1. Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus
- Author
-
Supriya Srivastava, Ming Teh, Yi Hui Melissa Lim, Asim Shabbir, Kazuyoshi Kohu, Akihiro Yamamura, Linda Shyue Huey Chuang, Junichi Matsuo, Go Shioi, Shu Chin Pang, Kazuto Suda, Jimmy Bok Yan So, Napat Nuttonmanit, Takaya Abe, Yoshiaki Ito, Sabirah Chen, Mitsuhiro Shimura, Guowei Kim, Khay Guan Yeoh, Michiaki Unno, and Daisuke Douchi
- Subjects
Transcriptional Activation ,Genes, APC ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,Stomach Neoplasms ,Gastric glands ,Metaplasia ,medicine ,Pepsinogen C ,Animals ,Cell Lineage ,Genetic Predisposition to Disease ,Progenitor cell ,Cell Proliferation ,Chief Cells, Gastric ,Hepatology ,Integrases ,urogenital system ,Gastroenterology ,Cancer ,Cell Dedifferentiation ,medicine.disease ,Gastric chief cell ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Luminescent Proteins ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Phenotype ,Dysplasia ,Mutation ,Cancer research ,PDX1 ,medicine.symptom ,Tumor Suppressor Protein p53 ,Carcinogenesis ,Precancerous Conditions - Abstract
Background & Aims Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (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 and histologic 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 and 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.
- Published
- 2020