Role of PI3Kinase Gamma in Tumor Progression and Metastasis

描述(由申请人提供)：慢性炎症促进肿瘤的发展，因为感染性和化学性因素以及慢性炎症性疾病已被证明增加了发生肿瘤的风险。实体瘤大量包被肿瘤相关巨噬细胞，促进血管生成、免疫抑制和肿瘤生长、进展和转移。靶向控制髓系细胞向肿瘤募集的机制是抑制肿瘤生长和转移的一种有前途的方法。我们最近发现，髓系细胞向肿瘤的募集依赖于PI3K？(p110？)P110的药理或基因阻断？抑制髓系细胞与内皮细胞的黏附和对肿瘤的募集，抑制移植瘤和自发性肿瘤的血管生成、生长和转移，揭示p110？是肿瘤学中重要的治疗靶点。重要的是，p110？PI3-激酶的主要亚型是否在髓系细胞中表达；此外，髓系细胞是p110？的主要生理来源。P110的选择性抑制剂？因此可以作为治疗药物，通过阻断促进肿瘤炎症的多种途径来抑制肿瘤的恶性。这项建议的目的是：1)确定PI3K-γ在炎症、肿瘤进展和转移过程中调节髓系细胞运输的分子途径；2)评估PI3K？在肿瘤进展过程中对免疫抑制的调节，以及3)评估PI3-激酶的潜力？作为治疗乳腺癌的靶点。 公共卫生相关性：最近的研究表明，炎症在促进肿瘤生长、进展和转移方面发挥着关键作用。肿瘤相关巨噬细胞促进血管生成，抑制免疫，刺激肿瘤细胞的侵袭和存活，共同促进肿瘤的生长、扩散和器官功能障碍。这项研究的总体目标是探索PI3Kinase Gamma在调节肿瘤炎症、生长和转移中的机制作用，并评估这种髓系细胞激酶作为新的肿瘤治疗策略靶点的潜力。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.