MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis

• Published in: Oncogene Vol. 39; no. 8; pp. 1681 - 1695
• Main Authors: Sun, Chaoyang, Li, Xi, Guo, Ensong, Li, Na, Zhou, Bo, Lu, Hao, Huang, Jia, Xia, Meng, Shan, Wanying, Wang, Beibei, Li, Kezhen, Weng, Danhui, Xu, Xiaoyan, Gao, Qinglei, Wang, Shixuan, Hu, Junbo, Lu, Yiling, Mills, Gordon B, Chen, Gang
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2020
• Subjects: 1-Phosphatidylinositol 3-kinase; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; AKT protein; Animal models; Animals; Care and treatment; Cell Transformation, Neoplastic; Cellular signal transduction; Chemokine CCL2 - metabolism; Complications and side effects; Cytokines; Fat cells; Female; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Medical prognosis; Metastases; Metastasis; Metformin; Mice; Monocyte chemoattractant protein 1; Omentum; Ovarian cancer; Ovarian Neoplasms - pathology; Peritoneal Neoplasms - secondary; Peritoneum; Phenotype; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CCR2 - metabolism; Risk factors; TOR protein; TOR Serine-Threonine Kinases - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Xenografts; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-1090-1

Ovarian cancer selective metastasizes to the omentum contributing to the poor prognosis associated with ovarian cancer. However, the mechanism underlining this propensity and therapeutic approaches to counter this process has not been fully elucidated. Here, we show that MCP-1 produced by omental adipocytes binding to its cognate receptor CCR-2 on ovarian cancer cells facilitates migration and omental metastasis by activating the PI3K/AKT/mTOR pathway and its downstream effectors HIF-1α and VEGF-A in cell lines, xenografts, and transgenic murine models. MCP-1 antibody significantly decreased tumor burden and increased survival of mice in vivo. Interestingly, metformin decreased omental metastasis at least partially by inhibiting MCP-1 secretion from adipocytes independent of direct effects on cancer cells. Together this suggests a novel target of MCP-1/CCR-2 axis that could benefit ovarian cancer patients.