Chronic inflammation promotes tumor development, as infectious and chemical agents, as well as chronic inflammatory disorders, have been shown to increase the risk of developing tumors. Solid tumors are heavily invested with tumor-associated macrophages, which promote angiogenesis, immunosuppression and tumor growth, progression, and metastasis. Targeting the mechanisms controlling myeloid cell recruitment to tumors is a promising approach to suppressing tumor growth and metastasis. We recently found that myeloid cell recruitment to tumors depends on PI3kinase ? (p110?). Pharmacological or genetic blockade of p110? suppressed myeloid cell adhesion to endothelium and recruitment to tumors, as well as angiogenesis, growth and metastasis of implanted and spontaneous tumors, revealing that p110? is an important therapeutic target in oncology. Importantly, p110? is the major PI3-kinase isoform expressed in myeloid cells;furthermore, myeloid cells are the main physiological source of p110?. Selective inhibitors of p110? could thus serve as therapeutics to suppress tumor malignancy by blocking diverse pathways promoting tumor inflammation.
The aims of this proposal are 1) to determine the molecular pathways by which PI3kinase gamma regulates myeloid cell trafficking during inflammation, tumor progression and metastasis, 2) to evaluate the role of PI3K? in the regulation of immunosuppression during tumor progression, and 3) to evaluate the potential of PI3- kinase ? to serve as a therapeutic target for the treatment of breast cancer.
Recent studies have shown that inflammation plays a critical role in promoting tumor growth, progression and metastasis. Tumor associated macrophages promote angiogenesis, suppress immunity and stimulate tumor cell invasion and survival, which combine to promote tumor growth, spread and organ dysfunction. The overall goal of the proposed research is to explore the mechanistic roles of PI3kinase gamma in the regulation of tumor inflammation, growth and metastasis and to evaluate the potential of this myeloid cell kinase to serve as a target for novel tumor therapeutic strategies.
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