If every cell has the potential to accumulate DNA mutations, then statistically speaking, larger animals should have an increased risk of cancer. So how does an elephant with trillions of cells outlive a mouse by nearly four decades? Statistician and epidemiologist, Richard Peto, formulated this puzzling paradox in 1977 and many researchers have tried to solve it since then. Peto’s paradox is formulated under one crucial assumption – that cells of every animal have the same risk of cancer induction. However, researchers have unearthed species-specific cellular mechanisms that make long-lived animals naturally resistant to cancer. For example, elephants have extra copies of the tumor suppressor gene, TP53, which may contribute to their longevity. Understanding the plethora of mechanisms that allow animals to evade death by cancer will be crucial inspiration for strategies to conquer cancer.

Mole than meets the eye

A rather peculiar group of naturally cancer-resistant mammals are naked mole rats, a type of subterranean rodent known for their lack of hair. They are the longest-living rodent with a maximum lifespan of 32 years in captivity compared to 3 years for a house mouse. The proportion of animals that die from cancer is 50-90% in mice, but of the hundreds of naked mole rats in captivity, there are only 6 documented cases of tumors. Other than their unusual appearance, what makes these animals so special?

Controlling cell crowds. Cells have a protective mechanism called contact inhibition. Once a cell touches a neighbouring cell, a signalling cascade is initiated to stop cell division. The molecule, cyclin-dependent kinase (CDK) inhibitor, is an important player in this pathway. Compared to humans, naked mole rats have an exceptionally potent CDK inhibitor called pALT. Therefore, they are very effective at preventing cells from uncontrollably growing on top of each other and forming a tumor.

No need for skincare products. When your whole body is constantly drilling through dirt and rocks, you would want your skin to be durable too. That’s exactly the case for naked mole rats. If you’re familiar with skincare, you’ve probably heard of hyaluronic acid, an ingredient known for reducing fine lines and wrinkles by strengthening the matrix holding skin cells together. These subterranean rodents produce hyaluronic acid of an atypically high molecular weight with several documented anti-cancer properties. Their unique hyaluronic acid triggers early contact inhibition, strengthens the extracellular matrix to prevent tumor metastasis, and is an antioxidant that mitigates DNA damage.  

Lessons learned. Now that we know about the unique characteristics of naked mole rats, what do we do with this information? For one, we could take cells from these rodents, place them in a petri dish, harvest the novel molecules of interest and use them as a therapeutic. Indeed, a patent for producing high molecular weight hyaluronic acid in cultures of naked mole rat fibroblast cells was published in 2011. We can also take a rational drug design approach, for example, with the pALT CDK inhibitor . The 3D protein structures and specific amino acid residues that are required for their inhibitor function can be identified and chemically synthesized into a drug. Drug design is a difficult and laborious process, but by learning what works in other organisms, we don’t have to reinvent the wheel.

The biology of long-lived animals could be inspiration for novel cancer treatments, but what it should really teach us is that prevention is key. The concept is quite simple – if we eliminate the cause of cancer formation, then there is no need for a cure. We could save billions of dollars in healthcare and drug development costs, and most importantly, save millions of lives each year. Many research groups are trying to develop effective cancer vaccines and improve cancer detection methods. We, as conscious beings, can also control lifestyle factors like diet and smoking that are implicated in cancer development. For example, we should wear sunscreen to minimize DNA damage inflicted by the sun’s deadly UV rays. Perhaps one day, if proven clinically effective, we can even look forward to using naked mole rat-derived hyaluronic acid as part of our daily skincare routine!


References

  1. Seluanov, A., Gladyshev, V. N., Vijg, J., & Gorbunova, V. (2018). Mechanisms of cancer resistance in long-lived mammals. Nature Reviews Cancer18(7), 433-441.
  2. Gorbunova, V., Seluanov, A., Hine, C. (2011). International Publication No. WO2011119805A2.
  3. Drexler, M. (2020). The cancer miracle isn’t a cure. It’s prevention. Harvard Public Health.
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