Vascular communication in metastatic brain colonization

转移性脑定植中的血管通讯

基本信息

批准号：
8673646
负责人：
Richard L. Klemke
金额：
$ 32.16万
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：
2014
资助国家：
美国
起止时间：
2014-04-03 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8673646
关键词：
Adhesions Animal Model Blood - brain barrier anatomy Blood Vessels Brain Breast Breast Cancer Cell Breast Melanoma Cancer Center Cancer Patient Carbenoxolone Cell Communication Cell Survival Cell-Cell Adhesion Cell-Matrix Junction Cells Cessation of life Chickens Clinical Trials Collaborations Communication Computer software Connexin 43 Cutaneous Melanoma Data Diagnosis Disease Endothelium Environment Exhibits Gap Junctions Genes Genetic Engineering Goals Health Home environment Homing Human Image Immunofluorescence Immunologic Invaded Invasive Lesion Ions Laboratories Life Light Malignant Neoplasms Malignant neoplasm of brain Mammary Neoplasms Mediating Metastatic Lesion Metastatic Neoplasm to the Lung Metastatic malignant neoplasm to brain Methodology Methods MicroRNAs Micrometastasis Modeling Molecular Target Mus Mutation Neoplasm Metastasis Non-Malignant Operative Surgical Procedures Palpable Patients Peptides Permeability Play Primary Neoplasm Property Publishing Reporter Reporting Research Research Project Grants Research Proposals Resected Resolution Role Signal Transduction Staging Stem cells Stomach Surface Survival Rate Testing Therapeutic Therapeutic Agents Time Tissues Tumor Suppressor Proteins Work Zebrafish base brain tissue cancer cell cancer stem cell cell dedifferentiation epithelial to mesenchymal transition fluorescence imaging in vivo inhibitor/antagonist irradiation loss of function lymph nodes malignant breast neoplasm melanoma mutant neoplastic cell novel novel therapeutics outcome forecast overexpression pre-clinical repository stem stem cell biology

项目摘要

DESCRIPTION (provided by applicant): Breast cancer cells commonly metastasize to the brain using mechanisms that are not fully understood. Because there are no effective therapeutics and surgical treatments are often problematic, the survival rate of breast cancer patients that develop brain metastases is dismal (<10 months). Recent work indicates that only metastatic breast cancer cells that attach to the vascular surface in the brain survive to form microtumors. Cells that invade deep into the brain parenchyma do not survive. These findings indicate the brain microvasculature provides a unique niche for breast cancer cell survival and propagation. However, it is not known how breast cancer cells attach to the vessel wall and communicate with the endothelium. Our recent published findings and preliminary results presented in this proposal demonstrate that Cx43-mediated gap junction (GJ) adhesion and communication with the brain vasculature is required for brain metastasis. Furthermore, we find that brain homing, metastatic cells, represent a subpopulation of tumor cells with stem cell-like properties (referred to as breast cancer stem cells, BCSCs). Importantly, BCSCs specifically express Cx43, which facilitates robust formation of Cx43-GJs with the Cx43-enriched brain vasculature. These findings are important because it provides a plausible explanation for why breast cancer cells commonly home to the brain and grow in association with the brain vasculature. Our findings also provide a unique mechanism to target metastatic cells in the brain with established GJ therapeutics such as carbenoxolone (CBX) and function blocking, cell-permeable peptides, which are currently being evaluated in clinical trials. Therefore, work i this proposal will determine precisely how heterocellular GJ communication and signal transduction regulates BCSC olonization of the brain vasculature. For these studies, we will use powerful fluorescent stem cell reporter constructs and specific gain or loss of function cx43 gene mutants in combination with unique preclinical animal models that facilitate intravital tracking and analysis of BCSC metastasis in the brain. Our work will provide a fundamental understanding of how BCSCs colonize the brain using GJ communication and determine if perturbation of this communication network can be used to treat metastatic disease in the brain.

描述（由申请人提供）：乳腺癌细胞通常通过尚未完全了解的机制转移到大脑。由于没有有效的治疗方法，而且手术治疗往往存在问题，因此发生脑转移的乳腺癌患者的生存率很低（<10个月）。最近的研究表明，只有附着在大脑血管表面的转移性乳腺癌细胞才能存活并形成微肿瘤。侵入脑实质深处的细胞无法存活。这些发现表明大脑微血管系统为乳腺癌细胞的生存和繁殖提供了独特的利基。然而，目前尚不清楚乳腺癌细胞如何附着在血管壁上并与内皮细胞通讯。我们最近发表的研究结果和本提案中提出的初步结果表明，Cx43 介导的间隙连接 (GJ) 与脑血管系统的粘附和通讯是脑转移所必需的。此外，我们发现脑归巢的转移细胞代表了具有干细胞样特性的肿瘤细胞亚群（称为乳腺癌干细胞，BCSC）。重要的是，BCSC 特异性表达 Cx43，这有助于 Cx43-GJ 与富含 Cx43 的脑血管系统的稳健形成。这些发现很重要，因为它为为什么乳腺癌细胞通常驻留在大脑并与大脑脉管系统相关的生长提供了合理的解释。我们的研究结果还提供了一种独特的机制，可以通过已建立的 GJ 疗法（例如甘酸索隆 (CBX) 和功能阻断、细胞渗透性肽）靶向大脑中的转移细胞，这些疗法目前正在临床试验中进行评估。因此，本提案中的工作将精确确定异细胞 GJ 通讯和信号转导如何调节脑血管系统的 BCSC 克隆化。在这些研究中，我们将使用强大的荧光干细胞报告构建体和特定功能获得或丧失的 cx43 基因突变体，并结合独特的临床前动物模型，以促进 BCSC 脑内转移的活体跟踪和分析。我们的工作将提供对 BCSC 如何利用 GJ 通信在大脑中定殖的基本了解，并确定是否可以利用该通信网络的扰动来治疗大脑中的转移性疾病。