PI3-Kinase γ Promotes Rap1a-Mediated Activation of Myeloid Cell Integrin α4β1, Leading to Tumor Inflammation and Growth

Tumor inflammation, the recruitment of myeloid lineage cells into the tumor microenvironment, promotes angiogenesis, immunosuppression and metastasis. CD11b+Gr1lo monocytic lineage cells and CD11b+Gr1hi granulocytic lineage cells are recruited from the circulation by tumor-derived chemoattractants, which stimulate PI3-kinase gamma (PI3K gamma)-mediated integrin alpha 4 activation and extravasation. We show here that PI3K gamma activates PLC gamma, leading to RasGrp/CalDAG-GEF-I&II mediated, Rap1a-dependent activation of integrin alpha 4 beta 1, extravasation of monocytes and granulocytes, and inflammation-associated tumor progression. Genetic depletion of PLC gamma, CalDAG-GEFI or II, Rap1a, or the Rap1 effector RIAM was sufficient to prevent integrin alpha 4 activation by chemoattractants or activated PI3K gamma (p110 gamma CAAX), while activated Rap (RapV12) promoted constitutive integrin activation and cell adhesion that could only be blocked by inhibition of RIAM or integrin alpha 4 beta 1. Similar to blockade of PI3K gamma or integrin alpha 4 beta 1, blockade of Rap1a suppressed both the recruitment of monocytes and granulocytes to tumors and tumor progression. These results demonstrate critical roles for a PI3K gamma-Rap1a-dependent pathway in integrin activation during tumor inflammation and suggest novel avenues for cancer therapy.