Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: Role of VEGF-receptor 2 and host VEGF-A

Unlike vascular endothelial growth factor (VEGF)-A, the effect of VEGF-C on tumor angiogenesis, vascular permeability, and leukocyte recruitment is no t known. To this end, we quantified in vivo growth and vascular function in tumors derived from two VEGF-C-overexpressing (VC+) and mock-transfected c ell lines (T241 fibrosarcoma and VEGF-A(-/-) embryonic stem cells) grown in murine dorsal skinfold chambers. VC+ tumors grew more rapidly than mock-tr ansfected tumors and exhibited parallel increases in tumor angiogenesis. Fu rthermore, VEGF-C overexpression elevated vascular permeability in T241 tum ors, but not in VEGF-A(-/-) tumors. Surprisingly, unlike VEGF-A, VEGF-C did not increase leukocyte rolling or adhesion in tumor vessels. Administratio n of VEGF receptor (VEGFR)-2 neutralizing antibody DC101 reduced vascular d ensity and permeability of both VC+ and mock-transduced T241 tumors. These data suggest that VEGFR-2 signaling is critical for tumor angiogenesis and vascular permeability and that VEGFR-3 signaling does not compensate for VE GFR-2 blockade. An alternate VEGFR, VEGFR-1 or neuropilin-1, may modulate a dhesion of leukocytes to tumor vessels.