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 not known. To this end, we quantified in vivo growth and vascular function in tumors derived from two VEGF-C-overexpressing (VC+) and mock-transfected cell lines (T241 fibrosarcoma and VEGF-A-/- embryonic stem cells) grown in murine dorsal skinfold chambers. VC+ tumors grew more rapidly than mock-transfected tumors and exhibited parallel increases in tumor angiogenesis. Furthermore, VEGF-C overexpression elevated vascular permeability in T241 tumors, but not in VEGF-A-/- tumors. Surprisingly, unlike VEGF-A, VEGF-C did not increase leukocyte rolling or adhesion in tumor vessels. Administration of VEGF receptor (VEGFR)-2 neutralizing antibody DC101 reduced vascular density 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 VEGFR-2 blockade. An alternate VEGFR, VEGFR-1 or neuropilin-1, may modulate adhesion of leukocytes to tumor vessels.
Kadambi
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A
Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston 02114, USA.
Mouta Carreira
C
C
Yun
C O
CO
Padera
T P
TP
Dolmans
D E
DE
Carmeliet
P
P
Fukumura
D
D
Jain
R K
RK
D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology; D007962:Leukocytes / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C
D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D012313:RNA; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor