Intravascular Integrin - Mediated Steps in Breast Cancer Metastasis

血管内整合素 - 乳腺癌转移的介导步骤

基本信息

批准号：
8439926
负责人：
VLADISLAV V GLINSKII
金额：
$ 28.65万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439926
关键词：
Adhesions Adhesives Animal Experimentation Antigens Atomic Force Microscopy Binding Biological Blood Blood Vessels Bone Marrow Breast Cancer Cell Breast Carcinoma Breast Diseases Cancer Etiology Cancer Patient Carbohydrates Cell Adhesion Cell Communication Cell Line Cells Cellular biology Cessation of life Clinical Complex Confocal Microscopy Coupled Deposition Development Diagnosis Disease Distant Endothelial Cells Endothelium Event Extravasation Galactosides Galectin 3 Generations Hematogenous Hematogenous Spread Human Immigration Immunofluorescence Microscopy Integrins Interdisciplinary Study Knowledge Lectin Lesion Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mediating Modality Modeling Molecular Molecular Models Morbidity - disease rate Myosin ATPase Neoplasm Metastasis North America Organ Pathway interactions Process Research Signal Pathway Signal Transduction Takeda brand of pioglitazone hydrochloride Techniques Testing Therapeutic Thompson-Friedenreich Antigen Tight Junctions Transgenic Organisms Validation Woman Xenograft Model carbohydrate binding protein in vivo innovation malignant breast neoplasm molecular modeling mortality neoplastic neoplastic cell novel therapeutics prevent public health relevance research study spatiotemporal therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Metastasis is the major cause of morbidity and mortality associated with breast carcinoma, the most commonly diagnosed neoplastic disease and the second leading cause of cancer-related death among women in North America and worldwide. However, the development of efficient therapeutic modalities targeting specifically metastatic breast disease has been hindered by a limited knowledge of the molecular mechanisms governing hematogenous spread of cancer. This project outlines a multidisciplinary research effort to identify and investigate major molecular and cellular mechanisms underpinning the process of hematogenous breast cancer metastasis, when blood borne tumor cells interact with distant organ vasculature. The underlying hypothesis posits that the initial, transient metastatic cell arrest in target organ microvessels [mediated by cancer-associated Thomsen- Friedenreich antigen expressed on tumor cells and carbohydrate-binding protein galectin-3 (Gal-3) expressed on endothelial cells (EC) lining blood vessel walls] is further stabilized by the endothelial integrin ?3?1 inducing downstream Src/RhoA/ROCK-dependent signaling pathways, prompting EC contraction and retraction, neoplastic cell extravasation and ultimately the establishment of new metastatic deposits. An innovative integrated approach is proposed involving the use of modified parallel flow chamber techniques and atomic force microscopy to identify integrin molecules stabilizing breast cancer cell/EC adhesion in Aim 1; advanced immunofluorescence and confocal microscopy approaches coupled with cell biology experiments to investigate spatiotemporal dynamics and biological consequences of ?3?1/Src/RhoA activation in EC on tight junction disassembly, EC contraction, and tumor cell transendothelial migration in Aim 2; sophisticated animal experimentation utilizing transgenic Gal-3-/- and human breast carcinoma xenograft models for in vivo validation in Aim 3. Completing the aims of this study will significantly enhance our knowledge of the molecular mechanisms underpinning hematogenous spread of cancer, enable generation of a newly integrated molecular model of breast cancer metastasis, and provide rationale for developing new therapeutic strategies targeting several rate-limiting metastasis-associated processes simultaneously to control more efficiently and, perhaps, even prevent hematogenous breast cancer metastasis.

描述（由申请人提供）：转移是与乳腺癌相关的发病率和死亡率的主要原因，最常见的被诊断出的肿瘤疾病以及北美和全球女性癌症相关死亡的第二大主要原因。但是，针对特异性转移性乳腺疾病的有效治疗方式的发展受到对癌症血源性传播的分子机制有限的了解。该项目概述了多学科研究的工作，旨在识别和研究主要的分子和细胞机制，当时血液传播的肿瘤细胞与远处的器官脉管系统相互作用时，为血源性乳腺癌转移过程提供了基础。潜在的假设认为，靶器官微血管中的初始瞬时转移细胞停滞[由癌症相关的汤剂 - 弗里德氏菌抗原介导于肿瘤细胞和碳水化合物结合蛋白乳糖素3（GAL-3）上表达的抗原（GAL-3），在内皮细胞（EC）上表达（EC）（EC）（EC）（EC）（EC）衬里血管壁]由内皮整合素？3？1进一步稳定，从而诱导下游SRC/RhoA/岩石依赖性信号通路，促使EC收缩和缩回，肿瘤细胞渗出并最终建立新的转移沉积物。提出了一种创新的综合方法，其中涉及使用改良的平行流室技术和原子力显微镜来鉴定稳定乳腺癌细胞/EC粘附在AIM 1中的整合素分子；先进的免疫荧光和共聚焦显微镜方法以及细胞生物学实验，研究时空动力学和生物学后果，以及ec中EC中EC中的生物学后果，在紧密连接拆卸，EC的紧密连接，EC收缩，肿瘤细胞的肿瘤细胞跨性质迁移中，AIM 2;利用转基因GAL-3 - / - 和人类乳腺癌异种移植模型进行体内验证的复杂动物实验。完成这项研究的目的将显着增强我们对癌症血肿扩散的分子机制的了解，从而产生产生的分子机制乳腺癌转移的新分子模型，并为开发针对几种限制速率转移相关的过程的新的治疗策略提供了基本原理，以更有效地控制，甚至可以防止血肿的乳腺癌转移。