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

Kazuya Kuwada, Shunsuke Kagawa, Ryuichi Yoshida, Shuichi Sakamoto, Atene Ito, Megumi Watanabe, Takeshi Ieda, Shinji Kuroda, Satoru Kikuchi, Hiroshi Tazawa, Toshiyoshi Fujiwara

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Article number307
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
Publication statusPublished - Dec 11 2018

Keywords

  • Chemoresistance
  • Epithelial-to-mesenchymal transition
  • Pancreatic cancer
  • Peritoneal dissemination
  • Tumor-associated macrophages

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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