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      Role of the tumor microenvironment in pancreatic cancer

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          Abstract

          Pancreatic cancer remains a highly recalcitrant disease despite the development of systemic chemotherapies. New treatment options are thus urgently required. Dense stromal formation, so‐called “desmoplastic stroma,” plays controversial roles in terms of pancreatic cancer growth, invasion, and metastasis. Cells such as cancer‐associated fibroblasts, endothelial cells, and immune cells comprise the tumor microenvironment of pancreatic cancer. Pancreatic cancer is considered an immune‐quiescent disease, but activation of immunological response in pancreatic cancer may contribute to favorable outcomes. Herein, we review the role of the tumor microenvironment in pancreatic cancer, with a focus on immunological aspects.

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          Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

          Mara Sherman, Ruth T Yu, Dannielle D. Engle … (2014)
          The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK: Copyright © 2014 Elsevier Inc. All rights reserved.
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            Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

            Carolyn Clark, Sunil R Hingorani, Rosemarie Mick … (2007)
            The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early "elimination phase" of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer.
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              Integrin signaling.

              E Ruoslahti, F R Giancotti, ZHANG YUEGANG (1999)
              Cells reside in a protein network, the extracellular matrix (ECM), which they secrete and mold into the intercellular space. The ECM exerts profound control over cells. The effects of the matrix are primarily mediated by integrins, a family of cell surface receptors that attach cells to the matrix and mediate mechanical and chemical signals from it. These signals regulate the activities of cytoplasmic kinases, growth factor receptors, and ion channels and control the organization of the intracellular actin cytoskeleton. Many integrin signals converge on cell cycle regulation, directing cells to live or die, to proliferate, or to exit the cell cycle and differentiate.
              Article 0 comments Cited 337 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Itaru Endo:
                ORCID: http://orcid.org/0000-0001-5520-8114
                endoit@yokohama-cu.ac.jp
                Journal
                Journal ID (nlm-ta): Ann Gastroenterol Surg
                Journal ID (iso-abbrev): Ann Gastroenterol Surg
                Journal ID (doi): 10.1002/(ISSN)2475-0328
                Journal ID (publisher-id): AGS3
                Title: Annals of Gastroenterological Surgery
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2475-0328
                Publication date (Electronic): 04 January 2019
                Publication date Collection: March 2019
                Volume: 3
                Issue: 2 ( doiID: 10.1002/ags3.2019.3.issue-2 )
                Pages: 130-137
                Affiliations
                [ 1 ] Department of Gastroenterological Surgery Yokohama City University Graduate School of Medicine Yokohama Japan
                [ 2 ] AntiCancer, Inc. San Diego California
                [ 3 ] Department of Surgery University of California San Diego California
                Author notes
                [*] [* ] Correspondence

                Itaru Endo, Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

                Email: endoit@ 123456yokohama-cu.ac.jp

                Author information
                http://orcid.org/0000-0001-5520-8114
                Article
                Publisher ID: AGS312225
                DOI: 10.1002/ags3.12225
                PMC ID: 6422798
                PubMed ID: 30923782
                SO-VID: e0a20be6-95a0-4a9e-9a79-e30ee1a1cf8e
                Copyright © © 2019 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 21 July 2018
                Date revision received : 08 September 2018
                Date accepted : 04 November 2018
                Page count
                Figures: 1, Tables: 0, Pages: 8, Words: 5948
                Categories
                Subject: Review Article
                Subject: Review Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id ags312225
                cover-date March 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:18.03.2019

                Keywords: immune cell,immunomodulation,pancreatic cancer,tumor‐infiltrating lymphocyte,tumor microenvironment
                Data availability:
                Keywords: immune cell, immunomodulation, pancreatic cancer, tumor‐infiltrating lymphocyte, tumor microenvironment

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