Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma

We reported previously that vascular endothelial growth factor isoform A (VEGF-A) expression by Mel57 human melanoma cells led to tumor progression in a murine brain metastasis model in an angiogenesis-independent fashion by dilation of co-opted, pre-existing vessels and concomitant enhanced blood supply (B. Kusters et al., Cancer Res., 62: 341-345, 2002). Here, we compare the activities of the 121, 165, and 189 VEGF-A isoforms in this model by transfecting Mel57 cells with the respective cDNAs and by injecting the resulting stably transfected cell lines in the internal carotid arteries of nude mice (n = 10 for each isoform). Although the three isoforms had similar potency to induce endothelial cell proliferation, VEGF₁₂₁ expression did not result in sprouting angiogenesis but rather led to extensive vasodilation and increased permeability of preexisting, predominantly peritumoral vessels. Sometimes, proliferating endothelial cells accumulated in vessel lumina, giving these a microvascular, glomeruloid, proliferation-like appearance. Expression of VEGF₁₆₅ or VEGF₁₈₉ was associated with induction of an intratumoral neovascular bed. In VEGF ₁₆₅-expressing tumors, daughter endothelial cells were distributed among newly formed vessels that were extensively dilated. This also occurred in VEGF₁₈₉ tumors, but there, vasodilation was less pronounced. Using contrast-enhanced magnetic resonance imaging, the different vascular phenotypes were visualized on characteristic radiological images. VEGF₁₆₅ expression was the most unfavorable of the three. Mice carrying VEGF ₁₆₅ tumors became moribund earlier than those carrying VEGF ₁₂₁-expressing tumors (16 ± 4 days versus 22 ± 3 days). Our data demonstrate that VEGF-A isoforms differ in angiogenic properties that can be visualized by contrast-enhanced magnetic resonance imaging.