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Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway
Author(s) -
Yoshihara Masato,
Kajiyama Hiroaki,
Yokoi Akira,
Sugiyama Mai,
Koya Yoshihiro,
Yamakita Yoshihiko,
Liu Wenting,
Nakamura Kae,
Moriyama Yoshinori,
Yasui Hiroaki,
Suzuki Shiro,
Yamamoto Yusuke,
Ricciardelli Carmela,
Nawa Akihiro,
Shibata Kiyosumi,
Kikkawa Fumitaka
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32854
Subject(s) - cancer research , metastasis , stromal cell , ovarian cancer , protein kinase b , pi3k/akt/mtor pathway , cancer cell , tumor microenvironment , medicine , biology , immunology , cancer , signal transduction , microbiology and biotechnology , tumor cells
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.