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PI3Kγ(p110γ)。药物或基因阻断p110γ可抑制髓系细胞与内皮细胞的黏附和向肿瘤的募集，抑制移植瘤和自发性肿瘤的血管生成、生长和转移，提示p110γ是肿瘤治疗的重要靶点。重要的是，p110γ是髓系细胞表达的主要PI3-γ亚型；此外，髓系细胞是p110 DNA的主要生理来源。因此，p110γ的选择性抑制剂可以通过阻断促进肿瘤炎症的多种途径来抑制肿瘤的恶性程度。该建议的目的是：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)评价PI3Kγ在肿瘤进展过程中免疫抑制调节中的作用；3)评价PI3-KAMP作为乳腺癌治疗靶点的可能性。

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 γ (p110γ). Pharmacological or genetic blockade of p110γ suppressed myeloid cell adhesion to endothelium and recruitment to tumors, as well as angiogenesis, growth and metastasis of implanted and spontaneous tumors, revealing that p110γ is an important therapeutic target in oncology. Importantly, p110γ is the major PI3-kinase isoform expressed in myeloid cells; furthermore, myeloid cells are the main physiological source of p110γ. Selective inhibitors of p110γ 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 PI3Kγ in the regulation of immunosuppression during tumor progression, and 3) to evaluate the potential of PI3- kinase γ to serve as a therapeutic target for the treatment of breast cancer.