Collagen remodeling and tumor progression

胶原重塑和肿瘤进展

基本信息

批准号：
7887936
负责人：
VALERIE MARIE WEAVER
金额：
$ 43.88万
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/7887936
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 ERBB2 gene Engineering Enzymes Epidermal Growth Factor Receptor Epithelial Cells Epithelium Extracellular Matrix Family Fibrosis Focal Adhesions Future Genetic Goals Growth Growth Factor Growth Factor Receptors 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 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 public health relevance 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. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, of how collagen, a major component of breast density contributes to risk for breast cancer. The approaches used in this project will elucidate how the structural microenvironment may influence the critical conversion of pre-neoplastic breast epithelium to invasive breast cancer and invasive breast cancer to metastatic breast cancer. From these studies we hope to identify patient populations at higher risk for malignant progression so that these individuals can benefit from improved monitoring and specialized treatment. Our studies also should clarify the origins of nonpalpable versus palpable breast lesions. If we could understand the underlying molecular mechanisms driving mechano-mediated breast neoplastic progression, we will be able to develop better detection, prevention and treatment modalities.

描述（由申请人提供）：这项研究的全球目标是阐明间质性胶原蛋白重塑在乳腺肿瘤进展中的相关性。乳房中的肿瘤进展伴随着脱糖反应，其特征是对间质胶原蛋白的重塑显着重塑，并且与组织的逐渐僵硬有关。逐渐转化的乳腺上皮细胞（MEC）对细胞外基质（ECM）刚度敏感，这意味着它是动态发展的微环境与逐渐异常异常的乳腺上皮的对话，这是肿瘤进展的关键。 ECM降解基质金属蛋白酶（MMP）在基质裂解间质性胶原蛋白中表达，并有助于肿瘤进展的发病机理，并且MMP表达升高可预测人类乳腺病变的肿瘤进展。然而，使用MMP抑制剂进行的临床试验失败了，表明ECM重塑的其他参数调节肿瘤行为。酶的赖氨酰氧化酶和赖氨酸羟化酶家族也在基质中表达，它们可以交叉链接胶原纤维，以增强组织的机械完整性。这些酶在肿瘤中也升高，并导致组织纤维化。实际上，乳腺乳腺癌致密乳房的胶原蛋白和基质蛋白的水平升高，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，我们对胶原蛋白交叉与肿瘤进展的作用的理解是有限的。该提案的目的是通过分子和细胞生物学细节剖析胶原蛋白交联如何使ECM变硬，从而有助于乳腺癌发展为恶性表型。鉴于肿瘤进展是通过肿瘤基因的水平/活性升高和肿瘤抑制剂的降低/活性来介导的，我们建议胶原蛋白重塑/僵硬通过修饰关键的癌基因或肿瘤抑制子的水平/活性来影响肿瘤的进展。一致地，我们发现ECM的交联和刚度增强了整联蛋白和生长因子受体（GFR）信号传导，并调节抑制肿瘤抑制剂PTEN的水平。因此，我们假设胶原蛋白交联使组织结实，通过增强整联蛋白GFR信号传导并降低PTEN等肿瘤抑制剂的水平来促进乳房转化。该项目将采用工程方法采用跨学科的方法，以测量和操纵培养物和体内的ECM材料的特性和拓扑特性和拓扑结构，以及分子细胞生物学方法和遗传小鼠模型，研究胶原蛋白的重塑和交联是否通过增强乳房组织来增强整合性和GFR信号和/或组合的表达，以促进肿瘤的进展。来自高和低风险的胶原蛋白丰度和结构风险的妇女的肿瘤前乳腺组织的存档和新鲜活检将建立临床相关性。我们将利用自然和合成基质中的两维中器官培养物的活细胞成像，并具有修改的交联，刚度和拓扑，并将使用已在药理上进行药理或抗体模型的小鼠，以改变胶原蛋白结构，以质疑胶原率和僵硬的僵化和僵化的PI3 KIN pi3 kin pi3 kin pi3 kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin kin Durotaxis。这些实验将深入了解胶原蛋白的丰度和交联如何促进肿瘤前病变对浸润性乳腺癌的发展。这些知识将有助于开发鉴定和表征驱动乳腺肿瘤发展为侵袭的分子机制的方法。这些研究将为未来的研究奠定基础，以阐明组织ECM在转移和治疗反应中的作用。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。公共卫生相关性：乳腺癌是女性癌症死亡的第二大主要原因，是女性中最常见的癌症。这项研究介绍了妇女健康的一个重要方面，即胶原蛋白是乳腺密度的主要组成部分，这是如何促进乳腺癌风险的。该项目中使用的方法将阐明结构微环境如何影响肿瘤前乳腺上皮细胞对侵入性乳腺癌和侵入性乳腺癌转化为转移性乳腺癌的关键转化。从这些研究中，我们希望确定具有更高风险进展风险的患者人群，以便这些人可以从改进的监测和专业治疗中受益。我们的研究还应阐明不可钙与可触及的乳房病变的起源。如果我们能够理解驱动机械介导的乳腺肿瘤进展的潜在分子机制，我们将能够发展出更好的检测，预防和治疗方式。