Research Papers:

Sunitinib but not VEGF blockade inhibits cancer stem cell endothelial differentiation

Alessia Brossa _, Cristina Grange, Letizia Mancuso, Laura Annaratone, Maria Antonietta Satolli, Massimiliano Mazzone, Giovanni Camussi and Benedetta Bussolati

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Oncotarget. 2015; 6:11295-11309. https://doi.org/10.18632/oncotarget.3123

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Alessia Brossa1, Cristina Grange2, Letizia Mancuso1, Laura Annaratone2, Maria Antonietta Satolli3, Massimiliano Mazzone4,5, Giovanni Camussi2, Benedetta Bussolati1,3

1Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy

2Department of Medical Sciences, University of Torino, Torino, Italy

3Department of Oncology, University of Torino, Torino, Italy

4Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium

5Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium

Correspondence to:

Benedetta Bussolati, e-mail: [email protected]

Giovanni Camussi, e-mail: [email protected]

Keywords: tumor stem cells, VEGF, HIF, angiogenic therapy, angiogenesis

Received: September 24, 2014     Accepted: January 09, 2015     Published: February 28, 2015


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.

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