Sunitinib but not VEGF blockade inhibits cancer stem cell endothelial differentiation

Oncotarget. 2015 May 10;6(13):11295-309. doi: 10.18632/oncotarget.3123.

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.

Keywords: HIF; VEGF; angiogenesis; angiogenic therapy; tumor stem cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bevacizumab / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Hypoxia
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Endothelial Progenitor Cells / drug effects*
  • Endothelial Progenitor Cells / enzymology
  • Endothelial Progenitor Cells / pathology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Indoles / pharmacology*
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / pharmacology*
  • RNA Interference
  • Signal Transduction / drug effects
  • Sunitinib
  • Time Factors
  • Transfection
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrroles
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • endothelial PAS domain-containing protein 1
  • Bevacizumab
  • Vascular Endothelial Growth Factor Receptor-2
  • Sunitinib