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）：乳腺癌应被视为一个器官系统，其中生长和进展受到肿瘤细胞与周围基质元素之间复杂且相互的相互作用的控制。成纤维细胞是主要的基质细胞类型，可维持正常乳房的组织稳态，但促进乳腺癌的肿瘤进展。癌相关成纤维细胞（CAF）通过形态、基因表达和分泌因子与正常乳腺成纤维细胞（NMF）区分开来。我们的实验室表明，大多数乳腺癌中都会诱导 CAF 中细胞表面蛋白聚糖 Syndecan 1 (Sdc1) 的表达，并且 Sdc1 会刺激乳腺癌增殖。由于成纤维细胞的主要功能之一是细胞外基质（ECM）的组装，因此我们开始研究Sdc1表达是否影响ECM合成。我们的初步数据表明，CAF 中的 Sdc1 表达影响 ECM 支架的架构或精细结构。该提案的目标是详细了解 Sdc1 如何调节乳腺癌中的 ECM 组装，以及 Sdc1 依赖性 ECM 改变可能对癌症行为产生什么影响。基于我们的初步观察，我们提出以下假设：乳腺癌基质成纤维细胞的 Sdc1 异常表达导致 ECM 结构改变，从而允许乳腺癌细胞侵袭。我们认为这种改变的 ECM 结构会导致疾病自然史早期和晚期的侵袭事件，并缩短患者的生存期。为了检验这一假设，我们提出以下具体目标： 目标 1：检查 Sdc1 和 ECM 结构在乳腺癌侵袭中的作用。 ECM 架构将在人类乳腺癌样本中进行仔细分析。使用组织微阵列，我们将确定 ECM 结构特征是否可以预测患者预后。创新的离体侵袭测定将告诉我们 Sdc1 和/或 ECM 结构是否调节侵袭。最后，将使用 Sdc1 缺陷动物来检查 Sdc1 在确定 ECM 架构中的作用。目标 2：分析 Sdc1 和 ECM 结构在导管原位癌 (DCIS) 进展为浸润性癌中的作用。通过将新型 ECM 成像工具应用于人类样本和 DCIS 动物模型，我们将确定基质 Sdc1 表达是否会产生一种允许侵袭的 ECM，从而促进从 DCIS 进展为浸润性癌。目标 3 破译导致允许侵袭的 ECM 形成的分子机制。将通过结构域删除和替换实验在体外分析特定 Sdc1 分子结构域在调节 ECM 组装中的参与。将通过功能丧失和功能获得实验来研究整合素细胞粘附受体的协同作用。总之，这些目标将显着提高我们对乳腺癌 ECM 产生调节的认识。对 ECM 组装的机制理解是设计新型治疗剂的关键，这些治疗剂旨在“正常化”ECM，从而将肿瘤微环境从侵袭允许恢复为侵袭限制。 公共卫生相关性：美国每年约有 200,000 例新诊断病例，乳腺癌现在和将来仍然是一个主要的健康问题。即使有先进的治疗方案，每年仍有 40,000 名女性死亡。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侵袭和扩散。这项工作产生的知识可能会带来针对该支架结构并防止癌细胞逃逸的新疗法。