THE ROLE OF FIBROBLAST-DERIVED OSTEOPONTIN IN TUMORIGENESIS

描述（由申请人提供）：年龄是肿瘤发展的最大风险因素。对年龄如何导致癌症发病率增加的调查主要集中在早期癌细胞内自主突变的积累上。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，周围表面上正常的基质的变化也参与了这一过程，并可能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，衰老的成纤维细胞随着年龄的增长而积累，最近的数据表明它们在致瘤性中起着关键作用。我们假设，随着衰老的成纤维细胞在间质室内的增加，它们创造了一个促肿瘤的环境，支持肿瘤前细胞的生长和持续转化。为了确定支持肿瘤前细胞生长的衰老成纤维细胞衍生因子，我们进行了一项比较年轻和衰老成纤维细胞的无偏见微阵列分析。我们确定骨桥蛋白（OPN）是一种假定的基质因子，能够促进肿瘤前细胞增殖，因此假设它在肿瘤发生中起重要作用。为了支持这一假设，我们发现OPN在人类皮肤和乳房良性病变的间质室中表达。虽然OPN表达与肿瘤进展相关（33,34），但基质来源的OPN在早期病变中的作用尚未得到研究。本提案的目标是确定OPN影响转化过程早期阶段的分子机制。为此目的，本建议的具体目标是：目标1。识别由成纤维细胞来源的OPN参与的受体复合体和受体结合后激活的膜近端信号分子；目标2。确定成纤维细胞来源的OPN如何刺激肿瘤前细胞增殖；目标3。确定OPN的表达如何在衰老激活时被调节；和Aim 4。确定成纤维细胞来源的OPN对肿瘤发生的影响。公共卫生相关性：年龄是癌症发展的最大危险因素。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。该项目旨在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，我们将研究在衰老的促肿瘤细胞中升高的一种分子（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.