Abstract
Tumors arise initially as avascular masses in which central hypoxia induces expression of vascular endothelial growth factor‐A (VEGF‐A) and subsequently tumor vascularization. However, VEGF‐A can also be constitutively expressed as a result of genetic events. VEGF‐A is alternatively spliced to yield at least 6 different isoforms. Of these, VEGF‐A~121~ is freely diffusible whereas basically charged domains in the larger isoforms confer affinity for cell surface or extracellular matrix components. We previously reported that in a mouse brain metastasis model of human melanoma, VEGF‐A~121~ induced a qualitatively different tumor vascular phenotype than VEGF‐A~165~ and VEGF‐A~189~: in contrast to the latter ones, and VEGF‐A~121~ did not induce a neovascular bed but rather led to leakage and dilatation of preexistent brain vessels. Here, we correlate vascular phenotypes with spatial VEGF‐A expression profiles in clinical brain tumors (low grade gliomas; n = 6, melanoma metastases; n = 4, adenocarcinoma metastases; n = 4, glioblastoma multiforme; n = 3, sarcoma metastasis; n = 1, renal cell carcinoma metastasis; n = 1). We show that tumors that constitutively express VEGF‐A present with different vascular beds than tumors in which VEGF‐A is expressed as a response to central hypoxia. This phenotypic difference is consistent with a model where in tumors with constitutive VEGF‐A expression, all isoforms exert their effects on vasculature, resulting in a classical angiogenic phenotype. In tumors where only central parts express hypoxia‐induced VEGF‐A, the larger angiogenic isoforms are retained by extracellular matrix, leaving only freely diffusible VEGF‐A~121~ to exert its dilatation effects on distant vessels. © 2006 Wiley‐Liss, Inc.