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）：转移是乳腺癌相关发病和死亡的主要原因，乳腺癌是北美和全世界女性中最常诊断的肿瘤疾病，也是癌症相关死亡的第二大原因。然而，由于对控制癌症血行扩散的分子机制了解有限，阻碍了专门针对转移性乳腺疾病的有效治疗方式的开发。该项目概述了一项多学科研究工作，旨在识别和研究当血源性肿瘤细胞与远处器官脉管系统相互作用时支持血源性乳腺癌转移过程的主要分子和细胞机制。基本假设认为，靶器官微血管中最初的、短暂的转移细胞停滞[由肿瘤细胞上表达的癌症相关 Thomsen-Friedenreich 抗原和内皮细胞 (EC) 上表达的碳水化合物结合蛋白半乳糖凝集素 3 (Gal-3) 介导内皮整合素 ?3?1 进一步稳定血管壁，诱导下游 Src/RhoA/ROCK 依赖性信号通路，促进 EC 收缩和回缩、肿瘤细胞外渗并最终形成新的转移性沉积物。提出了一种创新的综合方法，涉及使用改进的平行流室技术和原子力显微镜来识别稳定乳腺癌细胞/ EC 粘附的整合素分子，目标 1；先进的免疫荧光和共聚焦显微镜方法与细胞生物学实验相结合，研究 EC 中 ?3?1/Src/RhoA 激活对紧密连接解体、EC 收缩和肿瘤细胞跨内皮迁移的时空动力学和生物学影响；目标 2；利用转基因 Gal-3-/- 和人乳腺癌异种移植模型进行复杂的动物实验，以在目标 3 中进行体内验证。完成本研究的目标将显着增强我们对癌症血行扩散分子机制的了解，从而能够产生新整合的乳腺癌转移分子模型，并为同时针对几种限速转移相关过程开发新的治疗策略提供了理论基础，以更有效地控制，甚至可能预防血行乳腺癌转移。