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      Role of the tumor microenvironment in pancreatic cancer.

      Author(s):
      Publication date:
      Journal: Annals of Gastroenterological Surgery
      Publisher: Wiley
      Keywords: tumor‐infiltrating lymphocyte, tumor microenvironment, immunomodulation, pancreatic cancer, immune cell

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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.
            Article 0 comments Cited 365 times – based on 0 reviews     Review now
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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 341 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                PubMed ID:: 30923782
                PMC ID:: 6422798
                DOI:: 10.1002/ags3.12225

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

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