Author/Authors :
Schmid، نويسنده , , Michael C. and Avraamides، نويسنده , , Christie J. and Dippold، نويسنده , , Holly C. and Franco، نويسنده , , Irene and Foubert، نويسنده , , Philippe and Ellies، نويسنده , , Lesley G. and Acevedo، نويسنده , , Lissette M. and Manglicmot، نويسنده , , Joan R.E. and Song، نويسنده , , Xiaodan and Wrasidlo، نويسنده , , Wolfgang and Blair، نويسنده , , Sara L. and Ginsberg، نويسنده , , Mark H. and Cheresh، نويسنده , , David A. and Hirsch، نويسنده , , Emilio and Field، نويسنده , , Seth J. and Varner، نويسنده , , Judith A.، نويسنده ,
Abstract :
Summary
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.
