Lysyl Oxidase Plays a Critical Role in Endothelial Cell Stimulation to Drive Tumor Angiogenesis

Cancer Res. 2013 Jan 15;73(2):583-94. doi: 10.1158/0008-5472.CAN-12-2447. Epub 2012 Nov 27.

Abstract

Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRβ, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Colorectal Neoplasms / blood supply*
  • Colorectal Neoplasms / metabolism*
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / metabolism*
  • Protein-Lysine 6-Oxidase / antagonists & inhibitors
  • Protein-Lysine 6-Oxidase / metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • Protein-Lysine 6-Oxidase