title: Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites.
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, VEGF(121) and VEGF(165), by human glioma U87 MG cells induced tumor-associated intracerebral hemorrhage, whereas expression of a third form, VEGF(189), 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 VEGF(165) or VEGF(189) grew more rapidly than the parental cells in both s.c. and intracranial (i.c.) locations. However, cells that overexpressed VEGF(121) only showed enhancement of i.c. tumor growth but had a minimal effect on s.c. glioma progression. At both anatomical sties, VEGF(165) and VEGF(189) strongly augmented neovascularization, whereas VEGF(121) 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 alpha(v)beta(3) and alpha(v)beta(5) integrins, detected in i.c. but not in s.c., gliomas. Endothelial cell migration stimulated by VEGF(121) was potentiated by vitronectin to a greater extent than that stimulated by VEGF(165). 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.
authors.affiliation: University of Pittsburgh Cancer Institute and Department of Pathology, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: P
authors.initials: P
authors.lastname: Guo
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Pan
authors.forename: R A
authors.initials: RA
authors.lastname: Brekken
authors.forename: S T
authors.initials: ST
authors.lastname: Yang
authors.forename: G B
authors.initials: GB
authors.lastname: Whitaker
authors.forename: M
authors.initials: M
authors.lastname: Nagane
authors.forename: P E
authors.initials: PE
authors.lastname: Thorpe
authors.forename: J S
authors.initials: JS
authors.lastname: Rosenbaum
authors.forename: H J
authors.initials: HJ
authors.lastname: Su Huang
authors.forename: W K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: S Y
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019096:Vitronectin; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor