Targeted deletion of Smad4 and PTEN in Lgr5(+) gastric stem cells in mice resulted in formation of invasive adenocarcinoma, whereas the same set of genetic maneuvers failed to induce tumorigenesis in differentiated cells, including antral parietal cells, pit cells, as well as corpus Lgr5(+) chief cells [28]. Here, SMAD4 is linked to adenocarcinoma.