Target Health Blog

Large Animals Appear to Have Developed Defenses to Cancer

April 8, 2019

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Quiz
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Capybara mother and three pups.
Photo credit: Clodomiro Esteves Junior - Own work, CC BY-SA 4.0,
https://commons.wikimedia.org/w/index.php?curid=58631372
Kurloff cell and a lymphocyte in a Guinea pig. These cells are also found in capybaras.
Graphic credit: By Paolaci - Own work, CC BY-SA 4.0,
https://commons.wikimedia.org/w/index.php?curid=52526973

Cancer is a consequence of multicellularity and a striking example of multi-level selection. The theory of cancer initiation and progression is deeply rooted in evolutionary and ecological concepts . Cancer develops through somatic evolution, with genetic and epigenetic instability generating fitness variation among the cells of a body. Selection at the level of organisms has led to the evolution of tumor suppressor mechanisms, such as cell cycle check points and apoptosis, which act as safe-guards to prevent somatic mutations from propagating in the cell population. Nonetheless, cancer occurs at astonishingly high rates and can be responsible for 20-46% of total deaths in multicellular animals ranging from mollusks to mammals.

Kurloff cells (also known as Foa-Kurloff cells, found in the blood and organs of guinea pigs, contain large secretory granules (also known as Kurloff bodies) of unknown function. They are also found in the capybara. Scientists speculate that these cells along with asparaginase may be what gives the guinea 1) ___ cancer resistant properties (Sharon Vanderlip, DVM). The Kurloff cell has NK cytotoxic activity in vitro.

The evolution of multicellularity required the suppression of cancer. If every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared to small, short-lived organisms. The lack of correlation between body size and cancer risk is known as Peto's Paradox. Animals with 1,000 times more cells than humans, do not exhibit an increased cancer risk, suggesting that natural mechanisms can suppress cancer 1,000 times more effectively than is done in human cells. Because cancer has proven difficult to cure, attention has turned to cancer prevention. Researchers want to understand how evolution has suppressed cancer in some species, to ultimately develop improved cancer prevention in 2) ___.

Scientists are interested in capybaras, the World's largest 3) ___, which has a surprising way of fighting cancer. Genetic analysis of this South American icon reveals how it became a gentle giant - and how it fends off increased cancer risk. Sixty times heavier than their closest modern relative, the world's largest living rodents are roughly the size of small adult humans. They spend their days munching grass along the riverbanks of South America, and they are relaxed enough to serve as chairs for countless other animals. It's not clear, what has enabled capybaras to become gentle giants until recently. In a new study posted on the pre-print service bioRxiv, a team of scientists from Colombia, Sweden, and the United States sequenced the capybara's DNA and found hints of a growth system on overdrive. Their work also uncovered the genetic signature of a putative anti-cancer mechanism that may one day inspire new treatments.

Lead study author Santiago Herrera-Alvarez began studying capybaras while he was a Master's student at the Universidad de los Andes in Bogota. A severe drought in 2014-15 dried up many of Colombia's rivers, leaving the countryside parched. With little vegetation for food, capybara numbers plunged. Herrera-Alvarez's interests, however, weren't in the immediate effects of the drought. Instead, the event sparked his curiosity about how this cute guinea pig-hippopotamus mashup evolved in the first place and has become an iconic 4) ___ American animal. The capybara's ancestors evolved in Africa around 80 million years ago and arrived in South America 40 million years later. Its relatives are all normal-size rodents; for instance, the related rock cavies, which live in the scrublands of eastern Brazil, weigh in at only two pounds each.

Rodents tend to be tiny because smaller animals can hide better, and much larger predators may consider them not worth the effort. But at the time the capybaras arrived in South America, the region was almost completely devoid of predators, which may have allowed their ancestors to start getting bigger. Without 5) ___, the pressures keeping the rodents small became relaxed. According to the new research, the secret to exactly how the capybara could grow by more than an order of magnitude had long been hidden in its DNA. Caviomorphs - the subgroup of rodents that contains capybaras - all have a unique form of insulin. Besides regulating blood sugar, insulin also tells cells to divide. However, the authors found that capybaras didn't have more insulin. Instead, millions of years of natural selection increased insulin's ability to tell their cells to divide, boosting their growth and giving rise to the shaggy, hundred-plus-pound animal. Large size mammals have drawbacks: besides requiring more 6) ___ to support a larger body, animals like capybaras had to contend with an increased cancer risk as it gained size.

If each cell has a fixed probability that it will become malignant, then animals with more cells should be more likely to develop 7) ___. Yet that's not what happens. For instance, despite being thousands of times larger than mice, elephants are no more likely to develop cancer, and this is called Peto's Paradox. Biologists have uncovered several mechanisms that larger animals have evolved, to stop cancer before it starts. Asian and African elephants, for example, are better at spell-checking their DNA when cells divide, which reduces the number of cancer-causing mutations. Bowhead whales, on the other hand, have evolved better mechanisms to keep cells from dividing unchecked. It appears that capybaras have evolved a completely new solution. Their genome showed signs that their immune system is far better at detecting and destroying 8) ___ that are dividing too rapidly. Capybaras have evolved their own form of cancer immunotherapy. Biologists hadn't realized that the immune system might be involved. What was found seems different from the physiology of other animals. Some animals have evolved these anti-cancer pathways, that need to be studied closely. So far, the results are only preliminary and need to be followed up with more experiments.

Throughout an organism's life, cells accumulate mutations caused by endogenous and exogenous damage, or errors in DNA synthesis, that is not properly repaired. In fact, somatic cells in tumors satisfy the three necessary and sufficient conditions for natural selection: There must be variation within the population. A tumor is a heterogeneous population of cells with somatic genetic and epigenetic alterations. The variation must be heritable. Genetic and epigenetic alterations (mutations) are inherited by both daughter cells when a cell divides. The challenge of suppressing somatic evolution dramatically increases with larger bodies and longer lifespans. Because cancer develops through the accumulation of mutations, each proliferating cell is at risk of malignant transformation, assuming all proliferating cells have similar probabilities of mutation. Therefore, if an organism has more cells, i.e. more chances to initiate a tumor, the probability of getting cancer should increase. Similarly, if an organism has an extended lifespan, its cells have more time to accumulate mutations. Because the probability of carcinogenesis is an increasing function of 9) ___, an organism's lifetime risk of cancer should also scale with its lifespan. It is well known that larger organisms generally have longer lifespans which exacerbates this problem. There appears to be no correlation between body size, longevity and cancer across species and the absence of such a relationship is referred to as Peto's Paradox. Cancer rates across multicellular animals only vary by approximately two-fold even though the difference of size among mammals alone can be on the order of a million-fold. Natural selection interacts with the life history of a species and should suppress cancer through the expected period of fertility of an organism. Therefore, given the relative age of an organism, we would expect cancer rates to be similar across species. The question of Peto's Paradox is how has natural selection changed the biology of large, long-lived organisms to achieve this scaling.

A proven strategy in drug development has been to seek natural products that have been honed by millions of years of evolution to generate the desired effect. The evolution of large multicellular organisms could hold the key to preventing cancer in humans. Peto's Paradox suggests that large, long-lived animals such as the blue whale (Balaenoptera musculus) have evolved mechanisms capable of suppressing cancer 1,000 times better than humans. Research on how these large animals are suppressing cancer holds the promise of dramatic improvements in cancer prevention for humans. There are not many large, long-lived organisms that have been fully sequenced yet, so testing Peto's Paradox by doing comparative genomic analyses is difficult with current data. We are also lacking robust epidemiological studies of cancer incidence in wildlife and captive populations. Captive populations will be useful for longitudinal studies and the predation-free environment will allow for better estimates of cancer rates. This will help researchers to better understand the nature of Peto's Paradox.

If if it is possible to discover and harness the cancer suppression mechanisms of large, long-lived organisms like capybaras and others, then we could potentially mitigate cancer as a public health threat in humans. A pharmaceutical company's initial step in developing a new class of drugs is to survey natural products to see if evolution has already invented a solution to their problem. Cancer prevention research can capitalize on the same strategy. People have been invested in cancer research for decades while evolution has been tuning cancer suppression mechanisms for over a billion 10) ___.

Sources: https://www.nationalgeographic.com/science/2018/09/news-worlds-largest-rodent-genetics-cancer-evolution/, Carrie Arnold; NIH.gov; Wikipedia

ANSWERS: 1) pig; 2) humans; 3) rodent; 4) South; 5) predators; 6) food; 7) cancer; 8) cells; 9) age; 10) years

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