Vascular endothelial growth factor receptor 2 inhibition in-vivo affects tumor vasculature in a tumor type-dependent way and downregulates vascular endothelial growth factor receptor 2 protein without a prominent role for miR-296

Anticancer Drugs. 2012 Feb;23(2):161-72. doi: 10.1097/CAD.0b013e32834dc279.

Abstract

The precise molecular effects that antiangiogenic drugs exert on tumor vasculature remain to be poorly understood. We therefore set out to investigate the molecular and architectural changes that occur in the vasculature of two different tumor types that both respond to vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor therapy. Mice bearing Lewis lung carcinoma (LLC) or B16.F10 melanoma were treated with vandetanib (ZD6474), a VEGFR2/epidermal growth factor receptor (EGFR)/REarranged during Transfection (RET) kinase inhibitor, resulting in a significant 80% reduction in tumor outgrowth. Although in LLC the vascular density was not affected by vandetanib treatment, it was significantly decreased in B16.F10. In LLC, vandetanib treatment induced a shift in vascular gene expression toward stabilization, as demonstrated by upregulation of Tie2 and N-cadherin and downregulation of Ang2 and integrin β3. In contrast, only eNOS and P-selectin responded to vandetanib treatment in B16.F10 vasculature. Strikingly, vandetanib reduced protein expression of VEGFR2 in both models, whereas mRNA remained unaffected. Analysis of miR-296 expression allowed us to exclude a role for the recently proposed microRNA-296 in VEGFR2 posttranslational control in LLC and B16.F10 in vivo. Our data demonstrate that VEGFR2/EGFR inhibition through vandetanib slows down both LLC and B16.F10 tumor growth. Yet, the underlying molecular changes in the vasculature that orchestrate the antitumor effect differ between tumor types. Importantly, in both models, vandetanib treatment induced loss of its pharmacological target, which was not directly related to miR-296 expression. Validation of our observations in tumor biopsies from VEGFR2 inhibitor-treated patients will be essential to unravel the effects of VEGFR2 inhibitor therapy on tumor vasculature in relation to therapeutic efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Carcinoma, Lewis Lung / blood supply
  • Carcinoma, Lewis Lung / drug therapy*
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Immunohistochemistry
  • Injections, Intraperitoneal
  • Male
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Piperidines / administration & dosage
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • MIRN296 microRNA, mouse
  • MicroRNAs
  • Piperidines
  • Quinazolines
  • Vascular Endothelial Growth Factor Receptor-2
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine