Copyright
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Promising xenograft animal model recapitulating the features of human pancreatic cancer
Jin-Xin Miao, Jian-Yao Wang, Hao-Ze Li, Hao-Ran Guo, Louisa S Chard Dunmall, Zhong-Xian Zhang, Zhen-Guo Cheng, Dong-Ling Gao, Jian-Zeng Dong, Zhong-De Wang, Yao-He Wang
Jin-Xin Miao, Jian-Yao Wang, Hao-Ze Li, Hao-Ran Guo, Zhong-Xian Zhang, Zhen-Guo Cheng, Dong-Ling Gao, Yao-He Wang, Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450000, Henan Province, China
Jin-Xin Miao, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
Louisa S Chard Dunmall, Yao-He Wang, Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London EC1M6BQ, United Kingdom
Jian-Zeng Dong, Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
Zhong-De Wang, Department of Animal Dairy, and Veterinary Sciences, Utah State University, Logan UT 84341, United States
Author contributions: Wang YH and Wang ZD conceived and supervised the study; Miao JX and Wang YH designed all experiments; Miao JX performed most experiments with Wang JY, Li HZ, Guo HR, and Zhang ZX; Gao DL did the histopathology staining and Cheng ZG reviewed histopathology; Dong JZ and Chard Dunmall LS revised the manuscript; Miao JX, Wang YH, and Wang ZD interpreted all results and wrote the manuscript.
Supported by the National Key R and D Program of China, No. 2016YFE0200800; Nature Sciences Foundation of China, No. 81771776; Nature Sciences Foundation of China, No. U1704282; and Medical Research of Council, No. MR/M015696/1.
Institutional review board statement: The study was reviewed and approved by the Academy of Medical Sciences, Zhengzhou University Institutional Review Board.
Institutional animal care and use committee statement: All animal experiments conformed to the Provision and General Recommendation of Chinese Experimental Animals Administration Legislation accepted principles for the care and use of laboratory animals (IACUC-ZZU-2016/Wang, The Ethics Committee on Animal Experiment of Zhengzhou University, Zhengzhou, Henan, China).
Conflict-of-interest statement: The authors disclose that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Yao-He Wang, MD, PhD, Professor, Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, No. 100 Kexue Road, Zhengzhou 450000, Henan Province, China. yaohe.wang@qmul.ac.uk
Received: April 14, 2020
Peer-review started: April 14, 2020
First decision: June 18, 2020
Revised: July 1, 2020
Accepted: August 4, 2020
Article in press: August 4, 2020
Published online: August 28, 2020
BACKGROUND
Multiple sites of metastasis and desmoplastic reactions in the stroma are key features of human pancreatic cancer (PC). There are currently no simple and reliable animal models that can mimic these features for accurate disease modeling.
AIM
To create a new xenograft animal model that can faithfully recapitulate the features of human PC.
METHODS
Interleukin 2 receptor subunit gamma (IL2RG) gene knockout Syrian hamster was created and characterized. A panel of human PC cell lines were transplanted into IL2RG knockout Syrian hamsters and severe immune-deficient mice subcutaneously or orthotopically. Tumor growth, local invasion, remote organ metastasis, histopathology, and molecular alterations of tumor cells and stroma were compared over time.
RESULTS
The Syrian hamster with IL2RG gene knockout (named ZZU001) demonstrated an immune-deficient phenotype and function. ZZU001 hamsters faithfully recapitulated most features of human PC, in particular, they developed metastasis at multiple sites. PC tissues derived from ZZU001 hamsters displayed desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotypes, whereas PC tissues derived from immune-deficient mice did not present such features.
CONCLUSION
ZZU001 hamsters engrafted with human PC cells are a superior animal model compared to immune-deficient mice. ZZU001 hamsters can be a valuable animal model for better understanding the molecular mechanism of tumorigenesis and metastasis and the evaluation of new drugs targeting human PC.
Core tip: Xenograft cell transplantation into immune-deficient mice has become the gold standard for assessing tumor progression and efficacy of cancer drugs. However, xenografting human pancreatic cancer (PC) models in nude mice rarely results in development of metastasis and thus does not accurately reflect tumor progression as seen in the human disease. Here, we created a new immune-deficient Syrian hamster with interleukin 2 receptor subunit gamma (IL2RG) gene knockout and demonstrated that the IL2RG-/- Syrian hamster is a promising animal model that can faithfully recapitulate most features of human PC, notably multiple sites of metastasis. Furthermore, this model can present other key features of human PC, such as stromal reaction and the communication between stromal cells and PC cells.
