Development of the tumor vascular bed in response to hypoxia-induced VEGF-A differs from that in tumors with constitutive VEGF-A expression

Autor: Roodink, I., Laak, J.A.W.M. van der, Kusters, B., Wesseling, P., Verrijp, K., Waal, R.M.W. de, Leenders, W.P.J.
Rok vydání: 2006
Předmět:
Zdroj: International Journal of Cancer, 119, 9, pp. 2054-62
International Journal of Cancer, 119, 2054-62
ISSN: 0020-7136
Popis: Contains fulltext : 50529.pdf (Publisher’s version ) (Open Access) 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.
Databáze: OpenAIRE
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