Age-related changes in stromal cancer modifier genes

间质癌修饰基因与年龄相关的变化

• 批准号: 7140498
• 负责人: Susan K. Gilmour
• 金额: $ 16.11万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140498
• 关键词: aging; animal genetic material tag; athymic mouse; biomarker; breast neoplasms; carcinogenesis; cell cell interaction; clinical research; colon neoplasms; epithelium; gene expression; gene expression profiling; genetic susceptibility; genetically modified animals; immunocytochemistry; laboratory mouse; microarray technology; neoplasm /cancer genetics; northern blottings; oncogenes; polymerase chain reaction; prostate neoplasms; skin neoplasms; stromal cells; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Although aging is a well-known risk factor for cancer, very little is known about how aging alters stromal-epithelial interactions thereby modulating tumorigenesis. Stromal cells become reactive when tissues undergo remodeling after wounding and in tumorigenesis. We propose to test the hypothesis that aging promotes the formation of reactive stroma in epithelial tissues such as skin and that these changes in the tissue stromal microenvironment may facilitate the formation and/or progression of cancer. Our experiments will utilize a sensitive genetically initiated ras transgenic mouse model in which skin tumor development is strongly age-dependent. We will analyze the stromal components of young and older tumor-free skin of Tg.AC v-Ha-ras transgenic mice to achieve the following specific aims: Specific Aim #1: To determine age-related changes in gene expression in the dermis of young vs. older Tg.AC v-Ha-ras transgenic mice that may be responsible for modifying the age-dependent skin tumor response in Tg.AC mice. Both abraded and distant nonabraded dermis of Tg.AC transgenic mouse skin will be examined by microarray analysis in order to obtain a list of candidate age-associated modifier genes that are differentially expressed in both activated and quiescent stroma. Specific Aim #2: To verify the contribution of age-related stromal changes in tumorigenesis using reconstitution studies in which young stromal cells overexpressing or downregulating the expression of 2-3 candidate age-related stromal genes, identified in Specific Aim #1, will be tested with premalignant epithelial cells for effects on tumorigenesis in athymic nude mice 1. following subcutaneous injection of cells, and 2. in tracheal xenotransplant assays. Our long term goal is to identify key stromal genes that are "activated" or suppressed with aging that may also contribute to the development of cancer in other epithelial tissues such as colon, prostate, and breast. Armed with this information, specific age-related stromal changes can serve as biomarkers for susceptibility for cancer in these tissues, and some of these "oncogenic" stromal changes can be targeted with chemopreventive agents.

描述（由申请人提供）： 尽管衰老是众所周知的癌症风险因素，但人们对衰老如何改变基质-上皮相互作用从而调节肿瘤发生知之甚少。 当组织在创伤后和肿瘤发生中经历重塑时，基质细胞变得具有反应性。 我们建议测试这一假设，即老化促进上皮组织如皮肤中反应性基质的形成，并且组织基质微环境的这些变化可能促进癌症的形成和/或进展。 我们的实验将利用敏感的基因启动ras转基因小鼠模型，其中皮肤肿瘤的发展是强烈的年龄依赖性。 我们将分析Tg.AC v-Ha-ras转基因小鼠的年轻和老年无肿瘤皮肤的基质成分，以实现以下特定目标： 具体目标1：确定年轻与老年Tg.AC v-Ha-ras转基因小鼠真皮中基因表达的年龄相关变化，这些变化可能是改变Tg.AC小鼠中年龄依赖性皮肤肿瘤反应的原因。 将通过微阵列分析检查Tg.AC转基因小鼠皮肤的磨损和远端未磨损真皮，以获得在活化和静止基质中差异表达的候选年龄相关修饰基因的列表。 具体目标#2：使用重建研究验证年龄相关基质变化在肿瘤发生中的作用，其中将使用癌前上皮细胞检测过表达或下调特定目标#1中确定的2-3种候选年龄相关基质基因表达的年轻基质细胞对无胸腺裸鼠肿瘤发生的影响1。皮下注射细胞后，和 2.在气管异种移植试验中。 我们的长期目标是确定关键的基质基因，这些基因随着年龄的增长而被“激活”或抑制，这些基因也可能有助于其他上皮组织（如结肠、前列腺和乳腺）中癌症的发展。 有了这些信息，特定的年龄相关的基质变化可以作为这些组织中癌症易感性的生物标志物，并且这些“致癌”基质变化中的一些可以用化学预防剂靶向。