The dormant in vivo phenotype of early stage primary human melanoma: termination by overexpression of vascular endothelial growth factor

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Abstract
Early stage primary human cutaneous melanoma is known to remain relatively avascular and dormant for up to a decade, after which it may give rise to more rapidly growing, vascular and metastatically-competent primary tumor. Clinical dormancy of early stage human melanomas can be recapitulated experimentally by injection of cell lines established from such tumors into nude mice. For example, WM1341B cells, which were isolated from a thin vertical growth phase (VGP) human melanoma, are non-tumorigenic in nude mice even though some of the cells remain viable for at least three weeks at the site of orthotopic injection. These cells produce little or no vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a potent stimulator of angiogenesis. In order to determine whether their in vivo dormant behaviour may therefore be related to an inability to induce tumor angiogenesis, subpopulations of WM1341B cells were engineered to constitutively overexpress the VEGF/VPF121 isoform. This apparently single modification was sufficient to induce overt and progressively growing tumors by several independent VEGF/VPF121 producing clones, which could be largely blocked by systemic treatment of mice with a monoclonal anti-VEGF neutralizing antibody (A 4.6.1). No evidence for an autocrine mechanism of growth stimulation by VEGF was found. Taken together, these results support the notion that defective angiogenesis may, at least in part, account for dormant phenotype of some early stage primary melanomas. Since the induction of an overt tumorigenic phenotype in several VEGF/VPF transfected WM1341B clones appears to depend exclusively on their expression of VEGF/VPF, such sublines should be useful for screening the activity of known or potential VEGF/VPF ligand or VEGF/VPF receptor antagonists in an in vivo context.

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