Abstract
Gastric adenocarcinoma is the third most common cause of cancer-related death worldwide. Here we report a novel, highly-penetrant mouse model of invasive gastric cancer arising from deregulated Hedgehog/Gli2 signaling targeted to Lgr5-expressing stem cells in adult stomach. Tumor development progressed rapidly: three weeks after inducing the Hh pathway oncogene GLI2A, 65% of mice harbored in situ gastric cancer, and an additional 23% of mice had locally invasive tumors. Advanced mouse gastric tumors had multiple features in common with human gastric adenocarcinomas, including characteristic histological changes, expression of RNA and protein markers, and the presence of major inflammatory and stromal cell populations. A subset of tumor cells underwent epithelial-mesenchymal transition, likely mediated by focal activation of canonical Wnt signaling and Snail1 induction. Strikingly, mTOR pathway activation, based on pS6 expression, was robustly activated in mouse gastric adenocarcinomas from the earliest stages of tumor development, and treatment with rapamycin impaired tumor growth. GLI2A-expressing epithelial cells were detected transiently in intestine, which also contains Lgr5+ stem cells, but they did not give rise to epithelial tumors in this organ. These findings establish that deregulated activation of Hedgehog/Gli2 signaling in Lgr5-expressing stem cells is sufficient to drive gastric adenocarcinoma development in mice, identify a critical requirement for mTOR signaling in the pathogenesis of these tumors, and underscore the importance of tissue context in defining stem cell responsiveness to oncogenic stimuli.
Highlights
Gastric cancer is the 5th most common cancer worldwide and the 3rd most common cause of cancerrelated death [1]
The Lgr5 promoter targets epithelial stem cells in skin and intestine, and while we previously showed that expression of GLI2A in this cell population in skin gives rise to basal cell carcinomas [15], we did not detect grossly apparent tumors in intestines of iLgr5;GLI2A mice
We show that tumors with multiple features mimicking invasive human gastric adenocarcinoma develop within 3 weeks after expressing the Hh pathway transcription factor GLI2A in mouse stomach
Summary
Gastric cancer is the 5th most common cancer worldwide and the 3rd most common cause of cancerrelated death [1]. Genetic mouse models have yielded insights into signaling alterations and effector molecules that can contribute to gastric tumor development. Prominent among these are models designed to mimic alterations in pro-inflammatory cytokines and signaling pathways that are deregulated in human gastric cancer, including IL-1β; IFNγ; Wnt/β-catenin; Cox and prostaglandin E2; Smad; and gp130, which transduces signals from the pro-inflammatory cytokines IL-6 and IL-11 (reviewed in [7]). The PTEN/PI3K/Akt pathway, which is frequently deregulated in human gastric cancer, was recently shown to promote development of mouse gastric cancer [8] Many of these models have a protracted tumor latency, incomplete penetrance, and a low frequency of invasion and metastasis. Little is known of the cell of origin of advanced gastric cancer
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