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

Abstract

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.

• Authors: Chaoyang Sun, Xi Li, Ensong Guo, Na Li, Bo Zhou, Hao Lu, Jia Huang, Meng Xia, Wanying Shan, Beibei Wang, Kezhen Li, Danhui Weng, Xiaoyan Xu, Qinglei Gao, Shixuan Wang, Junbo Hu, Yiling Lu, Gordon B Mills, Gang Chen
• Journal: Oncogene (Oncogene) Vol. 39 Issue 8 Pg. 1681-1695 (02 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 31705064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL2 protein, human
• Chemokine CCL2
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, CCR2
• Vascular Endothelial Growth Factor A
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Adipocytes (metabolism, pathology)
• Animals
• Cell Transformation, Neoplastic
• Chemokine CCL2 (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Ovarian Neoplasms (pathology)
• Peritoneal Neoplasms (secondary)
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, CCR2 (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)