Ovarian cancer-associated mesothelial cells induce acquired platinum-resistance in peritoneal metastasis via the FN1/Akt signaling pathway

Masato Yoshihara, Hiroaki Kajiyama, Akira Yokoi, Mai Sugiyama, Yoshihiro Koya, Yoshihiko Yamakita, Wenting Liu, Kae Nakamura, Yoshinori Moriyama, Hiroaki Yasui, Shiro Suzuki, Yusuke Yamamoto, Carmela Ricciardelli, Akihiro Nawa, Kiyosumi Shibata, Fumitaka Kikkawa

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

Original languageEnglish
Pages (from-to)2268-2280
Number of pages13
JournalInternational Journal of Cancer
Issue number8
Publication statusPublished - 15-04-2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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