Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma and regulators of tumor progression. CAFs are also involved in the intraperitoneal dissemination of gastric cancer cells. However, the molecular mechanism by which CAFs promote gastric cancer peritoneal dissemination should be further explored.
1. Cell migration ability was measured using Transwell assay. 2. Protein expression was analyzed by western blot. 3. Mouse model detects peritoneal metastasis of gastric cancer cells. 4. Affymetrix scanner 3000 was used to analyse the microarray genome-wide expression. 5. Statistical analysis. All values are expressed as means ± SD. The differences of the results between two groups were evaluated by Student’s t-test. P<0.05 was considered to be statistically significant.
In our study, we found CAFs enhance the migration of gastric cancer cells through the expression of VEGFA. While VEGFA neutralizing antibody bevacizumab markedly attenuated these CAFs-induced phenotypes in gastric cancer cells. Moreover, VEGFA enhances the gastric cancer cells' ability to diffuse and metastasize in the peritoneum. And the Bevacizumab could inhibit peritoneal metastatic nodules. We further found the migration of MGC-803 was increased with VEGFA stimulation, mainly through VEGFR1 but not VEGFR2.
Taken together, these results revealed that the activation of VEGFR1 by CAFs-derived VEGFA enhances the migration of gastric cancer cells. And VEGFA enhances the peritoneal metastasis capacity of gastric cancer cells. Our results suggested that inhibition of VEGFA and its receptor VEGFR1 to control downstream signaling may provide a promising therapeutic target for the treatment of tumors.
Clinical trial identification
Legal entity responsible for the study
National Natural Science of Foundation.
All authors have declared no conflicts of interest.