Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis

: Melanoma progression in general is characterized by an increase in both metastatic frequency and the vascular density of the tumour tissue. Although a direct correlation between these two parameters in individual cases seems to be lacking, it is clear that metastasis is invariably preceded by angiogenesis. One of the angiogenic factors that is produced by human melanoma cells is vascular endothelial growth factor (VEGF). To investigate the role of this factor in the angiogenic process in primary cutaneous melanoma we determined the mean vascular density and the presence of VEGF protein in biopsies of human lesions. The results were compared with those found in normal skin or uninvolved skin from melanoma patients. In addition, we studied morphological and antigenic features of the proliferating neovasculature. We show that (1) the mean vascular density gradually rises along with melanoma progression, (2) transition of horizontal to vertical growth phase melanoma is accompanied by induction of VEGF protein expression and accumulation of this factor in the stroma, (3) vertical growth phase melanoma is often organized in nodules separated by septa containing blood vessels, but without lymphatics, and (4) blood vessel lumina in vertical growth phase melanoma are separated from tumour nodules by two basal lamina containing collagen type IV and the endothelium shows activated morphology and focal expression of the adhesion molecule E-selectin. Our findings indicate that VEGF is a prominent angiogenic factor in melanoma angiogenesis. Although its expression is induced during progression, the effect of VEGF on the incidence of metastasis is probably indirect.