor site on an antibody carrier has greatly spurred the fields of medicinal chemistry and radionuclide chelate chemistry to produce such molecules. PMID:12676579

  9. 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. PMID:26951551

  10. 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

  11. Prostate cancer progression. Implications of histopathology.

    PubMed Central

    Ware, J. L.

    1994-01-01

    This review examines selected areas of contemporary prostate cancer research in terms of the impact of prostatic cellular and histopathological heterogeneity. Prostate tumor progression is accompanied by dysregulation of multiple growth factor networks as well as disruption of normal patterns of cell-cell interactions. Molecular and cytogenetic studies demonstrate that prostate cancer results from the accumulation of several different genetic defects. No single event predominates, but modifications in tumor suppressor genes or functional elimination of the suppressor gene product are more common than activation of known oncogenes. Intratumor heterogeneity is also detectable at the genetic level. This further complicates efforts to correlate modifications at specific loci with progression or outcome. The development of new in vitro and in vivo systems for the study of human prostate cancer should increase our understanding of this complex disease. In each approach, knowledge of the histopathology of the normal and neoplastic prostate is essential. PMID:7977655

  12. 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

  13. HOXB13 promotes ovarian cancer progression

    PubMed Central

    Miao, Jiangyong; Wang, Zuncai; Provencher, Heather; Muir, Beth; Dahiya, Sonika; Carney, Erin; Leong, Chee-Onn; Sgroi, Dennis C.; Orsulic, Sandra

    2007-01-01

    Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53−/− mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer. PMID:17942676

  14. 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 ...

  15. In vitro Enrichment of Ovarian Cancer Tumor-initiating Cells

    PubMed Central

    House, Carrie D.; Hernandez, Lidia; Annunziata, Christina M.

    2015-01-01

    Evidence suggests that small subpopulations of tumor cells maintain a unique self-renewing and differentiation capacity and may be responsible for tumor initiation and/or relapse. Clarifying the mechanisms by which these tumor-initiating cells (TICs) support tumor formation and progression could lead to the development of clinically favorable therapies. Ovarian cancer is a heterogeneous and highly recurrent disease. Recent studies suggest TICs may play an important role in disease biology. We have identified culture conditions that enrich for TICs from ovarian cancer cell lines. Growing either adherent cells or non-adherent ‘floater’ cells in a low attachment plate with serum free media in the presence of growth factors supports the propagation of ovarian cancer TICs with stem cell markers (CD133 and ALDH activity) and increased tumorigenicity without the need to physically separate the TICs from other cell types within the culture. Although the presence of floater cells is not common for all cell lines, this population of cells with innate low adherence may have high tumorigenic potential.Compared to adherent cells grown in the presence of serum, TICs readily form spheres, are significantly more tumorigenic in mice, and express putative stem cell markers. The conditions are easy to establish in a timely manner and can be used to study signaling pathways important for maintaining stem characteristics, and to identify drugs or combinations of drugs targeting TICs. The culture conditions described herein are applicable for a variety of ovarian cancer cells of epithelial origin and will be critical in providing new information about the role of TICs in tumor initiation, progression, and relapse. PMID:25742116

  16. Src Kinase Regulation in Progressively Invasive Cancer

    PubMed Central

    Xu, Weichen; Allbritton, Nancy; Lawrence, David S.

    2012-01-01

    Metastatic progression is a multistep process that involves tumor growth and survival, motility and invasion, and subsequent proliferation in an inappropriate environment. The Src protein tyrosine kinase has been implicated in many of the biochemical pathways that drive these behaviors. Although Src itself is only rarely mutated in human tumors, its aberrant activity has been noted in various cancers and suggested to serve as a barometer of metastatic potential. With these features in mind, we examined Src kinase regulation at the structural, enzymatic, and expression levels as a function of progressively invasive prostate cancer cell lines. Surprisingly, both total Src content and kinase activity decrease with increasing cell line aggressiveness, an observation that appears to be inconsistent with the well-documented role of Src in the signaling pathways that drive growth and invasion. However, we do observe a direct correlation between Src kinase specific activity (total Src kinase activity/total Src content) and metastatic aggressiveness, possibly suggesting that in highly aggressive cell lines, key signaling enzymes are globally recruited to drive the cancerous phenotype. In addition, although the expected enhanced phosphorylation of Src at Tyr-416 (activation site) is present in the most aggressive prostate cancer cell lines, unexpectedly high phosphorylation levels at the Tyr-527 inhibitory site are observed as well. The latter, rather than representative of inhibited enzyme, is more indicative of primed Src responsive to local phosphorylated binding partners. PMID:23145001

  17. 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

  18. 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. PMID:27362918

  19. 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

  20. The role of human cervical cancer oncogene in cancer progression.

    PubMed

    Li, Xin-Yu; Wang, Xin

    2015-01-01

    Human cervical cancer oncogene (HCCR) was identified by differential display RT-PCR by screened abnormally expressed genes in cervical human cancers. The overexpressed gene is not only identified in cervical tissues, but also in various human cancers as leukemia/lymphoma, breast, stomach, colon, liver, kidney and ovarian cancer. For its special sensitivities and specificities in human breast cancer and hepatocellular carcinoma, it is expected to be a new biomarker to replace or combine with the existing biomarkers in the diagnose. The HCCR manifests as a negative regulator of the p53 tumor suppressor gene, and its expression is regulated by the PI3K/Akt signaling pathway, modulated by TCF/β-catenin, it also participates in induction of the c-kit proto-oncogene, in activation of PKC and telomerase activities, but the accurate biochemical mechanisms of how HCCR contributes to the malignancies is still unknown. The aim of this review is to summarize the roles of HCCR in cancer progression and the molecular mechanisms involved. PMID:26309489

  1. Pancreatic Cancer: Current Progress and Future Challenges

    PubMed Central

    Hussain, S. Perwez

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the highly lethal malignancies. The highly refractory nature of clinically advanced disease and lack of a reliable biomarker for early detection are major obstructions in improving patient outcome. The recent efforts, however, in understanding the pancreatic tumor biology have resulted in the recognition of novel addictions as well as vulnerabilities of tumor cells and are being assessed for their clinical potential. This special issue highlights some of the recent progress, complexity and challenges towards improving disease outcome in patients with this lethal malignancy. PMID:26929733

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

    PubMed Central

    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. PMID:25455629

  3. 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. PMID:24477002

  4. 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

  5. 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

  6. Post-Newtonian initial data with waves: progress in evolution

    NASA Astrophysics Data System (ADS)

    Kelly, B. J.; Tichy, W.; Zlochower, Y.; Campanelli, M.; Whiting, B.

    2010-06-01

    In Kelly et al (2007 Phys. Rev. D 76 024008), we presented new binary black-hole initial data adapted to puncture evolutions in numerical relativity. These data satisfy the constraint equations to 2.5 post-Newtonian order, and contain a transverse-traceless 'wavy' metric contribution, violating the standard assumption of conformal flatness. We report on progress in evolving these data with a modern 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.

  7. 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."

  8. Hornerin Is Involved in Breast Cancer Progression

    PubMed Central

    Choi, Jinhyuk; Kim, Dong-Il; Kim, Jinkyoung; Kim, Baek-Hui

    2016-01-01

    Purpose The S100 gene family, which comprises over 20 members, including S100A1, S100A2, S100A8, S100A9, profilaggrin, and hornerin encodes low molecular weight calcium-binding proteins with physiological and pathological roles in keratinization. Recent studies have suggested a link between S100 proteins and human cancer progression. The purpose of the present study was to determine the expression levels of hornerin, S100A8, and S100A9 and evaluate their roles in the progression of invasive ductal carcinoma (IDC). Methods Seventy cases of ductal carcinoma in situ (DCIS), IDC, and metastatic carcinoma in lymph nodes (MCN) were included. Tissue microarrays were constructed from lesions of DCIS, IDC, and MCN from the same patients. Expression of hornerin, S100A8, and S100A9 was analyzed using immunohistochemistry. Results The expression of hornerin was associated with the estrogen receptor-negative (p=0.003) and the human epidermal growth factor receptor 2-positive (p=0.002) groups. The expression of S100A8 was associated with a higher pT stage (p=0.017). A significant (p<0.001) correlation between the expression of S100A9 and S100A8 was also found. The mean percentages of hornerin-positive tumor cells in DCIS, IDC, and MCN were 1.0%±3.3% (mean±standard deviation), 12.0%±24.0%, and 75.3%± 27.6%, respectively. The expression of hornerin significantly (p<0.001) increased with the progression of carcinoma. The mean levels of S100A8 and S100A9 in DCIS, IDC, and MCN were not significantly (p>0.050) different. The expression of hornerin increased in a stepwise manner (DCIScancer progression and malignant transformation from preinvasive lesions. PMID:27382389

  9. 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

  10. Towards Predictive Stochastic Dynamical Modeling of Cancer Genesis and Progression

    PubMed Central

    Ao, P.; Galas, D.; Hood, L.; Yin, L.; Zhu, X.M.

    2011-01-01

    Based on an innovative endogenous network hypothesis on cancer genesis and progression we have been working towards a quantitative cancer theory along the systems biology perspective. Here we give a brief report on our progress and illustrate that combing ideas from evolutionary and molecular biology, mathematics, engineering, and physics, such quantitative approach is feasible. PMID:20640781

  11. Progress of Photodynamic Therapy in Gastric Cancer

    PubMed Central

    Narahara, Hiroyuki; Otani, Toru; Okuda, Shigeru

    1999-01-01

    Progress of photodynamic therapy (PDT) in gastric cancer and the clinical outcome are described in this paper. (1) We included the whole lesion and a 5 mm margin in the field for irradiation. Marking by injection of India-ink showing the irradiation field was performed beforehand. (2) We established the standard light dose to be 90 J/cm2 for an argon dye laser and 60 J/cm2 for a pulse wave laser. (3) The size of cancerous lesion curable by PDT was expanded from 3 cm in diameter, i.e. 7 cm2 in area to 4 cm in diameter, i.e. 13 cm2 by employing a new excimer dye laser model, which could emit 4mJ/pulse with 80 Hz pulse frequency. (4) The depth of cancer invasion which could be treated by PDT was increased from about 4 mm, i.e. the superficial part of the submucosal layer (SM-1) to more than 10 mm in depth, i.e. the proper muscular layer. These improvements owe much to the pulse laser, the photodynamic action induced by which permits deeper penetration than that of a continuous wave laser. (5) We employed a side-viewing fiberscope for gastric PDT to irradiate the lesion from an angle of 90°. (6) We designed a simple cut quartz fiber for photoradiation with a spiral spring thickened toward the end. (7) We developed an endoscopic device for photoradiation in PDT which achieves accurate and efficient irradiation. As a result of these improvements a higher cure rate was obtained even with a lower light dose of irradiation. PMID:18493500

  12. The DACH/EYA/SIX gene network and its role in tumor initiation and progression.

    PubMed

    Liu, Yu; Han, Na; Zhou, Si; Zhou, Rong; Yuan, Xun; Xu, Hanxiao; Zhang, Cuntai; Yin, Tiejun; Wu, Kongming

    2016-03-01

    The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients. PMID:26096807

  13. CXCL5 Promotes Prostate Cancer Progression1

    PubMed Central

    Begley, Lesa A; Kasina, Sathish; Mehra, Rohit; Adsule, Shreelekha; Admon, Andrew J; Lonigro, Robert J; Chinnaiyan, Arul M; Macoska, Jill A

    2008-01-01

    CXCL5 is a proangiogenic CXC-type chemokine that is an inflammatory mediator and a powerful attractant for granulocytic immune cells. Unlike many other chemokines, CXCL5 is secreted by both immune (neutrophil, monocyte, and macrophage) and nonimmune (epithelial, endothelial, and fibroblastic) cell types. The current study was intended to determine which of these cell types express CXCL5 in normal and malignant human prostatic tissues, whether expression levels correlated with malignancy and whether CXCL5 stimulated biologic effects consistent with a benign or malignant prostate epithelial phenotype. The results of these studies show that CXCL5 protein expression levels are concordant with prostate tumor progression, are highly associated with inflammatory infiltrate, and are frequently detected in the lumens of both benign and malignant prostate glands. Exogenous administration of CXCL5 stimulates cellular proliferation and gene transcription in both nontransformed and transformed prostate epithelial cells and induces highly aggressive prostate cancer cells to invade through synthetic basement membrane in vitro. These findings suggest that the inflammatory mediator, CXCL5, may play multiple roles in the etiology of both benign and malignant proliferative diseases in the prostate. PMID:18320069

  14. 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

  15. Role of cyclooxygenase-2 in gastric cancer development and progression

    PubMed Central

    Cheng, Jian; Fan, Xiao-Ming

    2013-01-01

    Although the incidence of gastric cancer has been declining in recent decades, it remains a major public health issue as the second leading cause of cancer death worldwide. In China, gastric cancer is still the main cause of death in patients with malignant tumors. Most patients are diagnosed at an advanced stage and mortality is high. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer. The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated. Helicobacter pylori infection, tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer. The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells, while inhibiting apoptosis, assisting angiogenesis and lymphatic metastasis, and participating in cancer invasion and immunosuppression. This review is intended to discuss, comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression, and elucidate the molecular mechanisms which might be involved in the carcinogenesis. PMID:24259966

  16. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.

    PubMed

    Farazi, Paraskevi A; Glickman, Jonathan; Jiang, Shan; Yu, Alice; Rudolph, Karl Lenhard; DePinho, Ronald A

    2003-08-15

    Telomere maintenance and telomerase reactivation are near universal features of human hepatocellular carcinoma (HCC), yet the shorter telomeres and highly abnormal cytogenetic profiles of HCC suggest that telomere erosion and dysfunction may be operative during the formative stages of tumorigenesis. Previous studies have established that the cancer-enhancing or suppressing impact of telomere dysfunction is highly dependent on several parameters including cell type, tumor stage, and p53 status. Here, to understand better the pathogenetic role of telomere dysfunction in the initiation and progression in human HCC, we have used three mechanistically distinct liver cancer-prone model systems (urokinase plasminogen activator transgenic mice, carbon tetrachloride exposure, and diethylnistrosamine treatment) in the context of successive generations of telomerase-deficient mice null for the telomerase RNA component, mTERC. Across all of the HCC model systems, telomere dysfunction suppressed both the incidence and growth of HCC lesions, a trend that mirrored the level of intratumoral proliferative arrest and apoptosis. On the histological level, telomere dysfunction was associated with a significant increase in the number of early stage neoplastic lesions and a reciprocal decline in the occurrence of high-grade malignancies. These genetic data in the mouse indicate that telomere dysfunction exerts an opposing role in the initiation versus progression of HCC and provide a framework for understanding the intimate link among chronic liver disease, chromosomal instability, and increased HCC in humans. PMID:12941829

  17. Heparanase procoagulant activity in cancer progression.

    PubMed

    Nadir, Yona; Brenner, Benjamin

    2016-04-01

    Heparanase is an endo-β-D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix. This activity is strongly implicated in tumor metastasis and angiogenesis. We have earlier demonstrated that apart of its well characterized enzymatic activity, heparanase may also affect the hemostatic system in a non-enzymatic manner. We showed that heparanase up-regulated the expression of the blood coagulation initiator-tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we demonstrated that heparanase directly enhanced TF activity, which led to increased factor Xa production and subsequent activation of the coagulation system. In patients with cancer, increased heparanase procoagulant activity appeared to be a potential predictor of survival. We have also shown that JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor, a finding that may point to a new mechanism of thrombosis in JAK-2 positive patents with essential thrombocytosis. Recently, we found that the solvent accessible surface of TFPI-2 first Kunitz domain had a role in TF/heparanase complex inhibition. Peptides derived from TFPI-2 inhibitory site were shown to reduce coagulation activation induced by heparanase and to attenuate sepsis severity and tumor growth in a mouse model, without predisposing to significant bleeding tendency. These data imply that inhibition of heparanase procoagulant domain is potentially a good target for sepsis and cancer therapy. PMID:27067977

  18. 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. PMID:25225904

  19. The AURORA initiative for metastatic breast cancer

    PubMed Central

    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

    2014-01-01

    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. PMID:25225904

  20. Metastatic prostate cancer initially presenting as chylothorax: A case report

    PubMed Central

    YANG, YU-JIN; SEO, MINJUNG; JEON, HEE-JEONG; NOH, JIN-HEE; PARK, SEOL HOON; CHOI, YUNSUK; JO, JAE-CHEOL; BAEK, JIN HO; KOH, SU-JIN; KIM, HAWK; MIN, YOUNG JOO

    2016-01-01

    Chylothorax is caused by disruption or obstruction of the thoracic duct, which results in leakage of chyle in the pleural space. The most common etiologies are malignancy and trauma. Among the causative malignancies, lymphoma is the most common, followed by primary lung cancer, mediastinal tumors, and other metastatic malignancies. Conversely, prostate cancer has rarely been reported as the cause of chylothorax. We herein report a case of metastatic prostate cancer initially presenting as chylothorax, with disappearance of the pleural effusion after the initiation of androgen deprivation therapy. Moreover, we also discuss the various rare manifestations of metastatic prostate cancer, including chylothorax. PMID:27313861

  1. 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.

  2. 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

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

    PubMed

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

    2015-07-10

    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

  4. Neural Cell Adhesion Protein CNTN1 Promotes the Metastatic Progression of Prostate Cancer.

    PubMed

    Yan, Judy; Ojo, Diane; Kapoor, Anil; Lin, Xiaozeng; Pinthus, Jehonathan H; Aziz, Tariq; Bismar, Tarek A; Wei, Fengxiang; Wong, Nicholas; De Melo, Jason; Cutz, Jean-Claude; Major, Pierre; Wood, Geoffrey; Peng, Hao; Tang, Damu

    2016-03-15

    Prostate cancer metastasis is the main cause of disease-related mortality. Elucidating the mechanisms underlying prostate cancer metastasis is critical for effective therapeutic intervention. In this study, we performed gene-expression profiling of prostate cancer stem-like cells (PCSC) derived from DU145 human prostate cancer cells to identify factors involved in metastatic progression. Our studies revealed contactin 1 (CNTN1), a neural cell adhesion protein, to be a prostate cancer-promoting factor. CNTN1 knockdown reduced PCSC-mediated tumor initiation, whereas CNTN1 overexpression enhanced prostate cancer cell invasion in vitro and promoted xenograft tumor formation and lung metastasis in vivo. In addition, CNTN1 overexpression in DU145 cells and corresponding xenograft tumors resulted in elevated AKT activation and reduced E-cadherin (CDH1) expression. CNTN1 expression was not readily detected in normal prostate glands, but was clearly evident on prostate cancer cells in primary tumors and lymph node and bone metastases. Tumors from 637 patients expressing CNTN1 were associated with prostate cancer progression and worse biochemical recurrence-free survival following radical prostatectomy (P < 0.05). Collectively, our findings demonstrate that CNTN1 promotes prostate cancer progression and metastasis, prompting further investigation into the mechanisms that enable neural proteins to become aberrantly expressed in non-neural malignancies. PMID:26795349

  5. 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

  6. Progranulin: a novel regulator of gastrointestinal cancer progression

    PubMed Central

    DeMorrow, Sharon

    2013-01-01

    Progranulin (PGRN) is a soluble factor that regulates cell proliferation, motility and inflammation. A role for PGRN in the progression of ovarian and breast cancers is well established. However, the expression and subsequent consequences of PGRN on the progression of gastrointestinal tumors is not well recognized. This review briefly summarizes our current knowledge of the mechanisms of action of PGRN and highlights the role of this signaling molecule in various gastrointestinal cancers. PMID:24040621

  7. Cancer Progression and Tumor Growth Kinetics

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan; Kalpathy-Cramer, Jayashree; Wilkerson, Julia; Sprinkhuizen, Sara; Song, Yi-Qiao; Bates, Susan; Rosen, Bruce; Fojo, Tito

    2013-03-01

    We present and analyze tumor growth data from prostate and brain cancer. Scaling the data from different patients shows that early stage prostate tumors show non-exponential growth while advanced prostate and brain tumors enter a stage of exponential growth. The scaling analysis points to the existence of cancer stem cells and/or massive apoptosis in early stage prostate cancer and that late stage cancer growth is not dominated by cancer stem cells. Statistical models of these two growth modes are discussed. Work supported by the National Science Foundation and the National Institutes of Health

  8. 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. PMID:26939741

  9. 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.

  10. 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.

  11. The progression of gliomas is associated with cancer stem cell phenotype.

    PubMed

    Kong, Doo-Sik; Kim, Mi Hyun; Park, Woong-Yang; Suh, Yeon-Lim; Lee, Jung-Il; Park, Kwan; Kim, Jong Hyun; Nam, Do-Hyun

    2008-03-01

    Since cancer stem cells in brain tumors were introduced, there have been few explanations regarding the role of cancer stem cells in the progression of glioma. Here, we investigated their major molecular changes in tumor progression in relation to the stem cell subpopulation. Using 12 surgical specimens of gliomatosis cerebri (GC) in the early and advanced stages, we measured the expression of a panel of cell proliferation, microvessel density, microvessel areas, angiogenic factors and their associated receptors. In addition, expression of neural stem cell markers and associated cytokines were examined in tumor tissues by quantitative real-time RT-PCR. Comparing the biological characteristics between the initial infiltrating lesions (n=7) and progressed lesions (n=5), Sox2 and Musashi-1 were expressed in the tumor tissue at an early and a progressed state. Contrary to the early infiltrative phase representing angiogenesis-independent growth, GC with progression showed that nestin (+), PCNA (+) cells and total vessel area (angioectasia) were markedly increased with a higher expression of proangiogenic molecules and their receptors. These results suggest that tumor progression is mediated by cancer stem cells and cross-talk of cancer stem cells along with their environment and are closely associated with angiogenesis-dependent progression and -independent growth. PMID:18288395

  12. 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

  13. 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

  14. 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

  15. Crizotinib Improves Progression-Free Survival in Some Patients with Advanced Lung Cancer

    MedlinePlus

    ... Prevention Lung Cancer Screening Research Crizotinib Improves Progression-Free Survival in Some Patients with Advanced Lung Cancer ( ... starting treatment without their disease getting worse (progression-free survival), as assessed by radiologic review. Results Progression- ...

  16. Activation of Akt Signaling in Prostate Induces a TGFβ Mediated Restraint on Cancer Progression and Metastasis

    PubMed Central

    Bjerke, Glen A.; Yang, Chun-Song; Frierson, Henry F.; Paschal, Bryce M.; Wotton, David

    2014-01-01

    Mutations in the PTEN tumor suppressor gene are found in a high proportion of human prostate cancers, and in mice, Pten deletion induces high-grade prostate intra-epithelial neoplasia (HGPIN). However, progression from HGPIN to invasive cancer occurs slowly, suggesting that tumorigenesis is subject to restraint. We show that Pten deletion, or constitutive activation of the downstream kinase AKT, activates the transforming growth factor (TGF) β pathway in prostate epithelial cells. TGFβ signaling is known to play a tumor suppressive role in many cancer types, and reduced expression of TGFβ receptors correlates with advanced human prostate cancer. We demonstrate that in combination either with loss of Pten, or expression of constitutively active AKT1, inactivation of TGFβ signaling by deletion of the TGFβ type II receptor gene relieves a restraint on tumorigenesis. This results in rapid progession to lethal prostate cancer, including metastasis to lymph node and lung. In prostate epithelium, inactivation of TGFβ signaling alone is insufficient to initiate tumorigenesis, but greatly accelerates cancer progression. The activation of TGFβ signaling by Pten loss or AKT activation suggests that the same signaling events that play key roles in tumor initiation also induce the activity of a pathway that restrains disease progression. PMID:23995785

  17. 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

  18. 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. PMID:24588719

  19. Comprehensive cancer control: progress and accomplishments.

    PubMed

    Rochester, Phyllis W; Townsend, Julie S; Given, Leslie; Krebill, Hope; Balderrama, Sandra; Vinson, Cynthia

    2010-12-01

    The potential for Comprehensive Cancer Control (CCC) across the nation has been realized in the last decade with 69 Coalitions developing and implementing CCC plans. Many partners at all levels--national, state, jurisdictional, tribal and communities--have contributed to this success. This article details the contribution of these partners across these various levels, with a selection of the many activities contributing to this success. Consequently the cancer burden, although still of major importance, continues to be addressed in significant ways. Although there are future challenges, CCC coalitions continue to play an important role in addressing the cancer burden. PMID:21069448

  20. 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

  1. Time Course of Risk Factors in Cancer Etiology and Progression

    PubMed Central

    Wei, Esther K.; Wolin, Kathleen Y.; Colditz, Graham A.

    2010-01-01

    Patients with cancer increasingly ask what they can do to change their lifestyles and improve outcomes. Risk factors for onset of cancer may differ substantially from those that modify survival with implications for counseling. This review focuses on recent data derived from population-based studies of causes of cancer and of patients with cancer to contrast risk factors for etiology with those that impact survival. For different cancer sites, the level of information to inform the timing of lifestyle exposures and risk of disease onset or progression after diagnosis is often limited. For breast cancer, timing of some exposures, such as radiation, is particularly important. For other exposures, such as physical activity, higher levels may prevent onset and also improve survival. For colon cancer, study of precursor polyps has provided additional insight to timing. Extensive data indicate that physical activity reduces risk of colon cancer, and more limited data suggest that exposure after diagnosis improves survival. Dietary factors including folate and calcium may also reduce risk of onset. More limited data on prostate cancer point to obesity increasing risk of aggressive or advanced disease. Timing of change in lifestyle for change in risk of onset and for survival is important but understudied among patients with cancer. Counseling patients with cancer to increase physical activity and avoid weight gain may improve outcomes. Advice to family members on lifestyle may become increasingly important for breast and other cancers where family history is a strong risk factor. PMID:20644083

  2. Time course of risk factors in cancer etiology and progression.

    PubMed

    Wei, Esther K; Wolin, Kathleen Y; Colditz, Graham A

    2010-09-10

    Patients with cancer increasingly ask what they can do to change their lifestyles and improve outcomes. Risk factors for onset of cancer may differ substantially from those that modify survival with implications for counseling. This review focuses on recent data derived from population-based studies of causes of cancer and of patients with cancer to contrast risk factors for etiology with those that impact survival. For different cancer sites, the level of information to inform the timing of lifestyle exposures and risk of disease onset or progression after diagnosis is often limited. For breast cancer, timing of some exposures, such as radiation, is particularly important. For other exposures, such as physical activity, higher levels may prevent onset and also improve survival. For colon cancer, study of precursor polyps has provided additional insight to timing. Extensive data indicate that physical activity reduces risk of colon cancer, and more limited data suggest that exposure after diagnosis improves survival. Dietary factors including folate and calcium may also reduce risk of onset. More limited data on prostate cancer point to obesity increasing risk of aggressive or advanced disease. Timing of change in lifestyle for change in risk of onset and for survival is important but understudied among patients with cancer. Counseling patients with cancer to increase physical activity and avoid weight gain may improve outcomes. Advice to family members on lifestyle may become increasingly important for breast and other cancers where family history is a strong risk factor. PMID:20644083

  3. 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)

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

    DOE PAGESBeta

    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: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

  5. 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.

  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. Oct-4 is associated with gastric cancer progression and prognosis

    PubMed Central

    Jiang, Wen-Li; Zhang, Peng-Fei; Li, Guo-Feng; Dong, Jian-Hua; Wang, Xue-Song; Wang, Yuan-Yu

    2016-01-01

    Aim To investigate the clinical significance of Oct-4 in the development and progression of gastric cancer. Methods Immunohistochemistry was used to analyze Oct-4 expression in 412 gastric cancer cases. Oct-4 protein levels were upregulated in gastric cancer tissues compared with adjacent noncancerous tissues. Results Positive expression of Oct-4 correlated with age, depth of invasion, Lauren classification, lymph node metastasis, distant metastasis, and TNM stage. In stages I, II, and III, the 5-year survival rate of patients with high expression of Oct-4 was significantly lower than that in patients with low expression of Oct-4. In stage IV, Oct-4 expression did not correlate with the 5-year survival rate. Furthermore, multivariate analysis suggested that the depth of invasion, lymph node metastasis, distant metastasis, TNM stage, and upregulation of Oct-4 were independent prognostic factors of gastric cancer. Conclusion Oct-4 protein is a useful marker in predicting tumor progression and prognosis. PMID:26869797

  8. 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. PMID:25901861

  9. 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

  10. 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

  11. 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. PMID:16515531

  12. 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. PMID:26649828

  13. Somatic LKB1 Mutations Promote Cervical Cancer Progression

    PubMed Central

    Wingo, Shana N.; Gallardo, Teresa D.; Akbay, Esra A.; Liang, Mei-Chi; Contreras, Cristina M.; Boren, Todd; Shimamura, Takeshi; Miller, David S.; Sharpless, Norman E.; Bardeesy, Nabeel; Kwiatkowski, David J.; Schorge, John O.; Wong, Kwok-Kin; Castrillon, Diego H.

    2009-01-01

    Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence. PMID:19340305

  14. 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

  15. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention.

    PubMed

    Cavalieri, Ercole L; Rogan, Eleanor G

    2016-03-01

    Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens. PMID:26979321

  16. Tumor-promoting functions of transforming growth factor-β in progression of cancer

    PubMed Central

    2012-01-01

    Transforming growth factor-β (TGF-β) elicits both tumor-suppressive and tumor-promoting functions during cancer progression. Here, we describe the tumor-promoting functions of TGF-β and how these functions play a role in cancer progression. Normal epithelial cells undergo epithelial-mesenchymal transition (EMT) through the action of TGF-β, while treatment with TGF-β and fibroblast growth factor (FGF)-2 results in transdifferentiation into activated fibroblastic cells that are highly migratory, thereby facilitating cancer invasion and metastasis. TGF-β also induces EMT in tumor cells, which can be regulated by oncogenic and anti-oncogenic signals. In addition to EMT promotion, invasion and metastasis of cancer are facilitated by TGF-β through other mechanisms, such as regulation of cell survival, angiogenesis, and vascular integrity, and interaction with the tumor microenvironment. TGF-β also plays a critical role in regulating the cancer-initiating properties of certain types of cells, including glioma-initiating cells. These findings thus may be useful for establishing treatment strategies for advanced cancer by inhibiting TGF-β signaling. PMID:22111550

  17. 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.

  18. Pancreatic Cancer: Progress in Systemic Therapy

    PubMed Central

    Perkhofer, Lukas; Ettrich, Thomas J.; Seufferlein, Thomas

    2014-01-01

    Background 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. Summary 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. Key Message This review focuses on the current chemotherapy regimens for the systemic treatment of PDAC. Practical Implications 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. PMID:26672477

  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,...

  20. Lineage factors and differentiation states in lung cancer progression.

    PubMed

    Cheung, W K C; Nguyen, D X

    2015-11-19

    Lung cancer encompasses a heterogeneous group of malignancies. Here we discuss how the remarkable diversity of major lung cancer subtypes is manifested in their transforming cell of origin, oncogenic dependencies, phenotypic plasticity, metastatic competence and response to therapy. More specifically, we review the increasing evidence that links this biological heterogeneity to the deregulation of cell lineage-specific pathways and the transcription factors that ultimately control them. As determinants of pulmonary epithelial differentiation, these poorly characterized transcriptional networks may underlie the etiology and biological progression of distinct lung cancers, while providing insight into innovative therapeutic strategies. PMID:25823023

  1. Wound healing and cancer progression in Opisthorchis viverrini associated cholangiocarcinoma.

    PubMed

    Botelho, Monica C; Alves, Helena; Richter, Joachim

    2016-07-01

    Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). It was shown previously that O. viverrini-secreted proteins accelerate wound resolution in human cholangiocytes. Recombinant Ov-GRN-1 (O. viverrini-derived gene encoding granulin-like growth factor) induced angiogenesis and accelerated mouse wound healing. Given the striking similarities of wound healing and cancer progression, here we discuss the major implications of this finding for an infection-induced cancer of major public health significance in the developing world. PMID:27130317

  2. 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

  3. 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.

  4. New Progress of Epigenetic Biomarkers in Urological Cancer.

    PubMed

    Wu, Peng; Cao, Ziyi; Wu, Song

    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

  5. 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

  6. [Research progress of tumor infiltrating lymphocytes in breast cancer].

    PubMed

    Huang, Jiahui; Chen, Xiaosong; Shen, Kunwei

    2015-09-01

    Breast cancer is a heterogeneous disease. The formation and progression of tumor and the sensitivity to treatment differs from patient to patient. In addition to the widely used molecular subtype, novel markers are needed to better personalize the treatment of breast cancer. Tumor infiltrating lymphocyte (TIL) have been consistently documented in breast cancer lesions especially in triple negative and human epidermal growth factor receptor-2 positive breast cancer. Several clinical trials have revealed that TIL are associated with prognosis and can predict therapeutic efficacy of special therapy. TIL could be divided to different subtypes including CD8 + TIL, CD4 + TIL, cytotoxic T lymphocyte-associated antigen-4 + TIL, programmed death-1 + TIL. They play different roles in the process of anti-tumor immunity and can predict different prognosis. Screening out special TIL subtype which is well associated with prognosis and therapeutic efficacy and developing targeting immunotherapy can help to improve outcomes of breast cancer patients. PMID:26654152

  7. 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),...

  8. 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

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

    PubMed

    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

  10. Genetic progression and the waiting time to cancer.

    PubMed

    Beerenwinkel, Niko; Antal, Tibor; Dingli, David; Traulsen, Arne; Kinzler, Kenneth W; Velculescu, Victor E; Vogelstein, Bert; Nowak, Martin A

    2007-11-01

    Cancer results from genetic alterations that disturb the normal cooperative behavior of cells. Recent high-throughput genomic studies of cancer cells have shown that the mutational landscape of cancer is complex and that individual cancers may evolve through mutations in as many as 20 different cancer-associated genes. We use data published by Sjöblom et al. (2006) to develop a new mathematical model for the somatic evolution of colorectal cancers. We employ the Wright-Fisher process for exploring the basic parameters of this evolutionary process and derive an analytical approximation for the expected waiting time to the cancer phenotype. Our results highlight the relative importance of selection over both the size of the cell population at risk and the mutation rate. The model predicts that the observed genetic diversity of cancer genomes can arise under a normal mutation rate if the average selective advantage per mutation is on the order of 1%. Increased mutation rates due to genetic instability would allow even smaller selective advantages during tumorigenesis. The complexity of cancer progression can be understood as the result of multiple sequential mutations, each of which has a relatively small but positive effect on net cell growth. PMID:17997597

  11. CCN6: a modulator of breast cancer progression.

    PubMed

    Leask, Andrew

    2016-06-01

    The expression of the CCN family of matricellular proteins is highly dysregulated in connective tissue pathologies such as fibrosis and highly metastatic cancers. Strategies targeting members of this family, especially CCN2, are under development as novel therapeutic approaches to highly metastatic cancers such as pancreatic cancer. In prior reports, the Kleer laboratory and colleagues have linked reduced expression of CCN6 (WISP3) with aggressive breast cancers. Loss of CCN6 was associated with elevated Akt phosphorylation and TAK1 activation. In a recent report, the same group reports that, by modulating Notch signaling, CCN6 can promote the maintenance of an epithelial phenotype and also reduce cancer cell migration and invasion, tumor initiation, and metastasis (Oncotarget in press DOI: 10.18632/oncotarget.7734 ). These results are consistent with the hypothesis that addition of CCN6 peptides may represent a novel, viable therapeutic approach to blocking aggressive breast cancers. PMID:27086280

  12. 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…

  13. 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…

  14. Abdominal pain as initial presentation of lung cancer

    PubMed Central

    Eisa, Naseem; Alhafez, Bishr; Alraiyes, Abdul Hamid; Alraies, M Chadi

    2014-01-01

    Isolated spleen metastasis (ISM) in general is very rare with a reported incidence of 2.3–7.1% for all solid cancers. Lung cancers rarely metastasise to the spleen. It is very atypical for ISM to be the initial presentation of lung cancer as well. In our case, a 55-year-old woman presented with a 3-week history of left-sided abdominal fullness and dull pain. Workup was remarkable for splenic mass that turns out to be adenocarcinoma with unknown primary tumour. Biopsy of the mass with immunohistochemistry and whole body position emission tomography scan was able to identify lung cancer as the primary tumour. The patient underwent splenectomy, wedge resection of the lung mass along with short-course of chemotherapy. She never had any recurrences since then. PMID:24835801

  15. Extracellular Metabolic Energetics Can Promote Cancer Progression

    PubMed Central

    Loo, Jia Min; Scherl, Alexis; Nguyen, Alexander; Man, Fung Ying; Weinberg, Ethan; Zeng, Zhaoshi; Saltz, Leonard; Paty, Philip B.; Tavazoie, Sohail F.

    2014-01-01

    Summary Colorectal cancer primarily metastasizes to the liver and kills over 600,000 people annually. By functionally screening 661 miRNAs in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of extracellular phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastatic colonization, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting. PMID:25601461

  16. Extracellular metabolic energetics can promote cancer progression.

    PubMed

    Loo, Jia Min; Scherl, Alexis; Nguyen, Alexander; Man, Fung Ying; Weinberg, Ethan; Zeng, Zhaoshi; Saltz, Leonard; Paty, Philip B; Tavazoie, Sohail F

    2015-01-29

    Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting. PMID:25601461

  17. 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. PMID:24420815

  18. Amplification of the 20q chromosomal arm occurs early in tumorigenic transformation and may initiate cancer.

    PubMed

    Tabach, Yuval; Kogan-Sakin, Ira; Buganim, Yosef; Solomon, Hilla; Goldfinger, Naomi; Hovland, Randi; Ke, Xi-Song; Oyan, Anne M; Kalland, Karl-H; Rotter, Varda; Domany, Eytan

    2011-01-01

    Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification. PMID:21297939

  19. Amplification of the 20q Chromosomal Arm Occurs Early in Tumorigenic Transformation and May Initiate Cancer

    PubMed Central

    Buganim, Yosef; Solomon, Hilla; Goldfinger, Naomi; Hovland, Randi; Ke, Xi-Song; Oyan, Anne M.; Kalland, Karl-H.; Rotter, Varda; Domany, Eytan

    2011-01-01

    Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification. PMID:21297939

  20. Regulation of cancer progression by β-endorphin neuron.

    PubMed

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

    2012-02-15

    It is becoming increasingly clear that stressful life events can affect 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 β-endorphin plays a critical role in bringing the stress axis to a state of homeostasis. We have recently shown that enhancement of endogenous levels of β-endorphin in the hypothalamus via β-endorphin 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 β-endorphin is mediated through the suppression of sympathetic neuronal function, which results in increased peripheral natural killer cell and macrophage activities, elevated levels of anti-inflammatory cytokines, and reduced levels of inflammatory cytokines. β-endorphin inhibition of tumor progression also involves alteration in the tumor microenvironment, possibly because of suppression of catecholamine and inflammatory cytokine production, which are known to alter DNA repair, cell-matrix attachments, angiogenic process, and epithelial-mesenchymal transition. Thus, β-endorphin cell therapy may offer some therapeutic value in cancer prevention. PMID:22287549

  1. Therapeutic Cancer Vaccines in Prostate Cancer: The Paradox of Improved Survival Without Changes in Time to Progression

    PubMed Central

    Madan, Ravi A.; Fojo, Tito; Dahut, William L.

    2010-01-01

    Therapeutic cancer vaccines represent a new class of agents in the treatment of cancer. Sipuleucel-T is an antigen-presenting cell–based vaccine that recently demonstrated a significant 4.8-month improvement in overall survival in advanced prostate cancer patients and was well tolerated. The findings of that study have been met with skepticism, primarily because the agent did not change initial disease progression and yet led to longer survival. Although the commonly accepted treatment paradigm suggests that treatments should initially decrease tumor volume, perhaps vaccines work differently. Vaccines may induce delayed responses not seen in the first few months of therapy or they may initiate a dynamic immune response that ultimately slows the tumor growth rate, resulting in longer survival. Subsequent therapies may also combine with the induced immune response, resulting in a combination that is more effective than conventional treatments alone. Also, other treatments may alter tumor-associated antigen expression, enhancing the immune response. Future trials are currently planned to investigate these hypotheses; however, the results of the sipuleucel-T vaccine in prostate cancer should not be dismissed. Results with another vaccine in prostate cancer are similar, perhaps suggesting a class effect. In a broader context, clinicians may need to reconsider how they measure success. Several agents have been approved that produce superior disease progression results, but do not affect overall survival. Given the toxicity and costs of cancer therapies, perhaps studies should put more weight on long-term survival endpoints than on short-term endpoints that may be less consequential. PMID:20798195

  2. 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

  3. Cancer care. Cancer plan--progress report: must try even harder.

    PubMed

    Coombes, Rebecca

    2004-11-25

    Despite progress in some areas, major obstacle achieving a uniformly good service for cancer patients remain. PCTs' lack of expertise is holding back progress ending delays in diagnosis and treatment. SHAs need to be clearer with PCTs about the importance of meeting national targets. PMID:15597927

  4. 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

  5. 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

  6. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; Cuomo, Arturo; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression. PMID:26064880

  7. 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.

  8. Progress in the Development of a Shock Initiation Model

    NASA Astrophysics Data System (ADS)

    Howe, Philip M.; Benson, David J.

    2004-07-01

    We used an Eulerian hydrocode to guide the development of an engineering model of shock initiation. The model in its current form has two types of hotspots- one from void collapse, and one from interactions at grain boundaries. The dependence of hotspot and bulk temperatures upon shock strength is estimated using a Gruneisen equation of state for the bulk solid, calibrated against measurements of reaction times for steady state detonation. Arrhenius kinetics are used to predict ignition times associated with hotspot temperatures. The hotspots contribute a small amount of energy to the shock front, thereby causing some shock front acceleration, and also serve to initiate erosive burning. The two erosive burn reactions that result from the two different types of hotspots compete to consume the material. The energy release rate resulting from the competition of these reactions was used as input to a method of characteristics code. This in turn was used to calculate particle velocity — time profiles at various simulated gauge locations. These calculated profiles were compared with experiment.

  9. Dual role of GRK5 in cancer development and progression

    PubMed Central

    Gambardella, J; Franco, A; Giudice, C Del; Fiordelisi, A; Cipolletta, E; Ciccarelli, M; Trimarco, B; Iaccarino, G; Sorriento, D

    2016-01-01

    GRK5 is a multifunctional protein that is able to move within the cell in response to various stimuli to regulate key intracellular signaling from receptor activation, on plasmamembrane, to gene transcription, in the nucleus. Thus, GRK5 is involved in the development and progression of several pathological conditions including cancer. Several reports underline the involvement of GRK5 in the regulation of tumor growth even if they appear controversial. Indeed, depending on its subcellular localization and on the type of cancer, GRK5 is able to both inhibit cancer progression, through the desensitization of GPCR and non GPCR-receptors (TSH, PGE2R, PDGFR), and induce tumor growth, acting on non-receptor substrates (p53, AUKA and NPM1). All these findings suggest that targeting GRK5 could be an useful anti-cancer strategy, for specific tumor types. In this review, we will discuss the different effects of this kinase in the induction and progression of tumorigenesis, the molecular mechanisms by which GRK5 exerts its effects, and the potential therapeutic strategies to modulate them. PMID:27326393

  10. CYLD regulates keratinocyte differentiation and skin cancer progression in humans

    PubMed Central

    Alameda, J P; Fernández-Aceñero, M J; Moreno-Maldonado, R; Navarro, M; Quintana, R; Page, A; Ramírez, A; Bravo, A; Casanova, M L

    2011-01-01

    CYLD is a gene mutated in familial cylindromatosis and related diseases, leading to the development of skin appendages tumors. Although the deubiquitinase CYLD is a skin tumor suppressor, its role in skin physiology is unknown. Using skin organotypic cultures as experimental model to mimic human skin, we have found that CYLD acts as a regulator of epidermal differentiation in humans through the JNK signaling pathway. We have determined the requirement of CYLD for the maintenance of epidermal polarity, keratinocyte differentiation and apoptosis. We show that CYLD overexpression increases keratinocyte differentiation while CYLD loss of function impairs epidermal differentiation. In addition, we describe the important role of CYLD in the control of human non-melanoma skin cancer progression. Our results show the reversion of the malignancy of human squamous cell carcinomas that express increased levels of CYLD, while its functional inhibition enhances the aggressiveness of these tumors which progress toward spindle cell carcinomas. We have found that the mechanisms through which CYLD regulates skin cancer progression include the control of tumor differentiation, angiogenesis and cell survival. These findings of the role of CYLD in human skin cancer prognosis make our results relevant from a therapeutic point of view, and open new avenues for exploring novel cancer therapies. PMID:21900959

  11. 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.

  12. 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. PMID:26383164

  13. 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

  14. Supramolecular nanofibrils inhibit cancer progression in vitro and in vivo

    PubMed Central

    Kuang, Yi; Du, Xuewen; Zhou, Jie; Xu, Bing

    2014-01-01

    The recent discovery of the inverse comorbidity between cancer and Alzheimer’s disease implies that one may use amyloids to inhibit tumors. During the conversion of a dipeptide segment (Phe-Phe) in β-amyloid into a supramolecular hydrogelator, we obtained a small molecule (1) that can self-assembly into nanofibrils via multiple intermolecular hydrogen bonding and aromatic-aromatic interactions. Interestingly, while the monomers of 1 are innocuous, the nanofibrils formed by 1 can selectively inhibit the growth of glioblastoma cells over neuronal cells. To further assess the potential of this small molecular nanofibrils as anti-cancer agent, we exam the biological activity of the nanofibrils and demonstrate that the nanofibrils of 1 efficiently inhibit the progression of cancer cells (e.g., HeLa cells) both in cell assays and on xenograft mice model. This work suggests that nanofibrils derived from core motif of amyloid are effective agents for inhibiting cancer progression. Thus, this work contributes to a new approach that uses supramolecular nanofibrils as de novo molecular amyloids for inhibiting the growth of cancer cells. PMID:24574174

  15. 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. PMID:26522157

  16. [The mechanisms of prostate cancer progression through androgen receptor].

    PubMed

    Goto, Yusuke; Sakamoto, Shinichi; Ichikawa, Tomohiko

    2016-01-01

    Androgen receptor(AR) has a critical role in prostate cancer(PCa) progression and targeting AR axis signaling by androgen deprivation therapy is a standard treatment for advanced PCa. Recently, the role of AR even in castration-resistant PCa(CRPC) is well recognized and emerging evidence suggests survival advantages of treatment by targeting AR in CRPC. This review outlines AR functions that contribute to PCa progression, AR structural alterations and AR activation via intracrine, co-factors, and kinase pathways in CRPC. Finally, we describe about recently reported bipolar androgen therapy as a novel treatment for CRPC targeting AR. PMID:26793880

  17. Targeting Cancer-initiating Cells With Oncolytic Viruses

    PubMed Central

    Cripe, Timothy P; Wang, Pin-Yi; Marcato, Paola; Mahller, Yonatan Y; Lee, Patrick WK

    2009-01-01

    Recent studies in a variety of leukemias and solid tumors indicate that there is significant heterogeneity with respect to tumor-forming ability within a given population of tumor cells, suggesting that only a subpopulation of cells is responsible for tumorigenesis. These cells have been commonly referred to as cancer stem cells (CSCs) or cancer-initiating cells (CICs). CICs have been shown to be relatively resistant to conventional anticancer therapies and are thus thought to be responsible for disease relapse. As such, they represent a potentially critical therapeutic target. Oncolytic viruses are in clinical trials for cancer and kill cells through mechanisms different from conventional therapeutics. Because these viruses are not susceptible to the same pathways of drug or radiation resistance, it is important to learn whether CICs are susceptible to oncolytic virus infection. Here we review the available data regarding the ability of several different oncolytic virus types to target CICs for destruction. PMID:19672244

  18. 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

  19. A new model of time scheme for progression of colorectal cancer

    PubMed Central

    2014-01-01

    Background tumourigenesis can be regarded as an evolutionary process, in which the transformation of a normal cell into a tumour cell involves a number of limiting genetic and epigenetic events. To study the progression process, time schemes have been proposed for studying the process of colorectal cancer based on extensive clinical investigations. Moreover, a number of mathematical models have been designed to describe this evolutionary process. These models assumed that the mutation rate of genes is constant during different stages. However, it has been pointed that the subsequent driver mutations appear faster than the previous ones and the cumulative time to have more driver mutations grows with the growing number of gene mutations. Thus it is still a challenge to calculate the time when the first mutation occurs and to determine the influence of tumour size on the mutation rate. Results In this work we present a general framework to remedy the shortcoming of existing models. Rather than considering the information of gene mutations based on a population of patients, we for the first time determine the values of the selective advantage of cancer cells and initial mutation rate for individual patients. The averaged values of doubling time and selective advantage coefficient determined by our model are consistent with the predictions made by the published models. Our calculation showed that the values of biological parameters, such as the selective advantage coefficient, initial mutation rate and cell doubling time diversely depend on individuals. Our model has successfully predicted the values of several important parameters in cancer progression, such as the selective advantage coefficient, initial mutation rate and cell doubling time. In addition, experimental data validated our predicted initial mutation rate and cell doubling time. Conclusions The introduced new parameter makes our proposed model more flexible to fix various types of information based on

  20. Erlotinib Resistance in Lung Cancer: Current Progress and Future Perspectives

    PubMed Central

    Tang, Joy; Salama, Rasha; Gadgeel, Shirish M.; Sarkar, Fazlul H.; Ahmad, Aamir

    2012-01-01

    Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options. PMID:23407898

  1. Dietary energy balance modulates ovarian cancer progression and metastasis

    PubMed Central

    Al-Wahab, Zaid; Tebbe, Calvin; Chhina, Jasdeep; Dar, Sajad A.; Morris, Robert T.; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R.; Rattan, Ramandeep

    2014-01-01

    A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer. PMID:25026276

  2. 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

  3. Graphene as cancer theranostic tool: progress and future challenges.

    PubMed

    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

  4. 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

  5. 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

  6. The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the Apc(Min/+) mouse.

    PubMed

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

    2011-01-01

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

  7. 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. PMID:27080303

  8. 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

  9. Anoikis molecular pathways and its role in cancer progression.

    PubMed

    Paoli, Paolo; Giannoni, Elisa; Chiarugi, Paola

    2013-12-01

    Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix, behaving as a critical mechanism in preventing adherent-independent cell growth and attachment to an inappropriate matrix, thus avoiding colonizing of distant organs. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are vital steps during cancer progression and metastatic colonization, the ability of cancer cells to resist anoikis has now attracted main attention from the scientific community. Cancer cells develop anoikis resistance due to several mechanisms, including change in integrins' repertoire allowing them to grow in different niches, activation of a plethora of inside-out pro-survival signals as over-activation of receptors due to sustained autocrine loops, oncogene activation, growth factor receptor overexpression, or mutation/upregulation of key enzymes involved in integrin or growth factor receptor signaling. In addition, tumor microenvironment has also been acknowledged to contribute to anoikis resistance of bystander cancer cells, by modulating matrix stiffness, enhancing oxidative stress, producing pro-survival soluble factors, triggering epithelial-mesenchymal transition and self-renewal ability, as well as leading to metabolic deregulations of cancer cells. All these events help cancer cells to inhibit the apoptosis machinery and sustain pro-survival signals after detachment, counteracting anoikis and constituting promising targets for anti-metastatic pharmacological therapy. This article is part of a Special Section entitled: Cell Death Pathways. PMID:23830918

  10. Chemokines and their receptors in lung cancer progression and metastasis*

    PubMed Central

    Cheng, Zeng-hui; Shi, Yu-xin; Yuan, Min; Xiong, Dan; Zheng, Jiang-hua; Zhang, Zhi-yong

    2016-01-01

    Lung cancer is the leading cause of cancer-related mortality around the world. Despite advancements in diagnosis, surgical techniques, and neoadjuvant chemoradiotherapy over the last decade, the mortality rate is still high and the 5-year survival is a dismal 15%. Fortunately, early detection by low-dose computed tomography (LDCT) scans has reduced mortality by 20%; yet, overall, 5-year-survival remains low at less than 20%. Therefore, in order to ameliorate this situation, a thorough understanding of the underlying molecular mechanisms is urgently needed. Chemokines and their receptors, crucial microenvironmental factors, play important roles in lung tumor genesis, progression, and metastasis, and exploring the mechanisms of this might bring new insights into early diagnosis and precisely targeted treatment. Consequently, this review will mainly focus on recent advancements on the axes of chemokines and their receptors of lung cancer. PMID:27143261

  11. Export of sphingosine-1-phosphate and cancer progression

    PubMed Central

    Takabe, Kazuaki; Spiegel, Sarah

    2014-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis, lymphangiogenesis, and immune response; all are critical processes of cancer progression. Although some important roles of intracellular S1P have recently been uncovered, the majority of its biological effects are known to be mediated via activation of five specific G protein-coupled receptors [S1P receptor (S1PR)1–S1PR5] located on the cell surface. Secretion of S1P produced inside cells by sphingosine kinases can then signal through these receptors in autocrine, paracrine, and/or endocrine manners, coined “inside-out” signaling of S1P. Numerous studies suggest that secreted S1P plays important roles in cancer progression; thus, understanding the mechanism by which S1P is exported out of cells, particularly cancer cells, is both interesting and important. Here we will review the current understanding of the transport of S1P out of cancer cells and its potential roles in the tumor microenvironment. PMID:24474820

  12. 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. PMID:26099173

  13. Tpl2 induces castration resistant prostate cancer progression and metastasis.

    PubMed

    Lee, Hye Won; Cho, Hyun Jung; Lee, Se Jeong; Song, Hye Jin; Cho, Hee Jin; Park, Min Chul; Seol, Ho Jun; Lee, Jung-Il; Kim, Sunghoon; Lee, Hyun Moo; Choi, Han Yong; Nam, Do-Hyun; Joo, Kyeung Min

    2015-05-01

    Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC. PMID:25274482

  14. 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.

  15. A role for STEAP2 in prostate cancer progression.

    PubMed

    Whiteland, Helen; Spencer-Harty, Samantha; Morgan, Claire; Kynaston, Howard; Thomas, David Hywel; Bose, Pradeep; Fenn, Neil; Lewis, Paul; Jenkins, Spencer; Doak, Shareen H

    2014-12-01

    Prostate adenocarcinoma is the second most frequent cancer worldwide and is one of the leading causes of male cancer-related deaths. However, it varies greatly in its behaviour, from indolent non-progressive disease to metastatic cancers with high associated mortality. The aim of this study was to identify predictive biomarkers for patients with localised prostate tumours most likely to progress to aggressive disease, to facilitate future tailored clinical treatment and identify novel therapeutic targets. The expression of 602 genes was profiled using oligoarrays, across three prostate cancer cell lines: CA-HPV-10, LNCaP and PC3, qualitatively identifying several potential prognostic biomarkers. Of particular interest was six transmembrane epithelial antigen of the prostate (STEAP) 1 and STEAP 2 which was subsequently analysed further in prostate cancer tissue samples following optimisation of an RNA extraction method from laser captured cells isolated from formalin-fixed paraffin-embedded biopsy samples. Quantitative analysis of STEAP1 and 2 gene expression were statistically significantly associated with the metastatic cell lines DU145 and PC3 as compared to the normal prostate epithelial cell line, PNT2. This expression pattern was also mirrored at the protein level in the cells. Furthermore, STEAP2 up-regulation was observed within a small patient cohort and was associated with those that had locally advanced disease. Subsequent mechanistic studies in the PNT2 cell line demonstrated that an over-expression of STEAP2 resulted in these normal prostate cells gaining an ability to migrate and invade, suggesting that STEAP2 expression may be a crucial molecule in driving the invasive ability of prostate cancer cells. PMID:25248617

  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. Differential remodeling of extracellular matrices by breast cancer initiating cells.

    PubMed

    Raja, Anju M; Xu, Shuoyu; Zhuo, Shuangmu; Tai, Dean C S; Sun, Wanxin; So, Peter T C; Welsch, Roy E; Chen, Chien-Shing; Yu, Hanry

    2015-10-01

    Cancer initiating cells (CICs) have been the focus of recent anti-cancer therapies, exhibiting strong invasion capability via potentially enhanced ability to remodel extracellular matrices (ECM). We have identified CICs in a human breast cancer cell line, MX-1, and developed a xenograft model in SCID mice. We investigated the CICs' matrix-remodeling effects using Second Harmonic Generation (SHG) microscopy to identify potential phenotypic signatures of the CIC-rich tumors. The isolated CICs exhibit higher proliferation, drug efflux and drug resistant properties in vitro; were more tumorigenic than non-CICs, resulting in more and larger tumors in the xenograft model. The CIC-rich tumors have less collagen in the tumor interior than in the CIC-poor tumors supporting the idea that the CICs can remodel the collagen more effectively. The collagen fibers were preferentially aligned perpendicular to the CIC-rich tumor boundary while parallel to the CIC-poor tumor boundary suggesting more invasive behavior of the CIC-rich tumors. These findings would provide potential translational values in quantifying and monitoring CIC-rich tumors in future anti-cancer therapies. CIC-rich tumors remodel the collagen matrix more than CIC-poor tumors. PMID:25597396

  18. 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. PMID:27117662

  19. Cancer-associated mesenchymal stem cells aggravate tumor progression

    PubMed Central

    Kudo-Saito, Chie

    2015-01-01

    Mesenchymal stem cells (MSCs) have both stemness and multi-modulatory activities on other cells, and the immunosuppressive and tumor-promotive mechanisms have been intensively investigated in cancer. The role of MSCs appears to be revealed in tumor aggravation, and targeting MSCs seems to be a promising strategy for treating cancer patients. However, it is still impractical in clinical therapy, since the precise MSCs are poorly understood in the in vivo setting. In previous studies, MSCs were obtained from different sources, and were prepared by ex vivo expansion for a long term. The inconsistent experimental conditions made the in vivo MSCs obscure. To define the MSCs in the host is a priority issue for targeting MSCs in cancer therapy. We recently identified a unique subpopulation of MSCs increasing in mice and human with cancer metastasis. These MSCs are specifically expanded by metastatic tumor cells, and promote tumor progression and dissemination accompanied by immune suppression and dysfunction in the host, more powerfully than normal MSCs growing without interference of cancer. In this review, we summarize current knowledge of the role of MSCs in tumor aggravation, along with our new findings of the bizarre MSCs. PMID:25883937

  20. 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.

  1. 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.

  2. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression

    PubMed Central

    Chan, Chia-Hsin; Morrow, John Kenneth; Li, Chien-Feng; Gao, Yuan; Jin, Guoxiang; Moten, Asad; Stagg, Loren J.; Ladbury, John E.; Cai, Zhen; Xu, Dazhi; Logothetis, Christopher J.; Hung, Mien-Chie; Zhang, Shuxing; Lin, Hui-Kuan

    2013-01-01

    Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell cycle progression, senescence, metabolism, cancer progression and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival, Akt-mediated glycolysis as well as triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent anti-tumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression. PMID:23911321

  3. Comprehensive nucleosome mapping of the human genome in cancer progression

    PubMed Central

    Druliner, Brooke R.; Vera, Daniel; Johnson, Ruth; Ruan, Xiaoyang; Apone, Lynn M.; Dimalanta, Eileen T.; Stewart, Fiona J.; Boardman, Lisa; Dennis, Jonathan H.

    2016-01-01

    Altered chromatin structure is a hallmark of cancer, and inappropriate regulation of chromatin structure may represent the origin of transformation. Important studies have mapped human nucleosome distributions genome wide, but the role of chromatin structure in cancer progression has not been addressed. We developed a MNase-Transcription Start Site Sequence Capture method (mTSS-seq) to map the nucleosome distribution at human transcription start sites genome-wide in primary human lung and colon adenocarcinoma tissue. Here, we confirm that nucleosome redistribution is an early, widespread event in lung (LAC) and colon (CRC) adenocarcinoma. These altered nucleosome architectures are consistent between LAC and CRC patient samples indicating that they may serve as important early adenocarcinoma markers. We demonstrate that the nucleosome alterations are driven by the underlying DNA sequence and potentiate transcription factor binding. We conclude that DNA-directed nucleosome redistributions are widespread early in cancer progression. We have proposed an entirely new hierarchical model for chromatin-mediated genome regulation. PMID:26735342

  4. [Role of cancer stem cells in the progression and heterogeneity of melanoma].

    PubMed

    Széky, Balázs; Silló, Pálma; Fábián, Melinda; Mayer, Balázs; Kárpáti, Sarolta; Németh, Krisztián

    2016-08-01

    Over the past decade a rare cell population called cancer stem cells has been identified in both solid tumors and hematologic cancers. These cells are reminiscent of somatic and embryonic stem cells and play a critical role in the initiation and progression of malignancies. As all stem cells, they are able to undergo asymmetric cell division and hence renew themselves and create various other progenies with heterogenous phenotypes. A growing body of literature suggested that stem cell subpopulations contribute significantly to the growth and metastatic properties of melanoma. This review gives a comprehensive overview of the current literature on melanoma stem cells, with a special emphasis on the signaling pathways responsible for the homeostatic growth of melanocytes and the uncontrolled proliferation of melanoma cells. The importance of the local microenvironment are demonstrated through summarizing the role of various cell types, soluble factors and cell adhesion molecules in the progression of melanoma and the creation of treatment resistant cancer cell clones. Last but not least, the models of melanoma progression will be introduced and a variety of cellular markers will be presented that may be used to identify and therapeutically target melanoma. Orv. Hetil., 2016, 157(34), 1339-1348. PMID:27546799

  5. Mesenchymal Stem/Stromal Cells in Stromal Evolution and Cancer Progression

    PubMed Central

    Cammarota, Francesca; Laukkanen, Mikko O.

    2016-01-01

    The study of cancer biology has mainly focused on malignant epithelial cancer cells, although tumors also contain a stromal compartment, which is composed of stem cells, tumor-associated fibroblasts (TAFs), endothelial cells, immune cells, adipocytes, cytokines, and various types of macromolecules comprising the extracellular matrix (ECM). The tumor stroma develops gradually in response to the needs of epithelial cancer cells during malignant progression initiating from increased local vascular permeability and ending to remodeling of desmoplastic loosely vascularized stromal ECM. The constant bidirectional interaction of epithelial cancer cells with the surrounding microenvironment allows damaged stromal cell usage as a source of nutrients for cancer cells, maintains the stroma renewal thus resembling a wound that does not heal, and affects the characteristics of tumor mesenchymal stem/stromal cells (MSCs). Although MSCs have been shown to coordinate tumor cell growth, dormancy, migration, invasion, metastasis, and drug resistance, recently they have been successfully used in treatment of hematopoietic malignancies to enhance the effect of total body irradiation-hematopoietic stem cell transplantation therapy. Hence, targeting the stromal elements in combination with conventional chemotherapeutics and usage of MSCs to attenuate graft-versus-host disease may offer new strategies to overcome cancer treatment failure and relapse of the disease. PMID:26798356

  6. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells

    PubMed Central

    Scarlett, Uciane K.; Rutkowski, Melanie R.; Rauwerdink, Adam M.; Fields, Jennifer; Escovar-Fadul, Ximena; Baird, Jason; Cubillos-Ruiz, Juan R.; Jacobs, Ana C.; Gonzalez, Jorge L.; Weaver, John; Fiering, Steven

    2012-01-01

    We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity. PMID:22351930

  7. Checkpoint inhibition for colorectal cancer: progress and possibilities.

    PubMed

    Paul, Barry; O'Neil, Bert H; McRee, Autumn J

    2016-06-01

    Colorectal cancer (CRC) remains the third most common cause of cancer death in the USA. Despite an increase in the repertoire of treatment options available for CRC, median overall survival has plateaued at approximately 2.5 years. Strategies that engage the patient's native immune system to overcome checkpoint inhibition have proven to be promising in subsets of CRCs, specifically those with mismatch repair deficiency. Further studies are required to determine combinations of standard therapies with immunotherapy drugs and to discover the best biomarkers to predict response. This review provides insight into the progress made in treating patients with advanced CRC with immunotherapeutics and the areas that demand further research to make these drugs more effective in this patient population. PMID:27197538

  8. 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. PMID:26945016

  9. 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. PMID:27224890

  10. EGFR Mutation Positive Stage IV Non-Small-Cell Lung Cancer: Treatment Beyond Progression

    PubMed Central

    Van Assche, Katrijn; Ferdinande, Liesbeth; Lievens, Yolande; Vandecasteele, Katrien; Surmont, Veerle

    2014-01-01

    Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men and women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10–15% in Western countries, epidermal growth factor receptor (EGFR) mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper, we present three patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing. PMID:25538894

  11. Tissue transglutaminase-2 promotes gastric cancer progression via the ERK1/2 pathway

    PubMed Central

    Zhou, Quan; Wu, Xiongyan; Chen, Xuehua; Li, Jianfang; Zhu, Zhenggang; Liu, Bingya; Su, Liping

    2016-01-01

    Gastric cancer (GC) is one of the most common tumors worldwide and involves extensive local tumor invasion, metastasis, and poor prognosis. Understanding mechanisms regulating progression of GC is necessary for developing effective therapeutic strategies. Tissue transglutaminase-2 (TG2), a multifunctional member of the transglutaminase family, has been shown to be critical for tumor initiation and progression. However, how TG2 promotes the progression of GC is unknown. We report that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain- and loss-of-function approaches, we observed that TG2 promoted GC cell proliferation, migration, invasion, as well as tumorigenesis and peritoneal metastasis in vivo. These events were associated with the ERK1/2 pathway activation and an ERK1/2 inhibitor (U0126) inhibited cell proliferation, migration, and invasion induced by overexpression of TG2. In summary, TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer. PMID:26771235

  12. When Urothelial Differentiation Pathways Go Wrong: Implications for Bladder Cancer Development and Progression

    PubMed Central

    DeGraff, David J.; Cates, Justin M.; Mauney, Joshua R.; Clark, Peter E.; Matusik, Robert; Adam, Rosalyn M.

    2016-01-01

    Differentiation is defined as the ability of a cell to acquire full functional behavior. For instance, the function of bladder urothelium is to act as a barrier to the diffusion of solutes into or out of the urine after excretion by the kidney. The urothelium also serves to protect the detrusor muscle from toxins present in stored urine. A major event in the initiation and progression of bladder cancer is loss of urothelial differentiation. This is important because less differentiated urothelial tumors (higher histologic tumor grade) are typically associated with increased biologic and clinical aggressiveness. The differentiation status of urothelial carcinomas can be assessed by histopathologic examination and is reflected in the assignment of a histologic grade (low-grade or high-grade). Although typically limited to morphologic evaluation in most routine diagnostic practices, tumor grade can also be assessed using biochemical markers. Indeed, current pathological analysis of tumor specimens is increasingly reliant on molecular phenotyping. Thus, high priorities for bladder cancer research include identification of (1) biomarkers that will enable the identification of high grade T1 tumors that pose the most threat and require the most aggressive treatment; (2) biomarkers that predict the likelihood that a low grade, American Joint Committee on Cancer stage pTa bladder tumor will progress into an invasive carcinoma with metastatic potential; (3) biomarkers that indicate which pTa tumors are most likely to recur, thus enabling clinicians to prospectively identify patients who require aggressive treatment; and (4) how these markers might contribute to biological processes that underlie tumor progression and metastasis, potentially through loss of terminal differentiation. This review will discuss the proteins associated with urothelial cell differentiation, with a focus on those implicated in bladder cancer, and other proteins that may be involved in neoplastic

  13. Potential role of tumor microenvironment in the progression of oral cancer.

    PubMed

    Patil, Shankargouda; Rao, Roopa; Raj, Thirumal

    2015-03-01

    The stromal cells adjacent to the tumor including the fibroblasts, infammatory cells, lymphatic and vascular endothelial cells constitute the 'tumor microenvironment' (TM).(1) Recent in vivo and invitro studies have emphasized the role of stromal components on the growth, differentiation and invasiveness of the tumor cells. In addition, vascular, lymphatic or perineural invasion have proven to have independent prognostic value.(2) Despite the compelling evidence correlating the TM with the initiation and progression of cancer, our knowledge on the role of the genes mediating the various cellular interactions in the tumour stroma is limited.(2,3). PMID:26057928

  14. Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression

    PubMed Central

    2009-01-01

    Background It is well recognized that colorectal cancer does not frequently metastasize to bone. The aim of this retrospective study was to establish whether colorectal cancer ever bypasses other organs and metastasizes directly to bone and whether the presence of lung lesions is superior to liver as a better predictor of the likelihood and timing of bone metastasis. Methods We performed a retrospective analysis on patients with a clinical diagnosis of colon cancer referred for staging using whole-body 18F-FDG PET and CT or PET/CT. We combined PET and CT reports from 252 individuals with information concerning patient history, other imaging modalities, and treatments to analyze disease progression. Results No patient had isolated osseous metastasis at the time of diagnosis, and none developed isolated bone metastasis without other organ involvement during our survey period. It took significantly longer for colorectal cancer patients to develop metastasis to the lungs (23.3 months) or to bone (21.2 months) than to the liver (9.8 months). Conclusion: Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare, perhaps more rare than we previously thought. Our findings suggest that resistant metastasis to the lungs predicts potential disease progression to bone in the colorectal cancer population better than liver metastasis does. PMID:19664211

  15. Osteoarthritis disease progression model using six year follow-up data from the osteoarthritis initiative.

    PubMed

    Passey, Chaitali; Kimko, Holly; Nandy, Partha; Kagan, Leonid

    2015-03-01

    The objective was to develop a quantitative model of disease progression of knee osteoarthritis over 6 years using the total WOMAC score from patients enrolled into the Osteoarthritis Initiative (OAI) study. The analysis was performed using data from the Osteoarthritis Initiative database. The time course of the total WOMAC score of patients enrolled into the progression cohort was characterized using non-linear mixed effect modeling in NONMEM. The effect of covariates on the status of the disease and the progression rate was investigated. The final model provided a good description of the experimental data using a linear progression model with a common baseline (19 units of the total WOMAC score). The WOMAC score decreased by 1.77 units/year in 89% of the population or increased by 1.74 units/year in 11% of the population. Multiple covariates were found to affect the baseline and the rate of progression, including BMI, sex, race, the use of pain medications, and the limitation in activity due to symptoms. A mathematical model to describe the disease progression of osteoarthritis in the studied population was developed. The model identified two sub-populations with increasing or decreasing total WOMAC score over time, and the effect of important covariates was quantified. PMID:25212288

  16. 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...

  17. 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…

  18. Tumor-derived exosomes in cancer progression and treatment failure

    PubMed Central

    Shen, Bo; Feng, Jifeng

    2015-01-01

    Exosomes have diameter within the range of 30-100nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  19. Recent Progress in Light-Triggered Nanotheranostics for Cancer Treatment.

    PubMed

    Zhang, Pengcheng; Hu, Chunhua; Ran, Wei; Meng, Jia; Yin, Qi; Li, Yaping

    2016-01-01

    Treatments of high specificity are desirable for cancer therapy. Light-triggered nanotheranostics (LTN) mediated cancer therapy could be one such treatment, as they make it possible to visualize and treat the tumor specifically in a light-controlled manner with a single injection. Because of their great potential in cancer therapy, many novel and powerful LTNs have been developed, and are mainly prepared from photosensitizers (PSs) ranging from small organic dyes such as porphyrin- and cyanine-based dyes, semiconducting polymers, to inorganic nanomaterials such as gold nanoparticles, transition metal chalcogenides, carbon nanotubes and graphene. Using LTNs and localized irradiation in combination, complete tumor ablation could be achieved in tumor-bearing animal models without causing significant toxicity. Given their great advances and promising future, we herein review LTNs that have been tested in vivo with a highlight on progress that has been made in the past a couple of years. The current challenges faced by these LTNs are also briefly discussed. PMID:27217830

  20. Tumor-derived exosomes in cancer progression and treatment failure.

    PubMed

    Yu, Shaorong; Cao, Haixia; Shen, Bo; Feng, Jifeng

    2015-11-10

    Exosomes have diameter within the range of 30-100 nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  1. Recent Progress in Light-Triggered Nanotheranostics for Cancer Treatment

    PubMed Central

    Zhang, Pengcheng; Hu, Chunhua; Ran, Wei; Meng, Jia; Yin, Qi; Li, Yaping

    2016-01-01

    Treatments of high specificity are desirable for cancer therapy. Light-triggered nanotheranostics (LTN) mediated cancer therapy could be one such treatment, as they make it possible to visualize and treat the tumor specifically in a light-controlled manner with a single injection. Because of their great potential in cancer therapy, many novel and powerful LTNs have been developed, and are mainly prepared from photosensitizers (PSs) ranging from small organic dyes such as porphyrin- and cyanine-based dyes, semiconducting polymers, to inorganic nanomaterials such as gold nanoparticles, transition metal chalcogenides, carbon nanotubes and graphene. Using LTNs and localized irradiation in combination, complete tumor ablation could be achieved in tumor-bearing animal models without causing significant toxicity. Given their great advances and promising future, we herein review LTNs that have been tested in vivo with a highlight on progress that has been made in the past a couple of years. The current challenges faced by these LTNs are also briefly discussed. PMID:27217830

  2. Onco-Golgi: Is Fragmentation a Gate to Cancer Progression?

    PubMed Central

    Petrosyan, Armen

    2015-01-01

    The Golgi apparatus-complex is a highly dynamic organelle which is considered the “heart” of intracellular transportation. Since its discovery by Camillo Golgi in 1873, who described it as the “black reaction,” and despite the enormous volume of publications about Golgi, this apparatus remains one of the most enigmatic of the cytoplasmic organelles. A typical mammalian Golgi consists of a parallel series of flattened, disk-shaped cisternae which align into stacks. The tremendous volume of Golgi-related incoming and outgoing traffic is mediated by different motor proteins, including members of the dynein, kinesin, and myosin families. Yet in spite of the strenuous work it performs, Golgi contrives to maintain its monolithic morphology and orchestration of matrix and residential proteins. However, in response to stress, alcohol, and treatment with many pharmacological drugs over time, Golgi undergoes a kind of disorganization which ranges from mild enlargement to critical scattering. While fragmentation of the Golgi was confirmed in cancer by electron microscopy almost fifty years ago, it is only in recent years that we have begun to understand the significance of Golgi fragmentation in the biology of tumors. Below author would like to focus on how Golgi fragmentation opens the doors for cascades of fatal pathways which may facilitate cancer progression and metastasis. Among the issues addressed will be the most important cancer-specific hallmarks of Golgi fragmentation, including aberrant glycosylation, abnormal expression of the Ras GTPases, dysregulation of kinases, and hyperactivity of myosin motor proteins. PMID:27064441

  3. Imaging in Colorectal Cancer: Progress and Challenges for the Clinicians.

    PubMed

    Van Cutsem, Eric; Verheul, Henk M W; Flamen, Patrik; Rougier, Philippe; Beets-Tan, Regina; Glynne-Jones, Rob; Seufferlein, Thomas

    2016-01-01

    The use of imaging in colorectal cancer (CRC) has significantly evolved over the last twenty years, establishing important roles in surveillance, diagnosis, staging, treatment selection and follow up. The range of modalities has broadened with the development of novel tracer and contrast agents, and the fusion of technologies such as positron emission tomography (PET) and computed tomography (CT). Traditionally, the most widely used modality for assessing treatment response in metastasised colon and rectal tumours is CT, combined with use of the RECIST guidelines. However, a growing body of evidence suggests that tumour size does not always adequately correlate with clinical outcomes. Magnetic resonance imaging (MRI) is a more versatile technique and dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted (DW)-MRI may be used to evaluate biological and functional effects of treatment. Integrated fluorodeoxyglucose (FDG)-PET/CT combines metabolic and anatomical imaging to improve sensitivity and specificity of tumour detection, and a number of studies have demonstrated improved diagnostic accuracy of this modality in a variety of tumour types, including CRC. These developments have enabled the progression of treatment strategies in rectal cancer and improved the detection of hepatic metastatic disease, yet are not without their limitations. These include technical, economical and logistical challenges, along with a lack of robust evidence for standardisation and formal guidance. In order to successfully apply these novel imaging techniques and utilise their benefit to provide truly personalised cancer care, advances need to be clinically realised in a routine and robust manner. PMID:27589804

  4. No paradox, no progress: inverse cancer comorbidity in people with other complex diseases.

    PubMed

    Tabarés-Seisdedos, Rafael; Dumont, Nancy; Baudot, Anaïs; Valderas, Jose M; Climent, Joan; Valencia, Alfonso; Crespo-Facorro, Benedicto; Vieta, Eduard; Gómez-Beneyto, Manuel; Martínez, Salvador; Rubenstein, John L

    2011-06-01

    In the past 5 years, several leading groups have attempted to explain why individuals with Down's syndrome have a reduced risk of many solid tumours and an increased risk of leukaemia and testicular cancer. Niels Bohr, the Danish physicist, noted that a paradox could initiate progress. We think that the paradox of a medical disorder protecting against cancer could be formalised in a new model of inverse cancer morbidity in people with other serious diseases. In this Personal View, we review evidence from epidemiological and clinical studies that supports a consistently lower than expected occurrence of cancer in patients with Down's syndrome, Parkinson's disease, schizophrenia, diabetes, Alzheimer's disease, multiple sclerosis, and anorexia nervosa. Intriguingly, most comorbidities are neuropsychiatric or CNS disorders. We provide a brief overview of evidence indicating genetic and molecular connections between cancer and these complex diseases. Inverse comorbidity could be a valuable model to investigate common or related pathways or processes and test new therapies, but, most importantly, to understand why certain people are protected from the malignancy. PMID:21498115

  5. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer.

    PubMed

    Wu, Y-C; Tang, S-J; Sun, G-H; Sun, K-H

    2016-04-21

    In the tumor microenvironment, chemokine system has a critical role in tumorigenesis and metastasis. The acquisition of stem-like properties by cancer cells is involved in metastasis and drug resistance, which are pivotal problems that result in poor outcomes in patients with lung cancer. Patients with advanced lung cancer present high plasma levels of transforming growth factor-β1 (TGFβ1), which correlate with poor prognostic features. Therefore, TGFβ1 may be important in the tumor microenvironment, where chemokines are widely expressed. However, the role of chemokines in TGFβ1-induced tumor progression still remains unclear. In our study, TGFβ1 upregulated CXC chemokine receptor expression, migration, invasion, epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in lung adenocarcinoma. We found that CXCR7 was the most upregulated chemokine receptor induced by TGFβ1. CXCR7 knockdown resulted in reduction of migration, invasion and EMT induced by TGFβ1, whereas CXCR4 knockdown did not reverse TGFβ1-promoted EMT. CXCR7 silencing significantly decreased cancer sphere-forming capacity, stem-like properties, chemoresistance and TGFβ1-induced CSC tumor initiation in vivo. In clinical samples, high TGFβ1 and CXCR7 expression was significantly associated with the late stages of lung adenocarcinoma. Moreover, TGFβ1 and CXCR7 coexpression was positively correlated with the CSC marker, CD44, which is associated with lymph node metastasis. Besides, patients with high expression of both CXCR7 and TGFβ1 presented a significantly worse survival rate. These results suggest that the TGFβ1-CXCR7 axis may be a prognostic marker and may provide novel targets for combinational therapies to be used in the treatment of advanced lung cancer in the future. PMID:26212008

  6. Progress in the mechanism and drug development of castration-resistant prostate cancer.

    PubMed

    Zuo, Minzan; Xu, Xi; Li, Tinghan; Ge, Raoling; Li, Zhiyu

    2016-05-01

    Although prostate cancer can initially respond to androgen deprivation therapy, it will inevitably relapse and switch to a castration-resistant state. The progress in understanding the mechanism of castration-resistant prostate cancer (CRPC) has led to the evolution of novel agents, including sipuleucel-T as an immunomodulant agent, enzalutamide as an androgen receptor antagonist, docetaxel as a chemotherapeutic agent and radium-223 as a radiopharmaceutical agent. In this review, we discuss the main mechanisms of CRPC and the development of promising agents along with the novel therapies in the clinic. New therapeutic challenges remain, such as the identification of predictive biomarkers and the optimal combinations of agents. Future investigation is still needed for a better understanding of CRPC. PMID:27149562

  7. MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

    PubMed Central

    Gabay, Meital; Li, Yulin; Felsher, Dean W.

    2014-01-01

    The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the “hallmark” features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be “addicted” to MYC because of both tumor cell–intrinsic, cell-autonomous and host-dependent, immune cell–dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis. PMID:24890832

  8. Cancer stem-like cells contribute to cisplatin resistance and progression in bladder cancer.

    PubMed

    Zhang, Yi; Wang, Zhi; Yu, Jin; Shi, Jia zhong; Wang, Chun; Fu, Wei hua; Chen, Zhi wen; Yang, Jin

    2012-09-01

    A variety of cancer stem-like cells (CSCs) have been shown to be responsible for cancer tumorigenicity, relapse and metastasis. Despite several reports demonstrating the presence of CSCs in human bladder cancer, their identities are still under debate, and few studies have examined their roles in cisplatin resistance and related tumor progression. In this study, a subpopulation of CSCs was enriched following cisplatin selection from the bladder cell line T24. The cisplatin-resistant T24 cells displayed a greater self-renewal capacity as demonstrated by higher levels of sphere formation and stem cell marker expression, contained a larger proportion of side population cells and exhibited higher tumorigenicity. They also possessed epithelial-mesenchymal transition characteristics. Furthermore, a strong correlation between the levels of Bmi1 and Nanog expression and the degree of malignancy of urothelial cell carcinomas tissues was observed. We provide the first direct evidence that CSC-like cells exist in the population of cisplatin-resistant bladder cancer cells and may play a role in the progression and drug resistance of bladder cancer. PMID:22343321

  9. Aberrant nocturnal cortisol and disease progression in women with breast cancer.

    PubMed

    Zeitzer, Jamie M; Nouriani, Bita; Rissling, Michelle B; Sledge, George W; Kaplan, Katherine A; Aasly, Linn; Palesh, Oxana; Jo, Booil; Neri, Eric; Dhabhar, Firdaus S; Spiegel, David

    2016-07-01

    While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p < 0.004, Wilcoxon Signed-Rank). This cortisol aberration was associated with cancer progression such that the larger the aberration, the shorter the disease-free interval (time from initial diagnosis to metastasis; r = -0.30, p = 0.004; linear regression). The same aberrant spike was present in a similar percent of women without ABC and associated with concomitant sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer. PMID:27314577

  10. Role of MTA1 in Cancer Progression and Metastasis

    PubMed Central

    Sen, Nirmalya; Gui, Bin; Kumar, Rakesh

    2014-01-01

    The MTA1 protein contributes to the process of cancer progression and metastasis through multiple genes and protein targets and interacting proteins with roles in transformation, anchorage-independent growth, invasion, survival, DNA-repair, angiogenesis, hormone-independence, metastasis and therapeutic resistance. MTA proteins control a spectrum of cancer promoting processes by modulating the expression of target genes and/or the activity of MTA-interacting proteins. In the case of MTA1, these functions are manifested through post-translational modifications of MTA1 in response to upstream signals, MTA1 interaction with binding proteins and the expression of target gene products. The MTA1 coregulator interacts with nucleosomes through modified histones and is an integrator of extracellular signaling and gene activator. Studies delineating the molecular basis of dual functionality of MTA1 reveal that the functions of MTA1-chromatin modifying complexes in the context of target gene regulation are dynamic in nature. The nature and targets of MTA1-chromatin modifying complexes are also governed by the dynamic plasticity of the nucleosome landscape as well as kinetics of activation and inactivation of enzymes responsible for post-translational modifications on the MTA1 protein. These broadly applicable functions also explain why MTA1 may be a ‘hub’ gene, whose current understanding is limited to selective influences on gene with roles in cancer but further research may reveal a more global influence. Because the deregulation of enzymes and their substrates with roles in MTA1-biology is not necessarily limited to cancer, we speculate that the lessons from MTA1 as a prototype dual master coregulator will be relevant for other human diseases. In this context, the concept of the dynamic nature of corepressor versus coactivator complexes and the MTA1 proteome as a function of time to signal is likely to be generally applicable to other multi-proteins regulatory complexes

  11. The effect of vascular endothelial growth factor in the progression of bladder cancer and diabetic retinopathy

    PubMed Central

    Aldebasi, Yousef H; Rahmani, Arshad H; Khan, Amjad A; Aly, Salah Mesalhy

    2013-01-01

    Bladder cancer and diabetic retinopathy is a major public health and economical burden worldwide. Despite its high prevalence, the molecular mechanisms that induce or develop bladder carcinomas and diabetic retinopathy progression are poorly understood but it might be due to the disturbance in balance between angiogenic factors such as VEGF and antiangiogenic factors such as pigment epithelium derived growth factor. VEGF is one of the important survival factors for endothelial cells in the process of normal physiological and abnormal angiogenesis and induce the expression of antiapoptotic proteins in the endothelial cells. It is also the major initiator of angiogenesis in cancer and diabetic retinopathy, where it is up-regulated by oncogenic expression and different type of growth factors. The alteration in VEGF and VEGF receptors gene and overexpression, determines a diseases phenotype and ultimately the patient’s clinical outcome. However, expressional and molecular studies were made on VEGF to understand the exact mechanism of action in the genesis and progression of bladder carcinoma and diabetic retinopathy , but still how VEGF mechanism involve in such type of disease progression are not well defined. Some other factors also play a significant role in the process of activation of VEGF pathways. Therefore, further detailed analysis via molecular and therapeutic is needed to know the exact mechanisms of VEGF in the angiogenesis pathway. The detection of these types of diseases at an early stage, predict how it will behave and act in response to treatment through regulation of VEGF pathways. The present review aimed to summarize the mechanism of alteration of VEGF gene pathways, which play a vital role in the development and progression of bladder cancer and diabetic retinopathy. PMID:23641300

  12. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

    SciTech Connect

    Hao, Hui-fang; Takaoka, Munenori; Bao, Xiao-hong; Wang, Zhi-gang; Tomono, Yasuko; Sakurama, Kazufumi; Ohara, Toshiaki; Fukazawa, Takuya; Yamatsuji, Tomoki; Fujiwara, Toshiyoshi; Naomoto, Yoshio

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer A novel FAK inhibitor TAE226 suppressed FAK activity in HCT116 colon cancer cells. Black-Right-Pointing-Pointer TAE226 suppressed proliferation and migration, with a modest effect on adhesion. Black-Right-Pointing-Pointer Silencing of FAK by siRNA made no obvious difference on cancer cell attachment. Black-Right-Pointing-Pointer TAE226 treatment suppressed the progression of peritoneal dissemination. Black-Right-Pointing-Pointer Oral administration of TAE226 prolonged the survival of tumor-bearing mice. -- Abstract: Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken

  13. Tumor-initiating label-retaining cancer cells in human gastrointestinal cancers undergo asymmetric cell division.

    PubMed

    Xin, Hong-Wu; Hari, Danielle M; Mullinax, John E; Ambe, Chenwi M; Koizumi, Tomotake; Ray, Satyajit; Anderson, Andrew J; Wiegand, Gordon W; Garfield, Susan H; Thorgeirsson, Snorri S; Avital, Itzhak

    2012-04-01

    Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment. PMID:22331764

  14. Killing Is Not Enough: How Apoptosis Hijacks Tumor-Associated Macrophages to Promote Cancer Progression.

    PubMed

    Weigert, Andreas; Mora, Javier; Sekar, Divya; Syed, Shahzad; Brüne, Bernhard

    2016-01-01

    Macrophages are a group of heterogeneous cells of the innate immune system that are crucial to the initiation, progression, and resolution of inflammation. Moreover, they control tissue homeostasis in healthy tissue and command a broad sensory arsenal to detect disturbances in tissue integrity. Macrophages possess a remarkable functional plasticity to respond to irregularities and to initiate programs that allow overcoming them in order to return back to normal. Thus, macrophages kill malignant or transformed cells, rearrange extracellular matrix, take up and recycle cellular as well as molecular debris, initiate cellular growth cascades, and favor directed migration of cells. As an example, apoptotic death of bystander cells is sensed by macrophages, initiating functional responses that support all hallmarks of cancer. In this chapter, we describe how tumor cell apoptosis hijacks tumor-associated macrophages to promote tumor growth. We propose that tumor therapy should not only kill malignant cells but also target the interaction of the host with apoptotic cancer cells, as this might be efficient to limit the protumor action of apoptotic cells and boost the antitumor potential of macrophages. Leaving the apoptotic cell/macrophage interaction untouched might also limit the benefit of conventional tumor cell apoptosis-focused therapy since surviving tumor cells might receive overwhelming support by the wound healing response that apoptotic tumor cells will trigger in local macrophages, thereby enhancing tumor recurrence. PMID:27558823

  15. ZNF367 Inhibits Cancer Progression and Is Targeted by miR-195

    PubMed Central

    Jain, Meenu; Zhang, Lisa; Boufraqech, Myriem; Liu-Chittenden, Yi; Bussey, Kimberly; Demeure, Michael J.; Wu, Xiaolin; Su, Ling; Pacak, Karel; Stratakis, Constantine A.; Kebebew, Electron

    2014-01-01

    Background Several members of the zinc finger protein family have been recently shown to have a role in cancer initiation and progression. Zinc finger protein 367 (ZNF367) is a member of the zinc finger protein family and is expressed in embryonic or fetal erythroid tissue but is absent in normal adult tissue. Methodology/Principal Findings We show that ZNF367 is overexpressed in adrenocortical carcinoma, malignant pheochromocytoma/paraganglioma and thyroid cancer as compared to normal tissue and benign tumors. Using both functional knockdown and ectopic overexpression in multiple cell lines, we show that ZNF367 inhibits cellular proliferation, invasion, migration, and adhesion to extracellular proteins in vitro and in vivo. Integrated gene and microRNA expression analyses showed an inverse correlation between ZNF367 and miR-195 expression. Luciferase assays demonstrated that miR-195 directly regulates ZNF367 expression and that miR-195 regulates cellular invasion. Moreover, integrin alpha 3 (ITGA3) expression was regulated by ZNF367. Conclusions/Significance Our findings taken together suggest that ZNF367 regulates cancer progression. PMID:25047265

  16. Changes in cellular mechanical properties during onset or progression of colorectal cancer

    PubMed Central

    Ciasca, Gabriele; Papi, Massimiliano; Minelli, Eleonora; Palmieri, Valentina; De Spirito, Marco

    2016-01-01

    Colorectal cancer (CRC) development represents a multistep process starting with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations confer a selective growth advantage to colonic epithelial cells that form first dysplastic crypts, and then malignant tumours and metastases. All these steps are accompanied by deep mechanical changes at the cellular and the tissue level. A growing consensus is emerging that such modifications are not merely a by-product of the malignant progression, but they could play a relevant role in the cancer onset and accelerate its progression. In this review, we focus on recent studies investigating the role of the biomechanical signals in the initiation and the development of CRC. We show that mechanical cues might contribute to early phases of the tumour initiation by controlling the Wnt pathway, one of most important regulators of cell proliferation in various systems. We highlight how physical stimuli may be involved in the differentiation of non-invasive cells into metastatic variants and how metastatic cells modify their mechanical properties, both stiffness and adhesion, to survive the mechanical stress associated with intravasation, circulation and extravasation. A deep comprehension of these mechanical modifications may help scientist to define novel molecular targets for the cure of CRC. PMID:27621568

  17. Changes in cellular mechanical properties during onset or progression of colorectal cancer.

    PubMed

    Ciasca, Gabriele; Papi, Massimiliano; Minelli, Eleonora; Palmieri, Valentina; De Spirito, Marco

    2016-08-28

    Colorectal cancer (CRC) development represents a multistep process starting with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations confer a selective growth advantage to colonic epithelial cells that form first dysplastic crypts, and then malignant tumours and metastases. All these steps are accompanied by deep mechanical changes at the cellular and the tissue level. A growing consensus is emerging that such modifications are not merely a by-product of the malignant progression, but they could play a relevant role in the cancer onset and accelerate its progression. In this review, we focus on recent studies investigating the role of the biomechanical signals in the initiation and the development of CRC. We show that mechanical cues might contribute to early phases of the tumour initiation by controlling the Wnt pathway, one of most important regulators of cell proliferation in various systems. We highlight how physical stimuli may be involved in the differentiation of non-invasive cells into metastatic variants and how metastatic cells modify their mechanical properties, both stiffness and adhesion, to survive the mechanical stress associated with intravasation, circulation and extravasation. A deep comprehension of these mechanical modifications may help scientist to define novel molecular targets for the cure of CRC. PMID:27621568

  18. Primary progressive aphasia as the initial manifestation of corticobasal degeneration. A "three in one " syndrome?

    PubMed

    Ioannides, Panos; Karacostas, Dimitris; Hatzipantazi, Maria; Ioannis, Milonas

    2005-01-01

    In 1994, the term "Pick complex" was proposed to indicate significant clinical and pathological overlapping between primary progressive aphasia, frontal lobe dementia and corticobasal degeneration. We report the case of a 60-year-old man, who initially presented progressive non-fluent aphasia with orofacial apraxia, and subsequently, over a period of 3 years, developed mutism, pathological laughter, extrapyramidal rigidity, dystonia, alien hand syndrome and bulbar signs. An extensive haematological, immunological and biochemical work up was normal. The results of neuroimaging studies and neuropsychological tests, along with the clinical evolution, finally led us to the ?three in one? diagnosis, supporting the concept of Pick complex. PMID:16324238

  19. Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression

    PubMed Central

    Skubitz, Amy P.N.; Taras, Elizabeth P.; Boylan, Kristin L.M.; Waldron, Nate N.; Oh, Seunguk; Panoskaltsis-Mortari, Angela; Vallera, Daniel A.

    2013-01-01

    Objectives While most women with ovarian cancer will achieve complete remission after treatment, the majority will relapse within two years, highlighting the need for novel therapies. Cancer stem cells (CSC) have been identified in ovarian cancer and most other carcinomas as a small population of cells that can self-renew. CSC are more chemoresistant and radio-resistant than the bulk tumor cells; it is likely that CSC are responsible for relapse, the major problem in cancer treatment. CD133 has emerged as one of the most promising markers for CSC in ovarian cancer. The hypothesis driving this study is that despite their low numbers in ovarian cancer tumors, CSC can be eradicated using CD133 targeted therapy and tumor growth can be inhibited. Methods Ovarian cancer cell lines were evaluated using flow cytometry for expression of CD133. In vitro viability studies with an anti-CD133 targeted toxin were performed on one of the cell lines, NIH:OVCAR5. The drug was tested in vivo using a stably transfected luciferase-expressing NIH:OVCAR5 subline in nude mice, so that tumor growth could be monitored by digital imaging in real time. Results Ovarian cancer cell lines showed 5.6% to 16.0% CD133 expression. dCD133KDEL inhibited the in vitro growth of NIH:OVCAR5 cells. Despite low numbers of CD133-expressing cells in the tumor population, intraperitoneal drug therapy caused a selective decrease in tumor progression in intraperitoneal NIH: OVCAR5-luc tumors. Conclusions Directly targeting CSC that are a major cause of drug resistant tumor relapse with an anti-CD133 targeted toxin shows promise for ovarian cancer therapy. PMID:23721800

  20. In situ quantification of genomic instability in breast cancer progression

    SciTech Connect

    Ortiz de Solorzano, Carlos; Chin, Koei; Gray, Joe W.; Lockett, Stephen J.

    2003-05-15

    Genomic instability is a hallmark of breast and other solid cancers. Presumably caused by critical telomere reduction, GI is responsible for providing the genetic diversity required in the multi-step progression of the disease. We have used multicolor fluorescence in situ hybridization and 3D image analysis to quantify genomic instability cell-by-cell in thick, intact tissue sections of normal breast epithelium, preneoplastic lesions (usual ductal hyperplasia), ductal carcinona is situ or invasive carcinoma of the breast. Our in situ-cell by cell-analysis of genomic instability shows an important increase of genomic instability in the transition from hyperplasia to in situ carcinoma, followed by a reduction of instability in invasive carcinoma. This pattern suggests that the transition from hyperplasia to in situ carcinoma corresponds to telomere crisis and invasive carcinoma is a consequence of telomerase reactivation afertelomere crisis.

  1. A fluid model of cancer progression and treatment

    NASA Astrophysics Data System (ADS)

    Wise, Steven; Cristini, Vittorio; Lowengrub, John; Zheng, Xiaoming

    2003-11-01

    In this talk, we will present recent progress on a computer simulator of cancer based on a fluid model of tumor growth. The tumor is represented as an incompressible fluid with a source that represents cell-proliferation. Angiogenesis and its complex nonlinear interplay with cell-growth are included as well as the effects of traditional and new therapies. We find that tumors while growing develop shape instabilities that lead to tissue invasion and possible metastasization. In addition, traditional therapy may have a two-fold effect while causing a tumor to shrink by killing the tumor cells, a shape instability may occur leading to tumor fragmentation leading to migration of small cell-clusters through the external tissue and blood vessels thus enhancing the potential for mestastasization.

  2. Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients

    PubMed Central

    Kato, Kikuya; Uchida, Junji; Kukita, Yoji; Kumagai, Toru; Nishino, Kazumi; Inoue, Takako; Kimura, Madoka; Oba, Shigeyuki; Imamura, Fumio

    2016-01-01

    Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5–100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies. PMID:27381430

  3. Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients.

    PubMed

    Kato, Kikuya; Uchida, Junji; Kukita, Yoji; Kumagai, Toru; Nishino, Kazumi; Inoue, Takako; Kimura, Madoka; Oba, Shigeyuki; Imamura, Fumio

    2016-01-01

    Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5-100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies. PMID:27381430

  4. Alterations in mechanical properties are associated with prostate cancer progression.

    PubMed

    Wang, Xuejian; Wang, Jianbo; Liu, Yingxi; Zong, Huafeng; Che, Xiangyu; Zheng, Wei; Chen, Feng; Zhu, Zheng; Yang, Deyong; Song, Xishuang

    2014-03-01

    Cancer progression and metastasis have been shown to be accompanied by alterations in the mechanical properties of tissues, but the relationship between the mechanical properties and malignant behavior in prostate cancer (Pca) is less clear. The aims of this study were to detect the mechanical properties of benign prostatic hyperplasia (BPH) and Pca tissues on both the macro- and micro-scales, to explore the relationships between mechanical properties and malignant behavior and, finally, to identify the important molecules in the mechanotransduction signaling pathway. We demonstrated that the strain index of Pca tissue was significantly higher than that of BPH tissue on the macro-scale but the Young's modulus of the Pca tissues, especially in advanced Pca, was lower than that of BPH tissues on the micro-scale. These two seemingly contradictory results can be explained by the excessive proliferation of tumor cells (Ki-67) and the degradation of scaffold proteins (collagens). These data indicate that alterations of the macro- and micro-mechanical properties of Pca tissues with malignant behavior are contradictory. The mechanical properties of tissues might be useful as a new risk factor for malignancy and metastasis in Pca. Furthermore, collagens, matrix metalloproteinase, fibronectin, and integrins might be the important molecules in the mechanotransduction signaling pathway. PMID:24504844

  5. Apigenin blocks IKKα activation and suppresses prostate cancer progression.

    PubMed

    Shukla, Sanjeev; Kanwal, Rajnee; Shankar, Eswar; Datt, Manish; Chance, Mark R; Fu, Pingfu; MacLennan, Gregory T; Gupta, Sanjay

    2015-10-13

    IKKα has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKα inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKα inhibitor. Here we report apigenin, in micro molar range, inhibits IKKα kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKα, attenuates IKKα kinase activity and suppresses NF-ĸB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145. We also showed that apigenin caused cell cycle arrest similar to knockdown of IKKα in prostate cancer cells. Studies in xenograft mouse model indicate that apigenin feeding suppresses tumor growth, lowers proliferation and enhances apoptosis. These effects correlated with inhibition of p-IKKα, NF-ĸB/p65, proliferating cell nuclear antigen and increase in cleaved caspase 3 expression in a dose-dependent manner. Overall, our results suggest that inhibition of cell proliferation, invasiveness and decrease in tumor growth by apigenin are mediated by its ability to suppress IKKα and downstream targets affecting NF-ĸB signaling pathways. PMID:26435478

  6. Loss of SPARC in bladder cancer enhances carcinogenesis and progression

    PubMed Central

    Said, Neveen; Frierson, Henry F.; Sanchez-Carbayo, Marta; Brekken, Rolf A.; Theodorescu, Dan

    2013-01-01

    Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis. PMID:23321672

  7. Syndecans as Modulators and Potential Pharmacological Targets in Cancer Progression

    PubMed Central

    Barbouri, Despoina; Afratis, Nikolaos; Gialeli, Chrisostomi; Vynios, Demitrios H.; Theocharis, Achilleas D.; Karamanos, Nikos K.

    2014-01-01

    Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs “shed SDCs” in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma. PMID:24551591

  8. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

    PubMed Central

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  9. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells.

    PubMed

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O'Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  10. Progression in Substance Use Initiation: A Multilevel Discordant Monozygotic Twin Design

    PubMed Central

    Richmond-Rakerd, Leah S.; Slutske, Wendy S.; Deutsch, Arielle R.; Lynskey, Michael T.; Agrawal, Arpana; Madden, Pamela A.F.; Bucholz, Kathleen K.; Heath, Andrew C.; Martin, Nicholas G.

    2015-01-01

    Considerable attention has been paid to the “gateway” pattern of drug use initiation in which individuals progress from tobacco and alcohol use to cannabis and other illicit drugs. The extent to which this sequence reflects a causal impact of licit substance use on illicit substance involvement remains unclear. Clarifying the mechanisms underlying substance use initiation may help inform our understanding of risk for psychopathology, as increasing research is demonstrating associations between initiation patterns and heavier involvement. This study examined patterns of substance use initiation using a discordant twin design. Participants were 3,476 monozygotic twins (37% male) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation. Multilevel proportional hazard regression models were employed to (a) estimate within-twin-pair and between-twin-pair contributions to associations between the ages of onset of different drugs; and (b) examine whether the magnitude of effects differed as a function of the order of substance use initiation. Finding significant effects within twin pairs would support the hypothesis that the age of initiation of one substance causally influences the age of initiation of a subsequent substance. Finding significant effects between twin pairs would support the operation of familial influences that explain variation in the ages of initiation of multiple drugs. Within-twin-pair effects for typical patterns were modest. When initiation was atypical, however, larger within-twin-pair effects were observed and causal influences were more strongly implicated. Results support the utility of examining the timing and ordering of substance use initiation within sophisticated, genetically informative designs. PMID:26098047