Syndecan-1 in Stromal Fibroblasts of Breast Carcinomas

描述（由申请人提供）：浸润性癌的特征是引发反应性基质反应，并且越来越多的证据表明肿瘤基质成纤维细胞相互促进肿瘤的发育和生长。 细胞表面硫酸乙酰肝素蛋白聚糖 Syndecan-1 (Sdc1) 被认为是生长因子和细胞外基质相互作用的辅助受体，并且 Sdc1 表达在小鼠和人的乳腺癌反应性基质细胞中被诱导。 Sdc1 发生靶向突变的小鼠表现出对癌基因表达的反应减少的肿瘤发育，以及对与基质 Sdc1 诱导相关的其他病理刺激的反应改变。 我们的初步数据进一步证明了乳腺癌细胞与其基质之间的生长促进循环取决于 Sdc1 的活性。 假设：Sdc1 是介导乳腺癌上皮-间质相互作用的关键分子。 间充质基质细胞表达 Sdc1 通过为上皮癌细胞提供有丝分裂信号来促进肿瘤生长。 该假设将通过解决以下具体目标进行检验。 目标 1：确定基质成纤维细胞介导的癌症生长刺激所需的 Sdc1 核心蛋白：将使用一组缺失突变体来评估不同 Sdc1 核心蛋白结构域的各自贡献。 Sdc1 介导的基质效应将使用生理相关的三维共培养系统进行评估。 目标 2：表征表达 Sdc1 的基质成纤维细胞促进癌细胞生长的分子机制：该目标将检查表达 Sdc1 的基质成纤维细胞刺激癌症生长的潜在机制。 具体来说，我们将研究基质金属蛋白酶和硫酸乙酰肝素依赖性旁分泌生长因子的作用。 基质 Sdc1 调节细胞外基质组装的可能性也将被研究。 目标 3：确定基质 Sdc1 诱导在体内乳腺癌肿瘤发生中的作用：将在人类乳腺癌样本中检查基质 Sdc1 表达，并将在啮齿动物模型中系统评估基质细胞 Sdc1 对癌症生长的贡献。 更好地了解所涉及的分子机制将有助于开发旨在破坏有害的上皮基质信号传导的治疗方法。

DESCRIPTION (provided by applicant): Infiltrating carcinomas characteristically elicit a reactive stroma response, and accumulating evidence indicates that tumor stroma fibroblasts reciprocally promote tumor development and growth. The cell surface heparan sulfate proteoglycan, syndecan-1 (Sdc1) is thought to function as a coreceptor for growth factor and extracellular matrix interactions, and Sdc1 expression is induced in reactive stromal cells of breast carcinomas in both mice and man. Mice with a targeted mutation in Sdc1 show reduced tumor development in response to oncogene expression, and altered responses to other pathological stimuli that are associated with the induction of stromal Sdc1. Our preliminary data further demonstrate a growth-promoting loop between breast cancer cells and their stroma that depends upon the activity of Sdc1. Hypothesis: Sdc1 is a key molecule mediating epithelial-stromal interactions in breast carcinoma. Expression of Sdc1 by mesenchymal stromal cells promotes tumor growth by providing a mitogenic cue to epithelial carcinoma cells. This hypothesis will be tested by addressing the following specific aims. Aim 1: Determine the Sdc1 core protein requirements for stromal fibroblast-mediated carcinoma growth stimulation: The respective contribution of distinct Sdc1 core protein domains will be evaluated with a panel of deletion mutants. Sdc1-mediated stroma effects will be assessed using a physiologically relevant three-dimensional co-culture system. Aim 2: Characterize the molecular mechanism by which Sdc1-expressing stromal fibroblasts promote carcinoma cell growth: This aim will examine potential mechanisms of carcinoma growth stimulation by Sdc1-expressing stromal fibroblasts. Specifically, we will investigate the role of matrix metalloproteases and heparan sulfate-dependent paracrine growth factors. The possibility that stromal Sdc1 modulates extracellular matrix assembly will also be investigated. Aim 3: Determine the role of stromal Sdc1 induction in breast carcinoma tumorigenesis in vivo: Stromal Sdc1 expression will be examined in human breast carcinoma samples and the contribution of stromal cell Sdc1 to carcinoma growth will be systematically evaluated in rodent models. A better understanding of the molecular mechanisms involved will help in developing therapeutic approaches designed to disrupt detrimental epithelial-stromal signaling.