Role of PI3Kinase Gamma in Tumor Progression and Metastasis

PI3激酶γ在肿瘤进展和转移中的作用

• 批准号: 9033872
• 负责人: Judith A VARNER
• 金额: $ 42.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033872
• 关键词: 1-Phosphatidylinositol 3-Kinase; Antigen Presentation; Breast Cancer Treatment; Breast Carcinoma; Cell Adhesion; Cell Maturation; Chemical Agents; Chemicals; Chemotactic Factors; Chronic; Dendritic Cells; Development; Disease; Endothelium; Exhibits; Family member; Functional disorder; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Goals; Growth; ITGAM gene; Immunity; Immunosuppression; Immunosuppressive Agents; Implant; Infectious Agent; Inflammation; Inflammatory; Integration Host Factors; Integrin alpha4; Integrin alpha4beta1; Interferons; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-10; Interleukin-12; Interleukin-6; MYLK gene; Malignant Neoplasms; Mammary Neoplasms; Mediating; Molecular; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Neoplasm Metastasis; Organ; Pathway interactions; Phenotype; Phosphotransferases; Physiological; Platelet-Derived Growth Factor; Play; Protein Isoforms; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Research; Risk; Role; Small Interfering RNA; Solid Neoplasm; Source; Suppressor-Effector T-Lymphocytes; Surrogate Markers; T-Cell Activation; Therapeutic; Toll-like receptors; Transforming Growth Factor beta; Tumor Angiogenesis; Tumor Cell Invasion; Tumor Immunity; Tumor Markers; Tumor Suppression; Tumor-Derived; Vascular Endothelial Growth Factors; angiogenesis; arginase; blood vessel development; cancer cell; diagnostic biomarker; genetic signature; in vivo; inhibitor/antagonist; killer T cell; macrophage; mouse model; novel; oncology; prevent; therapeutic target; trafficking; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：慢性炎症促进肿瘤发展，因为感染剂和化学物质以及慢性炎症性疾病已被证明会增加发生肿瘤的风险。实体瘤富含肿瘤相关巨噬细胞，可促进血管生成、免疫抑制以及肿瘤生长、进展和转移。针对控制骨髓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，骨髓细胞向肿瘤的募集依赖于 PI3 激酶 γ (p110γ)。 p110γ的药理学或基因阻断可抑制骨髓细胞与内皮的粘附和向肿瘤的募集，以及植入性和自发性肿瘤的血管生成、生长和转移，表明p110γ是肿瘤学中的重要治疗靶点。重要的是，p110γ 是骨髓细胞中表达的主要 PI3 激酶亚型；此外，骨髓细胞是p110γ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作为抑制肿瘤恶性肿瘤的治疗药物。该提案的目的是 1) 确定 PI3激酶 γ 在炎症、肿瘤进展和转移过程中调节骨髓细胞运输的分子途径，2) 评估 PI3Kγ 在肿瘤进展过程中免疫抑制调节中的作用，以及 3) 评估 PI3-激酶 γ 作为乳腺癌治疗靶点的潜力。