Age-related changes in stromal cancer modifier genes

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间质-上皮相互作用从而调节肿瘤发生知之甚少。当组织在创伤后发生重塑和在肿瘤形成过程中，基质细胞变得活跃。我们建议检验这一假设，即衰老促进皮肤等上皮组织中反应性间质的形成，以及组织间质微环境的这些变化可能促进癌症的形成和/或进展。我们的实验将利用一种敏感的基因启动的ras转基因小鼠模型，在该模型中，皮肤肿瘤的发展强烈依赖于年龄。我们将分析Tg.AC v-Ha-ras转基因小鼠年轻和老年无瘤皮肤的基质成分，以实现以下特定目的： 具体目的#1：确定年轻Tg.AC v-Ha-ras转基因小鼠与老年Tg.AC v-Ha-ras转基因小鼠真皮中基因表达的年龄相关变化，这可能是导致Tg.AC小鼠年龄依赖性皮肤肿瘤反应的原因。Tg.AC转基因小鼠皮肤磨损和远距离未磨损的真皮都将通过微阵列分析进行检查，以获得在激活和静止基质中差异表达的候选年龄相关修饰基因列表。 具体目标#2：通过重建研究验证年龄相关间质改变在肿瘤发生中的作用，在重建研究中，特定目标#1确定的年轻间质细胞过度表达或下调2-3个候选年龄相关间质基因的表达，将与癌前上皮细胞一起测试对裸鼠肿瘤发生的影响1.皮下注射细胞后，以及 2.在异种气管移植试验中。 我们的长期目标是确定随着年龄的增长而被激活或抑制的关键基质基因，这些基因也可能导致其他上皮组织如结肠癌、前列腺癌和乳腺癌的发展。有了这些信息，特定的与年龄相关的间质变化可以作为这些组织中癌症易感性的生物标记物，其中一些“致癌”间质变化可以作为化学预防药物的靶点。

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.