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Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions
Open accessAbstract
Background & Aims Gastric cancer develops in the context of parietal cell loss, spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM). We investigated whether expression of the activated form of Ras in gastric chief cells of mice leads to development of SPEM, as well as progression of metaplasia. Methods We studied Mist1-CreERT2Tg/+;LSL-K-Ras(G12D)Tg/+ (Mist1-Kras) mice, which express the active form of Kras in chief cells upon tamoxifen exposure. We studied Mist1-CreERT2Tg/+;LSL-KRas (G12D)Tg/+;R26RmTmG/+ (Mist1-Kras-mTmG) mice to examine whether chief cells that express active Kras give rise to SPEM and IM. Some mice received intraperitoneal injections of the MEK inhibitor, selumetinib, for 14 consecutive days. Gastric tissues were collected and analyzed by immunohistochemistry, immunofluorescence, and quantitative PCR. Results Mist1-Kras mice developed metaplastic glands, which completely replaced normal fundic lineages and progressed to IM within 3–4 months after tamoxifen injection. The metaplastic glands expressed markers of SPEM and IM, and were infiltrated by macrophages. Lineage tracing studies confirmed that the metaplasia developed directly from Kras (G12D)-induced chief cells. Selumetinib induced persistent regression of SPEM and IM and reestablished normal mucosal cells, which were derived from normal gastric progenitor cells. Conclusions Expression of activated Ras in chief cells of Mist1-Kras mice led to the full range of metaplastic lineage transitions, including SPEM and IM. Inhibition of Ras signaling by inhibition of MEK might reverse pre-neoplastic metaplasia in the stomach.
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Comprehensive molecular characterization of gastric adenocarcinoma
The Cancer Genome Atlas Research Network (2014) · Nature · doi:10.1038/nature13480 · Cited by 6,498
A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Chen, Z., Cheng, K., Walton, Z., Wang, Y., Ebi, H., Shimamura, T., Liu, Y., Tupper, T., Ouyang, J., Li, J., et al. (2012) · Nature · doi:10.1038/nature10937 · Cited by 446
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Zhang, P., Yang, M., Zhang, Y., Xiao, S., Lai, X., Tan, A., Du, S., & Li, S. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.052 · Cited by 478
Yu, S., Yang, M., Lim, K.-M., Cho, Y., Kim, H., Lee, K., Jeong, S.-H., Coffey, R. J., Goldenring, J. R., & Nam, K. T. (2018) · The American Journal of Pathology · doi:10.1016/j.ajpath.2018.08.006 · Cited by 19
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Metadata
- Authors
- Choi, E., Hendley, A. M., Bailey, J. M., Leach, S. D., & Goldenring, J. R.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 150
- Issue
- 4
- Pages
- 918-930.e13
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2195841564
- Cited by
- 166
- References
- 2
- FWCI
- 10.94
- Type
- journal article
- Language
- en
- Open access
- green
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- Choi, E., Hendley, A. M., Bailey, J. M., Leach, S. D., & Goldenring, J. R. (2016). Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions. Gastroenterology. https://doi.org/10.1053/j.gastro.2015.11.049
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