Cancer – a disease notorious for its deadliness. Till now, be it chemotherapy or immunotherapy, it still has no perfect cures. A sad truth indeed, but have you ever thought about cancers in other animals, like mice and elephants? Make a guess on the likelihood of these animals getting cancer – the answer may come as a surprise.

First, how exactly does cancer develop? In general, it can be caused by mutations in proto-oncogenes or tumor suppressor genes, both of which function to regulate normal cell growth and division. There are multiple cell cycle checkpoints to ensure that the genome is properly replicated. Tumor suppressor genes may kick in to repair damaged DNA, arrest cell cycle or induce apoptosis (cell suicide) when DNA replication goes wrong. However, when these genes are mutated, the cell may gain the ability to escape from the protective mechanisms and divide in an uncontrolled manner, forming a tumor.

Judging from this mechanism, it is reasonable to deduce that larger organisms, which clearly have more cells, are more prone to developing cancer because cell division has obviously occurred many more times in those creatures. Random mutations (mistakes in replication) may take place in every round of cell division, so the chance of larger and older individuals having cells accumulating enough of those deadly mutations should be higher. However, just as organisms with 1,000 times more cells than humans don’t have an increased risk of developing cancer, we are not more cancer-prone than mice [1]. Such a lack of correlation between body size and risk of cancer is called the Peto’s paradox (footnote 1), named after the English statistician and epidemiologist Richard Peto [2].

Simply terming the phenomenon as a paradox is not enough for scientists – currently, there are two general explanations for the anomaly, with the first one being genetics. The TP53 gene, which encodes p53 proteins, is one of the tumor suppressor genes. These proteins are located at the nuclei of cells, monitoring the DNA. When the DNA is damaged, p53 proteins will pause the cell cycle and activate other DNA repair genes if the damage is repairable, otherwise cell death will be induced to prevent further replication and perpetuation of the potentially harmful mutated DNA [3, 4]. Previous studies have demonstrated that loss-of-function mutations in TP53 (which in turn produces p53 proteins that are not fully functional) was found in over 50% of human cancers, suggesting the importance of this mechanism in cancer suppression [5].

Subjected to higher mutation risks, elephants have evolved to contain 20 copies of the TP53 gene, whereas humans only have one copy [6]. This means the extra copies in elephants can compensate for mutated ones, retaining the ability to kill cancerous cells in the case of mutations. In contrast, if the only TP53 gene in humans is mutated, it can lead to an inheritable genetic condition called the Li-Fraumeni Syndrome, in which the individual is susceptible to a wide range of cancers at a young age [7]. In addition to the number of TP53 copies, a recent study also revealed that elephants had historically restored the function of an ancient, non-functioning gene remnant called LIF6. In response to DNA damage, LIF6 proteins can be activated by p53 proteins to effectively induce apoptosis and kill abnormal cells before they become cancerous [8]. This could be the reason why elephant can evolve into the only paenungulate (footnote 2) with an exceptionally large body size while being resilient to cancer. Therefore, larger organisms could have unique tumor suppression mechanisms to genetically fight against cancer.

Hypertumors, the tumors of tumors, are the second explanation of Peto’s paradox. Unlike normal cells, cancerous ones are competitive and not cooperative in nature. This is characterized by tumor angiogenesis, the formation of blood vessels to provide extra blood supply (with oxygen and nutrients) for proliferation [9]. Based on this fact, it is not hard to imagine that any tumor would try to capture resources by any means. Research had predicted that the competing nature of cancer cells favor the formation of parasitic hypertumors, which feed on the parent tumor’s blood vessels [10]. Before a tumor can grow to a lethal size in large organisms, hypertumors would have emerged and stop the evil plan of the parent tumor by depriving their resources and keeping them at a sublethal size [10]. Nevertheless, this cannot be achieved in smaller organisms because a small tumor, which takes much less time for a single cancer cell to develop to, is already life-threatening to the host. Hypertumors simply do not have enough time to develop. In a nutshell, there could be literally be cancers killing cancers in large organisms.

With the cruel words of “there is no treatment”, the earliest description of cancer called the Edwin Smith Papyrus was found in Egypt in about 3000 B.C. [11]. Still being incurable at present, it is not an overstatement to say that cancer is the “king of disease”. The good of studying Peto’s paradox is that scientists may gain insights into how organisms cope with cancer and develop new therapeutic strategies.

1 Paradox: A contradiction that often goes against common sense.

2 Paenungulate: Members in the clade Paenungulata, which includes smaller creatures like hyrax and manatee (whose body size is still significantly smaller than that of an elephant) [8].

References:

[1] Caulin, A. F., & Maley, C. C. (2011). Peto’s Paradox: Evolution’s Prescription for Cancer Prevention. Trends in Ecology & Evolution, 26(4), 175–182.

[2] Peto, R., Roe, F. J., Lee, P. N., Levy, L., & Clack, J. (1975). Cancer and ageing in mice and men. British Journal of Cancer, 32(4), 411–426. doi:10.1038/bjc.1975.242

[3] National Institute of Health. (2020). TP53 gene. Retrieved from https://medlineplus.gov/genetics/gene/tp53/

[4] Mathews, C., van Holde, K., Appling, D., & Anthony-Cahill, A. (2013). Biochemistry (4th ed.). Toronto: Pearson.

[5] Ozaki, T., & Nakagawara, A. (2011). Role of p53 in Cell Death and Human Cancers. Cancers (Basel), 3(1), 994–1013. doi:10.3390/cancers3010994

[6] Callaway, E. (2015). How elephants avoid cancer. Nature. Retrieved from https://www.nature.com/articles/nature.2015.18534

[7] American Society of Clinical Oncology. (2020). Li-Fraumeni Syndrome. Retrieved from https://www.cancer.net/cancer-types/li-fraumeni-syndrome

[8] Vazquez, J. M., Sulak, M., Chigurupati, S., & Lynch, V. J. (2018). A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage. Cell reports, 24(7), 1765–1776. doi:10.1016/j.celrep.2018.07.042

[9] National Cancer Institute. (2018). Angiogenesis Inhibitors. Retrieved from https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet

[10] Nagy, J. D., Victor, E. M., & Cropper, J. H. (2007). Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox. Integrative and Comparative Biology, 47(2), 317–328. doi:10.1093/icb/icm062

[11] American Cancer Society. (2018). Understanding What Cancer Is: Ancient Times to Present. Retrieved from https://www.cancer.org/treatment/understanding-your-diagnosis/history-of-cancer/what-is-cancer.html