Their origin is still debated but it has been suggested that, at the moment of tumor initiation, the acquisition of CSC phenotype from either transformed differentiated cells (stochastic model) or transformed tissue-resident stem cells (hierarchical model) is promoted by the overexpression of oncogenes and the inhibition of tumor suppressor genes (e.g., APC, TP53, TGFBR2, SMAD4, PTEN, and RAS). Here, SMAD4 is linked to neoplasm.