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      The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer

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          Abstract

          Background

          The peritoneum is one of the most frequent metastatic sites in pancreatic cancer patients, and peritoneal dissemination makes this disease refractory due to aggressive progression and chemoresistance. Although the role of the tumor microenvironment in cancer development is recognized, the correlation between the peritoneal environment and refractoriness of peritoneal dissemination remains unclear. The intraperitoneal tumor-microenvironment and its potential role in the progression of peritoneal dissemination and chemo-refractoriness, focusing especially on macrophages, were investigated.

          Materials and methods

          Peritoneal washes were obtained from pancreatic cancer patients, and cellular components were subjected to immunofluorescence assays. The effects of macrophages induced from monocytic THP-1 cells on pancreatic cancer cells were examined in co-culture conditions. The in vivo effects of macrophages on tumor growth and chemo-sensitivity were investigated by subcutaneously or intraperitoneally co-injecting cancer cells with macrophages into mice.

          Results

          CD204-positive macrophages were present along with cancer cells in the peritoneal washes. In in vitro co-culture, tumor-associated macrophages affected pancreatic cancer cells, induced the epithelial-to-mesenchymal transition (EMT), and made them more resistant to chemotherapeutic agents. M2 macrophages promoted growth of both subcutaneous tumors and peritoneal dissemination in mice. Furthermore, co-inoculation of M2 macrophages conferred chemoresistance in the peritoneal dissemination mouse model, which significantly shortened their survival.

          Conclusion

          Intraperitoneal tumor-associated macrophages potentially play an important role in promotion of peritoneal dissemination and chemoresistance of pancreatic cancer via EMT induction.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-018-0981-2) contains supplementary material, which is available to authorized users.

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          Most cited references24

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          Distinct role of macrophages in different tumor microenvironments.

          Claire Lewis, Jeffrey W Pollard (2006)
          Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes.
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            Macrophages regulate the angiogenic switch in a mouse model of breast cancer.

            Elaine Y Lin, Jiu-Feng Li, Leoid Gnatovskiy … (2006)
            The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy.
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              Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer.

              Thiruvengadam Arumugam, Vijaya Ramachandran, Keith F. Fournier … (2009)
              A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI(50) (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.
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                Author and article information

                Contributors
                Kazuya Kuwada: kuwatamomoka@yahoo.co.jp
                Shunsuke Kagawa:
                ORCID: http://orcid.org/0000-0002-3610-8211
                +81-86-2357257 , skagawa@md.okayama-u.ac.jp
                Ryuichi Yoshida: r9232001@yahoo.co.jp
                Shuichi Sakamoto: ss226153@yahoo.co.jp
                Atene Ito: atene0117110@yahoo.co.jp
                Megumi Watanabe: pfdf2jtm@s.okayama-u.ac.jp
                Takeshi Ieda: takeshi0306@s.okayama-u.ac.jp
                Shinji Kuroda: shinkuro@okayama-u.ac.jp
                Satoru Kikuchi: pv1j0l8j@okayama-u.ac.jp
                Hiroshi Tazawa: htazawa@md.okayama-u.ac.jp
                Toshiyoshi Fujiwara: toshi_f@md.okayama-u.ac.jp
                Journal
                Journal ID (nlm-ta): J Exp Clin Cancer Res
                Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res
                Title: Journal of Experimental & Clinical Cancer Research : CR
                Publisher: BioMed Central (London )
                ISSN (Print): 0392-9078
                ISSN (Electronic): 1756-9966
                Publication date (Electronic): 11 December 2018
                Publication date PMC-release: 11 December 2018
                Publication date Collection: 2018
                Volume: 37
                Electronic Location Identifier: 307
                Affiliations
                [1 ]ISNI 0000 0001 1302 4472, GRID grid.261356.5, Department of Gastroenterological Surgery, , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, ; 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558 Japan
                [2 ]ISNI 0000 0004 0631 9477, GRID grid.412342.2, Minimally Invasive Therapy Center, Okayama University Hospital, ; Okayama, Japan
                [3 ]ISNI 0000 0004 0631 9477, GRID grid.412342.2, Center for Innovative Clinical Medicine, Okayama University Hospital, ; Okayama, Japan
                Author information
                http://orcid.org/0000-0002-3610-8211
                Article
                Publisher ID: 981
                DOI: 10.1186/s13046-018-0981-2
                PMC ID: 6288926
                PubMed ID: 30537992
                SO-VID: 783c9367-8538-4a40-8ccf-14e2a8883fa3
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 3 August 2018
                Date accepted : 26 November 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP15K15193
                Award ID: JP16H05416
                Award ID: JP18K08679
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003478, Ministry of Health, Labour and Welfare;
                Award ID: 14525167
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: tumor-associated macrophages,chemoresistance,epithelial-to-mesenchymal transition,peritoneal dissemination,pancreatic cancer
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: tumor-associated macrophages, chemoresistance, epithelial-to-mesenchymal transition, peritoneal dissemination, pancreatic cancer

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