Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation

揭示老化基质影响肿瘤发生的机制

• 批准号: 8658021
• 负责人: Sheila A Stewart
• 金额: $ 30.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658021
• 关键词: Address; Affect; Age; Aging; Animal Model; Animals; Appearance; Breast; Cancer Etiology; Cell Aging; Cell Proliferation; Cell physiology; Cells; Chimerism; Clinical; Data; Dermal; Development; ERBB2 gene; Environment; Fibroblasts; Gene Mutation; Genetic; Goals; Human; Immune; Immune system; Incidence; Inflammatory; Inflammatory Response; Intervention; Investigation; Lead; Lesion; Malignant Neoplasms; Mammary Neoplasms; Mediator of activation protein; Medical; Metastatic Neoplasm to the Lung; Modeling; Mouse Mammary Tumor Virus; Mouse Strains; Mus; Mutation; Neoplasms; Normal Cell; Oncogenes; Organ; PTPRC gene; Papilloma; Penetrance; Population; Process; Protocols documentation; Recruitment Activity; Risk Factors; Shapes; Skin; Skin Carcinogenesis; Skin Neoplasms; Skin graft; Stromal Cells; Testing; Tissues; Xenograft Model; age related; aged; breast tumorigenesis; cancer cell; cancer risk; cell growth; cytokine; growth promoting activity; human tissue; juvenile animal; neoplastic cell; new therapeutic target; novel; osteopontin; recombinase; senescence; therapeutic target; tumor; tumor growth; tumor initiation; tumor microenvironment; tumorigenesis; tumorigenic

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.

描述（由申请人提供）：肿瘤微环境中与年龄相关的变化被假设为显著影响肿瘤发生。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，这些突变是转化过程中不可或缺的一部分，但现在人们普遍认为，周围的基质在这一过程中起作用，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的发生。我们假设，随着年龄的增长，间质室中衰老成纤维细胞的数量增加，它们创造了促进肿瘤发生的促肿瘤环境。为了验证这一假设，我们创建了“fast”（成纤维细胞加速基质支持肿瘤发生）小鼠，这是一种新颖的模型，允许我们在时间和空间上控制年轻小鼠基质室中衰老的激活，并询问这如何影响肿瘤的潜伏期，外显率和进展。使用fast模型，我们发现，在经典的两步皮肤癌发生方案下，年轻动物中衰老间质的存在加速了乳头状瘤的出现。本研究的目的是阐明衰老基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及其直接刺激肿瘤前细胞增殖的能力，以及它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，我们将这些研究扩展到包括对乳腺肿瘤发生的分析，这使我们能够提出一个关键问题；衰老是否创造了一种普遍的促肿瘤状态，或者它的活动是组织和癌基因特异性的？这些问题提供的数据将塑造我们对肿瘤发生的一般理解，并可能导致新的基质特异性治疗靶点的确定。本提案的具体目的是：目的1：确定衰老间质细胞的促癌作用是局部的还是系统的，在一个特征明确的两步皮肤癌发生模型中；目的2：确定衰老间质加速肿瘤发生的OPN依赖和独立机制；目的3：确定衰老间质对乳腺肿瘤发生的促瘤能力。