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.
