While billions of dollars are invested in cancer research each year, some animals have already solved the problem. Several species, including moles and elephants, have evolved strong cancer-resistant traits. Unfortunately, however, the disease is consistently one of the leading causes of death in humans. What if these resistant species hold the secret to curing cancer? Over the past decade, researchers have attempted to unlock the secret to curing cancer, using these highly-adaptive species as a guide. 

What is Cancer?

Cancer is a disease that occurs when genetic changes in a cell’s DNA lead to unregulated growth. These genetic changes can be inherited, damaged by environmental factors, or simply unlucky errors when replicating DNA. The uncontrolled proliferation of cancer cells is damaging to tissues around them. For example, a rapidly growing cluster of cells, called a tumor, can signal and rewire surrounding tissues to consume more nutrients and energy, harming nearby cells. 

Why do our immune systems struggle to identify these rapidly-replicating cells? Since cancer cells are often very similar to normal cells, immune cells cannot effectively recognize and target them. Additionally, cancer cells can develop mechanisms to evade immune detection or suppress immune responses, allowing them to grow and spread unchecked.

Above: Graphic representing the cancer cell proliferation and its spread across tissues. Image courtesy of the National Cancer Institute.

Peto’s Paradox

Within metazoans, or multicellular animals, cancer is considered a universal disease. Research has found that cancer exists in almost all animals—from humans to fish to invertebrates. When studying individual species, scientists have identified general trends. Bigger and older organisms are more likely to have cancerous cells because they offer more chances for mutations to aggregate. Because of this pattern, scientists had originally assumed larger animals should have a shorter lifespan because they have more cells that can become cancerous. However, Sir Richard Peto proved this wrong in 1975.

Above: In nature, the expected cancer rate and observed cancer rate are highly variable. Image courtesy of Zhang, 2023.

Sir Richard Peto postulated that the risk of carcinogenesis is not correlated with the size of an animal. To test his hypothesis, he compared mice with humans. Since the average human has about 1000 times the number of cells of a mouse, the mechanisms of cancer suggest that humans would have a shorter life span than mice. However, simple observation indicates that this is not the case. In fact, scientists have not identified any trends in the animal kingdom that predict the risk of carcinogenesis in any species. 

But how do we explain the lack of patterns correlating animal size with carcinogenesis? Scientists believe that a resolution to Peto’s Paradox lies in the co-evolution of larger body sizes and anticancer mechanisms, allowing for longer life spans. Various animals employ numerous tumor-suppressing mechanisms to suppress carcinogenesis. Scientists can study variations in cancer vulnerability between similar species to discover other mechanisms.

Cancer-Resistant Animals

While numerous animals maintain some level of cancer resistance, a few species appear completely cancer-resistant. An underlying theme amongst many longer-living animals is the redundancy of tumor-suppressing genes. Despite the loss of function mutations in one system, the cells possess some level of regulation for cell growth, preventing rapid proliferation. Naked mole rats, for instance, employ these techniques to live ten times longer than the average rodent. Understanding the mechanisms behind mitotic regulation in these non-model animals can open the door to new treatments for cancer.

Left: Naked mole rat. Image courtesy of Antonio Olmos. 

Center: Lucas's Short-nosed Fruit Bat. Image courtesy of Bat Conservation International. 

Right: Elephant. Image courtesy of BBC Earth.

Naked Mole Rat — Scientists have found that naked mole rats are resistant to both spontaneous (natural) and experimentally induced tumors. The most promising discoveries about their natural cancer resistance lie in their extracellular components. Naked mole rats secrete high levels of a unique high molecular mass hyaluronan (HMM-HA) into their extracellular matrix. Naked mole rats need increased HMM-HA to increase skin elasticity, supporting their subterranean lifestyle. As a result, naked mole rats have both more and longer hyaluronan molecules compared to other rodents. Importantly, the HMM-HA suppresses tumors through anti-proliferative, anti-inflammatory, and anti-metastatic properties. This advantageous side effect of HMM-HA has helped naked mole rats remain essentially immune to cancers. 

Bats — Throughout all species of bats (about 1400), there are very few documented cases of cancer. Many species share similar traits that provide enhanced cancer resistance. Like the naked mole rat, bats have evolved advantageous resistance due to other characteristics. Because bats can fly, they have evolved systems to counteract oxidative stress in the mitochondria. These alterations in the mitochondria may also suppress the proliferation of energy-consuming cancer cells. 

‍Elephants and Whales — These larger animals are the clearest examples of Peto’s Paradox. Despite being over 2,000 times larger than humans, they have about the same lifespan. While blue whales are not currently well-studied, scientists have much more information about elephants. Elephants have large numbers of redundant p53 genes, critical regulators of cell division and carcinogenesis. This redundancy provides room for error in case of loss of function mutations that inhibit mitotic regulation. Additionally, elephants have more sensitive p53 genes, serving as a stricter regulatory barrier. The combination of these two mechanisms causes precancerous cells to be apoptosed before there is any potential for cancerous tumors to form. Furthermore, all large mammals have slower metabolism to accommodate for their size. As a result, their cells undergo less mutation and cellular damage, decreasing the likelihood of a deleterious mutation.

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Above: Mechanisms used by animals for cancer resistance when tested in mouse models, and their potential for anticancer treatments in human patients. Image courtesy of Gorbunova et al., 2018.

Future Directions

Throughout the 21st century, research using non-model animals has proven effective for understanding cancer mechanisms. This research continues to evolve. In 2024, researchers discovered a new peptide in a bat species that has cancer-resistant properties. These findings contribute to the body of knowledge used to manufacture cancer therapeutics. Although researchers have not yet developed a cancer treatment using these unique species, their well-adapted traits may be promising guides for future research.