Please use this identifier to cite or link to this item: https://doi.org/10.1053/j.gastro.2021.08.013
Title: Induction of gastric cancer by successive oncogenic activation in the corpus.
Authors: Douchi, Daisuke
AKIHIRO YAMAMURA 
JUNICHI MATSUO 
LIM YI HUI MELISSA 
NAPAT NUTTONMANIT 
MITSUHIRO SHIMURA 
KAZUTO SUDA 
SABIRAH CHEN XI BTE MUHD FIRDAUS TAN CJ 
PANG SHUCHIN 
KAZUYOSHI KOFU 
Abe, Takaya
Shioi, Go
GUOWEI KIM 
ASIM SHABBIR 
Supriya Srivastava 
Unno, Michiaki
SO BOK YAN,JIMMY 
TEH MING 
YEOH KHAY GUAN 
CHUANG SHYUE HUEY LINDA 
ITO,YOSHIAKI 
Keywords: Gastric Carcinogenesis
Intramucosal Dysplasia
Invasive and Metastatic Gastric Cancer
Metaplasia
Mouse Model
Issue Date: 12-Aug-2021
Publisher: Elsevier BV
Citation: Douchi, Daisuke, AKIHIRO YAMAMURA, JUNICHI MATSUO, LIM YI HUI MELISSA, NAPAT NUTTONMANIT, MITSUHIRO SHIMURA, KAZUTO SUDA, SABIRAH CHEN XI BTE MUHD FIRDAUS TAN CJ, PANG SHUCHIN, KAZUYOSHI KOFU, Abe, Takaya, Shioi, Go, GUOWEI KIM, ASIM SHABBIR, Supriya Srivastava, Unno, Michiaki, SO BOK YAN,JIMMY, TEH MING, YEOH KHAY GUAN, CHUANG SHYUE HUEY LINDA, ITO,YOSHIAKI (2021-08-12). Induction of gastric cancer by successive oncogenic activation in the corpus.. Gastroenterology. ScholarBank@NUS Repository. https://doi.org/10.1053/j.gastro.2021.08.013
Abstract: BACKGROUND & AIMS: Metaplasia and dysplasia in the corpus are reportedly derived from dedifferentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C-transcript expressing cells (PGC-transcript expressing cells) represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model. METHODS: We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments, histological and immunofluorescence staining. We further established Pgc-CreERT2;KrasG12D/+ mice and investigated whether PGC-transcript expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC-transcript expressing cells with activated Kras, inactivated Apc and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D, Apcflox, Trp53flox mice. RESULTS: Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;KrasG12D/+ mice, PGC-transcript expressing cells with KrasG12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven KrasG12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+;Apcflox/flox mice presented intramucosal dysplasia/carcinoma, while Pgc-CreERT2;KrasG12D/+;Apcflox/flox;Trp53flox/flox mice presented invasive and metastatic gastric carcinoma. CONCLUSIONS: The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development.
Source Title: Gastroenterology
URI: https://scholarbank.nus.edu.sg/handle/10635/198495
ISSN: 0016-5085
1528-0012
DOI: 10.1053/j.gastro.2021.08.013
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