PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination

Yang Peng, Hiroaki Kajiyama, Hong Yuan, Kae Nakamura, Masato Yoshihara, Akira Yokoi, Kayo Fujikake, Hiroaki Yasui, Nobuhisa Yoshikawa, Shiro Suzuki, Takeshi Senga, Kiyosumi Shibata, Fumitaka Kikkawa

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The mesothelium, covered by a continuous monolayer of mesothelial cells, is the first protective barrier against metastatic ovarian cancer. However, mesothelial cells release tumor-promoting factors that accelerate the process of peritoneal metastasis. We identified cancer-associated mesothelial cells (CAMs) that had tumor-promoting potential. Here, we found that plasminogen activator inhibitor-1 (PAI-1) induced the formation of CAMs, after which CAMs increasingly secreted the oncogenic factors interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5), further promoting the metastasis of ovarian cancer cells in a feedback loop. After the formation of CAMs, PAI-1 activated the nuclear factor kappa B (NFκB) pathway in the CAMs, thus transcriptionally upregulating the expression of the downstream NFκB targets IL-8 and CXCL5. Moreover, PAI-1 correlated with peritoneal metastasis in ovarian cancer patients and indicated a poor prognosis. In both ex vivo and in vivo models, after PAI-1 expression was knocked down, the metastasis of ovarian cancer cells decreased significantly. Therefore, targeting PAI-1 may provide a potential target for future therapeutics to prevent the formation of CAMs and alleviate peritoneal metastasis in ovarian cancer patients.

Original languageEnglish
Pages (from-to)181-192
Number of pages12
JournalCancer Letters
Volume442
DOIs
Publication statusPublished - 01-02-2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Peng, Y., Kajiyama, H., Yuan, H., Nakamura, K., Yoshihara, M., Yokoi, A., Fujikake, K., Yasui, H., Yoshikawa, N., Suzuki, S., Senga, T., Shibata, K., & Kikkawa, F. (2019). PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination. Cancer Letters, 442, 181-192. https://doi.org/10.1016/j.canlet.2018.10.027