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pubmed:abstractText |
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 p110? in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110? in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110? in a Ras/p87-dependent manner. Once activated, p110? promotes inside-out activation of a single integrin, ?4?1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110? suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology.
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