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pancreatic cancer microenvironment

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https://www.readbyqxmd.com/read/28292435/obstacles-posed-by-the-tumor-microenvironment-to-t%C3%A2-cell-activity-a-case-for-synergistic-therapies
#1
REVIEW
Kristin G Anderson, Ingunn M Stromnes, Philip D Greenberg
T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28289164/challenges-and-opportunities-in-modeling-pancreatic-cancer
#2
Michael E Feigin, David A Tuveson
The ability to faithfully model complex processes lies at the heart of experimental biology. Although a reductionist approach necessarily reduces this complexity, it is nevertheless required for untangling the contributions and interactions of the various system components. It has long been appreciated that cancer is a complex process that involves positive and negative interactions between tumor cells, normal host tissue, and the associated cells of the tumor microenvironment. However, accurate models for studying these complex interactions in vitro have remained elusive...
March 13, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28286568/immunotherapy-in-pancreatic-cancer-treatment-a-new-frontier
#3
REVIEW
Komal Thind, Leslie J Padrnos, Ramesh K Ramanathan, Mitesh J Borad
Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy...
January 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/28276831/pancreatic-cancer-stroma-controversies-and-current-insights
#4
Daniel Ansari, Maria Carvajo, Monika Bauden, Roland Andersson
Pancreatic cancer is characterized by a dense stromal response. The stroma includes a heterogeneous mass of cells, including pancreatic stellate cells, fibroblasts, immune cells and nerve cells, as well as extracellular matrix proteins, cytokines and growth factors, which interact with the tumor cells. Previous research has indicated that stromal elements contribute to tumor growth and aggressiveness. However, recent studies suggest that some elements of the stroma may actually restrain the tumor. This review focuses on the complex interactions between the stromal microenvironment and tumor cells, discussing molecular mechanisms and potential future diagnostic and therapeutic approaches by targeting the stroma...
February 24, 2017: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/28260082/cancer-associated-fibroblasts-enhance-pancreatic-cancer-cell-invasion-by-remodeling-the-metabolic-conversion-mechanism
#5
Tao Shan, Shuo Chen, Xi Chen, Wan Run Lin, Wei Li, Jiancang Ma, Tao Wu, Xijuan Cui, Hong Ji, Yiming Li, Ya'an Kang
We investigated the mechanism of cancer-associated fibroblasts (CAFs) in promoting the invasion and metastasis of pancreatic cancer cells in a non-vascular manner. We verified the original generation of isolated cultured CAFs and normal fibroblasts (NFs) based on the expression of α-SMA and vimentin, and we examined the cell glycolysis level through glucose consumption and lactate production experiments. The mRNA and protein expression of CAF glycolytic enzymes, lactate dehydrogenase and pyruvate kinase m2, were examined by RT-PCR and western blotting, respectively...
February 28, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28259298/the-cornerstone-k-ras-mutation-in-pancreatic-adenocarcinoma-from-cell-signaling-network-target-genes-biological-processes-to-therapeutic-targeting
#6
REVIEW
Nicolas Jonckheere, Romain Vasseur, Isabelle Van Seuningen
RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence...
March 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28254412/bromodomain-inhibitors-jq1-and-i-bet-762-as-potential-therapies-for-pancreatic-cancer
#7
Ana S Leal, Charlotte R Williams, Darlene B Royce, Patricia A Pioli, Michael B Sporn, Karen T Liby
Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells...
February 27, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28253833/emerging-antibodies-for-the-treatment-of-pancreatic-cancer
#8
Kalliopi Andrikou, Chiara Peterle, Stefania Pipitone, Massimiliano Salati, Stefano Cascinu
Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC. Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment...
March 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/28249896/lipocalin-2-promotes-pancreatic-ductal-adenocarcinoma-by-regulating-inflammation-in-the-tumor-microenvironment
#9
Sobeyda Gomez-Chou, Agnieszka Swidnicka-Siergiejko, Niharika Badi, Myrriah Chavez-Tomar, Gregory B Lesinski, Tanios Bekaii-Saab, Matthew R Farren, Thomas A Mace, Carl Schmidt, Yan Liu, Defeng Deng, Rosa F Hwang, Liran Zhou, Todd T Moore, Deyali Chatterjee, Huamin Wang, Xiaohong Leng, Ralph B Arlinghaus, Craig D Logsdon, Zobeida Cruz-Monserrate
Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation and PDAC development. Mice with acinar cell-specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN) and PDAC...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28249796/biological-determinants-of-radioresistance-and-their-remediation-in-pancreatic-cancer
#10
REVIEW
Parthasarathy Seshacharyulu, Michael J Baine, Joshua J Souchek, Melanie Menning, Sukhwinder Kaur, Ying Yan, Michel M Ouellette, Maneesh Jain, Chi Lin, Surinder K Batra
Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy...
February 27, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28209609/pancreatic-cancer-progress-and-challenges-in-a-rapidly-moving-field
#11
Eric A Collisson, Kenneth P Olive
"Pancreatic Cancer: Advances in Science and Clinical Care," a Special Conference of the American Association for Cancer Research, was held in Orlando, FL, on May 12 to 15, bringing together more than 450 basic, translational, clinical, and epidemiologic pancreatic cancer researchers as well as pancreatic cancer patients, survivors, and advocates. Pancreatic cancer remains one of the great challenges in medicine, but the accelerating pace of research and early hints of clinical successes to come were palpable throughout the meeting...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28186976/32-phosphorus-selectively-delivered-by-listeria-to-pancreatic-cancer-demonstrates-a-strong-therapeutic-effect
#12
Dinesh Chandra, Benson Chellakkan Selvanesan, Ziqiang Yuan, Steven K Libutti, Wade Koba, Amanda Beck, Kun Zhu, Arturo Casadevall, Ekaterina Dadachova, Claudia Gravekamp
Our laboratory has developed a novel delivery platform using an attenuated non-toxic and non-pathogenic bacterium Listeria monocytogenes that infects tumor cells and selectively survives and multiplies in metastases and primary tumors with help of myeloid-derived suppressor cells (MDSC) and immune suppression in the tumor microenvironment (TME). 32P was efficiently incorporated into the Listeria bacteria by starvation of the bacteria in saline, and then cultured in phosphorus-free medium complemented with 32P as a nutrient...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28182192/dabigatran-potentiates-gemcitabine-induced-growth-inhibition-of-pancreatic-cancer-in-mice
#13
Kun Shi, Helene Damhofer, Joost Daalhuisen, Marieke Ten Brink, Dick J Richel, C Arnold Spek
Pancreatic cancer is one of the most lethal solid malignancies with little treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives progression and induces chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we addressed the effect of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth whereas it significantly increased tumor dissemination throughout the peritoneal cavity...
February 6, 2017: Molecular Medicine
https://www.readbyqxmd.com/read/28179999/cancer-stem-like-cells-can-be-induced-through-dedifferentiation-under-hypoxic-conditions-in-glioma-hepatoma-and-lung-cancer
#14
Pan Wang, Wen-Wu Wan, Shuang-Long Xiong, Hua Feng, Nan Wu
Traditional studies have shown that transcription factors, including SOX-2, OCT-4, KLF-4, Nanog and Lin-28A, contribute to the dedifferentiation and reprogramming process in normal tissues. Hypoxia is a physiological phenomenon that exists in tumors and promotes the expression of SOX-2, OCT-4, KLF-4, Nanog and Lin-28A. Therefore, an interesting question is whether hypoxia as a stimulating factor promotes the process of dedifferentiation and induces the formation of cancer stem-like cells. Studies have shown that OCT-4 and Nanog overexpression induced the formation of cancer stem cell-like cells through dedifferentiation and enhanced malignancy in lung adenocarcinoma, and reprogramming SOX-2 in pancreatic cancer cells also promoted the dedifferentiation process...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28155598/development-of-in-vitro-co-culture-model-in-anti-cancer-drug-development-cascade
#15
Ruiling Xu, Frances M. Richards
Tumour microenvironment is recognized as a major determinant of intrinsic resistance to anticancer therapies. In solid tumour types, such as breast cancer, lung cancer and pancreatic cancer, stromal components provide a fibrotic niche, which promotes stemness, EMT, chemo- and radio-resistance of tumour. However, this microenvironment is not recapitulated in the conventional cell monoculture or xenografts, hence these in vitro and in vivo preclinical models are unlikely to be predictive of clinical response; which might attribute to the poor predictivity of these preclinical drug-screening models...
February 1, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28154177/glycosyltransferase-st6gal-i-protects-tumor-cells-against-serum-growth-factor-withdrawal-by-enhancing-survival-signaling-and-proliferative-potential
#16
Colleen M Britain, Kaitlyn A Dorsett, Susan L Bellis
A hallmark of cancer cells is the ability to survive and proliferate when challenged with stressors such as growth factor insufficiency. In the current study we report a novel glycosylation-dependent mechanism that protects tumor cells from serum growth factor withdrawal. Results herein suggest that the ST6Gal-I sialyltransferase, which is upregulated in numerous cancers, promotes the survival of serum-starved cells. Using ovarian and pancreatic cancer cell models with ST6Gal-I overexpression or knockdown, we find that serum-starved cells with high ST6Gal-I levels exhibit increased activation of pro-survival signaling molecules including pAkt, p-p70S6K and pNFkB...
January 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28153670/designing-a-bio-inspired-biomimetic-in-vitro-system-for-the-optimization-of-ex-vivo-studies-of-pancreatic-cancer
#17
REVIEW
Stella Totti, Spyros I Vernardis, Lisiane Meira, Pedro A Pérez-Mancera, Eithne Costello, William Greenhalf, Daniel Palmer, John Neoptolemos, Athanasios Mantalaris, Eirini G Velliou
Pancreatic cancer is one of the most aggressive and lethal human malignancies. Drug therapies and radiotherapy are used for treatment as adjuvants to surgery, but outcomes remain disappointing. Advances in tissue engineering suggest that 3D cultures can reflect the in vivo tumor microenvironment and can guarantee a physiological distribution of oxygen, nutrients, and drugs, making them promising low-cost tools for therapy development. Here, we review crucial structural and environmental elements that should be considered for an accurate design of an ex vivo platform for studies of pancreatic cancer...
January 30, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28146435/loss-of-mtss1-results-in-increased-metastatic-potential-in-pancreatic-cancer
#18
Ann E Zeleniak, Wei Huang, Mary K Brinkman, Melissa L Fishel, Reginald Hill
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 7%. This dismal prognosis is largely due to the inability to diagnose the disease before metastasis occurs. Tumor cell dissemination occurs early in PDAC. While it is known that inflammation facilitates this process, the underlying mechanisms responsible for this progression have not been fully characterized. Here, we functionally test the role of metastasis suppressor 1 (MTSS1) in PDAC. Despite evidence showing that MTSS1 could be important for regulating metastasis in many different cancers, its function in PDAC has not been studied...
January 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28129119/improving-chimeric-antigen-receptor-modified-t-cell-function-by-reversing-the-immunosuppressive-tumor-microenvironment-of-pancreatic-cancer
#19
Somala Mohammed, Sujita Sukumaran, Pradip Bajgain, Norihiro Watanabe, Helen E Heslop, Cliona M Rooney, Malcolm K Brenner, William E Fisher, Ann M Leen, Juan F Vera
The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28121247/targeting-inos-to-increase-efficacy-of-immunotherapies
#20
Suhendan Ekmekcioglu, Elizabeth A Grimm, Jason Roszik
Inducible NO synthase (iNOS/NOS2) protein expression is a well-studied predictor of poor outcome in multiple cancers, and it has also been associated with inflammatory and immunosuppressive processes in the tumor microenvironment. Immunotherapies are becoming increasingly key components in cancer treatment, and iNOS is receiving more attention as a potential regulator of treatment resistance. As we have reported in pancreatic cancer, by modulation of effector T-cell activity, iNOS overexpression may allow the tumor to escape the immune response through creating a microenvironment which causes recalcitrance to immunotherapy...
January 25, 2017: Human Vaccines & Immunotherapeutics
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