Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites

P. Guo, L. Xu, S. Pan, R. A. Brekken, S. T. Yang, G. B. Whitaker, M. Nagane, P. E. Thorpe, J. S. Rosenbaum, H. J S Huang, W. K. Cavenee, S. Y. Cheng

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73 Scopus citations

Abstract

The gene for the major angiogenic factor, vascular endothelial growth factor (VEGF), encodes several spliced isoforms. We reported previously that overexpression of two VEGF isoforms, VEGF121 and VEGF165, by human glioma U87 MG cells induced tumor-associated intracerebral hemorrhage, whereas expression of a third form, VEGF189, did not cause vessel rupture. Here, we test whether these VEGF isoforms have distinct activities for enhancing vascularization and growth of gliomas in mice. U87 MG cells that overexpressed VEGF165 or VEGF189 grew more rapidly than the parental cells in both s.c. and intracranial (i.c.) locations. However, cells that overexpressed VEGF121 only showed enhancement of i.c. tumor growth but had a minimal effect on s.c. glioma progression. At both anatomical sties, VEGF165 and VEGF189 strongly augmented neovascularization, whereas VEGF121 only increased vessel density in brain tumors. In each type of glioma, expression of VEGF receptors -1 and -2 largely phenocopied the tumor vasculature, because increased VEGF/VEGF receptor-activated microvessel densities were strongly correlated with the angiogenicity and tumorigenicity elicited by the VEGF isoforms at both anatomical sites. One notable difference between the sites was the expression of vitronectin, a prototypic ligand of αvβ3 and αvβ5integrins, detected in i.c. but not in s.c., gliomas. Endothelial cell migration stimulated by VEGF121 was potentiated by vitronectin to a greater extent than that stimulated by VEGF165. This data demonstrates that VEGF isoforms have distinct activities at different anatomical sites and suggest that the microenvironment of different tissues affects the function of VEGF isoforms.

Original languageEnglish (US)
Pages (from-to)8569-8577
Number of pages9
JournalCancer research
Volume61
Issue number23
StatePublished - Dec 1 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Guo, P., Xu, L., Pan, S., Brekken, R. A., Yang, S. T., Whitaker, G. B., Nagane, M., Thorpe, P. E., Rosenbaum, J. S., Huang, H. J. S., Cavenee, W. K., & Cheng, S. Y. (2001). Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer research, 61(23), 8569-8577.