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      CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

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          Abstract

          CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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          CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment.

          Jan A Burger, Thomas J Kipps (2006)
          Signals from the microenvironment have a profound influence on the maintenance and/or progression of hematopoietic and epithelial cancers. Mesenchymal or marrow-derived stromal cells, which constitute a large proportion of the non-neoplastic cells within the tumor microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 secretion by stromal cells attracts cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and nonhematopoietic tumor cells. CXCR4 promotes tumor progression by direct and indirect mechanisms. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed, and thereby allows tumor cells to access cellular niches, such as the marrow, that favor tumor-cell survival and growth. Second, stromal-derived CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion. Third, CXCL12 can promote tumor angiogenesis by attracting endothelial cells to the tumor microenvironment. CXCR4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. Promising results in preclinical tumor models indicate that CXCR4 antagonists may have antitumor activity in patients with various malignancies. Collectively, these observations reveal that CXCR4 is an important molecule involved in the spread and progression of a variety of different tumors. As such, CXCR4 antagonists, although initially developed for treatment of AIDS, actually may become effective agents for the treatment of neoplastic disease.
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            Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.

            Abasi Ene-Obong, Andrew Clear, Jennifer Watt … (2013)
            Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis) and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We also analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice and the effects of all-trans retinoic acid (ATRA) on these processes. Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase(+) and CD68(+) cells compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8(+), FoxP3(+), CD56(+), or CD20(+) cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8(+) T cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8(+) T cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8(+) T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8(+) T cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective antitumor immune response. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Sonic hedgehog promotes desmoplasia in pancreatic cancer.

              Thomas Caffery, J. Bailey, P Eggers … (2008)
              We investigated the contribution of Sonic hedgehog (SHH) to pancreatic cancer progression. We expressed SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), and evaluated the effects on tumor growth. We also directly inhibited the activity of SHH in vivo by administering a blocking antibody to mice challenged orthotopically with the Capan-2 pancreatic cancer cell line, which is known to express SHH and form moderately differentiated tumors in nude mice. Our data provide evidence that expression of SHH influences tumor growth by contributing to the formation of desmoplasia in pancreatic cancer. We further show that SHH affects the differentiation and motility of human pancreatic stellate cells and fibroblasts. These data suggest that SHH contributes to the formation of desmoplasia in pancreatic cancer, an important component of the tumor microenvironment.
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                Author and article information

                Contributors
                Matteo Giulietti:
                ORCID: http://orcid.org/0000-0002-9871-265X
                Journal
                Journal ID (nlm-ta): J Oncol
                Journal ID (iso-abbrev): J Oncol
                Journal ID (publisher-id): JO
                Title: Journal of Oncology
                Publisher: Hindawi
                ISSN (Print): 1687-8450
                ISSN (Electronic): 1687-8469
                Publication date Collection: 2019
                Publication date (Electronic): 2 June 2019
                Volume: 2019
                Electronic Location Identifier: 9681698
                Affiliations
                Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona 60020, Italy
                Author notes

                Guest Editor: Nathaniel Weygant

                Author information
                http://orcid.org/0000-0002-9871-265X
                Article
                DOI: 10.1155/2019/9681698
                PMC ID: 6582792
                PubMed ID: 31275385
                SO-VID: e26445cb-9bcb-4582-b3a4-d8f581eb045a
                Copyright © Copyright © 2019 Alessandra Righetti et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 27 March 2019
                Date accepted : 9 May 2019
                Funding
                Funded by: Fondazione Cariverona
                Award ID: 2017.0570
                Funded by: AIRC fellowship for Italy
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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