title: Sunitinib but not VEGF blockade inhibits cancer stem cell endothelial differentiation.
abstract: Different mechanisms of angiogenesis and vasculogenesis are involved in the development of the tumor vasculature. Among them, cancer stem cells are known to contribute to tumor vasculogenesis through their direct endothelial differentiation. Here, we investigated the effect of anti-angiogenic therapy on vasculogenesis of cancer stem cells derived from breast and renal carcinomas. We found that all the anti-angiogenic approaches impaired proliferation and survival of cancer stem cells once differentiated into endothelial cells in vitro and reduced murine angiogenesis in vivo. At variance, only VEGF-receptor inhibition using the non-specific tyrosine kinase inhibitor Sunitinib or the anti-VEGF-receptor 2 neutralizing antibody, but not VEGF blockade using Bevacizumab, impaired the process of endothelial differentiation in vitro, suggesting a VEGF-independent mechanism. In addition, tyrosine kinase inhibition by Sunitinib but not VEGF blockade using the soluble VEGF trap sFlk1 inhibited the cancer stem cell-induced vasculogenesis in vivo. Accordingly, Sunitinib but not Bevacizumab inhibited the induction of hypoxia-inducible factor pathway occurring during endothelial differentiation under hypoxia. The present results highlight a differential effect of VEGF-receptor blockade versus VEGF inhibition in tumor vascularization. VEGFR blockade inhibits the process of tumor vasculogenesis occurring during tumor hypoxia whereas the effect of VEGF inhibition appears restricted to differentiated endothelial cells.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Brossa
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Grange
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Mancuso
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Annaratone
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Satolli
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, KU Leuven, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bussolati
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D000068258:Bevacizumab / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D000068258:Bevacizumab; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C467484:VEGFA protein, human
keywords: HIF; VEGF; angiogenesis; angiogenic therapy; tumor stem cells