SECRETION OF VEGF-C BY PANCREATIC CANCER CELL LINES PROMOTES LYMPHATIC ENDOTHELIAL CELL MIGRATION DURING TUMOR LYMPHANGIOGENESIS

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Background : The mechanisms of tumor-associated lymphangiogenesis are gaining interest. Immunohistochemical expression of vascular endothelial growth factor (VEGF)-C in various cancers correlates with the rate of metastasis to lymph nodes. Objective : To investigate the mechanisms underlying lymphatic node metastasis in pancreatic cancer, we examined the roles of VEGF-C in tumor lymphangiogenesis. Methods: We used RT-PCR and ELISA to characterize VEGF-C secretion by pancreatic cancer cell lines. We also examined the effects of different cell lines on lymphatic endothelial cells (LECs) in vitro and investigated the relation between lymphangiogenesis and lymph node metastasis in an orthotopic nude mouse tumor model. Results: We identified VEGF-C high-secretion (MIA PaCa-2) and low-secretion (BxPC-3) cell lines. In migration assays, rVEGF-C treatment increased the number of migrating LECs in a dose-dependent manner. Addition of MIA PaCa-2 culture supernatant enhanced LEG migration 1.61-fold more than did BxPC-3 supernatant (P<0.01). In LEC/fibroblast co-culture system, LEG capillary formation was significantly enhanced by co-culture with MIA PaCa-2 compared with BxPC-3 cells (1.84-fold) (P<0.01). These effects were significantly inhibited by addition of rVEGF receptor 3 (R3)/Fc chimera. When nude mice were orthotopically implanted with MIA PaCa-2 cells, infiltrating tumor cells were observed in some lymphatic vessels in the tumor periphery, and numbers of lymph node metastasis tended to be increased. Conclusions: Secretion of VEGF-C by pancreatic cancer cells may play an important role in LEG migration in pancreatic cancer lymphangiogenesis. It is possible that rVEGF R3/Fc chimera may have a role in controlling lymph node metastasis.
名古屋市立大学の論文

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