title: Overexpression of vascular endothelial growth factor 189 in breast cancer cells leads to delayed tumor uptake with dilated intratumoral vessels.
abstract: Vascular endothelial growth factor (VEGF) is essential for breast cancer progression and is a relevant target in anti-angiogenesis. Although VEGF121 and VEGF165, the fully or partially secreted isoforms, respectively, have been the focus of intense studies, the role of the cell-associated VEGF189 isoform is not understood. To clarify the contribution of VEGF189 to human mammary carcinogenesis, we established several clones of MDA-MB-231 cells stably overexpressing VEGF189 (V189) and VEGF165 (V165). V189 and V165 clones increased tumor growth and angiogenesis in vivo. Remarkably, V165 induced the most rapid tumor uptake, whereas V189 increased vasodilation. In vitro overexpression of VEGF165 and VEGF189 increases the proliferation and chemokinesis of these cancer cells. Interestingly, overexpression of VEGF189 increased cell adhesion on fibronectin (1.9-fold) and vitronectin (1.6-fold), as compared to VEGF165, through alpha5beta1 and alphavbeta5 integrins. Using the BIACore system we demonstrated for the first time that VEGF189 binds directly to neuropilin-1, which is strongly expressed in MDA-MB-231 cells. In contrast, VEGF-R2 was not significantly expressed and VEGF-R1 was expressed at low level. Our in vitro results suggest an autocrine effect of VEGF189 on breast cancer cells, probably through neuropilin-1. In conclusion, our data indicate that VEGF189 participates in mammary tumor growth through both angiogenesis and nonangiogenic functions. Whether VEGF189 overexpression is correlated to prognosis in human breast tumors remains to be established.
authors: INSERM U553, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, University of Paris VII, Paris, France.
authors: Marie-Astrid
authors: MA
authors: Hervé
authors: Hélène
authors: H
authors: Buteau-Lozano
authors: Roger
authors: R
authors: Vassy
authors: Ivan
authors: I
authors: Bieche
authors: Guillaume
authors: G
authors: Velasco
authors: Marika
authors: M
authors: Pla
authors: Gérard
authors: G
authors: Perret
authors: Samia
authors: S
authors: Mourah
authors: Martine
authors: M
authors: Perrot-Applanat
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse