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Vascular Endothelial Growth Factor Isoforms Display Distinct Activities in Promoting Tumor Angiogenesis at Different Anatomic Sites¹

University of Pittsburgh Cancer Institute and Department of Pathology, Pittsburgh, Pennsylvania 15213 [P. G., L. X., S. P., S-T. Y., S-Y. C.]; Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104-2016 [R. A. B.]; and Cardiovascular Research, Procter and Gamble Pharmaceuticals, Mason, Ohio 45040 [G. B. W., J. S. R.]; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, 75235-9111 [P. E. T.]; and Ludwig Institute for Cancer Research, San Diego Branch, Department of Medicine, and Center for Molecular Genetics, University of California, San Diego, La Jolla, California, 92093-0660 [M. N., H.-J. S. H., W. K. C.]

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 _vß₃ and _vß₅ integrins, 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.

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