A Mosaic Mouse Model of Astrocytoma Identifies alphavbeta8 Integrin as a Negative Regulator of Tumor Angiogenesis

Oncogene. 2010 Aug 5;29(31):4460-72. doi: 10.1038/onc.2010.199. Epub 2010 Jun 7.

Abstract

Angiogenesis involves a complex set of cell-cell and cell-extracellular matrix (ECM) interactions that coordinately promote and inhibit blood vessel growth and sprouting. Although many factors that promote angiogenesis have been characterized, the identities and mechanisms of action of endogenous inhibitors of angiogenesis remain unclear. Furthermore, little is known about how cancer cells selectively circumvent the actions of these inhibitors to promote pathological angiogenesis, a requisite event for tumor progression. Using mosaic mouse models of the malignant brain cancer, astrocytoma, we report that tumor cells induce pathological angiogenesis by suppressing expression of the ECM protein receptor alphavbeta8 integrin. Diminished integrin expression in astrocytoma cells leads to reduced activation of latent TGFbetas, resulting in impaired TGFbeta receptor signaling in tumor-associated endothelial cells. These data reveal that astrocytoma cells manipulate their angiogenic balance by selectively suppressing alphavbeta8 integrin expression and function. Finally, these results show that an adhesion and signaling axis normally involved in developmental brain angiogenesis is pathologically exploited in adult brain tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytoma / blood supply*
  • Astrocytoma / genetics*
  • Astrocytoma / pathology
  • Brain Neoplasms / blood supply*
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Disease Models, Animal
  • Down-Regulation
  • Humans
  • Integrins / genetics
  • Integrins / physiology*
  • Male
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Mosaicism
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / prevention & control
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • Integrins
  • integrin alphavbeta8