Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation

描述（由申请人提供）：假设肿瘤微环境中的肿瘤相关变化会显著影响肿瘤发生。 对年龄如何导致癌症发病率增加的研究集中在早期癌细胞内自主突变的积累上。 虽然很明显这些突变是转化过程中不可或缺的，但现在普遍认为周围的基质在该过程中协同作用，从而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促进肿瘤发生。 我们推测，随着年龄的增长，基质区室中衰老成纤维细胞的数量增加，它们创造了一个促肿瘤发生的环境，促进肿瘤发生。 为了验证这一假设，我们创建了“FASST”（成纤维细胞加速基质支持的肿瘤发生）小鼠，这是一种新的模型，允许我们在时间和空间上控制年轻小鼠的基质室中衰老的激活，并询问这如何影响肿瘤潜伏期，转移率和进展。 使用FASST模型，我们表明，在年轻的动物衰老间质的存在下，加速乳头状瘤的外观后，一个经典的两步皮肤癌变协议。 该建议的目的是阐明衰老间质促进肿瘤发生的机制。 首先，我们将确定衰老是否通过局部和/或全身作用加速肿瘤发生。 因为我们已经证明骨桥蛋白（OPN）是皮肤中一种重要的衰老基质衍生因子，我们将重点关注OPN及其直接刺激癌前细胞增殖的能力，以及其引发促肿瘤炎症反应的能力，并确定这如何影响FASST模型中的肿瘤发生。 最后，我们扩展这些研究，包括分析乳腺肿瘤的发生，这使我们能够问一个关键的问题，衰老是否创造一个一般的促肿瘤状态或其活动的组织和癌基因特异性？ 这些问题提供的数据将塑造我们对肿瘤发生的一般理解，并可能导致识别新的基质特异性治疗靶点。 本提案的具体目标是：目的1：确定衰老基质细胞的促癌作用是局部还是全身作用于特征良好的两步皮肤癌发生模型目的2：确定衰老基质加速肿瘤发生的OPN依赖性和非依赖性机制目的3：确定衰老基质对乳腺肿瘤发生的促癌能力。

DESCRIPTION (provided by applicant): Age-related changes in the tumor microenvironment are hypothesized to significantly impact tumorigenesis. 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 mutations are integral to the transformation process, it is now well accepted that the surrounding stroma collaborates in the process and thus contributes to age-dependent increases 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 promote tumorigenesis. We hypothesize that as the number of senescent fibroblasts increase within the stromal compartment with age, they create a pro-tumorigenic environment that promotes tumorigenesis. To test this hypothesis, we created the "FASST" (fibroblasts accelerate stromal-supported tumorigenesis) mouse, which is a novel model that allows us to temporally and spatially control the activation of senescence in the stromal compartment of a young mouse and ask how this impacts tumor latency, penetrance and progression. Using the FASST model, we show that the presence of senescent stroma in young animals accelerates the appearance of papillomas following a classic two-step skin carcinogenesis protocol. The goal of this proposal is to elucidate the mechanisms by which senescent stroma promotes tumorigenesis. First, we will determine if senescence accelerates tumorigenesis by acting locally and/or systemically. Because we have already demonstrated that osteopontin (OPN) is an important senescent stromal-derived factor in the skin, we will focus on OPN and its ability to stimulate preneoplastic cell proliferation directly and its ability elicit a pro-tumor inflammatory response and determine how this impacts tumorigenesis in the FASST model. Finally, we expand these studies to include analysis of tumorigenesis in the breast, which allows us to ask a critical question; does senescence create a general pro-tumorigenic state or is its activities tissue and oncogene specific? The data provided by these questions will shape our general understanding of tumorigenesis and may lead to the identification of novel stromal-specific therapeutic targets. The specific aims of this proposal are: Aim 1: Determine whether cancer promotion by senescent stromal cells acts locally or systemically in a well-characterized two-step skin carcinogenesis model Aim 2: Identify the OPN dependent and independent mechanisms by which senescent stroma accelerate tumorigenesis Aim 3: Determine the tumor-promoting abilities of senescent stroma on breast tumorigenesis.