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Vascular Endothelial Growth Factor Isoform Expression as a Determinant of Blood Vessel Patterning in Human Melanoma Xenografts¹

Sunnybrook and Women’s College Health Sciences Centre, Molecular and Cellular Biology Research, Toronto, Ontario M4N 3M5, Canada [J. L. Y., G. K., R. S. K.]; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5S 1A1 Canada; [J. L. Y., R. S. K.]; and Henderson Research Centre, McMaster University, Hamilton, Ontario, L8V 1C3 Canada [J. W. R.]

Vascular endothelial growth factor (VEGF) occurs in at least five different isoforms because of alternative splicing of the gene. To investigate the roles of different VEGF isoforms in tumor blood vessel formation and tumorigenicity, the three major isoforms (VEGF₁₂₁, VEGF₁₆₅, and VEGF₁₈₉) were overexpressed in an early-stage human melanoma cell line (WM1341B), which is VEGF-negative and nontumorigenic in immunodeficient mice. Although overexpression of VEGF₁₂₁ and VEGF₁₆₅ resulted in aggressive tumor growth, WM1341B cells transfected with VEGF₁₈₉ remained nontumorigenic and dormant on injection. Although tumor growth rate depended on the level and not the isoform of VEGF expressed, striking isoform-specific differences in vascular patterning were associated with VEGF₁₂₁- versus VEGF₁₆₅-dependent tumorigenic conversion of human melanoma. Thus, tumors overexpressing VEGF₁₆₅ generated dense, highly heterogeneous vessel networks that were distinctly different from those of tumors expressing VEGF₁₂₁ (poorly vascularized and necrotic). Paradoxically, although VEGF₁₆₅ expression appears to result in the most effective tumor perfusion, it is the expression of VEGF₁₂₁ that is observed during human malignant melanoma progression. Indeed, unbiased selection of spontaneously tumorigenic variants of WM1341B (by coinjection with Matrigel) led to predominant expression of the VEGF₁₂₁ isoform. The vascular patterning in these tumors (1341-P3N1, 1341-P3N2) resembled that of the VEGF₁₂₁-transfected WM1341B tumors. These results suggest that, for reasons that remain to be elucidated, a "minimal" program of tumor vascularization may be favored during melanoma progression.

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