THE ROLE OF FIBROBLAST-DERIVED OSTEOPONTIN IN TUMORIGENESIS

SAtBatSeTmReAntCoTf假设和具体目标 年龄是肿瘤发生的最大危险因素。关于年龄如何影响的调查 癌症发病率的增加主要集中在早期癌症中自主突变的积累。 细胞。虽然这些细胞自主变化显然是转换过程中不可或缺的，但它已经 很明显，在这个过程中，周围表面上正常的间质的变化会协同作用，并可能 导致癌症发病率随年龄的增加而增加。事实上，肿瘤内的“正常”成纤维细胞 分泌促进肿瘤细胞生长的因子。就像基因突变一样，衰老的成纤维细胞会随着 年龄，最近的数据表明，它们在肿瘤的发生中起着关键作用。我们假设 衰老的成纤维细胞在间质间隔内增加，它们创造了促肿瘤形成 支持癌前细胞生长和持续转化的环境。要确定 支持癌前细胞生长的衰老成纤维细胞衍生因子，我们进行了一项无偏见的研究 比较年轻和衰老成纤维细胞的微阵列分析。我们发现骨桥蛋白(OPN)是一种 假定基质因子能够促进癌前细胞的增殖，因此假设它发挥了作用 在肿瘤发生中起着重要作用。为了支持这一假设，我们发现OPN在 人体皮肤和乳房良性病变的间质间质。而OPN的表达已经 与肿瘤进展相关(33，34)，间质来源的OPN在早期病变中所起的作用尚未见报道 被调查过了。这项建议的目标是确定OPN的分子机制 影响转换过程的早期阶段。为此，这项建议的具体目标是： 目的1.鉴定成纤维细胞来源的骨桥蛋白与膜结合的受体复合体 受体结合时激活的近端信号分子 目的2.确定成纤维细胞来源的骨桥蛋白如何刺激癌前细胞的增殖 目的3.确定OPN的表达如何在衰老激活时进行调节 目的4.确定成纤维细胞来源的骨桥蛋白在肿瘤发生中的作用

SAtBatSeTmReAntCoTf Hypothesis and Specific Aims Age is the single largest risk factor for the development of neoplasia. Investigation into how age contributes to increased cancer incidence has focused on accumulation of autonomous mutations within incipient cancer cells. While it is clear that these cell autonomous changes are integral to the transformation process, it has become evident that changes in the surrounding, ostensibly normal stroma collaborate in the process and may contribute to the age-dependent increase in cancer incidence. Indeed, "normal" fibroblasts within a tumor secrete factors that promote tumor cell growth. Like genetic mutations, senescent fibroblasts accumulate with age, and recent data suggests that they play a pivotal role in tumorigenicity. We hypothesize that as senescent fibroblasts increase within the stromal compartment they create a pro-tumorigenic environment that supports the growth and continued transformation of preneoplastic cells. To identify senescent fibroblast-derived factors that support preneoplastic cell growth, we carried out a nonbiased microarray analysis comparing young and senescent fibroblasts. We identified osteopontin (OPN) as a putative stromal factor capable of enhancing preneoplastic cell proliferation and thus hypothesize that it plays an important role in tumorigenesis. In support of this hypothesis, we found that OPN is expressed within the stromal compartment of benign human lesions of the skin and breast. While OPN expression has been correlated with tumor progression (33, 34), the role that stromal-derived OPN plays in early lesions has not been investigated. The goal of this proposal is to determine the molecular mechanisms by which OPN influences the early stages of the transformation process. To that end, the specific aims of this proposal are: Aim 1. Identify the receptor complex(es) engaged by fibroblast-derived OPN and the membrane proximal signaling molecules activated upon receptor binding Aim 2. Determine how fibroblast-derived OPN stimulates preneoplastic cell proliferation Aim 3. Determine how OPN expression is regulated upon activation of senescence Aim 4. Determine the impact of fibroblast-derived OPN on tumorigenesis