THE ROLE OF FIBROBLAST-DERIVED OSTEOPONTIN IN TUMORIGENESIS

描述(申请人提供)：年龄是肿瘤发生的最大危险因素。关于年龄如何导致癌症发病率上升的研究，一直集中在早期癌细胞中自主突变的积累上。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，但很明显，周围表面正常的间质的变化在这一过程中协同作用，并可能导致癌症发病率的年龄相关性增加。事实上，肿瘤内的“正常”成纤维细胞会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的增长而积累，最近的数据表明，它们在肿瘤发生中发挥了关键作用。我们假设，当衰老的成纤维细胞在间质间隔内增加时，它们创造了一个支持癌前细胞生长和持续转化的促肿瘤环境。为了确定支持癌前细胞生长的衰老成纤维细胞来源的因子，我们进行了一项无偏见的微阵列分析，比较了年轻和衰老的成纤维细胞。我们发现骨桥蛋白(OPN)是一种可能的基质因子，能够促进癌前细胞的增殖，因此推测它在肿瘤发生中起重要作用。为了支持这一假说，我们发现OPN在人类皮肤和乳房良性病变的间质中表达。虽然OPN的表达与肿瘤进展相关(33，34)，但间质来源的OPN在早期病变中所起的作用尚未被研究。这项建议的目标是确定OPN影响转化过程早期阶段的分子机制。为此，本提案的具体目的是：目的1.确定成纤维细胞来源的OPN所参与的受体复合体(ES)和受体结合时激活的膜近端信号分子；目的2.确定成纤维细胞来源的OPN如何刺激癌前细胞的增殖；目的3.确定OPN在衰老激活时如何调节；以及目的4.确定成纤维细胞来源的OPN在肿瘤发生中的影响。公共卫生相关性：年龄是癌症发展的最大风险因素。因此，了解影响癌症发展的年龄相关变化将增加我们对这一过程的理解，并为我们提供更好的医疗干预。该项目建议研究肿瘤周围正常细胞(称为基质细胞)的变化如何影响肿瘤的发展。为此，我们将研究一种在老年促肿瘤细胞中升高的分子(骨桥蛋白)，并确定它如何促进癌症的发展。

DESCRIPTION (provided by applicant): 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; and Aim 4. Determine the impact of fibroblast-derived OPN on tumorigenesis. PUBLIC HEALTH RELEVANCE: Age is the largest risk factor for the development of cancer. Therefore, understanding the age related changes that impact cancer development will increase our understanding of the process and supply us with better medical interventions. This project proposes to study how changes in the normal cells that surround a tumor (referred to as stromal cells) influence tumor development. To this end, we will study a molecule (osteopontin) elevated in aged, tumor promoting cells and determine how it promotes the development of cancer.