The functional diversity and phenotypic heterogeneity of CAF has been extended with the help of epigenetics study, and the most in-depth investigation is the conversion of quiescent fibroblasts into activated CAF in various cancers [97, 133–135], while one of the most classic down-streaming targets is TGF-β1 signaling and its critical mediator SMAD3. This evidence concerns the gene SMAD3 and cancer.