Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth

Cell Death Differ. 2006 Sep;13(9):1442-53. doi: 10.1038/sj.cdd.4401816. Epub 2005 Nov 18.

Abstract

Administration of active TG2 to two different in vitro angiogenesis assays resulted in the accumulation of a complex extracellular matrix (ECM) leading to the suppression of endothelial tube formation without causing cell death. Matrix accumulation was accompanied by a decreased rate of ECM turnover, with increased resistance to matrix metalloproteinase-1. Intratumor injection of TG2 into mice bearing CT26 colon carcinoma tumors demonstrated a reduction in tumor growth, and in some cases tumor regression. In TG2 knockout mice, tumor progression was increased and survival rate reduced compared to wild-type mice. In wild-type mice, an increased presence of TG2 was detectable in the host tissue around the tumor. Analysis of CT26 tumors injected with TG2 revealed fibrotic-like tissue containing increased collagen, TG2-mediated crosslink and reduced organized vasculature. TG2-mediated modulation of cell behavior via changes in the ECM may provide a new approach to solid tumor therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Coculture Techniques
  • Collagen / biosynthesis
  • Endothelial Cells / enzymology
  • Endothelial Cells / pathology
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / pathology
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • GTP-Binding Proteins / pharmacology
  • Humans
  • Matrix Metalloproteinase 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / enzymology
  • Neovascularization, Pathologic / pathology*
  • Rats
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*
  • Transglutaminases / pharmacology
  • Transplantation, Heterologous

Substances

  • Collagen
  • transglutaminase 2
  • Transglutaminases
  • Matrix Metalloproteinase 1
  • GTP-Binding Proteins