Role of inflammation in epigenetic alterations of metastatic cancer cells

间质成纤维细胞中肿瘤抑制基因的缺失诱导上皮癌的发生，提示间质在上皮稳态中起重要作用。确切的分子介质仍有待确定。我们发现，间质Tgfbr2的缺失导致邻近上皮的遗传和表观遗传变化，包括细胞周期蛋白依赖性激酶（CDK）抑制剂p15和p16的缺失。此外，肿瘤细胞中p21启动子区p53结合位点的甲基化增加。介导上皮细胞和间质间相互作用的机制涉及cox -2介导的炎症。我们的研究表明，基质TGFb信号的衰减诱导炎症，进而导致DNA损伤以及上皮细胞的表观遗传和遗传改变。因此，炎症和肿瘤微环境的靶向治疗可能有助于治疗基质中TGFb信号下调的癌症。我们目前正在研究癌症相关炎症如何通过表观遗传重编程影响转移性癌细胞的定植。

Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelia homeostasis. The precise molecular mediators remain to be identified. We found that stromal deletion of Tgfbr2 resulted in genetic and epigenetic changes in the adjacent epithelia including a loss of the cyclin dependent kinase (CDK) inhibitors p15 and p16. In addition, there was increased methylation at the p53-binding site of the p21 promoter region in the tumor cells. The mechanisms mediating the crosstalk between the epithelia and the stroma involved COX-2-mediated inflammation. Our studies demonstrate that attenuation of stromal TGFb signaling induces inflammation that, in turn, causes DNA damage as well as epigenetic and genetic alterations in epithelia. Therefore, therapeutic targeting of inflammation and the tumor microenvironment may be useful in treating cancers with downregulation of TGFb signaling in the stroma. Wa are currently investigating how cancer associated inflammation affect metastatic cancer cell colonization through epigenetic reprogramming.