title: Blocking αvβ3 integrin by a recombinant RGD disintegrin impairs VEGF signaling in endothelial cells.
abstract: Vascular endothelial growth factor (VEGF) and αvβ3 integrin are key molecules that actively participate in tumor angiogenesis and metastasis. Some integrin-blocking molecules are currently under clinical trials for cancer and metastasis treatment. However, the mechanism of action of such inhibitors is not completely understood. We have previously demonstrated the anti-angiogenic and anti-metastatic properties of DisBa-01, a recombinant His-tag RGD-disintegrin from Bothrops alternatus snake venom in some experimental models. DisBa-01 blocks αvβ3 integrin binding to vitronectin and inhibits integrin-mediated downstream signaling cascades and cell migration. Here we add some new information on the mechanism of action of DisBa-01 in the tumor microenvironment. DisBa-01 supports the adhesion of fibroblasts and MDA-MB-231 breast cancer cells but it inhibits the adhesion of these cells to type I collagen under flow in high shear conditions, as a simulation of the blood stream. DisBa-01 does not affect the release of VEGF by fibroblasts or breast cancer cells but it strongly decreases the expression of VEGF mRNA and of its receptors, vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) in endothelial cells. DisBa-01 at nanomolar concentrations also modulates metalloprotease 2 (MMP-2) and 9 (MMP-9) activity, the latter being decreased in fibroblasts and increased in MDA-MB-231 cells. In conclusion, these results demonstrate that αvβ3 integrin inhibitors may induce distinct effects in the cells of the tumor microenvironment, resulting in blockade of angiogenesis by impairing of VEGF signaling and in inhibition of tumor cell motility.
authors.affiliation: Dep. Ciências Fisiológicas, Universidade Federal de São Carlos, Rodovia Washington Luis km 235, 13565-905 Sao Carlos, SP, Brazil.
authors.forename: Cyntia F
authors.initials: CF
authors.lastname: Montenegro
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Salla-Pontes
authors.forename: Juliana U
authors.initials: JU
authors.lastname: Ribeiro
authors.forename: Aline Z
authors.initials: AZ
authors.lastname: Machado
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Ramos
authors.forename: Camila C
authors.initials: CC
authors.lastname: Figueiredo
authors.forename: Verônica
authors.initials: V
authors.lastname: Morandi
authors.forename: Heloisa S
authors.initials: HS
authors.lastname: Selistre-de-Araujo
mesh_terms: D000818:Animals; D017837:Bothrops; D001943:Breast Neoplasms / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism; D019483:Disintegrins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012910:Snake Venoms / Q000737:chemistry / Q000494:pharmacology*; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D019483:Disintegrins; D039302:Integrin alphaVbeta3; D010455:Peptides; D012910:Snake Venoms; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2