Vascular endothelial growth factor-C secreted by pancreatic cancer cell line promotes lymphatic endothelial cell migration in an in vitro model of tumor lymphangiogenesis.

OBJECTIVES: To investigate mechanisms underlying lymphatic node metastasis in pancreatic cancer, we examined roles of vascular endothelial growth factor-C (VEGF-C) in tumor lymphangiogenesis.

METHODS: We measured VEGF-C secretion by pancreatic cancer cell lines using enzyme-linked immunosorbent assay and examined effects of different cell lines on lymphatic endothelial cells (LECs) in vitro.

RESULTS: We identified VEGF-C high-secretion (MIA PaCa-2) and low-secretion cell lines (BxPC-3). The trend of enhancement of LEC proliferation by recombinant human VEGF-C (rVEGF-C) was not statistically significant. Numbers of migrating cells were increased by rVEGF-C treatment in a dose-dependent manner. The MIA PaCa-2 cell culture supernatant caused greater LEC migration than the BxPC-3 supernatant. The VEGF-C effects were significantly inhibited by rVEGF receptor 3 (rVEGF R3)/Fc chimera. In LEC/fibroblast coculture on collagen gel, LEC capillary formation was significantly enhanced by coculture with MIA PaCa-2 cells compared with BxPC-3 cells. Enhanced capillary formation with MIA PaCa-2 cells was inhibited by rVEGF R3/Fc chimera, implying VEGF-C involvement in progression of LEC sprouting in a tumor microenvironment.

CONCLUSIONS: Because VEGF-C secreted by pancreatic cancer cells plays an important role in LEC migration in pancreatic cancer lymphangiogenesis, it is possible that rVEGF R3/Fc chimera might have a role in controlling lymph node metastasis.