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Lives without cancer


In his first post for The Bigger Picture, Professor Mel Greaves offers insights into the evolution of cancer defence mechanisms in large animals – and what these might mean for human cancers.

Posted on 01 June, 2015 by Professor Mel Greaves

The idea that cancer clones evolve by a process essentially the same as natural selection of variants or species in ecosystems is now part and parcel of cancer biology. And one way to look at why cancer is such a big problem is to see it as reflecting the intrinsic risk, or trade-off, that comes from the mutability of DNA, required for evolutionary adaptation, in proliferating stem cells, required for tissue resilience and longevity (see, Greaves M. Cancer. The Evolutionary Legacy. Oxford University Press: Oxford, 2000). 

But you would also expect that evolution, by natural selection, would provide effective restraints on cancer, or to diminish intrinsic risk. It’s sometimes argued that as cancer is largely a post-reproductive disease, natural selection will be ineffective, as Peter Medawar and JBS Haldane both argued with respect to ageing in humans. But this is perhaps the wrong way to look at it.

The success or integrity of multi-cellularity as a lifestyle, ‘invented’ some 600 million years ago, would have been contingent upon the selfish replication of individual cells being restrained (also see, Buss LW. The evolution of individuality. Princeton University Press: Princeton, New Jersey, 1987). In this respect, it is interesting that most so-called cancer suppressor genes appeared on the scene around the same time as multi-cellularity itself. DNA repair genes, as you might expect, arose 2–3 billion years earlier with bacteria.

Tissue-specific cancer incidence rates very broadly track with the proliferative activity of stem cells in those tissues, reflecting the pool of cells most at risk. This suggests that cancer suppressor mechanisms might have had to be elaborated, over time, as animals become more complex, big or longer lived, or as risk escalated.

And this does appear to have happened. A striking feature of certain long-lived or large animals is not just that they don’t have increased cancer rates but, it would appear, very little cancer at all. The best examples of this are with subterranean rodents – naked mole rats and blind rats which, exceptionally for small rodents, live for 30 or more years. And large whales.

Peto's Paradox 

The fact that large whales such as the bowhead can live for more than 200 years, apparently without cancer, is commonly referred to as ‘Peto’s Paradox’ – following Richard Peto’s observation that you would expect such gargantuan species with more than 1,000 times as many cells as humans to have a very big problem with cancer.

When I first came across this dilemma, I had a somewhat cynical response, which was: first, how do you know they don’t get cancer? And second, how come Peto doesn’t see that whales don’t smoke: that’s a paradox? I’ll come to risk of cancer in humans and ‘lifestyle’ exposures in a moment but for mole rats and large cetaceans, the paradox is probably real. The blind mole rat, at least, seems to be resistant to both spontaneous and experimentally-induced cancer. If evolution has indeed equipped some species to frustrate cancer, then this is clearly of great interest and potentially something we could exploit.

A resolution may be at hand from recent comparative genomics. And it looks like the answer could well be that different species have acquired distinctive protective mechanisms. Compared with the minke whale that has a relatively modest lifespan, the bowfin (which diverged from the minke some 25–30 million years ago) has unique variants in the gene ERCC1 involved in DNA repair and in HDAC1 and 2, which regulate chromatin structure and gene expression.

Naked mole rats produce a high molecular mass hyaluronan which appears to facilitate contact inhibition of cancer cells. Hyaluronan is also a potent anti-oxidant. Genomics of the naked mole rats also suggests they have unique hybrid variants of the cell cycle suppressor 15/p16 12. Rather extraordinarily, the blind mole rats also have constitutive substitutions in Arg174 of p53 that mimic mutations found in human cancer. The authors speculate, plausibly, that this is an adaptation to the hypoxic stress of living underground.

This is, however, a paradox in itself as a loss of function p53 variant should, if anything, place mole rats more rather than less at risk of cancer. The authors suggest that adaptation to subterranean life, via p53 mutation, will have required the co-evolution of much more effective anti-cancer mechanisms, including changes to inflammatory responses.

These comparative genomic screens are only just beginning and require more in-depth analysis, functional validation and extension to other long-lived species such as other cetaceans and elephants. But they do indeed suggest that evolution has done some long-lived animals a favour with respect to cancer.

Have humans missed out? 

So, the next question should be: humans are relatively long-lived as mammals and great apes; how come we appear to have missed out?

Well, maybe not entirely. I’ve argued that the acquisition of black skin (via variants in the melanocortin receptor MC1R) early on in our evolution may have been an adaptation to a high rate of UVB-induced skin cancer at young ages in equatorial Africa 1–2 million years ago.

Subterranean rats and long-lived whales reproduce for most of their long lives, so natural selection has an opportunity to act, restraining the increased risk derived from inherent evolutionary design coupled to longevity, and has had several millions years to do so.

And humans? We are unusual and perhaps unique. We can and do live for decades after we have ceased reproduction. Menopause is a uniquely human attribute and old men with andropausal decline are only likely to reproduce if they are rich and powerful. Or just lucky. Moreover, it's only relatively recently that long lives has been the norm. So there has been no real opportunity for adaptive evolution or natural selection to work to counter the increased risk from longer life.

Combine that salutary fact with the observation that uniquely, we have rapidly evolved, socially, exotic lifestyles that greatly ratchet up cancer risk via mismatch with our ‘Stone Age’ genetics; for example with respect to skin pigmentation and female reproductive traits. It’s perhaps then not so surprising that we have a problem. As a sapient species, we’ve evolved socially too fast and live too long, post-reproductively, for nature to cope by the usual mechanism.

And, as a striking parallel, or proof of principle, when we artificially and rapidly manipulate the lifestyle and bodies of domesticated animals, as with perpetual egg-laying chickens and large heavy dogs, the same thing happens – cancer rates shoot up – in tissues where you would expect it to: in ovaries and long bones respectively. Darwin would have surely spotted that evolutionary clue.

Finally, there may be some special but very informative exceptions to the rule in humans. Exceptional longevity appears to run in families and probably has a constitutive, genetic basis. Cancer rates actually decline substantially after 80 years of age (bet you didn’t know that), despite some well entrenched and risky habits.

Good luck, or good genes?

To note:  Dr João Pedro de Magalhães, a leading light in the field of ageing, cancer and genomics in relation to Peto’s Paradox will be visiting the ICR and giving a lecture on 23 June 2015. Let me know if you wish to meet him. His lecture will be part of a half-day discussion meeting on Peto’s Paradox and will include a talk by Carlo Maley

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