Epithelial ovarian cancer (EOC) is considered to secrete various factors in order to promote peritoneal dissemination through cell-to-cell interaction between cancer and mesothelial cells. We previously revealed that TGF-β secreted from EOC induces normal human peritoneal mesothelial cells (HPMCs) to differentiate into cancer-associated mesothelial cells (CAMCs). However, the relationship between tumor cells and CAMCs in EOC is still unclear. We hypothesized that CAMCs also secrete chemokines that attract cancer cells and induce peritoneal dissemination of EOC. We examined chemokines secreted from HPMCs and CAMCs by human chemokine array, and revealed that conditioned medium of CAMCs (CAMCs-CM) included many types of chemokines. The signals of CCL2 were the highest compared with other chemokines. The secretion and relative expression of CCL2 were significantly higher in CAMCs. Recombinant CCL2 promoted trans-mesothelial migration of HPMCs and the migration and invasion by EOC cells. In addition, CCL2 secreted from CAMCs promoted invasion of EOC cells. Furthermore, the neutralizing antibody of CCL2 reduced invasion by EOC. Clinical outcomes of patients whose tissue expressed higher CCR2 were significantly poorer than in patients whose tissue expression was lower. CCL2 activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK). In addition, CAMCs-CM activated the p38 MAPK pathway. Phosphorylation of p38 MAPK reduced with the presence of neutralizing antibody of CCL2. In conclusion, these data indicate CCL2 in CAMCs-CM promoted the malignant potential of EOC. CCL2 plays a crucial role in the tumor microenvironment of EOC.
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We sincerely thank Mr. Y. Koya and Y. Yamakita (Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine) for various forms of technical support.
This study was supported by JSPS (Japan Society for the Promotion of Science) KAKENHI Grants-in-Aid for Scientific Research: Grant Numbers 17H04338 and 16K15704.
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Fig. S4 Schematic summary of the current study. Enhanced production of CCL2 from CAMCs is crucial for the development of peritoneal carcinomatosis of EOC through the adhesion-, migration-, and invasion-promoting effects of tumor cells. These findings indicate the scheme of the auto-stimulatory triangle axis among cancer, ascites, and the mesothelium (JPG 528 kb)
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Yasui, H., Kajiyama, H., Tamauchi, S. et al. CCL2 secreted from cancer-associated mesothelial cells promotes peritoneal metastasis of ovarian cancer cells through the P38-MAPK pathway. Clin Exp Metastasis 37, 145–158 (2020). https://doi.org/10.1007/s10585-019-09993-y
- Ovarian carcinoma
- Peritoneal dissemination
- Mesothelial cells