Collagen remodeling and tumor progression

胶原重塑和肿瘤进展

基本信息

批准号：
8249347
负责人：
VALERIE MARIE WEAVER
金额：
$ 41.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-07 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249347
关键词：
1-Phosphatidylinositol 3-Kinase 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Actomyosin Address Antibodies Archives Automobile Driving Behavior Biological Biological Assay Biopsy Breast Cancer Etiology Cells Cellular biology Cessation of life Chemotaxis Cleaved cell Clinical Trials Collagen Collagen Fibril Data Desmoplastic Detection Development Dimensions Dominant-Negative Mutation Engineering Enzymes Epidermal Growth Factor Receptor Epithelial Cells Epithelium Extracellular Matrix Family Fibrosis Focal Adhesions Future Genetic Goals Growth Growth Factor Growth Factor Receptors Health Human Image In Vitro Incidence Individual Integrins Knowledge Lesion Life Link Malignant - descriptor Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mechanics Mediating Metastatic Neoplasm to the Breast Methods Modality Molecular Monitor Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Oncogenes Organoids PDZ protein PTEN gene Palpable Pathogenesis Play Prevention Property Protein-Lysine 6-Oxidase Proteins Receptor Signaling Regulation Reporting Research Risk Role Signal Transduction Structure Testing Tissues Transgenic Mice Tumor Cell Invasion Tumor Suppressor Proteins Woman Women&apos s Health Work breast density breast lesion cell growth cell motility cellular imaging clinically relevant crosslink gain of function genetic manipulation high risk human BCAR1 protein improved in vivo inhibitor/antagonist insight interdisciplinary approach interstitial loss of function malignant breast neoplasm malignant phenotype mammary epithelium migration mouse model mutant neoplastic patient population receptor research study response time use treatment response tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The global objective of this research is to clarify the relevance of interstitial collagen remodeling in breast tumor progression. Neoplastic progression in the breast is accompanied by a desmoplastic response which is characterized by significant remodeling of interstitial collagen and is associated with a progressive stiffening of the tissue. Progressively transformed mammary epithelial cells (MECs) become sensitized to extracellular matrix (ECM) stiffness, implying that it is the dialogue between a dynamically evolving microenvironment and a progressively aberrant mammary epithelium that is key for neoplastic progression. ECM-degrading matrix metalloproteinases (MMPs) expressed in the stroma cleave interstitial collagen and contribute to the pathogenesis of tumor progression, and elevated MMP expression is predictive of neoplastic progression of human breast lesions. Yet clinical trials with MMP inhibitors failed, suggesting other parameters of ECM remodeling modulate tumor behavior. The lysyl oxidase and lysyl hydroxylase family of enzymes are also expressed in the stroma where they cross-link collagen fibrils to enhance the mechanical integrity of the tissue. These enzymes are also elevated in tumors and contribute to tissue fibrosis. Indeed, the levels of collagen and matrix proteins that enhance ECM stiffness are elevated in women with mammographically dense breasts, who are at higher risk for breast cancer. These data emphasize the importance of collagen cross-linking as well as MMP-degradation to breast cancer progression. Nevertheless, our understanding of the role of collagen cross linking to tumor progression is limited. The goal for this proposal is to dissect, in molecular and cell biological detail, how collagen cross-linking, which stiffens the ECM, contributes to breast cancer progression to a malignant phenotype. Given that tumor progression is mediated through elevated levels/activity of oncogenes and reduced levels/activity of tumor suppressors we suggest that collagen remodeling/stiffening influences tumor progression by modifying the levels/activity of key oncogenes or tumor suppressors. Consistently, we found that ECM cross-linking and stiffness enhance integrin and growth factor receptor (GFR) signaling and regulate levels of the tumor suppressor PTEN. Accordingly, we hypothesize that collagen cross-linking stiffens the tissue to promote breast transformation by enhancing integrin-GFR signaling and reducing the levels of tumor suppressors such as PTEN. The project will take an interdisciplinary approach, using engineering methods to measure and manipulate ECM materials properties and topology in culture and in vivo, together with molecular cell biology methods and genetic mouse models to investigate whether collagen remodeling and cross-linking promote tumor progression by stiffening the breast tissue to enhance integrin and GFR signaling and/or compromising PTEN expression/function. Archived and fresh biopsies of pre-neoplastic breast tissue from women at high and low risk for collagen abundance and structure will establish clinical relevance. We will exploit live cell imaging of organotypic cultures in two- and three-dimensions in natural and synthetic matrices with modified cross-linking, stiffness and topology and will use mice that have been pharmacologically or antibody-modified to have altered collagen structures to interrogate whether collagen cross-linking and stiffness influence MEC motility and invasion by enhancing PI3 kinase signaling to promote chemotaxis and durotaxis. These experiments will give insight into how collagen abundance and cross-linking contribute to the progression of pre-neoplastic lesions to invasive breast cancer. This knowledge will assist in the development of approaches to identify and characterize molecular mechanisms driving breast tumor progression to invasion. The studies will lay the groundwork for future studies aimed at clarifying the role of the tissue ECM in metastasis and treatment response. The work will eventually help to achieve the long-term goal of finding cures for breast cancer and is directly pertinent for other tumor types.

描述（由申请人提供）：本研究的总体目标是阐明间质胶原重塑在乳腺肿瘤进展中的相关性。乳房肿瘤进展伴随着促纤维增生反应，其特征是间质胶原蛋白的显着重塑，并与组织逐渐变硬相关。逐渐转化的乳腺上皮细胞（MEC）对细胞外基质（ECM）硬度变得敏感，这意味着动态演变的微环境和逐渐异常的乳腺上皮之间的对话是肿瘤进展的关键。基质中表达的 ECM 降解基质金属蛋白酶 (MMP) 可裂解间质胶原并促进肿瘤进展的发病机制，并且 MMP 表达升高可预测人类乳腺病变的肿瘤进展。然而，MMP 抑制剂的临床试验失败了，这表明 ECM 重塑的其他参数可以调节肿瘤行为。赖氨酰氧化酶和赖氨酰羟化酶家族也在基质中表达，它们在基质中交联胶原纤维以增强组织的机械完整性。这些酶在肿瘤中也会升高并导致组织纤维化。事实上，在乳房 X 光检查致密乳房的女性中，增强 ECM 硬度的胶原蛋白和基质蛋白水平升高，她们患乳腺癌的风险更高。这些数据强调了胶原蛋白交联以及 MMP 降解对乳腺癌进展的重要性。然而，我们对胶原交联对肿瘤进展的作用的理解是有限的。该提案的目标是从分子和细胞生物学细节剖析胶原蛋白交联（使 ECM 变硬）如何导致乳腺癌进展为恶性表型。鉴于肿瘤进展是通过癌基因水平/活性升高和抑癌基因水平/活性降低介导的，我们认为胶原蛋白重塑/硬化通过改变关键癌基因或肿瘤抑制基因的水平/活性来影响肿瘤进展。我们一致发现 ECM 交联和硬度增强了整合素和生长因子受体 (GFR) 信号传导并调节肿瘤抑制因子 PTEN 的水平。因此，我们假设胶原蛋白交联通过增强整合素-GFR 信号传导和降低 PTEN 等肿瘤抑制因子的水平来使组织变硬，从而促进乳房转化。该项目将采用跨学科方法，利用工程方法测量和操纵培养物和体内的ECM材料特性和拓扑结构，并结合分子细胞生物学方法和遗传小鼠模型来研究胶原蛋白重塑和交联是否通过硬化来促进肿瘤进展。乳腺组织以增强整合素和 GFR 信号传导和/或损害 PTEN 表达/功能。对胶原丰度和结构高风险和低风险女性的肿瘤前乳腺组织进行存档和新鲜活检将建立临床相关性。我们将利用经过修饰的交联、硬度和拓扑结构的天然和合成基质中的二维和三维器官型培养物的活细胞成像，并将使用经过药理学或抗体修饰以改变胶原结构的小鼠来询问是否胶原交联和硬度通过增强 PI3 激酶信号传导促进趋化性和杜罗性来影响 MEC 运动和侵袭。这些实验将深入了解胶原蛋白丰度和交联如何促进肿瘤前病变发展为浸润性乳腺癌。这些知识将有助于开发识别和表征驱动乳腺肿瘤进展至侵袭的分子机制的方法。这些研究将为未来旨在阐明组织 ECM 在转移和治疗反应中的作用的研究奠定基础。这项工作最终将有助于实现寻找乳腺癌治疗方法的长期目标，并且与其他肿瘤类型直接相关。