Published online Aug 28, 2020. doi: 10.3748/wjg.v26.i32.4802
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
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.
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.
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.
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.
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.
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.
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.