Collagen remodeling and tumor progression

胶原重塑和肿瘤进展

• 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
• 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' 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

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（由申请方提供）：本研究的总体目的是阐明乳腺肿瘤进展中间质胶原重塑的相关性。 乳腺肿瘤进展伴随促结缔组织增生反应，其特征在于间质胶原蛋白的显著重塑，并与组织的进行性硬化相关。 进行性转化的乳腺上皮细胞（MEC）变得对细胞外基质（ECM）硬度敏感，这意味着动态演变的微环境和进行性异常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）切割间质胶原，并有助于肿瘤进展的发病机制，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，在基质中它们交联胶原纤维以增强组织的机械完整性。 这些酶在肿瘤中也升高，并有助于组织纤维化。 事实上，增强ECM硬度的胶原蛋白和基质蛋白水平在乳房X线摄影致密乳房的女性中升高，这些女性患乳腺癌的风险更高。 这些数据强调了胶原交联以及MMP降解对乳腺癌进展的重要性。 然而，我们对胶原交联在肿瘤进展中的作用的理解是有限的。 该提案的目标是在分子和细胞生物学细节上剖析胶原交联如何使ECM变硬，从而促进乳腺癌进展为恶性表型。 鉴于肿瘤进展是通过癌基因水平/活性升高和肿瘤抑制因子水平/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因子的水平/活性来影响肿瘤进展。 一致地，我们发现ECM交联和刚度增强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，我们假设胶原交联通过增强整合素-GFR信号传导和降低肿瘤抑制因子如PTEN的水平来硬化组织以促进乳腺转化。 该项目将采取跨学科的方法，使用工程方法来测量和操纵ECM材料的性质和拓扑结构在培养和体内，与分子细胞生物学方法和遗传小鼠模型一起，以研究胶原蛋白重塑和交联是否通过硬化乳腺组织来促进肿瘤进展，以增强整合素和GFR信号传导和/或损害PTEN表达/功能。 来自胶原蛋白丰度和结构高风险和低风险女性的肿瘤前乳腺组织的存档和新鲜活检将建立临床相关性。 我们将利用活细胞成像的器官型培养物在二维和三维的天然和合成基质与修改后的交联，刚度和拓扑结构，并将使用小鼠已被标记或抗体修饰有改变的胶原蛋白结构，以询问胶原蛋白交联和刚度是否影响MEC的运动和入侵，通过增强PI 3激酶信号，以促进趋化性和durotaxis。 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进展为浸润性乳腺癌。 这些知识将有助于开发方法来识别和表征推动乳腺肿瘤进展至侵袭的分子机制。 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。 公共卫生相关性：乳腺癌是妇女癌症死亡的第二大原因，也是妇女最常见的癌症。 这项研究解决了女性健康的一个重要方面，即胶原蛋白（乳腺密度的主要成分）如何增加患乳腺癌的风险。 本项目中使用的方法将阐明结构微环境如何影响癌前乳腺上皮向浸润性乳腺癌和浸润性乳腺癌向转移性乳腺癌的关键转化。 通过这些研究，我们希望确定恶性进展风险较高的患者人群，以便这些人可以从改善的监测和专业治疗中受益。 我们的研究还应该澄清不可触及与可触及的乳腺病变的起源。 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，我们将能够开发更好的检测，预防和治疗模式。