Why blue whales don't get cancer

Introduction: What is Peto’s Paradox?

Cancer is a disease that occurs when cells divide uncontrollably, owing to genetic and epigenetic factors. Theoretically, the more cells an organism possesses, the higher the probability should be for it to develop cancer. Imagine that you have one tiny organism – a mouse, and a huge organism – an elephant. Since an elephant has more cells than a mouse, it should have a higher chance of developing cancer, right?

This is where things get mysterious. In reality, animals with 1,000 times more cells than humans are not more likely to develop cancer. Notably, blue whales, the largest mammals, hardly develop cancer. Why? In order to understand this phenomenon, we must dive deep into Peto’s Paradox.

Peto’s paradox is the lack of correlation between body size and cancer risk. In other words, the number of cells you possess does not dictate how likely you are to develop cancer. Furthermore, research has shown body mass and life expectancy are unlikely to impact the risk of death from cancer. (see figure 1)

Peto’s Paradox: Protective Mechanisms

Mutations, otherwise known as changes or alterations in the deoxyribonucleic acid (DNA) sequence, play a role in cancer and ageing. Research scientists have analysed mutations in the intestines of several mammalian species, ranging from mice, monkeys, cats, dogs, humans, and giraffes, to tigers and lions. Their results reveal that these mutations mostly come from processes that occur inside the body, such as chemicals causing changes in DNA. These processes were similar in all the animals they studied, with slight differences.

Interestingly, annually, animals with longer lifespans were found to have fewer mutations in their cells (figure 2). These findings suggest that the rate of mutations is associated with how long an animal lives and might have something to do with why animals age. Furthermore, even though these animals have very different lifespans and sizes, the amount of mutations in their cells at the end of their lives was not significantly different – this is known as cancer burden.

Since animals with a larger size or longer lifespan have a larger number of cells (and hence DNA) that could undergo mutation, and a longer time of exposure to mutations, how is it possible that they do not have a higher cancer burden?

Evolution has led to the formation of mechanisms in organisms that suppress the development of cancerous cells. Animals possessing 1,000 times as many cells as humans do not display a higher susceptibility to cancer, indicating that natural mechanisms can suppress cancer roughly 1,000 times more efficiently than they operate in human cells. Does this mean larger animals have a more efficient protective mechanism against cancer?

A tumour is an abnormal lump formed by cells that grow and multiply uncontrollably. A tumour suppressor gene acts like a bodyguard in your cells. They help prevent the uncontrollable division of cells that could form tumours. Previous analyses have shown that the addition of one or two tumour suppressor gene mutations would be sufficient to reduce the cancer risk of a whale to that of a human. However, evidence does not suggest that an increased number of tumour suppressor genes correlated with increasing body mass and longevity. Although a study by Caulin et al. identified biomarkers in large animals that may explain Peto’s paradox, more experiments need to be conducted to confirm the biological mechanisms involved.

Just over a month ago, an investigation of existing evidence on such mechanisms revealed a list of factors that may contribute to Peto’s paradox. This includes replicative immortality, cell senescence, genome instability and mutations, proliferative signalling, growth suppression evasion and cell resistance to death. As far as we know, different strategies have been followed to prevent cancer in species with larger sizes or longer lifespans. However, more studies must be conducted in the future in order to truly explain Peto’s paradox.

Peto’s Paradox: Other Theories

There are several theories that attempt to explain Peto’s paradox. One of which explains that large organisms have a lower basal metabolic rate, leading to less reactive oxygen species. This means that cells in larger organisms incur less oxidative damage, causing a lower mutation rate and lower risk of developing cancer.

Another popular theory is the formation of hypertumours. As cells divide uncontrollably in a tumour, “cheaters” could emerge. These “cheaters”, known as hypertumours, are cells which grow and feed on their original tumour, ultimately damaging or destroying the original tumour. In large organisms, tumours have more time to reach lethal size. Therefore, hypertumours have more time to evolve, thereby destroying the original tumours. Hence, in large organisms, cancer may be more common but is less lethal.

Clinical Implications

Curing cancer has posed significant challenges. Consequently, the focus on cancer treatment has shifted towards cancer prevention. Extensive research is currently underway to investigate the behaviour and response of cancer cells to the treatment process. This is done through a multifaceted approach; investigating the tumour microenvironment and diagnostic or prognostic biomarkers. Going forward, a deeper understanding of these fields enables the development of prognostic models as well as targeted treatment methods.

One example of an exciting discovery is the revelation of TP53. The discovery of this tumour suppressor gene indicates that it plays a role in making elephant cells more responsive to DNA damage and in triggering apoptosis by regulating the TP53 signaling pathway. These findings imply that having more copies of TP53 may have directly contributed to the evolution of extremely large body sizes in elephants, helping resolve Peto’s paradox. Particularly, there are 20 copies of the TP53 gene in elephants, but only one copy of the TP53 gene in humans (see figure 3). Through more robust studies and translational medicine, it would be fascinating to see how such discoveries could be applied into human medicine (figure 4).

Conclusion

The complete mechanism of how evolution has enabled organisms that are larger in size and have longer lifespans than humans is still a mystery. There is a multitude of hypotheses that need to be extensively investigated with large-scale experiments. By unravelling the mysteries of Peto’s paradox, these studies could provide invaluable insights into cancer resistance and potentially transform cancer prevention strategies for humans.

By Joecelyn Kirani Tan

Related articles: Biochemistry of cancer / Orcinus orca (killer whale)