Vascular mechanisms regulating breast cancer brain metastasis

调节乳腺癌脑转移的血管机制

基本信息

批准号：
8371828
负责人：
Brian P Eliceiri
金额：
$ 36.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/8371828
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 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 vascular bed

项目摘要

DESCRIPTION (provided by applicant): 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 application 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. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common cancer in women that frequently spreads. In more than one third of women with advancing breast cancer, the disease will spread 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, the mortality in patients with brain metastatic breast cancer is extremely high. We propose to define mechanisms that regulate the permeability of the blood brain barrier, where circulating breast cancer cells must penetrate to colonize the brain.

描述（由申请人提供）：乳腺癌是女性最常见的癌症类型，且经常扩散。在 30-40% 的晚期乳腺癌患者中，疾病会转移到大脑，并且对当前的治疗没有反应。尽管原发性乳腺癌和脑外病变的早期检测和治疗取得了进展，但乳腺癌脑转移仍然是致命的。拟议的研究将遗传和原位模型结合在一起，以检查控制血管完整性作为乳腺癌脑转移调节剂的机制。在 Eliceiri 和 Felding 实验室之间，我们将使用明确的遗传和治疗模型来研究血管渗漏、血管正常化以及血小板对脑转移性病变的起始、生长和侵袭的贡献的病理生理学相关性。我们的实验设计利用我们实验室开发的补充和创新方法来研究乳腺癌脑转移中血管正常化的特定介质。我们合作的独特重点将挑战乳腺癌脑定植和转移性病变进展的确定遗传宿主模型中血管正常化的教条。该应用未满足的需求和具体挑战是部署我们小组开发的进展，并检查 Src 激酶、内皮粘着斑激酶 (FAK) 和血小板功能在脑转移中介导脑血管完整性的贡献。我们将使用独特的生物发光模型来评估血管周围星形胶质细胞和小胶质细胞的激活、细胞外基质成分介导的信号传导以及支持我们的遗传模型发现的候选疗法。目标 1 将确定 Src 介导的血管通透性在乳腺癌脑转移过程中在宿主室中的作用。目标 2 将表明通过内皮特异性删除 FAK 来增加血管正常化是否可以保护大脑免受乳腺癌转移。目标 3 将确定血小板如何影响脑转移和血脑屏障的内皮完整性。这些实验将为更好地理解脑血管正常化控制乳腺癌脑转移的机制提供功能基础。该结果可能验证Src、内皮FAK和特定血小板功能作为预防和治疗乳腺癌患者脑转移的关键靶点。公共卫生相关性：乳腺癌是女性最常见的癌症，且经常扩散。在超过三分之一的晚期乳腺癌女性中，这种疾病会扩散到大脑，并且对当前的治疗没有反应；尽管原发性乳腺癌和脑外病变的早期检测和治疗取得了进展，但脑转移性乳腺癌患者的死亡率极高。我们建议定义调节血脑屏障渗透性的机制，循环乳腺癌细胞必须穿透血脑屏障才能在大脑中定殖。