Preclinical studies suggest, that during tumor progression, key components of the canonical TGF-β pathway (e.g., SMAD2/3, SMAD4, TGFBR1/2) are often epigenetically downregulated via histone modifications, potentially leading to non-canonical pathway activation with pro-tumorigenic signaling routes [46, 47]. This evidence concerns the gene SMAD4 and neoplasm.