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Gastroenterology. 2019 Oct 1. pii: S0016-5085(19)41368-1. doi: 10.1053/j.gastro.2019.09.026. [Epub ahead of print]

Mouse Models of Human Gastric Cancer Subtypes with Stomach-Specific CreERT2-Mediated Pathway Alterations.

Author information

1
Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
2
Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
3
Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Institute for Medical Informatics and Biometry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Core Unit for Data Management and Analytics (CDMA), National Center for Tumor Diseases (NCT), Dresden, Germany.
5
Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumour Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany.
6
Institute of Pathology and Tumour- and Normal Tissue Bank of the University Cancer Center (UCC), University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumour Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria.
9
Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: daniel.stange@ukdd.de.

Abstract

BACKGROUND & AIMS:

Patterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes.

METHODS:

We searched database to identify Anxa10 with exclusive expression in the stomach epithelium. We generated mice with tamoxifen-inducible Cre recombinase (CreERT2) in the Anxa10 gene locus. We created 3 mouse models with alterations in pathways that characterize the chromosomal instability (CIN) and the genomically stable (GS) subtypes of human gastric cancer: Anxa10-CreERT2;KrasG12D/+;Tp53R172H/+;Smad4fl/f (CIN mice), Anxa10-CreERT2; Cdh1fl/fl; KrasG12D/+, Smad4fl/fl (GS-TGBF mice), and Anxa10-CreERT2; Cdh1fl/fl; KrasG12D/+; Apcfl/fl (GS-Wnt mice). We analyzed tumors that developed in these mice by histology for cell types and metastatic potential. We derived organoids from the tumors and tested their response to chemotherapeutic agents and the EGFR signaling pathway inhibitor trametinib.

RESULTS:

The gastric tumors from the CIN mice had an invasive phenotype and formed liver and lung metastases. The tumor cells had a glandular morphology, similar to human intestinal type gastric cancer. The gastric tumors from the GS-TGFB mice were poorly differentiated with diffuse morphology and signet ring cells, resembling human diffuse-type gastric cancer. Cells from these tumors were invasive and mice developed peritoneal carcinomatosis as well as lung metastases. GS-Wnt mice developed adenomatous tooth-like gastric cancer. Organoids derived from tumors of GS-TGBF and GS-Wnt mice were more resistant to docetaxel, whereas organoids from the CIN tumors were more resistant to trametinib.

CONCLUSIONS:

Using a stomach-specific CreERT2 system, we created mice that develop tumors with morphologic similarities to subtypes of human gastric cancer. These tumors have different patterns of local growth, metastasis, and response to therapeutic agents. They can be used to study different subtypes of human gastric cancer.

KEYWORDS:

Cre/loxP system; carcinogenesis; stomach cancer; targeted therapy

PMID:
31585123
DOI:
10.1053/j.gastro.2019.09.026
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