Why do we need mice models in the study of cancer?

Namrata Nilavar

Reading time: 5 minutes

During the COVID-19 pandemic, many researchers have ‘simulated’ the progression of the pandemic, which often involves researchers using a computer program that allows them to understand how the pandemic might pan out. These programs can help us predict ‘real-world’ scenarios. Similarly, we can simulate or imitate the progression of cancer and various other diseases in smaller animals, which biologists call ‘model systems.’ Using a living system allows us to see what changes can be expected in a human patient and how medicines can alter their response to a disease. A living system also often offers a reliable model to study fundamental processes such as DNA replication, protein synthesis, etc.

The first widely known scientific study to use a model system was the investigation of the transmission of traits by Gregor Mendel. He used the pea plant to show how a certain trait/characteristic, like the height of a pea plant is inherited. There have been many model systems after the pea plant. Scientists have used fungi, fishes, flies, worms, and mice. But mice remain one of the most important models in studying cancer. The mouse provides us with a complete system that is very similar to humans. When compared to humans’, mouse proteins share 80% similarity in function. The humble mouse provides researchers with a perfect miniature system that encompasses the nervous, circulatory, and lymphatic systems, to name a few.

The use of mice for experiments has been documented as far back as the 17^th and 18^th century. The earliest study using mice was reported by William E Castle and Clarence C Little at Harvard University for studying breast tumors. The duo purchased their mice from a retired schoolteacher, Abbie Lathrop, who bred mice as pets. All the current laboratory mice are descendants of the common house mouse (Mus musculus).

Many mutations (i.e., genetic changes) are known to cause cancer. The most commonly known are the BRCA1 mutations in breast cancers. To study the development of cancer and to check the role of other genes, scientists again fall back on mice models. Researchers use ‘immunodeficient’ mice or mice with non-functioning immune-system. In these immunodeficient mice human cancer cells are injected to study the progress of cancer (such models are also called as xenograft models) and also check the role of mutations in increasing the speed and spread of cancer. Mario Capecchi, Oliver Smithies, and Martin Evans received the Nobel Prize in Physiology or Medicine in the year 2007 for the technology in development for introduction of specific mutations of mammalian genes and transferring these mutations to the mouse germline. They developed a method to generate mutations in mice embryos. This helped in making mice models which had a stable mutation and this mutation could be passed on to baby mice. Thus, we could study if any mutation could lead to increased cancer risk. p53 gene was one of the first genes to be studied to show increased risk of blood cancers in mice using genetically mutated mice.

There have been many more improvements in mice models. Now we can “knockin” that is, introduce a new gene into the mouse genomic DNA or “knockout” that is, remove a gene from the DNA. These methods were previously quite cumbersome to generate but the advancement in gene-editing through CRISPR has allowed the study of single DNA base mutations. Advances have also been achieved in the generation of ‘humanized’ mice. These models either express a human gene on their immune cells which helps in generation of a xenograft model, or the mouse immune system is erased by radiation and human immune cells are injected in these mice. Both these models are derived from immunocompromised mice models. This has helped for easier study of cancer therapies, since reaction to drugs in mice could be similar to humans because of the similarity in the genetic makeup. These models can also aid researchers in understanding how experimental drugs may work in humans, and determine potential dosing and side effects to anticipate when the drug is eventually tested in human participants.

An interesting concept that has gathered pace in the past few years is the development of immunotherapy against cancer. Multiple drugs and cell therapies are being studied against cancer. But the question of which cells and how the immune system reacts to these cells is a mystery. Typically, our immune system conducts surveillance on all circulating antigens (segments of proteins), whether self or non-self, to ensure our bodies are not exposed to external threats, like bacteria and viruses. The reaction of the immune system to a new antigen (aka neoantigen) is of great importance since not all antigens are recognized as non-self, and immune response to antigens can be variable. This ability of our immune system to react to mutant proteins generated in various cancers can be studied by generating specific mouse models. And the expression of neoantigens in a spatial (specific to an organ or type of cells) and temporal (expression of the new antigen only at or for a set time) fashion allows for an attractive model. This will help understand which cells from our immune system can detect the cancerous antigen and at what time. 

            As we move closer to personalized therapy, we can now know what specific mutation does the patient have and this knowledge can be used for personalized medicine, either in the form of a drug or immunotherapy. But prior to the use of personalized drugs and immunotherapy in humans, their potency and side-effects need to be investigated in mice. And if we can make a mouse model for the exact mutation we observed in the patient then we can design better strategies for treatment and elimination of the disease.

Edited by Manisit Das

Header Image: Wikimedia Commons

References

1. Zhang W, Moore L, Ji P. Mouse models for cancer research. Chin J Cancer. 2011 Mar;30(3):149-52. doi: 10.5732/cjc.011.10047. PMID: 21352691; PMCID: PMC4013310.

2. ​​Vandamme TF. Use of rodents as models of human diseases. J Pharm Bioallied Sci. 2014 Jan;6(1):2-9. doi: 10.4103/0975-7406.124301. PMID: 24459397; PMCID: PMC3895289.3. Lampreht Tratar U, Horvat S, Cemazar M. Transgenic Mouse Models in Cancer Research. Front Oncol. 2018 Jul 20;8:268. doi: 10.3389/fonc.2018.00268. PMID: 30079312; PMCID: PMC6062593.