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pancreatic cancer microenvironment

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https://www.readbyqxmd.com/read/29330807/evaluation-of-macrophage-polarization-in-pancreatic-cancer-microenvironment-under-hypoxia
#1
Kuldeep S Attri, Kamiya Mehla, Pankaj K Singh
Hypoxic microenvironment found in pancreatic ductal adenocarcinoma and other solid tumors is central to physiological and metabolic alterations of immune cells that significantly impact tumor growth dynamics. Hypoxic adaptations in the immune cells are primarily mediated by the stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), which regulates cellular metabolism by modulating glycolysis and other interconnected metabolic pathways. HIF-1α plays distinct roles in M1 and M2 macrophage polarization, which, in turn, regulates tumor cell immune escape and growth...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29330793/hypoxia-induced-metabolomic-alterations-in-pancreatic-cancer-cells
#2
Venugopal Gunda, Sushil Kumar, Aneesha Dasgupta, Pankaj K Singh
Hypoxic conditions in the pancreatic tumor microenvironment lead to the stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), which acts as the master regulator of cancer cell metabolism. HIF-1α-mediated metabolic reprogramming results in large-scale metabolite perturbations. Characterization of the metabolic intermediates and the corresponding metabolic pathways altered by HIF-1α would facilitate the identification of therapeutic targets for hypoxic microenvironments prevalent in pancreatic ductal adenocarcinoma and other solid tumors...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29329547/microfluidic-co-culture-of-pancreatic-tumor-spheroids-with-stellate-cells-as-a-novel-3d-model-for-investigation-of%C3%A2-stroma-mediated-cell-motility-and-drug-resistance
#3
Ji-Hyun Lee, Seul-Ki Kim, Iftikhar Ali Khawar, Su-Yeong Jeong, Seok Chung, Hyo-Jeong Kuh
BACKGROUND: Pancreatic stellate cells (PSCs), a major component of the tumor microenvironment in pancreatic cancer, play roles in cancer progression as well as drug resistance. Culturing various cells in microfluidic (microchannel) devices has proven to be a useful in studying cellular interactions and drug sensitivity. Here we present a microchannel plate-based co-culture model that integrates tumor spheroids with PSCs in a three-dimensional (3D) collagen matrix to mimic the tumor microenvironment in vivo by recapitulating epithelial-mesenchymal transition and chemoresistance...
January 12, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29320425/targeting-pancreatic-cancer-cell-plasticity-the-latest-in-therapeutics
#4
REVIEW
Jacob M Smigiel, Neetha Parameswaran, Mark W Jackson
Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and survival signaling. As efforts to target RAS and its downstream effectors continue, parallel research aimed at identifying novel targets is also needed in order to improve therapeutic options and efficacy. Recent studies demonstrate that self-renewing cancer stem cells (CSCs) contribute to metastatic dissemination and therapy failure, the causes of mortality from PDAC...
January 10, 2018: Cancers
https://www.readbyqxmd.com/read/29301364/immune-evasion-in-pancreatic-cancer-from-mechanisms-to-therapy
#5
REVIEW
Neus Martinez-Bosch, Judith Vinaixa, Pilar Navarro
Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery...
January 3, 2018: Cancers
https://www.readbyqxmd.com/read/29290958/stromal-annexin-a2-expression-is-predictive-of-decreased-survival-in-pancreatic-cancer
#6
Adrian G Murphy, Kelly Foley, Agnieszka A Rucki, Tao Xia, Elizabeth M Jaffee, Chiung-Yu Huang, Lei Zheng
Pancreatic ductal adenocarcinoma (PDA) is renowned for high rates of metastasis and poor survival. Its notoriously dense fibrotic stroma contributes to chemoresistance. Stromal signaling in PDA is recognized for its multiple roles in regulating tumor invasion and metastasis. However, no stromal biomarker which can predict survival in PDA exists. Annexin A2 (AnxA2) was formerly identified as a metastasis-associated protein in PDA and tumoral overexpression is associated with poor survival. In this study, we examined AnxA2 expression in the tumor microenvironment in a preclinical model of PDA which suggests its role in tumor colonization...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29288236/cd47-blockade-as-an-adjuvant-immunotherapy-for-resectable-pancreatic-cancer
#7
Alex D Michaels, Timothy E Newhook, Sara J Adair, Sho Morioka, Bernadette J Goudreau, Sarbajeet Nagdas, Matthew G Mullen, Jesse B Persily, Timothy Bullock, Craig L Slingluff, Kodi S Ravichandran, J Thomas Parsons, Todd W Bauer
PURPOSE: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. EXPERIMENTAL DESIGN: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors...
December 29, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29286387/establishment-of-an-extracellular-acidic-ph-culture-system
#8
Ayano Kondo, Tsuyoshi Osawa
Conditions of the tumor microenvironment, such as hypoxia or nutrient starvation, play critical roles in cancer progression and malignancy. However, the role of acidic extracellular pH in tumor aggressiveness and its underlying mechanism has not been extensively studied compared to hypoxic or nutrient starvation conditions. In addition, a well-defined culture method to mimic the acidic extracellular tumor microenvironment has not been fully reported. Here we present a simple in vitro culture method to maintain acidic extracellular pH using reduced bicarbonate and increased lactate or HCl concentrations in the culture medium...
November 19, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29273547/-molecular-characterisation-defines-several-subtypes-of-pancreatic-ductal-adenocarcinoma
#9
REVIEW
Jérôme Raffenne, Jérôme Cros
Multi-omics high throughput analyses lead to the description of multiple molecular subtypes of pancreatic adenocarcinoma with major prognostic impact for most of them. There is no consensual multilevel integrative classification yet like in colon or breast cancers. Genomic classifications have identified a tumor subtype (15% of the patients) with deficient homologous DNA repair-system leading to increase sensitivity to platinum-based therapies and possibly to PARP inhibitors and immunotherapies. Transcriptomic classifications are still debated but all have identified an aggressive subtype with a very poor prognosis, presumably unfit for a surgical approach...
December 19, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29245934/apolipoprotein-a-i-mimetic-peptide-4f-suppresses-tumor-associated-macrophages-and-pancreatic-cancer-progression
#10
Meiyu Peng, Qi Zhang, Yingnan Cheng, Shuyu Fu, Huipeng Yang, Xiangdong Guo, Jieyou Zhang, Lina Wang, Lijuan Zhang, Zhenyi Xue, Yan Li, Yurong Da, Zhi Yao, Liang Qiao, Rongxin Zhang
Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29242097/emerging-trends-in-the-immunotherapy-of-pancreatic-cancer
#11
Kasturi Banerjee, Sushil Kumar, Kathleen A Ross, Shailendra Gautam, Brittany Poelaert, Mohd Wasim Nasser, Abhijit Aithal, Rakesh Bhatia, Michael J Wannemuehler, Balaji Narasimhan, Joyce C Solheim, Surinder K Batra, Maneesh Jain
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 45,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating patient's immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC...
December 11, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29235360/halo-109-301-a-phase-iii-trial-of-pegph20-with-gemcitabine-and-nab-paclitaxel-in-hyaluronic-acid-high-stage-iv-pancreatic-cancer
#12
Gary J Doherty, Margaret Tempero, Pippa G Corrie
The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients...
October 23, 2017: Future Oncology
https://www.readbyqxmd.com/read/29233887/st6gal-i-sialyltransferase-promotes-tumor-necrosis-factor-tnf-mediated-cancer-cell-survival-via-sialylation-of-the-tnf-receptor-1-tnfr1-death-receptor
#13
Andrew T Holdbrooks, Colleen M Britain, Susan L Bellis
Activation of the TNFR1 death receptor by TNF induces either cell survival or cell death. However, the mechanisms mediating these distinct outcomes remain poorly understood. In the present study, we report that the ST6Gal-I sialyltransferase, an enzyme upregulated in numerous cancers, sialylates TNFR1, and thereby protects tumor cells from TNF-induced apoptosis. Using pancreatic and ovarian cancer cells with ST6Gal-I knockdown or overexpression, we determined that α2-6 sialylation of TNFR1 had no effect on early TNF-induced signaling events including the rapid activation of NFκB, JNK, ERK, and Akt (occurring within 15m)...
December 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29223362/autophagy-inhibition-in-pancreatic-adenocarcinoma
#14
REVIEW
Brian A Boone, Herbert J Zeh, Nathan Bahary
Although some progress has been made in recent years with the development of more effective chemotherapy regimens, new treatment approaches are needed to improve outcomes for patients with pancreatic adenocarcinoma. The cellular process of autophagy, a cell survival mechanism that allows cancer cells to survive the hazardous conditions of the tumor microenvironment and treatment, has emerged as a viable target in pancreatic cancer. We review the mechanism of autophagy, its role in pancreatic carcinogenesis, the preclinical and clinical evidence supporting targeting autophagy in patients with pancreatic adenocarcinoma, and areas of future investigation that hold promise for improving this treatment approach...
October 28, 2017: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/29195672/tobacco-and-alcohol-as-risk-factors-for-pancreatic-cancer
#15
REVIEW
Murray Korc, Christie Y Jeon, Mouad Edderkaoui, Stephen J Pandol, Maxim S Petrov
Pancreatic cancer is projected to become the leading cause of cancer deaths by 2050. The risk for pancreatic cancer may be reduced by up to 27% by modifying lifestyle risk factors, most notably tobacco smoking. Based on analysis of more than 2 million unselected individuals from general population, this article quantified the risk of pancreatic cancer in relation to lifelong tobacco smoking and alcohol consumption status, both alone and in combination. It also provided a state-of-the-art review of animal studies on the effect of tobacco smoke and alcohol on genetically engineered mouse models of pancreatic precursor lesions, as well as the role of immune microenvironment in pancreatic carcinogenesis activated by tobacco and alcohol...
October 2017: Best Practice & Research. Clinical Gastroenterology
https://www.readbyqxmd.com/read/29191507/viscoelastic-properties-of-human-pancreatic-tumors-and-in-vitro-constructs-to-mimic-mechanical-properties
#16
Andres Rubiano, Daniel Delitto, Song Han, Michael Gerber, Carly Galitz, Jose Trevino, Ryan M Thomas, Steven J Hughes, Chelsey S Simmons
Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal, in large part due to a protective fibrotic barrier generated by tumor-associated stromal (TAS) cells. This barrier is thought to promote cancer cell survival and confounds attempts to develop effective therapies. We present a 3D in vitro system that replicates the mechanical properties of the PDAC microenvironment, representing an invaluable tool for understanding the biology of the disease. Mesoscale indentation quantified viscoelastic metrics of resected malignant tumors, inflamed chronic pancreatitis regions, and histologically normal tissue...
November 27, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/29189332/clinical-management-metastatic-disease
#17
Andrew H Ko
Most patients with pancreatic cancer either present with or eventually develop metastatic disease during the course of their illness. For such individuals, systemic therapy, namely, cytotoxic therapy, represents the mainstay of treatment and is administered with noncurative intent. Of the various chemotherapy options now available for treating metastatic pancreatic cancer, 2 combination regimens, FOLFIRINOX (infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the doublet of gemcitabine and albumin-bound paclitaxel, have emerged as frontline standards of care, based on phase III studies demonstrating a significant survival benefit compared with single-agent gemcitabine...
November 2017: Cancer Journal
https://www.readbyqxmd.com/read/29189327/the-pancreatic-cancer-microenvironment
#18
Stephanie K Dougan
Pancreatic ductal adenocarcinoma (PDAC) is composed of a minority of malignant cells within a microenvironment of extracellular matrix, fibroblasts, endothelial cells, and immune cells. Therapeutic failures of chemotherapy, targeted therapy, and immunotherapy have all been attributed to the PDAC microenvironment. In this review, we dissect the components of the microenvironment and explain how each cell type contributes to form a highly immunosuppressive, hypoxic, and desmoplastic cancer. New efforts in single-cell profiling will enable a better understanding of the composition of the microenvironment in primary and metastatic PDAC, as well as an understanding of how the microenvironment may respond to novel therapeutic approaches...
November 2017: Cancer Journal
https://www.readbyqxmd.com/read/29187440/liprin-%C3%AE-4-as-a-possible-new-therapeutic-target-for-pancreatic-cancer
#19
Akio Yamasaki, Kazunori Nakayama, Akira Imaizumi, Makoto Kawamoto, Akiko Fujimura, Yasuhiro Oyama, Shuntaro Nagai, Kosuke Yanai, Hideya Onishi
BACKGROUND/AIM: In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. MATERIALS AND METHODS: In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated...
December 2017: Anticancer Research
https://www.readbyqxmd.com/read/29187403/photodynamic-priming-mitigates-chemotherapeutic-selection-pressures-and-improves-drug-delivery
#20
Huang-Chiao Huang, Imran Rizvi, Joyce Liu, Sriram Anbil, Ashish Kalra, Helen Lee, Yan Baglo, Nancy Paz, Douglas Hayden, Stephen P Pereira, Brian W Pogue, Jonathan B Fitzgerald, Tayyaba Hasan
Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival...
November 29, 2017: Cancer Research
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