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pancreatic cancer microenvironment

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https://www.readbyqxmd.com/read/29789416/macrophage-derived-granulin-drives-resistance-to-immune-checkpoint-inhibition-in-metastatic-pancreatic-cancer
#1
Michael C Schmid, Valeria Quaranta, Carolyn Rainer, Sebastian Rune Nielsen, Meirion Llŷr Raymant, Muhammad S Ahmed, Dannielle D Engle, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel H Palmer, David A Tuveson, Ainhoa Mielgo
The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers...
May 22, 2018: Cancer Research
https://www.readbyqxmd.com/read/29771768/high-density-infiltration-of-v-domain-immunoglobulin-suppressor-of-t-cell-activation-up-regulated-immune-cells-in-human-pancreatic-cancer
#2
Jinʼe Liu, Xiaoxue Xie, Chunxiao Xuan, Tingting Li, Lanlan Wang, Lianghong Teng, Jun Liu
V-domain immunoglobulin suppressor of T-cell activation (VISTA) is constitutively expressed in hematopoietic lineage and is highly up-regulated in tumor infiltrated myeloid cells and regulatory T cells in animal models. However, its expression in human pancreatic tumor microenvironment remains unknown. In this research, we aimed at the expression of VISTA in human pancreatic cancer samples. METHODS: We performed immunohistochemistry to determine VISTA expression in human pancreatic cancer samples...
May 15, 2018: Pancreas
https://www.readbyqxmd.com/read/29764866/lrrc15-is-a-novel-mesenchymal-protein-and-stromal-target-for-antibody-drug-conjugates
#3
James W Purcell, Sonia G Tanlimco, Jonathan A Hickson, Melvin Fox, Mien Sho, Lisa Durkin, Tamar Uziel, Rick Powers, Kelly D Foster-Duke, Thomas McGonigal, Subashri Kumar, Josue Samayoa, Dong Zhang, Joann P Palma, Sasmita Mishra, Diane Hollenbaugh, Kurt Gish, Susan E Morgan-Lappe, Eric D Hsi, Debra T Chao
Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29737600/stromal-barriers-to-nanomedicine-penetration-in-the-pancreatic-tumor-microenvironment
#4
REVIEW
Hiroyoshi Y Tanaka, Mitsunobu R Kano
Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention (EPR) effect that promotes selective accumulation of nanometer-sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer due to stromal barriers within the tumor microenvironment (TME)...
May 8, 2018: Cancer Science
https://www.readbyqxmd.com/read/29733315/an-in-vivo-murine-sciatic-nerve-model-of-perineural-invasion
#5
Sylvie Deborde, Yasong Yu, Andrea Marcadis, Chun-Hao Chen, Ning Fan, Richard L Bakst, Richard J Wong
Cancer cells invade nerves through a process termed perineural invasion (PNI), in which cancer cells proliferate and migrate in the nerve microenvironment. This type of invasion is exhibited by a variety of cancer types, and very frequently is found in pancreatic cancer. The microscopic size of nerve fibers within mouse pancreas renders the study of PNI difficult in orthotopic murine models. Here, we describe a heterotopic in vivo model of PNI, where we inject syngeneic pancreatic cancer cell line Panc02-H7 into the murine sciatic nerve...
April 23, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29731898/role-of-exosomes-in-pancreatic-cancer
#6
REVIEW
Yunmeng Yan, Guangzhen Fu, Liang Ming
Pancreatic cancer is one of the most lethal malignancies. Exosomes, which are released by multiple cell types, such as cancer cells, contain functional biomolecules (including proteins, nucleic acids and lipids) that can be horizontally delivered to recipient cells. Exosomes act as the most prominent mediator of intercellular communication and can regulate, instruct and re-educate their surrounding microenvironment and target specific organs. The present review performed an extensive search of multiple databases from 2005 to April 23 2017, for eligible literature relating to exosomes and their role in pancreatic cancer...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29728788/chimeric-antigen-receptor-t-cell-therapy-in-pancreatic-cancer-from-research-to-practice
#7
REVIEW
Vishal Jindal, Ena Arora, Muhammad Masab, Sorab Gupta
Chimeric antigen receptor (CAR) T cell therapy is genetically engineered tumor antigen-specific anticancer immunotherapy, which after showing great success in hematological malignancies is currently being tried in advanced solid tumors like pancreatic cancer. Immunosuppressive tumor microenvironment and dense fibrous stroma are some of the limitation in the success of this novel therapy. However, genetic modifications and combination therapy is the topic of the research to improve its efficacy. In this article, we summarize the current state of knowledge, limitations, and future prospects for CAR T cell therapy in pancreatic cancer...
May 4, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29717355/the-function-of-trp-channels-in-neutrophil-granulocytes
#8
REVIEW
Karolina Najder, Boris Musset, Otto Lindemann, Etmar Bulk, Albrecht Schwab, Benedikt Fels
Neutrophil granulocytes are exposed to widely varying microenvironmental conditions when pursuing their physiological or pathophysiological functions such as fighting invading bacteria or infiltrating cancer tissue. Examples for harsh environmental challenges include among others mechanical shear stress during the recruitment from the vasculature or the hypoxic and acidotic conditions within the tumor microenvironment. Chemokine gradients, reactive oxygen species, pressure, matrix elasticity, and temperature can be added to the list of potential challenges...
May 1, 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29685122/treatment-of-pancreatic-ductal-adenocarcinoma-with-tumor-antigen-specific-targeted-delivery-of-paclitaxel-loaded-plga-nanoparticles
#9
Shu-Ta Wu, Anthony J Fowler, Corey B Garmon, Adam B Fessler, Joshua D Ogle, Kajal R Grover, Bailey C Allen, Chandra D Williams, Ru Zhou, Mahboubeh Yazdanifar, Craig A Ogle, Pinku Mukherjee
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) remains the most aggressive cancers with a 5-year survival below 10%. Systemic delivery of chemotherapy drugs has severe side effects in patients with PDA and does not significantly improve overall survival rate. It is highly desirable to advance the therapeutic efficacy of chemotherapeutic drugs by targeting their delivery and increasing accumulation at the tumor site. MUC1 is a membrane-tethered glycoprotein that is aberrantly overexpressed in > 80% of PDA thus making it an attractive antigenic target...
April 23, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29681184/tam-infiltration-differences-in-tumor-first-and-zheng-first-models-and-the-underlying-inflammatory-molecular-mechanism-in-pancreatic-cancer
#10
Feng-Jiao Wang, Peng Wang, Lian-Yu Chen, Ya-Wen Geng, Hao Chen, Zhi-Qiang Meng, Lu-Ming Liu, Zhen Chen
BACKGROUND: Syndrome ( ZHENG in Chinese) in traditional Chinese medicine (TCM) refers to the intrinsic characteristics of a pathological process at a certain stage; these characteristics are influenced by internal and external environments and reveal the nature of a disease. Proper syndrome differentiation is the basic principle that guides clinical treatment. OBJECTIVE: To have a good understanding of tumor progression and the different mechanisms related to ZHENG that have occurred before and after tumor development and to explore the valid evaluation criteria of different pancreatic cancer syndromes to improve the guiding role of TCM syndrome differentiation in pancreatic cancer treatment...
April 1, 2018: Integrative Cancer Therapies
https://www.readbyqxmd.com/read/29670543/phosphoinositide-3-kinase-signaling-pathway-in-pancreatic-ductal-adenocarcinoma-progression-pathogenesis-and-therapeutics
#11
REVIEW
Divya Murthy, Kuldeep S Attri, Pankaj K Singh
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its sudden manifestation, rapid progression, poor prognosis, and limited therapeutic options. Genetic alterations in key signaling pathways found in early pancreatic lesions are pivotal for the development and progression of pancreatic intraepithelial neoplastic lesions into invasive carcinomas. More than 90% of PDAC tumors harbor driver mutations in K-Ras that activate various downstream effector-signaling pathways, including the phosphoinositide-3-kinase (PI3K) pathway...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29670110/tumor-associated-macrophages-promote-progression-and-the-warburg-effect-via-ccl18-nf-kb-vcam-1-pathway-in-pancreatic-ductal-adenocarcinoma
#12
Huilin Ye, Quanbo Zhou, Shangyou Zheng, Guolin Li, Qing Lin, Lusheng Wei, Zhiqiang Fu, Bin Zhang, Yimin Liu, Zhihua Li, Rufu Chen
Tumor-associated macrophages (TAMs) are frequently found near pancreatic cancer cells, but it is uncertain whether they are involved in pancreatic cancer progression and the Warburg effect. Here, we show that CCL18 secreted by TAMs facilitates malignant progression and induced a glycolytic phenotype in pancreatic cancer, partially owing to paracrine induction of VCAM-1 in pancreatic cancer cells. Reciprocally, VCAM-1-induced lactate production from pancreatic cancer cells with enhanced aerobic glycolysis activates macrophages to a TAM-like phenotype, forming a positive feedback loop...
April 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29661773/integrated-genomic-and-immunophenotypic-classification-of-pancreatic-cancer-reveals-three-distinct-subtypes-with-prognostic-predictive-significance
#13
Martin Wartenberg, Silvia Cibin, Inti Zlobec, Erik Vassella, Serenella M M Eppenberger-Castori, Luigi Terracciano, Micha Eichmann, Mathias Worni, Beat Gloor, Aurel Perren, Eva Karamitopoulou
PURPOSE: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC-cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. EXPERIMENTAL DESIGN: A well-characterized PDAC-cohort (n=110) underwent next-generation sequencing with a hotspot cancer panel, while Next-generation Tissue-Microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM) and DNA mismatch-repair proteins...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29619850/salinomycin-nanoparticles-interfere-with-tumor-cell-growth-and-the-tumor-microenvironment-in-an-orthotopic-model-of-pancreatic-cancer
#14
Zahra Daman, Homa Faghihi, Hamed Montazeri
Recently, Salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly (lactic-co-glycolic acid) (PLGA) nanoparticles. The nanoparticles were physico-chemically characterized and evaluated for cytotoxicity on Luciferase-transduced AsPC-1 cells in vitro as well as implanted orthotopically into the pancreas of nude mice. SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy...
April 5, 2018: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/29618658/pancreatic-cancer-therapy-with-combined-mesothelin-redirected-chimeric-antigen-receptor-t-cells-and-cytokine-armed-oncolytic-adenoviruses
#15
Keisuke Watanabe, Yanping Luo, Tong Da, Sonia Guedan, Marco Ruella, John Scholler, Brian Keith, Regina M Young, Boris Engels, Suvi Sorsa, Mikko Siurala, Riikka Havunen, Siri Tähtinen, Akseli Hemminki, Carl H June
Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy...
April 5, 2018: JCI Insight
https://www.readbyqxmd.com/read/29617184/targeting-interleukin-22-for-cancer-therapy
#16
Anamarija Markota, Stefan Endres, Sebastian Kobold
Interleukin-22 (IL-22) is a member of IL-10 family of cytokines. IL-22 induces proliferative and anti-apoptotic signaling pathways and production of anti-microbial molecules that enhance tissue regeneration and host defense. IL-22 has also been identified as a cancer-promoting cytokine since deregulation of the IL-22-IL-22R1 system is linked to different cancer entities including lung, breast, gastric, pancreatic and colon cancers. T cells and innate lymphoid cells are the main cellular sources of IL-22. Expression of its specific receptor IL-22R1 is restricted to the non-hematopoietic cells which makes the IL-22-IL-22R1 pathway an attractive target for anti-cancer therapy...
April 4, 2018: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29615514/targeting-galectin-1-inhibits-pancreatic-cancer-progression-by-modulating-tumor-stroma-crosstalk
#17
Carlos A Orozco, Neus Martinez-Bosch, Pedro E Guerrero, Judith Vinaixa, Tomás Dalotto-Moreno, Mar Iglesias, Mireia Moreno, Magdolna Djurec, Françoise Poirier, Hans-Joachim Gabius, Martin E Fernandez-Zapico, Rosa F Hwang, Carmen Guerra, Gabriel A Rabinovich, Pilar Navarro
Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression...
April 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29611542/complex-roles-of-the-stroma-in-the-intrinsic-resistance-to-gemcitabine-in-pancreatic-cancer-where-we-are-and-where-we-are-going
#18
REVIEW
Chen Liang, Si Shi, Qingcai Meng, Dingkong Liang, Shunrong Ji, Bo Zhang, Yi Qin, Jin Xu, Quanxing Ni, Xianjun Yu
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis...
December 1, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29610286/immunotherapy-for-pancreatic-cancer-more-than-just-a-gut-feeling
#19
Erick Riquelme, Anirban Maitra, Florencia McAllister
<b/> Development of pancreatic cancer in spontaneous murine models is associated with enrichment of specific strains of gut and intratumoral bacteria that induce a tolerogenic immunosuppressive microenvironment favoring cancer progression and resistance to immunotherapies. Ablation of the microbiome with antibiotics reshapes the tumor microenvironment, inducing T-cell activation, improving immune surveillance, and increasing sensitivity to immunotherapy in established tumors. Cancer Discov; 8(4); 386-8...
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29605510/immunotherapy-for-pancreatic-cancer-a-long-and-hopeful-journey
#20
Jian-Wei Xu, Lei Wang, Yu-Gang Cheng, Guang-Yong Zhang, San-Yuan Hu, Bin Zhou, Han-Xiang Zhan
Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials...
July 1, 2018: Cancer Letters
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