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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Most cited references 58

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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.

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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

Itaru Endo 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

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

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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Role of the tumor microenvironment in pancreatic cancer

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Cancer Metabolism

Most cited references 58

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

Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

Integrin signaling.

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