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：
8657944
负责人：
Brian P Eliceiri
金额：
$ 34.67万
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/8657944
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

项目摘要

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.

抽象的乳腺癌是女性最常见的癌症类型，且经常扩散。 30-40% 的患者当乳腺癌进展时，该疾病会转移到大脑，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，乳腺癌脑转移都是致命的。拟议的研究将遗传和原位结合在一起模型来检查控制血管完整性作为乳腺癌脑转移调节器的机制。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针对血管渗漏的病理生理学相关性、血管正常化以及血小板对血管渗漏的贡献脑转移病灶的发生、生长和侵袭。我们的实验设计利用了互补性以及我们实验室开发的创新方法来研究血管的特定介质乳腺癌脑转移正常化。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中血管正常化的教条和转移病灶的进展。该提案未满足的需求和具体挑战是部署我们小组取得的进展并检查了 src 激酶、内皮粘着斑激酶的贡献（FAK）和血小板功能在脑转移中介导脑血管完整性。我们将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的激活，以及由细胞外基质成分以及支持我们遗传模型研究结果的候选疗法。目标 1 将确定 Src 介导的血管通透性在乳房发育期间宿主室中的作用癌症脑转移。目标 2 将显示是否通过内皮细胞增加血管正常化 FAK 的特异性缺失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内皮完整性。这些实验将提供更好地理解脑血管正常化机制的功能基础控制乳腺癌脑转移。结果可验证 src、内皮 FAK 和特定血小板作为预防和治疗乳腺癌患者脑转移的关键靶点。