Development of the tumor vascular bed in response to hypoxia-induced VEGF-A differs from that in tumors with constitutive VEGF-A expression.
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.
Roodink
Ilse
I
Department of Pathology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
van der Laak
Jeroen
J
Kusters
Benno
B
Wesseling
Pieter
P
Verrijp
Kiek
K
de Waal
Robert
R
Leenders
William
W
D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology; D001254:Astrocytoma / Q000098:blood supply / Q000473:pathology; D002455:Cell Division; D015687:Cell Hypoxia; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D008545:Melanoma / Q000098:blood supply / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A