Abstract C61: A macrophage autonomous α4β1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth, and metastasis

Abstract

Abstract Macrophages, a major leukocyte population present in tumors, play an essential role in promoting tumor growth by affecting angiogenesis, immune suppression, invasion and metastasis. Despite considerable research efforts, the signal transduction events within macrophages which encode the complex cascade of events required for tumor growth and polarization of macrophages are poorly understood. Our previous findings demonstrate that α4β1 and αvβ3 integrin directed cell migration on specific extracellular matrices (ECM) requires a specific kinase-GTPase pair, Syk-Rac2. This pathway was shown to regulate the ECM dependent postnatal angiogenic response with no defect in vascular development. Herein, we have linked this ECM dependent signaling pathway in macrophages to the regulation of M2 macrophage differentiation and to the regulation of tumor growth, invasion and metastasis. Using mouse genetic models, we provide direct evidence that a macrophage specific, α4β1 integrin dependent Syk-Rac2 signaling axis acts in concert with the p110γ isoform (PTEN-PI-3 kinase pathway) to control HIF1α levels, tumor growth and metastasis. We report a novel proteasome/E3 ligase dependent mechanism by which PI-3 kinase regulates HIF1α levels under hypoxic conditions in the stromal compartment. Moreover, treatment with Syk or PI-3 kinase inhibitors demonstrate potent activity in multiple metastatic models. The results define a novel molecular mechanism for the regulation of HIF1α and a macrophage autonomous signaling pathway that is required for alterations in the ECM and the provisional integrin to regulate tumor metastasis and suggest treatment for metastatic disease targeting this pathway in the M2 macrophage compartment. Citation Format: Shweta Joshi, Alok Ranjan Singh, Muamera Zulcic, Bao Lei, Karen Messer, Donald L. Durden. A macrophage autonomous α4β1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C61.