The contribution of vascular endothelial growth factor induced angiogenesis to the progression of primary human melanoma

grantor: University of TorontoEarly stage primary human melanomas are known to remain relatively avascular and dormant for up to a decade or longer after which they may give rise to more rapidly growing, vascular and metastatically-competent primary tumors. The clinical behavior of melanoma recapitulated experimentally by injection of cell lines established from such tumors into nude mice. WM1341B cells, which were isolated from early stage human melanoma, are non-tumorigenic and display a dormant phenotype in nude mice. These cells produce little or no vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis, in culture. In order to determine whether their in vivo dormant behavior may be related to an inability to induce tumor angiogenesis, subpopulations of WM1341B cells were engineered to constitutively overexpress the VEGF$\sb{121}$ isoform. This modification was sufficient to induce overtly progressively growing tumors by several independent VEGF$\sb{121}$ producing clones and could be strongly suppressed by treatment of mice with a monoclonal anti-VEGF neutralizing (A4.6.1) antibody. These results support the notion that defective angiogenesis may, in part, account for the dormant phenotype of early stage primary melanoma lesions. Furthermore, this system may be useful as a tool to screen new anti-angiogenic agents for cancer therapy.M.Sc