Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis

J Exp Med. 2013 Sep 23;210(10):1937-45. doi: 10.1084/jem.20121571. Epub 2013 Sep 16.

Abstract

Understanding the direct, tumor cell-intrinsic effects of PI 3-kinase (PI3K) has been a key focus of research to date. Here, we report that cancer cell-extrinsic PI3K activity, mediated by the p110α isoform of PI3K, contributes in an unexpected way to tumor angiogenesis. In syngeneic mouse models, inactivation of stromal p110α led to increased vascular density, reduced vessel size, and altered pericyte coverage. This increased vascularity lacked functionality, correlating with enhanced tumor hypoxia and necrosis, and reduced tumor growth. The role of p110α in tumor angiogenesis is multifactorial, and includes regulation of proliferation and DLL4 expression in endothelial cells. p110α in the tumor stroma is thus a regulator of vessel formation, with p110α inactivation giving rise to nonfunctional angiogenesis, which can stunt tumor growth. This type of vascular aberration differs from vascular endothelial growth factor-centered antiangiogenesis therapies, which mainly lead to vascular pruning. Inhibition of p110α may thus offer a new antiangiogenic therapeutic opportunity in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Melanoma, Experimental
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism

Substances

  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • delta protein
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase
  • Pik3cd protein, mouse