These data indicate that Smad4 haploinsufficiency is likely to play a causative role in GI tumor formation by exerting a 'landscaping' effect from within the microenvironment as originally proposed by Kinzler and Vogelstein [12], and its complete loss of function in the epithelial cells at later tumor stages accompanies progression towards malignancy [5,6]. The gene discussed is SMAD4; the disease is digestive system neoplasm.