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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.

摘要