Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2–VEGFA axis
Open Access
- 22 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (3), 459-470
- https://doi.org/10.1038/s41416-020-0898-3
Abstract
Background Gastric cancer (GC) patients frequently develop peritoneal metastasis; however, the underlying mechanism remains unknown. We hypothesised that omental adipocytes (OmAd) trigger GC cells towards malignant activity to induce peritoneal metastasis. Methods We analysed interactions among human GC cells, endothelial cells and OmAd using a 3D co-culture system. We also employed a multipronged animal study, including subcutaneous and orthotopic tumours, and humanised omental adipose tissue models. Urinary levels of CXCL2 were analysed in human GC patients with and without peritoneal metastasis. Results Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects. In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2. OmAd promoted GC growth in a humanised omental adipose tissue model using NSG mice, but silencing CXCL2 in OmAd cancelled OmAd-induced tumour growth. Finally, urinary levels of CXCL2 were significantly higher in GC patients with peritoneal metastasis than in those without. Conclusion Omental adipocytes trigger GC cells to an aggressive phenotype through CXCL2 secretion, which induces angiogenesis followed by cell growth and peritoneal metastasis.Keywords
Funding Information
- MEXT | Japan Society for the Promotion of Science (15K15295)
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