Role of inflammation in epigenetic alterations of metastatic cancer cells

Division Of Basic Sciences - Nci

Investigators

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Abstract

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. We further discovered that the inflammatory tumor microenvironment induces the expression of DNA methyltransferase 3B (DNMT3B) which silence tumor suppressor genes through promoter hypermethylation. These tumor suppressor genes are critical in suppressing metastatic colonization. We are currently investigating the molecular mechanisms as how cancer associated inflammation affect metastatic cancer cell colonization through epigenetic reprogramming. Our studies suggest that therapeutic targeting the inflammatory tumor microenvironment could be useful in treating cancers with down-regulation of tumor suppressor genes that posses anti-inflammatory functions.