What Does An Animal’s Size Have To Do With Its Cancer Risk?

FLORA LICHTMAN: This is Science Friday. I’m Flora Lichtman. If you throw a huge party, there’s more of a chance of something going haywire than if you host a quiet little get-together with a couple of friends. And it makes sense, right? More people, more chance for chaos. So it also kind of makes sense that in an organism, a bigger species with more cells might have more of a chance of something going wrong with one of those cells, like a mutation leading to cancer.

Back in 1977, a British epidemiologist named Richard Peto observed that that didn’t seem to be true. Bigger animals didn’t seem to have a greater risk of cancer than smaller ones. This became known as Peto’s Paradox, and also the source of phrases like “elephants don’t get cancer,” which, side note, elephants do, in fact, get cancer.

Anyway, research published this week in the Proceedings of the National Academy of Sciences takes a new look at Peto’s Paradox using an unusual set of data– death reports from zoos around the world. Joining me now to explain is Dr. Sarah Amend. She’s an associate professor of urology and oncology at Johns Hopkins University Medical School, and one of the authors of that paper. Sarah, welcome to Science Friday.

SARAH AMEND: Thanks so much for having me.

FLORA LICHTMAN: OK, is Peto’s Paradox like a hot topic in cancer circles?

SARAH AMEND: The cancer research community is a really big place, but there is certainly a growing interest in this idea of comparative oncology. So what can we learn about cancer rates and how cancer grows or doesn’t grow in organisms in order to understand human disease? So this isn’t just one simple, small study. This isn’t just us interested in this question. We’re really building upon the work of a lot of scientists since Richard Peto in 1977 and many of our colleagues today.

FLORA LICHTMAN: And is it debated still, or is it sort of accepted as gospel?

SARAH AMEND: So that’s a difficult question to answer because it was largely accepted, except for perhaps a few outlier species, largely because of a limitation in what samples we had. So you mentioned that really special data set that drew from veterinary autopsies from zoos, and we were only able to do the analysis that we did because that data set was published. It’s the largest of its kind. It was generated by other scientists and was published last year. So the only way we could even begin to answer these questions that were really posed by Peto’s Paradox was because of this data.

FLORA LICHTMAN: OK, so does Peto’s Paradox hold up? Do big animals not get as much cancer as smaller animals?

SARAH AMEND: This was one of the exciting things about this study, is that our results show that Peto’s Paradox is false, that larger species have an increased prevalence of cancer, compared to smaller species. So it didn’t hold up. There are, again, a handful of species that are those outliers. So you talked about at the top this myth that elephants don’t get cancer. They do get cancer, but they are more resistant to it.

FLORA LICHTMAN: Well, what explains that? That’s kind of interesting.

SARAH AMEND: So the elephant has been the poster child for this for a long time, and it has been well published that they get less cancers you would expect for their size because they have many, many copies of a particular tumor suppressor gene, p53. So they have that higher protection level than other species do.

FLORA LICHTMAN: Do we know why they have that higher protection level? Like why do they have that tumor suppressor gene in higher levels?

SARAH AMEND: This starts to get into some of the things we try to probe in our study, and that others have tried to probe, in understanding how these outliers come to be. So one thing in particular that we looked at was the evolution of a particular trait. So in this case, we’re thinking a lot about body size, of course. But when we think about the evolution of a trait, it’s different species to species.

And so if we consider the relationship of cancer prevalence and body size, we can also look at the rate that that body size evolved. So how fast, how quickly did the species evolve to get to the size now? We find that the species that went through that rapid change in body size, so those that got much bigger or much smaller very quickly, have a decreased prevalence of cancer than a species of the same size.

FLORA LICHTMAN: Wait, wait, wait. So if you evolved quickly in terms of body size, big or small, you have less of a chance of getting cancer?

SARAH AMEND: Correct. That’s what our data say. And to bring it back around to the Asian elephant, that elephant had a very high rate of evolution for body size. They got big really fast. So in practical terms, that means that the Asian elephant has an expected cancer rate of a smaller animal, like the tiger.

FLORA LICHTMAN: Do we understand the mechanism, though, linking those things?

SARAH AMEND: So this is really where we can now move to understand the specific mechanisms of that cancer resistance. I think that’s something really exciting that we can learn from this data is looking at those outliers. So we highlighted the elephant. But other animals also don’t get very much cancer. For example, the naked mole rat has–

FLORA LICHTMAN: Love naked mole rats. Yeah.

SARAH AMEND: They have very low rates of cancer, and it’s through a number of different mechanisms. And something that I think is exciting as a cancer biologist is that they’re different mechanisms than the elephant. There are species that have much higher rates of cancer than would be expected for body size. But for example, the common budgie, the bird, it only weighs about an ounce, about 30 grams, and it has cancer rates about 40 times higher than would be expected for body size. We also know that chickens, for example, have high rates of cancer, and hedgehogs. On the other side of the coin, we know that dolphins, for example, have very low rates of cancer.

FLORA LICHTMAN: So you found big animals do get cancer more than smaller ones, with the exception of some of these outliers. But to be clear, when we talk about humans, does that mean, like, a tall person is more cancer prone than a short person?

SARAH AMEND: So that’s a great question. Our study is strictly at the species level. It’s not the individual level. So we compare between species, not within species. Humans in particular are difficult to understand in this setting because we have access to modern medicine. We have a longer life than perhaps we would expect of animals in zoos. But all that said, our models would predict that a human-size species would have a cancer prevalence similar to the size of a bat.

FLORA LICHTMAN: So you mentioned the elephants’ protection. What are some of the other adaptations that might protect against cancer?

SARAH AMEND: There are a few different mechanisms that would be protective against cancer. So I already mentioned an expansion of a tumor suppressor gene, p53. And that’s been shown in the elephant. There are other tumor suppressor roles, for example, in the naked mole rat, where they express both p16 and p27, which are also tumor suppressor genes. In other cases, there are reports of changing the tumor microenvironment, so what the cells are actually responding to in the body. For example, naked mole rats have extremely high molecular weight hyaluronan.

FLORA LICHTMAN: Hmm. How do you think these findings could be adapted to human health?

SARAH AMEND: So I think something that’s really excited about understanding both the species that get cancer, as you would expect with their body size, with each cell division, that tells us a lot about what cancer biology can look like in a patient. I think what’s also really exciting is that looking at these outliers, so those organisms that are getting cancer more or less frequently than you would expect, it gives us places to start so that we can understand human cancer better.

So for example, we can understand the role of p53, a tumor suppressor, in human cancer, the role of p16 or ribosomes that make error-free proteins better in the cancer setting in human patients with the disease. And that will mean that we can understand those mechanisms better, and so that then we can intervene better. So by studying the successful species, we can understand how cancers develop in patients and discover new ways to fight the disease. It gives us another place to start asking questions.

FLORA LICHTMAN: How has your paper been received? Are people up in arms and banging their desks about it?

SARAH AMEND: Yeah, I think that this is a really beautiful example of how science is supposed to work. This work would not have been possible by this data set that was generated by other scientists. And we know these scientists. We talk with them at meetings. We have calls with them. We ask each other questions about our work, both related to this and sort of more broadly. And so when this community of scientists can come together, it’s good to disagree.

And so the response to this has been, I think, overwhelmingly positive, not just because people are agreeing with us, though some people are, but some people are challenging. Some people are saying, is this actually paradigm shifting? Some people are saying, are you using the appropriate statistical models? What nobody is saying is that this is bad science. What’s exciting is that this is coming together, and we are pushing forward and asking new questions within the scientific community.

FLORA LICHTMAN: Thank you so much for taking the time to talk.

SARAH AMEND: Absolutely. Thanks for having me.

FLORA LICHTMAN: Dr. Sarah Amend, associate professor of urology and oncology at Johns Hopkins University Medical School in Maryland.

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