Hallmarks of cancer cell development

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Published: 27 Apr 2017
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Dr Douglas Hanahan - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland

Dr Hanahan speaks with ecancer at the 1st Cancer Research @ Bath Symposium about the hallmarks of cancer cell development, combination therapies, and the priorities of cancer prevention and disease management.

Dr Hanahan expounds the social factors behind disease prevention and management, including tobacco and exercise, and how that compares to chemoprevention with repurposed aspirin.

In the case of melanoma, he considers the utility of immunotherapy as a new treatment of disease alongside effective sun-care practices to block UV damage, and weighs the predictive value of heritable disease predisposition genes.

I was asked to present an organising principle hypothesis that Robert Weinberg of MIT and I conceived of seventeen years ago to try to rationalise the complexity of cancer which is, in many ways, overwhelming in its dimensionality and diversity. We proposed a simple concept that most tumours acquire a similar set of capabilities but they do so through differing strategies. Therefore, underlying all this complexity is really an outlaw machine, as it were, and for the machine to operate it needs to have certain capabilities and that, one way or another, cancers are acquiring these capabilities. So I was presenting this broad concept for thinking about cancer because we tend in our discussions to focus in and drill in deep on particular precise aspects of the cancer problem that one or another lab is studying and you don’t often step back and look at the big picture. So I was asked to present a big picture view of cancer and how we might think about it.
I certainly brought up the notion that we are in this era of targeted therapies for which there was great anticipation that by understanding mechanisms and targeting mechanisms that we would really be able to hit cancer harder and have more enduring responses. The reality check, however, is that cancer is really a disease of Darwinian evolution, that because cancer cells acquire during their ontogeny instability in their genomes they are able to rearrange their genomes in a population and variants that arise that are able to circumvent a particular targeted therapy will then grow out. So I presented this reality that if you target individual hallmarks invariably that’s not enough because of this Darwinian flexibility of cancers to evolve and adapt to whatever you throw at them. So I presented the hypothesis, looking forward, that what we’re facing is a future of a modern warfare where you don’t just march at the enemy across the field, you go by air, by land and by sea in complex combinatorial attacks. The future, as I see it, is going to involve multi-targeting differing hallmarks with the notion that then you’re going to be able to significantly slow down the ability of tumours to adapt and develop adaptive resistance.
How do you feel quality of life is best managed?
Absolutely, so that is another concept which is increasingly discussed and that is that we don’t necessarily eradicate cancer, if we have to eradicate it completely if we can keep it in check, so so-called cancer without disease. That’s also a reasonable goal, that we’re going to die of something sooner or later so if you can render a cancer indolent, even if you can’t eradicate it, that’s a reasonable goal.
How does this compare to prevention?
It is important, there are different kinds of prevention. One is prevention altogether; another is really prevention, again this is back to cancer without disease, of detecting incipient cancers and preventing their progression to malignant disease. That may be, as we develop more precise methods for early detection, that may be a really desirable goal. Because it has been argued recently, for example, that a significant fraction of cancers arise simply by so-called bad luck, that just in the course of maintaining the integrity of the genome mutations are created with some frequency and if you look in tumours you can find signatures just of these. These are not caused by environment or whatever, they just relate to the maintenance of the genome and the fact that stem cells proliferate slowly in the body and every time they proliferate they have the potential to develop a mutation. So it’s been argued that a significant fraction of cancer relates to this inborn error-prone maintenance of the genome and that’s probably nothing that can be changed.
However, there is prevention but there, of course, it’s fine to talk about aspirin and getting more exercise but the elephant in the room is smoking, that lung cancer is the top, the most lethal, cancer and the health burden from smoking, lung cancer, emphysema is just staggering. But the world’s society cannot deal with that reality of this addictive drug that’s a multi-trillion dollar industry and so we talk about prevention of cancers that are less pronounced just because no-one wants to face that. Which is not to say that… I agree completely, though, exercise is terrific and obesity is another issue that’s really helping to fuel cancers. Then when you do get an incipient cancer if you’re obese it’s much more likely to progress more aggressively. So obesity is a problem, that is something that we really need to work on because clearly that affects all other kinds of quality of life as well. So there are aspects of prevention which we should be addressing but this is really socio-economic, more so than identifying… There are going to be the aspirins but I think the big benefits in terms of prevention are socio-economic. So that’s where the big gains are going to be made.
Another good example of that is melanoma skin cancer which is one of the cancers that I discussed yesterday because metastatic melanoma has been a death sentence and targeted therapies don’t work very long but now immunotherapies that are harnessing the immune system really work in some patients but they don’t work in all patients. However, melanoma is, to some degree, preventable; melanoma is initiated in a large part by mutations caused by UV radiation from the sun. There are recent statistics that the incidence of melanoma is going up throughout the Western world because everyone loves to go to the beach, except in Israel which is a very hot and sunny country, and the explanation for that is that they have a really ambitious and effective educational campaign to persuade people to use sun block. So this is another example of societal approaches to prevention. I get asked a lot about prevention and it just seems to me that our biggest opportunities for prevention are in these domains rather than finding a pill that you can take every day. I take low dose aspirin, maybe it will help but I think there are some cancers for which we could really make major headway if we had the courage and social resolve to do so.
How about preventative surgery based off genetic risk factors?
It’s definitely true that if you have one of these mutations that that really heavily dispose you to breast cancer and ovarian cancer then there’s a clear path of action. But it’s not clear that that should be extrapolated in general to women with breast cancer because if you don’t have one of these inherited mutations then the likelihood even of your tumour progressing is uncertain. So that’s an area where we need to learn more about ways to diagnose tumours and predict how aggressive they’re likely to become. That’s another area of future opportunity.
Do you not feel that it fuels patient awareness of screening possibilities?
Yes, I think so but we also have a better understanding again that at least with some of these it’s back to the issue of the fidelity of early detection. Because for women that don’t have BRCA mutations there have been a lot of mastectomies done probably from small breast tumours that were never going to progress. This is the same problem with the PSA test for prostate cancer, that now large studies have suggested that elevated PSA levels do not necessarily predict that your cancer is going to progress. So people are getting over-treated because of an early detection method, mastectomy or PSA levels, which is imprecise. So the other big opportunity for the future is that we need more precise methods for early detection because these are two examples of early detection where you can then say, ‘OK, there’s an incipient neoplasia and we can do something.’ But the question is is that incipient neoplasia going to progress to be an aggressive lethal cancer or is it not? So do we have to treat it super-aggressively or can we treat it more lightly with less toxicity? So this is where we need better knowledge about the factors that will destine a tumour to become highly aggressive or not.
Do you have a summary message?
We are in an exciting time but we’ve got a long way to go. So we definitely need physician scientists who are really thinking about the tumours that they are treating. We’re also in an era where there’s increasing ability to convince patients to undergo biopsies, despite the fact that they can be somewhat irritating, because the other thing is we’re learning a tremendous amount by analysing patients’ tumours before treatment, when they’re responding and when they’re failing. This has really been a huge change in the last twenty years from a time when physicians said, ‘Well, we really can’t ask our patients to accept the risks of biopsies because there is a risk.’ Whereas now there really is more of a willingness to engage the patient and say, ‘Look, you can help yourself and others because otherwise we can’t tell what’s going on.’ So this dialogue between physicians and researchers and patients is a really important opportunity for the future.