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: 8461250
• 负责人: Sheila A Stewart
• 金额: $ 29.65万
• 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/8461250
• 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）：假设肿瘤微环境与年龄相关的变化可显着影响肿瘤发生。 研究年龄如何促进癌症发病率的促进，重点是在初期癌细胞中自主突变的积累。 尽管这些突变显然是转化过程不可或缺的一部分，但现在已经公认的是，周围的基质在此过程中合作，因此有助于年龄依赖性癌症发病率的增加。 确实，肿瘤内的“正常”成纤维细胞分泌促进肿瘤细胞生长的因素。 像遗传突变一样，衰老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了肿瘤发生。 我们假设，随着衰老成纤维细胞的数量随着年龄的增长而增加，它们创造了促肿瘤的环境，促进肿瘤发生。 为了检验这一假设，我们创建了“ FASST”（成纤维细胞加速基质支持的肿瘤发生）小鼠，这是一个新型模型，它使我们能够暂时和空间控制年轻小鼠基质中的衰老激活，并询问这如何影响肿瘤延迟，渗透性，渗透率，进展。 使用FASST模型，我们表明，在经典的两步皮肤致癌方案之后，幼小动物中衰老基质的存在加速了乳头状瘤的出现。 该提案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/或系统地作用加速肿瘤发生。 由于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素，因此我们将重点关注OPN及其直接刺激促肿瘤细胞增殖的能力及其能力及其能力产生促肿瘤的炎症反应并确定FASST模型中这如何影响肿瘤。 最后，我们将这些研究扩展到包括对乳房中肿瘤发生的分析，这使我们能够提出一个关键的问题。衰老会产生一般的促肿瘤状态，还是其活性组织和特定于癌基因？ 这些问题提供的数据将影响我们对肿瘤发生的一般理解，并可能导致鉴定新的基质特异性治疗靶标。 该提案的具体目的是：目标1：确定衰老基质细胞促进癌症是否在局部或系统上在良好的两步性的两步性皮肤癌变模型目标中起作用目标2：确定OPN依赖性和独立的机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制，通过这些机制加速了肿瘤的肿瘤肿瘤性肿瘤症状症状肿瘤性肿瘤性肿瘤性肿瘤性肿瘤性肿瘤性的肿瘤能力上的肿瘤性肿瘤性肿瘤性肿瘤性肿瘤性均受到肿瘤的效应。