Improving Cancer Models with Humanized Mice

Mouse models have been instrumental in elucidating the pathobiology of cancer formation and inhibition, including that of Colorectal Cancers (CRC) and Prostate Cancers. With the renewed focus on immunotherapy-based approaches, animal models need to express proteins and neo-antigens that a human tumor would normally express while also being capable of responding to standard of care therapies, such as the AR-antagonist enzalutamide used as a therapy for prostate cancer. Typical xenograft models rely on tumor growth in immunocompromised mice, and, as such, cannot be used to study tumor-immune interactions or evaluate potential immunotherapies.

Humanized mouse models can more closely replicate cancer pathologies in humans – from onset to metastasis – providing valuable insights into oncogenesis mechanisms, validation of novel therapeutic targets, and as a predictive platform to test chemopreventives and treatments. Developing humanized mouse models that replicate both the human disease pathology and an intact (human) immune system are a top priority to facilitate the challenge of translating biologics and enable evaluation of concomitant therapies.

 

Understanding the Genome’s Role in Colorectal Cancer (CRC) Pathology

CRC begins as intestinal epithelial cells lose function of Apc, part of the Wnt-β-catenin pathway, which causes Tcf-4 to upregulate proto-oncogene expression of c-Myc, Cdk4, and cyclin D1 – dysregulating cell growth in intestinal epithelial cells and resulting in polyp formation. Additional loss of function or mutations in k-ras, DCC, DPC4, JV18-1, or p53 also further development of CRC. Furthermore, mutations in DNA mismatch repair (MMR) genes MSH2, MLHJ, PMSJ, and PMS2 are known to cause hereditary nonpolyposis colorectal cancer (HNPCC). Beyond these genetic considerations, factors such as undefined genetic background, specific second site genetic modifiers, and environmental variables may yield dramatic differences in the tumorigenesis in models of CRC.

Mouse models have been developed which offer robust methods to study both potential treatments and preventives as well as the pathogenic and metastatic properties of CRC. Conditional knockout mouse models are useful for mitigating undesired symptomology, such as the co-development of lymphoma with intestinal neoplasia in MMR-disrupted mouse models – addressed by a mouse model similar to HNPCC wherein Msh2 is knocked down in villin-expressing tissues and MMR activity is preserved in the rest of the body1. Familial adenomatous polyposis (FAP) also involves a germline mutation in one Apc allele - Apc mutant mice (e.g. FabplCre; Apc15lox/+) are now capable of producing adenomas that are similar to the adenogenesis observed in FAP patients. Additionally, studies have shown that the location of the mutation within the Apc gene has an influence on adenoma multiplicity.

 

New Developments in Humanized Models for Prostate Cancer

Dr. Steve Kregel presented work at the 2019 American Association for Cancer Research (AACR) conference describing a humanized mouse model of metastatic castration resistant prostate cancer that could help improve preclinical prostate cancer modeling. Utilizing humanized mice subcutaneously engrafted with 22Rv1.Luc2, an aggressive prostate cancer cell line that retains AR expression & is tagged with luciferase, Dr. Kregel demonstrated clinically-relevant metastasis and suggested that enzalutamide works better in humanized mice (per significant decreases in the femur, liver, kidneys, and lymph node metastases). It was also shown that the AR-antagonist enzalutamide led to increased T-infiltration and T-cell activation within the tumors. Given the scarcity of researchers testing therapies on models that have a human immune system and also metastasize to clinically relevant locations, the potential impact of this new humanized mouse model is readily apparent.

Given the complexity of genetic and environmental factors in creating humanized mouse models, it is imperative to consider how each area may be optimized to generate a model with cancer pathogenesis & immunity that provides the most clinical relevance to humans. 

Cyagen’s experts can help you design the perfect custom rodent models to accelerate your research on preventives and treatments for prostate cancers, CRCs, and many more. If your research involves Apc and its role in CRCs, we can help design your custom rodent models utilizing cKO, marker tagged KI and conditional point mutation models via our proprietary TurboKnockout technology. Models may be used study candidate genomic CRC drivers that are conserved in human CRC to facilitate translation into effective treatments.


References
  1. Karim, B. O., & Huso, D. L. (2013). Mouse models for colorectal cancer. American Journal of Cancer Research,3(3), 240-250. doi:2156-6976/ajcr0000196
  2. Metastatic Prostate Cancer Modeling with Humanized Mice. (2019, June 24). Retrieved from https://www.taconic.com/taconic-insights/oncology-immuno-oncology/humanized-metastatic-prostate-cancer-models-interview.html
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