Receptor Tyrosine Kinases and TLR/IL1Rs Unexpectedly Activate Myeloid Cell PI3kγ, a Single Convergent Point Promoting Tumor Inflammation and Progression

Cancer Cell. 2011 Jun 14;19(6):715-27. doi: 10.1016/j.ccr.2011.04.016.

Abstract

Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110γ in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110γ in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110γ in a Ras/p87-dependent manner. Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Movement
  • Class Ib Phosphatidylinositol 3-Kinase / physiology*
  • Disease Progression
  • Humans
  • Inflammation / etiology*
  • Integrin alpha4beta1 / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasms / pathology*
  • Neoplasms / prevention & control
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptors, Interleukin-1 / physiology*
  • Toll-Like Receptors / physiology*
  • ras Proteins / physiology

Substances

  • Integrin alpha4beta1
  • Receptors, Interleukin-1
  • Toll-Like Receptors
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • ras Proteins