Syndecan-1 in Stromal Fibroblasts of Breast Carcinomas

乳腺癌基质成纤维细胞中的 Syndecan-1

• 批准号: 8208079
• 负责人: ANDREAS FRIEDL
• 金额: $ 28.84万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208079
• 关键词: Adult; Affect; Animal Model; Animals; Architecture; Behavior; Biological Assay; Biology; Breast; Breast Cancer Cell; Breast Carcinoma; Cancer Cell Growth; Carcinoma; Cell Adhesion; Cell surface; Cells; Complex; Connective Tissue; Data; Development; Ductal; Elements; Employee Strikes; Endothelial Cells; Epithelial Cells; Event; Extracellular Matrix; Fiber; Fibroblasts; Fibronectins; Gene Expression; Generations; Goals; Growth; Growth Factor; Head; Health; Homeostasis; Human; Imaging Device; Immune system; In Situ Lesion; In Vitro; Individual; Integrins; Invaded; Knowledge; Lead; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Measures; Mechanics; Mesenchymal; Molecular; Morphogenesis; Morphology; Movement; Neoplasm Metastasis; Newly Diagnosed; Noninfiltrating Intraductal Carcinoma; Normal tissue morphology; Outcome; Pathway interactions; Patients; Pattern; Phase; Play; Primary Carcinoma; Production; Property; Proteoglycan; Regulation; Research; Research Personnel; Role; Sampling; Signal Transduction; Stromal Cells; Structure; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissue Microarray; Tissues; Woman; Work; Xenograft Model; adhesion receptor; base; body system; cancer cell; cell motility; cell type; design; disease natural history; fibrillogenesis; gain of function; improved; in vivo; inhibitor/antagonist; innovation; loss of function; malignant breast neoplasm; molecular domain; neoplastic cell; novel; novel therapeutics; outcome forecast; paracrine; prevent; prototype; public health relevance; receptor; research study; scaffold; syndecan; tissue support frame; tool; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer should be viewed as an organ system in which growth and progression are governed by complex and reciprocal interactions between tumor cells and surrounding stromal elements. Fibroblasts, which comprise a predominant stromal cell type, maintain tissue homeostasis in normal breast but promote tumor progression in breast cancer. Carcinoma-associated fibroblasts (CAF) distinguish themselves from normal mammary fibroblasts (NMF) by morphology, gene expression and secreted factors. Our lab has shown that expression of the cell surface proteoglycan syndecan 1 (Sdc1) in CAF is induced in the majority of breast carcinomas and that Sdc1 stimulates breast carcinoma proliferation. Because one of the main functions of fibroblasts is the assembly of an extracellular matrix (ECM), we have begun to examine whether Sdc1 expression affects ECM synthesis. Our preliminary data indicate that Sdc1 expression in CAF influences the architecture, or fine structure, of the ECM scaffold. It is the goal of this proposal to understand in detail how Sdc1 regulates ECM assembly in breast carcinomas and what consequences Sdc1-dependent ECM alterations might have on carcinoma behavior. Based on our preliminary observations, we state the following hypothesis: The aberrant expression of Sdc1 by breast carcinoma stromal fibroblasts leads to an altered ECM architecture, which is permissive to breast carcinoma cell invasion. We posit that this altered ECM architecture contributes to invasion events early and late during the natural history of the disease and shortens patient survival. To test this hypothesis, we propose the following specific aims: Aim 1: Examine the role of Sdc1 and ECM architecture in breast carcinoma invasion. The ECM architecture will be carefully analyzed in human breast carcinoma samples. Using tissue microarrays, we will determine whether ECM architectural features predict patient prognosis. Innovative ex vivo invasion assays will inform us whether Sdc1 and/or the ECM architecture regulate invasion. Lastly, the involvement of Sdc1 in determining the ECM architecture will be examined with Sdc1-deficient animals. Aim 2: Analyze the role of Sdc1 and ECM architecture in the progression from ductal carcinoma in situ (DCIS) to invasive carcinoma. By applying novel ECM imaging tools to human samples and to a DCIS animal model, we will determine whether stromal Sdc1 expression creates an invasion-permissive ECM that facilitates progression from DCIS to invasive carcinoma. Aim 3 Decipher the molecular mechanisms responsible for the formation of an invasion-permissive ECM. The involvement of specific Sdc1 molecular domains in regulating ECM assembly will be analyzed in vitro with domain deletion and substitution experiments. The cooperative role of integrin cell adhesion receptors will be investigated with loss of function and gain of function experiments. Together, these aims will significantly advance our knowledge about the regulation of ECM production in breast cancer. A mechanistic understanding of ECM assembly is key to the design of novel therapeutic agents that are aimed at "normalizing" the ECM and thus revert the tumor microenvironment from invasion-permissive to invasion-restrictive. PUBLIC HEALTH RELEVANCE: With approximately 200,000 newly diagnosed cases in the US per year, breast cancer is and remains a major health issue. Even with the advanced treatment options available, 40,000 women die annually. Our project aims at understanding how the architecture of the connective tissue scaffold in breast cancer is regulated and how it affects cancer invasion and spread. The knowledge generated with this work may lead to novel therapies that target the structure of this scaffold and prevent the escape of cancer cells.

描述（由申请人提供）：应将乳腺癌视为一种器官系统，其中生长和进展受肿瘤细胞与周围基质元素之间复杂和相互相互作用的控制。构成主要基质细胞类型的成纤维细胞维持正常乳房的组织稳态，但促进乳腺癌的肿瘤进展。癌相关的成纤维细胞（CAF）通过形态学，基因表达和分泌因子将自己与正常乳腺成纤维细胞（NMF）区分开来。我们的实验室表明，在大多数乳腺癌中诱导了CAF中细胞表面蛋白聚糖联合1（SDC1）的表达，并且SDC1刺激了乳腺癌的增殖。由于成纤维细胞的主要功能之一是细胞外基质（ECM）的组装，因此我们开始检查SDC1表达是否影响ECM合成。我们的初步数据表明，CAF中的SDC1表达会影响ECM支架的结构或精细结构。该提案的目的是详细了解SDC1如何调节乳腺癌中的ECM组装以及SDC1依赖性ECM改变可能对癌行为产生什么后果。根据我们的初步观察，我们指出以下假设：乳腺癌基质成纤维细胞对SDC1的异常表达导致ECM结构改变，这对乳腺癌细胞侵入允许。我们认为，这种改变的ECM结构在疾病的自然史上有助于入侵事件，并缩短患者的生存。为了检验这一假设，我们提出了以下特定目的：目标1：检查SDC1和ECM结构在乳腺癌入侵中的作用。 ECM结构将在人类乳腺癌样品中仔细分析。使用组织微阵列，我们将确定ECM架构特征是否预测了患者的预后。创新的离体入侵测定法将告知我们SDC1和/或ECM建筑是否规范入侵。最后，将使用SDC1缺陷动物检查SDC1在确定ECM结构中的参与。 AIM 2：分析SDC1和ECM结构在从导管癌（DCIS）到浸润性癌的进展中的作用。通过将新型的ECM成像工具应用于人类样品并将其应用于DCIS动物模型，我们将确定基质SDC1表达是否会产生侵入性的ECM，从而促进从DCIS到侵入性癌的发展。 AIM 3破译了负责侵入性ECM形成的分子机制。特异性SDC1分子结构域参与调节ECM组装的参与将在体外通过域缺失和取代实验进行分析。整联蛋白细胞粘附受体的合作作用将通过功能丧失和功能实验增益进行研究。总之，这些目标将大大提高我们对乳腺癌中ECM生产的调节的了解。对ECM组装的一种机械理解是设计新型治疗剂的关键，旨在将ECM“正常化”，从而使肿瘤微环境从入侵 - 渗透到侵袭性限制性侵略限制中恢复。 公共卫生相关性：每年美国大约有200,000例新诊断的病例，乳腺癌一直是一个主要的健康问题。即使有高级治疗方案，每年有40,000名妇女死亡。我们的项目旨在了解乳腺癌中结缔组织支架的结构如何受到调节，以及它如何影响癌症的入侵和扩散。这项工作产生的知识可能会导致针对这种支架结构并防止癌细胞逃脱的新型疗法。