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All Cancers, Great and Small

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All Cancers, Great and Small

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In 2014, Croatian geneticist Dr. Tomislav Domazet-Lošo and his colleagues at the University of Kiel in Germany published a paper describing tumors in two different species of tiny freshwater Hydra.  Little more than a tube with tentacles, Hydra comprise three distinct groups of stem cells. One of these groups, known as interstitial stem cells, turned out to be the source of the cancers, which severely impacted growth and fertility. It’s important to note that these tumors were entirely spontaneous: the researchers didn’t use any techniques such as genetic modifications or treatment with chemical agents to induce them. But while Hydra may be the simplest organisms currently known to develop cancer, they are far from the only example outside our own species.

Cancer has been found on virtually every branch of the tree of multicellular life, from the simplest to the most complex. Invasive cancer is medically defined by whether or not tumor cells have broken through the basement membrane that wraps around tissues and organs. Some types of organisms don’t have this barrier layer yet can still be affected by cells multiplying out of control. For example, plants develop large growths – known as galls – that are usually the result of infection or parasitism. Tumor-like masses can be found in red algae and invasive growths have been spotted in mushrooms, while simple molds can start proliferating in abnormal ways that are similar to cancer.

A menagerie of malignancy


One
recently published list of animals known to be affected by cancer stretches over more than twenty pages, including a line-up of marine creatures that reads like the menu from the world’s weirdest sushi restaurant. There are  cockles, clams, crabs, catfish, cavefish, cod, corals and quahogs. Damselfish, angelfish, jewelfish and goldfish. Smelt, salmon, sea bream, weedy sea dragons and more. Curiously, comb jellyfish and sponges seem to be remarkably resistant to cancer, with no known examples of tumors documented to date. One species of sponge, Tethya wilhelma, can withstand around 100 times the dose of X-ray radiation that would kill a human, providing a fascinating model system for studying cancer resistance that could reveal clues to help our own species stave off the disease.

Tumors turn up in frogs, toads and other amphibians, and have been spotted in a range of reptiles such as snakes, turtles, tortoises and lizards. Cancers appear in many species of bird from parakeets to penguins, cockatoos to cassowaries, black-bellied whistling ducks and common-or-garden budgerigars, not to mention the curious case of a
three-legged robin with a cancerous mass in its belly, which arrived in the possession of a Mr H. K. Coale of Chicago one day in 1919. From aardwolf to zebra, our fellow mammals are also affected by all manner of cancers: whales, wallabies, baboons, badgers, bongos and everything in between.

These surveys of cancer across life have challenged the persistent but incorrect belief that sharks don’t get cancer. Tumors have been spotted in
multiple species of sharks including the most notorious of the family, the great white. Regardless, this misconception has led to the needless slaughter of millions of sharks to make cartilage pills that are sold to desperate cancer patients, despite multiple clinical trials showing that they are ineffective.

There is also evidence of cancer in animal species stretching back through the fossil record. In 2003, a research team visited the museums of North America with a portable X-ray machine, taking images of over 10,000 dinosaur bones and revealing
signs of tumors in multiple individuals from the duck-billed Hadrosaur family. In 2020, Canadian researchers published a diagnosis of osteosarcoma in a specimen of the fossilized herbivorous horned dinosaur Centrosaurus apertus, dating back around 75 million years. There’s even a likely tumor in the leg bone of an ancient stem turtle that last roamed the Triassic seas around 240 million years ago.

The widespread existence of cancer across species and back through evolutionary time tells us that the development of cancer is inextricably linked to multicellular life. And if there’s complex multicellular alien life out there in the universe, the odds are that most of those creatures will be susceptible to cancer too. If you have many cells in your body, whatever species you are, there is a chance that some of them will start rebelling against the "rules" of their cellular "society" and start heading along the road to cancer.

Solving the cancer paradox


Even though we can definitively say that cancer isn’t a uniquely human disease, there is still a widely held assumption that the disease is more prevalent in our own species than in any other. Despite the challenges inherent in carrying out a comprehensive survey of cancer across the animal kingdom, the evidence we have so far suggests that this isn’t the case, especially when you take unhealthy human habits such as smoking out of the equation. When comparing baseline cancer risk across species, humans fall somewhere in the middle. We are much less likely to get cancer in our lifetime than mice, but more susceptible than the giants of the mammalian world such as elephants and whales.

Something doesn’t add up here. If cancer is an inevitable consequence of multicellular life, then it should follow that the more cells in an animal, the more likely it is to get cancer. Furthermore, this problem should be exacerbated in animals that live for a very long time, including humans. Yet, based on the data we have, the changes of developing cancer as a function of body mass and lifespan are
roughly the same across most species. This observation that cancer risk doesn’t track neatly with lifespan or size is known as Peto’s Paradox (named after Richard Peto, the British statistician who first noticed it back in the 1970s).

In 2020,
Dr. Amy Boddy at the University of California, Santa Barbara, and her collaborators published further evidence supporting Peto’s paradox in an impressive study looking at cancer incidence across 37 different mammalian species kept in captivity at the San Diego Zoo and Safari Park. Their findings show that there is no correlation between lifespan, body mass and the prevalence of cancer across species. However, they did find that relatively short-lived species like opossums and prairie dogs that have large litters are more likely to develop tumors than animals such as seals and elephants that live longer and have fewer young.

This study, and others like it, reveal an evolutionary trade-off between growth, longevity and reproduction. There is a spectrum ranging from small mammals that "live fast and die young" – existing for just a few short years and producing as many offspring as possible – to "slow burners" that tend to grow large, live for decades and have smaller litters.
Studying nature’s slow burners is revealing intriguing insights as to how these species manage to stave off cancer for so long, which we might be able to turn to our advantage.

Insights from other species


Perhaps the most famous example of a long-lived, cancer-resistant mammal is the naked mole rat, a colony-dwelling rodent that can live for up to three decades and most closely resembles a wrinkly sausage with teeth. Although it’s sometimes said that these creatures never get cancer, there have been a few documented cases in captive colonies, yet the disease is unusually rare for a small rodent. The exact reasons for their remarkable cancer resistance are unknown and, in some areas,
highly contentious.

One idea is that the animals’ low-calorie, low-temperature lifestyle reduces the production of damaging free radicals within their cells. Another explanation lies in altered levels of hormones and other molecules that drive cell growth, in their polyphenol-rich vegetarian diet, or in the highly unusual repertoire of immune cells found in naked mole rats compared with mice.

Naked mole rat tissues make an unusually large and sticky version of hyaluronan, a kind of "cellular glue" that might reinforce contacts and communication between cells, preventing them from becoming cancerous. Cells from naked mole rats are also more resistant to stress and DNA damage than those from other small rodents, and are highly sensitive to contact inhibition, ceasing to proliferate if they become overcrowded.

Other species have solved Peto’s paradox in their own way. For example,
capybaras have particularly vigilant immune cells that seek out and destroy rogue cells before they can grow into a tumor. Elephants have evolved multiple copies of a gene encoding a molecule called p53 – the so-called "Guardian of the Genome" – which rapidly activates the apoptosis cell suicide pathway in damaged cells before they have the chance to become cancerous.

Studying cancer in other species helps us to gain deeper insights into the vulnerabilities in our own human cells and how we might overcome them. We are now able to open nature’s toolbox, revealing the recipes and ingredients that have evolved over millions of years to produce different cancer defense mechanisms and modify risk.

About the author

Kat Arney is a writer, broadcaster and Creative Director of the life sciences communications agency First Create The Media. Her latest book,
Rebel Cell: Cancer, evolution and the science of life (Weidenfeld & Nicolson) is out now.

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