Mouse Models of Metaplasia in the Stomach using Tff1-Cre mouse

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15927
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Kinoshita Hiroto 東京大学, 医学部附属病院, 助教 (50645322)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 胃癌 / 胃炎 / マウスモデル

Outline of Final Research Achievements

We established a Tff1-Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomachs of Tff1-Cre;LSL-KrasG12D mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue-positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide-expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Tff1-Cre;Ptenflox/flox mice displayed similar changes to those seen in Tff1-Cre;LSL-KrasG12D mice, both with aberrant ERK activation within 3 months. Tff1-Cre;Cdh1flox/flox mice developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1-Cre;Cdh1flox/flox mice was completely replaced by squamous epithelium which expanded from the forestomach.

Free Research Field

消化管の炎症および発癌

Academic Significance and Societal Importance of the Research Achievements

既報では、胃の仮性性変化は腺底部の成熟した主細胞が起源であり、分化転換によって生じるとされてきた。Tff1-Creマウスでは主として腺管の表層部で遺伝子改変が起こるため、仮性性変化は表層部から、おそらくは狭部の組織幹細胞から生じたものと考えられた。本研究は、胃の化成性変化発生メカニズムの新たな側面を示唆するものと考えられた。また、扁平上皮仮性のモデルはこれまで報告がないユニークなものであり、扁平上皮と腺上皮の境界が競合によって定まるるという「競合モデル」を支持するものと考えられた。