Second, the epigenetic status is heritable and microenvironmentally induced, and is therefore likely to fit the dynamics of fibroblast activation.64 For example, TGF-β and other growth factor signals result in global changes in the methylation status of fibroblast genes.62,65 In lung cancer stroma, SMAD3 was one of the genes found to be silenced by hypermethylation, which elicited a hyper-responsiveness of CAFs to TGF-β signalling, leading to an increased expression of wound-response genes such as COL1A1, thereby linking TME methylation to increased ECM deposition by CAFs.66 Here, TGFB1 is linked to lung carcinoma.