Vascular mechanisms regulating breast cancer brain metastasis

调节乳腺癌脑转移的血管机制

• 批准号: 8495298
• 负责人: Brian P Eliceiri
• 金额: $ 33.6万
• 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: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495298
• 关键词: Accounting; Address; Affect; Alpha Granule; Architecture; Astrocytes; Bioluminescence; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood Vessels; Brain; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Cancer Patient; Cell Survival; Cerebrum; Cessation of life; Clinical; Collaborations; Development; Disease; Early Diagnosis; Early treatment; Event; Experimental Designs; Extracellular Matrix; Extravasation; Fibrin; Focal Adhesion Kinase 1; Genetic; Genetic Models; Growth; Hematogenous; Hemostatic function; Knock-out; Knockout Mice; Laboratories; Lesion; Leukocyte Trafficking; Life Expectancy; Link; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; Metastatic Lesion; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Modeling; Molecular; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Penetration; Permeability; Phenotype; Platelet Activation; Platelet Count measurement; Prevention; Primary Brain Neoplasms; Publishing; Radiation; Refractory; Resistance; Role; Signal Transduction; Stream; Systemic disease; Testing; Therapeutic; Thrombocytopenia; Tumor Cell Biology; Vascular Endothelial Growth Factors; Vascular Permeabilities; Woman; abstracting; base; breast lesion; cancer type; capillary bed; effective therapy; host neoplasm interaction; innovation; malignant breast neoplasm; mortality; neoplastic cell; prevent; research study; response; src-Family Kinases; tool; tumor; tumor microenvironment; vascular bed

Abstract Breast cancer is the most common cancer type in women that frequently spreads. In 30-40% of patients with advancing breast cancer, the disease will metastasize to the brain and not respond to current therapies. Despite advances in early detection and treatment of primary breast cancer and lesions outside the brain, breast cancer brain metastasis is uniformly fatal. The proposed studies bring together genetic and orthotopic models to examine mechanisms that control vascular integrity as a regulator of breast cancer brain metastasis. Between the Eliceiri and Felding labs, we will use defined genetic and therapeutic models to target the pathophysiological relevance of vascular leak, vascular normalization and the contribution of platelets to the initiation, growth and invasion of brain metastatic lesions. Our experimental design exploits the complementary and innovative approaches developed in our laboratories to investigate specific mediators of vascular normalization in breast cancer brain metastasis. The unique focus of our collaboration will challenge the dogma of vascular normalization in defined genetic host models of breast cancer brain colonization and progression of metastatic lesions. The unmet need and specific challenge of this proposal is to deploy advances developed in our groups and examine contributions of src kinase, endothelial focal adhesion kinase (FAK), and platelet functions to mediate cerebral vascular integrity in brain metastasis. We will use unique bioluminescence models to assess peri-vascular astrocyte and microglial activation, signaling mediated by extracellular matrix components, and candidate therapeutics that support the findings from our genetic models. Aim 1 will determine the role of Src-mediated vascular permeability in the host compartment during breast cancer brain metastasis. Aim 2 will show whether an increase in vascular normalization through endothelial- specific deletion of FAK protects the brain from breast cancer metastasis. Aim 3 will determine how platelets affect brain metastasis and endothelial integrity of the blood brain barrier. These experiments will provide a functional basis for a better understanding of mechanisms through which cerebral vascular normalization controls breast cancer brain metastasis. The results may validate src, endothelial FAK and specific platelet functions as key targets for prevention and treatment of brain metastasis in breast cancer patients.

抽象的 乳腺癌是经常传播的女性最常见的癌症类型。在30-40％的患者中 促进乳腺癌，这种疾病会转移到大脑，而不会对当前疗法反应。 尽管在对原发性乳腺癌和大脑外病变的早期检测和治疗方面取得了进步，但 乳腺癌脑转移是致命的。拟议的研究汇集了遗传和原位 模型检查控制血管完整性作为乳腺癌脑转移的调节剂的机制。 在Eliceiri和Felding Labs之间，我们将使用定义的遗传和治疗模型来针对 血管泄漏，血管归一化和血小板贡献的病理生理相关性 脑转移性病变的启动，生长和侵袭。我们的实验设计利用了补充 以及我们的实验室中开发的创新方法，以调查血管的特定介体 乳腺癌脑转移的归一化。我们合作的独特重点将挑战 乳腺癌脑定植的确定遗传宿主模型和血管归一化的教条 转移性病变的进展。该建议的未满足需求和具体挑战是部署 在我们的小组中发展的进步并检查了SRC激酶，内皮局灶性粘附激酶的贡献 （FAK）和血小板功能介导脑转移中的脑血管完整性。我们将使用独特的 生物发光模型评估血管周围星形胶质细胞和小胶质细胞激活，由 细胞外基质成分和候选疗法，这些疗法支持我们的遗传模型中的发现。 AIM 1将确定SRC介导的血管渗透性在乳房期间宿主室中的作用 癌症脑转移。 AIM 2将表明是否通过内皮增加血管标准化是否会增加 FAK的特定缺失可保护大脑免受乳腺癌转移的侵害。 AIM 3将确定血小板如何 影响脑屏障的脑转移和内皮完整性。这些实验将提供 功能基础，以更好地理解脑血管归一化的机制 控制乳腺癌脑转移。结果可以验证SRC，内皮FAK和特定的血小板 作为预防和治疗乳腺癌患者脑转移的关键靶标。