SMAD4 and neoplasm: The stepwise model of human CRC development and progression proposed by Vogelstein and colleagues [12,13] (Figure 1) includes: 1) inactivation of the APC, SMAD4, and P53 tumor suppressors; 2) overactivation of the KRAS oncogene; and 3) development of genomic instability in the form of either chromosomal instability (CIN) [12-16] or microsatellite instability (MSI) [16,17].