The Ageing Soma, Cancer Evolution & Prevention

James DeGregori is a Professor of Biochemistry and Molecular Genetics at the University of Colorado. His lab seeks to understand how carcinogenic conditions promote cancer evolution and to discover pathway dependencies in cancers that can be exploited therapeutically. This interview is based around a recent commentary in Cancer Cell, which you can read here.

Can you explain the concept of ageing soma?

It’s really an evolutionary thing. In the wild, aged animals are a rarity- in a lab, mice live anywhere from 2-3 years, and in the wild, they’ll be lucky to live 2-3 months. From an evolutionary perspective, maintaining healthy soma in a mouse past 2 years would be a complete waste, because that would be energy that’s invested in the long game that would be better invested in the short game. That’s how we need to understand why we decline in old age. The difference between a mouse and a human is that humans have taken the long game, over evolutionary time we’ve produced mechanisms to avoid extrinsic hazards, meaning we live longer so that investment pays off. Mice will get cancer and many other maladies in their second year, whereas humans will be more likely to develop such maladies in the second half of a century.

What drove you to write this article?

Charlie Swanton reached out to me after meeting at a conference in New York. He saw my talk, and I had been discussing how the ageing soma provides fertile soil for the growth of malignancies. When the results of the NELSON lung cancer screening trial came out he wondered if it could be influencing the fact they didn’t see a significant drop in all-cause mortality. He thought with such an improvement in the early detection of cancer, that it would translate into more lives saved. Furthermore, he thought this made a connection with my lab’s theory. Charlie brought Peter Sasieni and Paul Pharoah on board because they have expertise in the screening, epidemiological and statistical approaches that I lack. It made for a much more balanced piece in the end.

Has it turned out differently from what you had in mind when you wrote the first draft?

Charlie and I lacked the cancer screening background, so the first draft was much more negative towards screening. We weren’t going to argue against screening, but we knew we were giving the impression that screening was less useful than previously thought. But as we learned from Peter and Paul, we realised that isn’t the case, that there’s great value in screening and we can use this understanding of the ageing and damaged soma to make things better and understand why reductions in all-cause mortality can be difficult. We want people to think that if someone comes in for a lung screening, has a positive nodule which turns out to be an adenocarcinoma, you can’t just remove that and pat yourself on the back- you need to realise they’re at higher risk of other maladies. You need to take a more holistic approach, and screen them for heart disease, or put them on a regiment that will try to improve their overall body fitness. Our goal is not only to explain the connections but to show that there is something we can do about it.

Forty-five years ago, Sir Richard Peto wrote a paper entitled “Cancer and ageing in mice and men”  that led to the so-called Peto’s Paradox. Do you think that recent advances in cancer evolution mean that Peto’s view on ageing is wrong?

Sir Richard Peto raised a great quandary. The solution to ‘Peto’s paradox’ hasn’t been wrong, but it’s off the mark. People haven’t appreciated that part of the way that an animal, whether a blue whale or a mouse, avoids cancer is the same way that it avoids heart disease, or kidney disease or other diseases of ageing. It’s by maintaining the soma, or tissue. If you maintain the soma, you don’t just avoid the loss of integrity of tissue functionally, but you also keep at bay malignancy, which thrives in a degraded environment. Everyone is focused on the role of mutations in Peto’s paradox, given that a blue whale which requires 10 million more cell divisions than a mouse can avoid cancer- because it has the potential to make 10 million more mistakes (mutations in DNA). People argue that it makes fewer mistakes- but there’s no good evidence for that. What we would argue is that the mutations happen, but cancer is avoided by maintaining structure, to make cancer not favourable.

What is your view of the relevance of the ageing soma to cancer screening and early detection?

The ageing soma is what can favour cancer occurrence. If we had markers for an ageing soma, we would know who to watch more carefully and tell us who is more at risk not just from cancer, but from everything. People who have an increased risk of cancer also have an increased risk of heart disease and other maladies. They’re all a manifestation of the same decline. You could think about it in the way that if a county is undergoing a decline, it’s going to be subject to multiple maladies, such as terrorism & crime because you’ve created an environment that’s not conducive to what we would consider ‘healthy’. If we think about the ageing soma- and lifestyle factors, such as smoking, also caused prematurely degraded soma- it’s ageing, plus our experiences of health combined.

Is this related to cancer evolution?

What we know from evolutionary biology is that environmental change drives selection for new types which are adapted to their new environment. What we’ve argued is that the same thing happens to our bodies. In our youth, we’re essentially maintaining our tissue in their ‘right’ state. When our tissue changes as we age, cells can be selected which have adapted to this new environment, and the likelihood that such cells can be malignant is higher- and the same thing happens in the lungs of a smoker, where you have a massive change in environmental conditions.

What do you think the implications of ageing soma are for cancer prevention and screening?

For cancer prevention, we need to recognise that it’s not just about mutations. If we can figure out how to better maintain tissue structure, we could limit malignancy- and we already know how to do this to an extent – don’t smoke, have a healthy diet and exercise. So, a good intervention would be to come up with ways to better preserve our tissue. What we look for right now is often the cancer-causing genetic events. If we could detect an altered tissue environment, we would know that while we can’t currently detect cancer, one is likely there and starting to thrive as the tissue environments change. We need to recognise that the tissue environment is the stimulus for malignant evolution.

What studies of tissue and liquid biopsies would you want to do in patients with screen-detected cancers and pre-cancers to further our understanding of the role of the soma?

We need to develop markers to show a healthy and unhealthy soma that could be detected in the blood. Right now, we don’t immediately know the answer. If you could then combine that with the detection of mutations, I think you could then come up with an overall test that would better measure risk. We’re not there yet because we don’t know what those factors are- but I think cytokine inflammations will be key.

Any other comments?

It was such a great experience working with Charlie, Peter and Paul. When you write something, you don’t normally learn as much as I learned from this experience. I feel like I’m a better cancer biologist after having worked with those guys than I was before.

Additional Reading:

Why Blue Whales Don’t Get Cancer – Peto’s Paradox

Darwin’s Ideas on Evolution Drive a Radical New Approach to Cancer Drug Use

The evolution of lifespan and age-dependent cancer risk

Pan-Cancer Early Detection: Hype or Hope?

Cancer Screening

Early Cancer Detection Should Stimulate Further Medical Testing- University of Colorado

The views expressed are those of the author. Posting of the blog does not signify that the Cancer Prevention Group endorse those views or opinions.

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