The cellular origin of gastric cancer remains elusive.Lgr5 is the first identified gastric stem cell marker.However, the role of Lgr5+ stem cells in driving gastric carcinogenesis is not fully validated.Here, we used the inducible Cre-LoxP system to concurrently delete Smad4 and PTEN genes in mouse gastric Lgr5+ stem cells, and meanwhile marked mutant Lgr5+ cells and their progeny by Cre-reporter Rosa26tdTomato.Smad4 and PTEN double mutant Lgr5+ stem cells located at mouse gastric antrum and gastro-forestomach junction gave rise to rapid onset and progression from microadenoma, macroscopic adenoma to invasive adenocarcinoma within 3 months.Mutant Lgr5+ cells remained at the very base of benign adenoma,and unexpectedly, extensively occupied throughout the invasive lesions following malignant transition.Furthermore, transformed Lgr5+ cells exhibited proliferative activity.In human gastric cancer samples from TCGA database, the elevated LGR5 expression was observed in human gastric cancer occurred at antrum and gastro-esophageal junction.In addition, the concurrent deletion of SMAD4 and PTEN genes, as well as their reduced expression and the deregulated downstream pathways,were observed in human gastric cancer.Thus, we demonstrated that Lgr5+ gastric stem cells were cancer-initiating cells, and might act as cancer-propagating cells to contribute to malignant transition and invasion in gastric cancer.