Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases

Cancer Cell. 2004 Dec;6(6):553-63. doi: 10.1016/j.ccr.2004.10.011.

Abstract

The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Angiopoietin-1 / physiology
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antigens / analysis
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Basement Membrane / drug effects
  • Basement Membrane / metabolism
  • Basement Membrane / pathology
  • Blood Vessels / chemistry
  • Blood Vessels / drug effects*
  • Blood Vessels / radiation effects
  • Blotting, Western
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / radiotherapy
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Collagen Type IV / analysis
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism
  • Combined Modality Therapy / methods
  • Dipeptides / pharmacology
  • Ephrin-B2 / genetics
  • Fluorescein Angiography
  • Gamma Rays / therapeutic use
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glioma / radiotherapy
  • Humans
  • Immunohistochemistry
  • Male
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Nude
  • Models, Biological
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / radiotherapy
  • Oligonucleotide Array Sequence Analysis
  • Oxygen / metabolism
  • Pericytes / chemistry
  • Pericytes / cytology
  • Pericytes / physiology
  • Proteoglycans / analysis
  • Receptor, TIE-2 / antagonists & inhibitors
  • Receptor, TIE-2 / immunology
  • Time Factors
  • Transfection
  • Up-Regulation / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / immunology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Angiopoietin-1
  • Antibodies, Monoclonal
  • Antigens
  • Collagen Type IV
  • Dipeptides
  • Ephrin-B2
  • Matrix Metalloproteinase Inhibitors
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • Proteoglycans
  • chondroitin sulfate proteoglycan 4
  • Receptor, TIE-2
  • Vascular Endothelial Growth Factor Receptor-2
  • Matrix Metalloproteinases
  • Oxygen