Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2020; 26(32): 4802-4816
Published online Aug 28, 2020. doi: 10.3748/wjg.v26.i32.4802
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
Processing time: 135 Days and 23.5 Hours
ARTICLE HIGHLIGHTS
Research background

Pancreatic cancer (PC) is an extremely aggressive cancer with a poor prognosis. Multiple sites of metastasis from PC remain a significant hurdle in treating this disease. Reliable animal models that can mimic the clinical features of the disease are needed to study disease progression and develop effective therapies. Xenograft cancer cell transplantation animal models are cost-effective and easily established methods by which to assess tumor progression, metastasis, and pre-clinical efficacy of cancer drugs. However, current xenograft tumor models of human PC in immune-deficient mice rarely develop metastasis. The development of a model that can reflect more accurately human PC progression is therefore required.

Research motivation

Syrian hamsters (Mesocricetus auratus) have advantages as models for various diseases due to the high similarities in anatomy, physiology, and pathology between Syrian hamsters and humans. The Syrian hamster is the only rodent species that develop PC in an almost identical manner to the respective human disease regarding such features as clinical symptoms, tumor morphology, tumor biology, metabolic abnormality, and molecular genetic alterations. We reasoned that the immune-deficient Syrian hamster might be a better animal species for establishing xenograft models of human PC and more faithfully recapitulate the features of PC, in particular the multiple sites of metastasis seen during progression of human PC.

Research objectives

This study aimed to create an immune-deficient Syrian hamster by knockout of interleukin 2 (IL-2) receptor subunit gamma (IL2RG), characterize the phenotypes of IL-2RG knockout (KO) Syrian hamsters, and evaluate whether this animal can present the distinguishing features of human PC.

Research methods

CRISPR/Cas9-mediated genetic editing and cytoplasmic injection into hamster zygotes were employed to create an IL2RG KO Syrian hamster. The phenotypes and immune functions of the IL2RG KO Syrian hamster were characterized. A panel of human PC cell lines were subcutaneously or orthotopically transplanted into IL2RG KO Syrian hamsters or immune-deficient mice. The tumor growth, local invasion of the tumor cells, and remote organ metastasis were compared over time. The histopathology of tumor xenografts, the molecular alterations of tumor cells, and the stroma within the xenograft tumors were investigated by hematoxylin and eosin and immunohistochemistry staining.

Research results

A new immune-deficient Syrian hamster with IL2RG gene knockout was created and named ZZU001. We demonstrated that ZZU001 Syrian hamsters have a lymphoid compartment that is greatly reduced in size and diversity and are impaired in their immune function. The comparison studies on xenografting tumors in ZZU001 and severely immune-deficient mice demonstrated that ZZU001 Syrian hamsters engrafted with human tumor cells are a promising animal model, which can recapitulate most of the features of human PC, in particular, the multiple-sites of metastasis. PC tissues derived from ZZU001 hamsters also displayed other key features of human PC, such as desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotype, whereas PC tissues derived from immune-deficient mice did not present such features.

Research conclusions

This work demonstrates that ZZU001 Syrian hamster can be an extremely valuable animal model for better understanding the molecular mechanisms of tumorigenesis, in particular the metastasis of human PC, and maybe more appropriate in comparison to xenograft mouse models for robust testing of the anti-tumor potential of novel therapeutics.

Research perspectives

Current findings provide a promising xenotransplantation animal model for human PC research. Its wider application requires further evaluation, but the strong similarities between progression of human and Syrian hamster PC may suggest a similarly useful application of this model for more accurately modeling the progression of other human tumors. The model characterized in this study may also provide a useful platform for identification of novel molecules and pathways that control the metastasis of human PC.