Cancer is one of the leading causes of death in most developed countries. Treatments are available, though not without side effects. Therefore, cancer research is mainly centered around finding cures that are non-toxic or less damaging. A different approach in cancer research focuses on preventing the occurrence of cancer rather than its treatment. This approach involves nontraditional models where nonconventional species are used as test subjects under abnormal stressors and unique environments to observe the adaptations that result from such pressures.
Each animal species varies greatly in their cancer rates and the ages at which the disease onsets. But even so taking a look at the different cancer resistance mechanisms of wild animals may aid in our understanding of the progression of cancer. Many know that mutational hits are required for malignant transformations, what most do not know is that the risk of cancer also depends on the body mass and lifespan of the species. Analysis of multiple species suggests that telomerase activity shows a massive negative correlation with body mass; large body sized species are at a higher cancer risk and must evolve mechanisms to prevent their occurrence. Larger species have solved this issue by evolving replicative senescence (an arrest of cell replication) while smaller species do not exhibit replicative senescence regardless of lifespan. However, with an increased lifespan, species have a higher chance of cancer due to the increased probability that mutation can occur in a wider timeframe. To counteract this, long-living species have developed other tumor suppressing methods. One such species is the naked mole rat.
Naked mole rats (NMR) are mouse sized hairless rodents that are native to East Africa and live in subterranean tunnels under a eusocial organization. They are quite popular as a nontraditional model for the field of cancer study as they have quite a long lifespan for a rodent and are famously known for their cancer resistance. Studies have investigated different aspects of the biology of NMRs to determine from where this cancer resistance stems. Comparative studies with NMRs and mice have shown that the NMR genome contains elevated pathways involved in DNA repair, some making it more active and efficient, and some increasing the stability of its genome as mechanisms to prevent cancer. Another form of resistance in NMRs is that they have developed robust mechanisms to prevent protein instability by using stricter protein damage surveillance methods. Such methods result in a higher rate of resistance to unfolding of proteins. In addition, a high turnover rate and an increased control of autophagy helps the NMR to remove damaged or unnecessary proteins to maintain overall protein homeostasis. The efficient functionality of the NMR's proteins is displayed with the oxidative stress theory. Oxidative stress theory suggests that the culmination of oxygen and its toxic byproducts leads to aging of cells and declines in their function. Likely due to an underground environment poor in air quality and nutrients, the NMR displays a higher tolerance towards oxidative damage and can maintain proper protein function. NMR cell cycles are also quite inflexible in their regulation due to their strict DNA surveillance for damage. Compared to mice cells, NMR cells remain in cell arrest far longer, firmly controlling senescence. Moreover, due to the level of control administered, NMR cells are more resistant to cellular transformations. With all these preventative adaptations, one can question whether NMRs are resistant to cancer or just good at avoiding it. However, avoidance does not seem to be the case as experiments at zoos have shown that NMRs, although rare and often benign, can develop neoplasms, favoring the resistance argument over avoidance.
In conclusion, the reason for naked mole rats’ high cancer resistance still begs further investigation. Yet, this does not diminish the fact that they are a hardy species against certain afflictions due to the specifics of their unique environment.
Writer: Beliz Yiğit
References:
Hadi, F., Smith, E. S. J., & Khaled, W. T. (2021). Naked Mole-Rats: Resistant to Developing Cancer or Good at Avoiding It?. In The Extraordinary Biology of the Naked Mole-Rat (pp. 341-352). Springer, Cham.
Seluanov, A., Gladyshev, V. N., Vijg, J., & Gorbunova, V. (2018, April 5). Mechanisms of cancer resistance in long-lived mammals. Nature News. Retrieved November 12, 2022, from https://www.nature.com/articles/s41568-018-0004-9
Shepard, A., & Kissil, J. L. (2020). The use of non-traditional models in the study of cancer resistance—the case of the naked mole rat. Oncogene, 39(28), 5083-5097.