title: Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions.
abstract: OBJECTIVE
  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 the 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 on 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 Mitogen-activated protein kinase kinase (MEK) inhibitor, selumetinib, for 14 consecutive days. Gastric tissues were collected and analyzed by immunohistochemistry, immunofluorescence, and quantitative polymerase chain reaction.
  
  
  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 re-established 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 preneoplastic metaplasia in the stomach.
authors.affiliation: Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences and the Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Hendley
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.affiliation: Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences and the Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: jim.goldenring@vanderbilt.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019872:Chief Cells, Gastric / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008679:Metaplasia; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D015533:Transcriptional Activation
chemical_list: C517975:AZD 6244; D016588:Anticarcinogenic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Carcinogenesis; Differentiation; MAP Kinase; Signal Transduction