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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.

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Acknowledgements

We thank our patients for donating biospecimens and clinical data. We thank Dr X. Jin and Dr Z. Yang for donating the SKOV3-ERFP and SKOV3 G3 cell lines. We thank Prof. Benjamin K. Tsang for donating the C13 and OV2008 cell lines.

Funding

This study was supported by the National Key R&D Program of China (2016YFC1303100), the National Basic Research Program of China (973 Program, 2015CB553903), Nature and Science Foundation of China (81272859, 81572569, 81402163, 81402164, 81501530, 81671394, and 81370469), the International S&T Cooperation Program of China (No. 2013DFA31400). GBM has support from NIH P50CA217685, Ovarian Cancer Research Foundation, and a kind gift from the Adelson Medical Research Fund.

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CS, XL, and EG did the western blot, ELISA, and IHC assays. NL, BZ, and HL did the animal assays. JH, MX, and WS did the cell culture. BW, KL, and DW collected clinical specimens. XX, QG, and SW were responsible for data analysis. JH were responsible for data disposal. YL did the RPPA assays. CS, XL, EG, and GBM wrote the paper. CS and GC designed the experiments.

Corresponding author

Correspondence to Gang Chen.

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Conflict of interest

GBM is a SAB member or Consultant with AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda, has Stock Options or Financial arrangements with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, Tarveda, has Licensed Technology with a HRD assay to Myriad Genetics and a DSP patent with Nanostring and has sponsored Research with Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Immunomet, Ionis, Komen Research Foundation, Nanostring, Ovarian Cancer Research Foundation, Pfizer, Prospect Creek Foundation, and Takeda/Millennium Pharmaceuticals. The authors declare that they have no conflict of interest.

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Sun, C., Li, X., Guo, E. et al. MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene 39, 1681–1695 (2020). https://doi.org/10.1038/s41388-019-1090-1

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