Genetic and epigenetic aberrations are well studied hallmarks of cancer cells. But in addition, an increasing number of reports have suggested that such changes can also occur in the non-neoplastic stromal cells that surround and intermingle with carcinoma cells. There are also recent functional data suggesting that tumorassociated stromal cells, including myofibroblasts and tumor-associated endothelial cells (TECs), can acquire new phenotypes, different from normal stromal cells, which actively contribute to tumor progression. An obvious challenge is to link these two lines of research, pinpointing the specific genetic and epigenetic changes that might account for the new phenotypic characteristics acquired by tumor-associated stromal cells. In this Project we will carry out a genome-wide analysis of chromosomal and sub-chromosomal aneuploidies (DNA copy number aberrations;CNA), loss of heterozygosity (LOH) and gains and losses of DNA methylation (GOM, LOM) in the myofibroblasts that proliferate in human cirrhotic livers and hepatocellular carcinomas, and in stromal myofibroblasts from gastric cancers. To achieve this objective, we will apply a new method, methylation-sensitive SNP chip analysis (MSNP), that we have recently tested and validated for combined genetic and epigenetic profiling in other types of human cancers and normal tissues. First, we will use MSNP to obtain comprehensive genetic (CNA, LOH) and epigenetic (GOM, LOM) profiles of myofibroblasts from normal human livers, cirrhotic human livers and human hepatocellular carcinomas. Second, we will carry out parallel experiments analyzing stromal myofibroblasts from human gastric cancers, comparing the epigenetic and genetic profiles of these cells to control myofibroblasts from normal human stomach. Third, we will validate the MSNP data for loci that show recurrent genetic or epigenetic changes, using independent molecular methods. We expect that the genetic and epigenetic data from this Project will allow the other Projects to formulate and test new biological hypotheses for the role of stromal cells in human liver and gastric cancers, as well as in pre-neoplastic liver cirrhosis.
Showing the most recent 10 out of 50 publications
