Vascular endothelial growth factor-D is a survival factor for human breast carcinoma cells.
Vascular endothelial growth factor-D (VEGF-D) stimulates growth of vascular and lymphatic endothelial cells by signaling through the tyrosine kinase receptors KDR (VEGFR-2) and Flt-4 (VEGFR-3). In the present study, we examined the effects of VEGF-D on apoptosis in human MCF-7 and MDA-MB-231 breast carcinoma cells. Because VEGF-D was not expressed constitutively in vitro, stable VEGF-D transfectants were produced. The VEGF-D-expressing MCF-7 and MDA-MB-231 lines displayed resistance to apoptosis induced by hypoxia, staurosporin and cycloheximide. Increased Bcl-2 expression, decreased homogenous caspase activities and inhibition of poly(ADP-ribose) polymerase cleavage were associated with inhibition of apoptosis in VEGF-D-expressing clones. Also, caspase-3 activation was suppressed in the VEGF-D expressing MDA-MB-231 clone. The antiapoptotic effect of VEGF-D in vitro was recapitulated in vivo using VEGF-D-expressing MDA-MB-231 xenografts. The lack of VEGFR-2 protein expression by Western blot and ineffectiveness of a neutralizing VEGFR-2 antibody in eliminating the antiapoptotic effects of VEGF-D suggest a different and yet unknown signaling mechanism. Our findings indicate that VEGF-D has a novel function as a survival factor of breast carcinoma cells in addition to its established functions as an angiogenic and lymphangiogenic factor.
Akahane
Manabu
M
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Akahane
Takemi
T
Matheny
Shannon L
SL
Shah
Amy
A
Okajima
Eijiro
E
Thorgeirsson
Unnur P
UP
D000917:Antibody Formation; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia; D002470:Cell Survival; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis / Q000502:physiology*
D042643:Vascular Endothelial Growth Factor D