THE ROLE OF FIBROBLAST-DERIVED OSTEOPONTIN IN TUMORIGENESIS

SAtBatSeTmReAntCoTf假说和具体目标 年龄是肿瘤发生的最大风险因素。调查年龄如何影响 癌症发病率的增加集中在早期癌症中自主突变的积累上 细胞虽然很明显，这些细胞自主变化是转化过程中不可或缺的一部分， 变得明显的是，周围的变化，表面上正常的基质在这个过程中合作， 导致癌症发病率的年龄依赖性增加。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。像基因突变一样，衰老的成纤维细胞积累了 年龄，最近的数据表明它们在致瘤性中起着关键作用。我们假设， 衰老的成纤维细胞在间质区室中增加，它们产生促肿瘤发生作用。 支持癌前细胞生长和持续转化的环境。以识别 支持癌前细胞生长的衰老成纤维细胞衍生因子，我们进行了一个无偏倚的 比较年轻和衰老成纤维细胞的微阵列分析。骨桥蛋白（OPN）是一种 一种假定的基质因子，能够增强癌前细胞增殖，因此假设它在肿瘤发生中起作用。 在肿瘤发生中起重要作用。为了支持这一假设，我们发现OPN在细胞内表达。 皮肤和乳房良性人类病变的基质区室。虽然OPN表达已被 与肿瘤进展相关（33，34），间质源性OPN在早期病变中的作用尚未确定。 被调查了该提案的目标是确定OPN的分子机制， 影响着转化过程的早期阶段。为此，本提案的具体目标是： 目标1。鉴定成纤维细胞源性OPN与膜结合的受体复合物 受体结合激活的近端信号分子 目标二。确定成纤维细胞来源的OPN如何刺激癌前细胞增殖 目标3：确定OPN表达在衰老激活后如何调节 目标4。确定成纤维细胞来源的OPN对肿瘤发生的影响

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