SMAD4 and neoplasm: Recent studies have suggested that numerous genetic mutations and epigenetic alterations causing abnormal activation of several oncogenes (KRAS [18,19], c-Myc [20], PIM1 [21]), and the inactivation of several tumor suppresser genes (APC [22], TP53 [23], SMAD4 [24], PTEN [25]), reprogram the metabolic pathway in CRC, mediating the Warburg effect.