A lipid kinase cousin cooperates to promote cancer

Abstract

Phosphoinositide 3-kinases (PI3Ks) are considered promising drug targets in oncology. In this issue of Cancer Cell, Schmid et al. demonstrate that the PI3Kγ isoform is required for inflammatory myeloid cells to traffic to tumors. Though tumor cells do not express PI3Kγ, selective inhibition of this isoform suppresses tumor growth and angiogenesis.

Figure 1. p110γ in myeloid cells mediates adhesion to endothelial cells, driving tumor inflammation and progression

Bone marrow-derived myeloid cells enter tumor sites by first adhering to endothelial cells in the local vasculature. Adhesion is driven by extracellular signals that increase avidity of the integrin α4β1. The extracellular signaling molecules are produced by both the tumor cells and local macrophages and include chemokines, growth factors and cytokines. Receptors for these diverse ligands each stimulate PI3Kγ, linking to the catalytic subunit p110γ through either the p87 or p101 regulatory subunits and through the Ras GTPase. Myeloid cells entering the tumor mature into macrophages (CD11b⁺Gr-1^loF4/80⁺) that secrete a partially overlapping set of chemotactic and angiogenic factors. The inflammation associated with progressive recruitment of myeloid cells enhances tumor growth and angiogenesis.