PI3-kinase ? promotes Rap1a-mediated activation of myeloid cell integrin ?4?1, leading to tumor inflammation and growth.

ABSTRACT: 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 ? (PI3K?)-mediated integrin ?4 activation and extravasation. We show here that PI3K? activates PLC?, leading to RasGrp/CalDAG-GEF-I&II mediated, Rap1a-dependent activation of integrin ?4?1, extravasation of monocytes and granulocytes, and inflammation-associated tumor progression. Genetic depletion of PLC?, CalDAG-GEFI or II, Rap1a, or the Rap1 effector RIAM was sufficient to prevent integrin ?4 activation by chemoattractants or activated PI3K? (p110?CAAX), while activated Rap (RapV12) promoted constitutive integrin activation and cell adhesion that could only be blocked by inhibition of RIAM or integrin ?4?1. Similar to blockade of PI3K? or integrin ?4?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?-Rap1a-dependent pathway in integrin activation during tumor inflammation and suggest novel avenues for cancer therapy.

SUBMITTER: Schmid MC 

PROVIDER: S-EPMC3614555 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature