TY - JOUR
T1 - PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination
AU - Peng, Yang
AU - Kajiyama, Hiroaki
AU - Yuan, Hong
AU - Nakamura, Kae
AU - Yoshihara, Masato
AU - Yokoi, Akira
AU - Fujikake, Kayo
AU - Yasui, Hiroaki
AU - Yoshikawa, Nobuhisa
AU - Suzuki, Shiro
AU - Senga, Takeshi
AU - Shibata, Kiyosumi
AU - Kikkawa, Fumitaka
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant (Number: 2617H04338 ). We also would like to thank Professor Yutaka Kondo and Dr. Miho Suzuki, Dr. Liang Weng, Dr. Peng Gu and Dr. Meng Zhao for their suggestions and warm help.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.canlet.2018.10.027
DO - 10.1016/j.canlet.2018.10.027
M3 - Article
C2 - 30429105
AN - SCOPUS:85056210634
VL - 442
SP - 181
EP - 192
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
ER -