Epigenetics and Genetics of Stromal Cells in Liver and Gastric Cancer

遗传和表观遗传异常是癌细胞的特征，已被广泛研究。但除此之外，越来越多的人 许多报告表明，这种变化也可以发生在非肿瘤性间质细胞中， 包围癌细胞并与之混合。最近的功能数据也表明，肿瘤与 基质细胞，包括肌成纤维细胞和肿瘤相关内皮细胞(TECs)，可以 获得不同于正常基质细胞的新表型，这些表型积极促进肿瘤进展。 一个明显的挑战是将这两条研究路线联系起来，准确定位特定的遗传和表观遗传 可能解释肿瘤相关间质获得新表型特征的变化 细胞。 在这个项目中，我们将对染色体和亚染色体非整倍体进行全基因组分析 (DNA拷贝数异常；CNA)、杂合性丢失(LOH)和DNA的得失 人肝硬变和肝细胞中增殖的肌成纤维细胞的甲基化(GOM、LOM) 癌和胃癌的间质肌成纤维细胞。为达致这个目标，我们会采用 我们最近测试和验证的新方法-甲基化敏感SNP芯片分析(MSNP) 用于在其他类型的人类癌症和正常组织中进行联合遗传和表观遗传学分析。首先，我们 将使用MSNP获得全面的遗传(CNA，LOH)和表观遗传(GOM，LOM)图谱 正常人肝、肝硬变人肝和人肝细胞癌的肌成纤维细胞。 第二，我们将进行平行实验分析人胃癌间质肌纤维母细胞， 比较这些细胞的表观遗传学和遗传学特征以控制正常人的肌成纤维细胞 胃。第三，我们将验证MSNP数据中显示反复遗传或表观遗传变化的基因座， 使用独立的分子方法。 我们预计，该项目的遗传和表观遗传学数据将使其他项目能够制定 并测试基质细胞在人类肝癌和胃癌中的作用的新的生物学假设，以及 在癌前肝硬变中。

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.