Syndecan-1 in Stromal Fibroblasts of Breast Carcinomas

描述(申请人提供)：浸润性癌典型地引起反应性间质反应，越来越多的证据表明，肿瘤间质成纤维细胞相互促进肿瘤的发展和生长。细胞表面硫酸乙酰肝素蛋白多糖-1(Syndecan-1，Sdc1)被认为是生长因子和细胞外基质相互作用的共同受体，在小鼠和人乳腺癌的反应性基质细胞中都能诱导Sdc1的表达。Sdc1基因定向突变的小鼠表现出对癌基因表达的反应减少了肿瘤的发展，并改变了对与诱导间质Sdc1相关的其他病理刺激的反应。我们的初步数据进一步表明，乳腺癌细胞和它们的间质之间存在一个依赖于Sdc1活性的促生长环路。假设：Sdc1是乳腺癌上皮-间质相互作用的关键分子。间充质基质细胞表达Sdc1通过为上皮性癌细胞提供有丝分裂信号来促进肿瘤生长。这一假设将通过解决以下具体目标来检验。目的1：确定基质成纤维细胞介导的肿瘤生长刺激所需的Sdc1核心蛋白：将通过一组缺失突变来评估不同的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。目的2：研究表达Sdc1基因的间质成纤维细胞促进癌细胞生长的分子机制：探讨表达Sdc1基因的间质成纤维细胞促进肿瘤生长的可能机制。具体地说，我们将研究基质金属蛋白酶和依赖于硫酸乙酰肝素的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。目的：探讨间质Sdc1在体内乳腺癌发生中的作用：在啮齿动物模型中检测间质Sdc1在人乳腺癌标本中的表达，并系统评价间质细胞Sdc1在肿瘤生长中的作用。更好地了解相关的分子机制将有助于开发旨在干扰有害的上皮-间质信号的治疗方法。

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.