Spending so much time on planes and airports (as I am doing lately) means that I have more time to read books, some of which were in my reading list for way too long. The book I am reading now is Dawkins’s The Extended Phenotype. I am a big fan of Dawkins so there’s no easy explanation for why it took me so long to start reading the book that Dawkins himself consider’s his most important.
In one of the earlier chapters (chapter 3), Dawkins mentions some constraints that put limits to commonly held view that evolution optimises the phenotypes of individuals in a species. These are:
1. Time lags: your usual living being has a genetic material that makes him very well adapted to an environment that, in many cases, has changed. Given enough time there are good chances that the species will evolve to adapt to the current situation but by then there might be new changes to adapt to. An example from the book: the hedgehog strategy of rolling up into a ball to escape predators doesn’t work too well when crossing a motorway. The fact that cancer phenotypes represent an adaptation to an environment that might have changed significantly means that tumour cells are more vulnerable when there is sudden change but using this fact therapeutically is dangerous as this will select for those cancer cells more able to cope with change, making tumours more difficult to treat in the long term.
2. Historical constraints: What you do today will limit and bias what you will do in the future. Same goes in evolution. Flatfish share a lot of their developmental programme with other fish but given their lifestyle (laying flat on the surface of the ocean) they are better off having both eyes on the same side of their head. Evolution has to work around the fact that both eyes are developed in different sides of the head by adding an extra step in which one of the eyes slowly shifts in the direction of the other. With the right knowledge of how a cell genotype maps into a phenotype, we could select for phenotypes that require genetic or molecular mutations that would make difficult or impossible to acquire, later on, more aggressive features. Although initially these phenotypes would be more fit than other tumour cells, in the long term their genotypes would make them evolutionary dead ends.
3. Available genetic variation: That one is pretty straightforward, evolution requires that individuals are different in a manner that can be passed on from parents to offspring. A population with little genetic diversity will always take longer to adapt (sometimes for all practical purposes will never succesfully adapt) to changes in the environment. We know that very selective microenvironments (those that exact a high toll on phenotypes that are not well adapted) will reduce the phenotypic (and hopefully the genotypic) diversity of the tumour. This could slow down the pace of tumour evolution but the selection should be such that does not select for more malignant phenotypes.
4. Costs: Even if time was not a constraint, some adaptations are more costly than others. An individual that devotes its time and resources doing something might not have enough to do something else even if that turned out to be beneficial. Like in engineering, evolution has to deal with costs and tradeoffs in which perfection is the enemy of good. We know that some adaptations are more costly than others. Gatenby and colleagues idea of double bind therapies, by which a treatment selects for phenotypes that have to pay a high fitness cost to survive, could be considered a tool based on the cost of adaptation evolutionary constraint.
5. Mistakes due to environmental unpredictability or malevolence: The environment of any given individual is extremely complex and dynamic. It would be rather difficult (and costly!) for evolution to produce individuals capable of coping optimally with every conceivable situation. What evolution does then is to evolve individuals that are good at coping with most situations, especially if they happen often enough and the consequence of mismanaging them would be too high. Providing a tumour with a stable microenvironment will select for phenotypes that could overadapt to this environment (and select against more generalistic tumour phenotypes as this generality comes at a fitness cost and provides little advantage in a stable environment). Such tumour would then be more sensitive to small (and big) alterations to the microenvironment.
While Dawkins places all these constraints in terms of classical ecological species (ants, wasps, fish…) there’s no reason to believe that this same constraints apply to the evolution in tissues where cancer has been initiated. Here I just put a few examples off the top of my head (very likely not very good ones) of ways in which these constraints could be exploited therapeutically but the point is that evolution, which makes cancer such a difficult disease, can also be used to fight it. Knowledge of these constraints could be a powerful tool to hinder tumour progression towards malignancy if we could have some degree of control over the selection pressure.
Great post David. The intersection of evolution and tumour biology is so interesting.
I’ve heard an evolution/ecology inspired idea batted about that we shouldn’t be trying to make tumour cells’ environments so harsh for them, as it encourages adaptation and migration. Instead we should keep ‘em happy (and doing as little damage as possible) in their original environment, so they don’t “need” to spread. It’s an interesting idea, but it’s hard to see how it could be translated into clinical practice. I don’t think I’d sign up to that clinical trial…
Thanks Cath, you are right that making the tumour microenvironment less harsh is far from being uncontroversial. The idea though of controlling it to select for the less aggressive phenotypes is slowly emerging (even here at Moffitt, see this article). Your point is quite timely as recent research suggests that keeping a tumour well fed and happy could be useful therapeutically (see article).
Yeah, I’ve been reading some of the articles on that topic. Turning cancer into a chronic condition that people can live with for long periods of time sounds, on the surface, like a viable proposition. But not only are we going to have to turn current treatment paradigms on their heads, we’re going to have to change patients’ and doctors’ psychology… even if it’s proven to work, ditching the “must kill every last tumour cell” thinking would be a massive hurdle to overcome!
Interesting post! There are also some reports that removing the primary tumor will increase metastasis growth. This may have several reasons, such as release of more tumor cells during surgery, of that the patient’s immune system is suppressed after surgery, but I have also heard the idea that the primary tumor is somehow suppressing the metastasis (although I can’t find the reference right now, I’m sorry about that). This might be in line with the notion to be “nicer” to the primary tumor. But I agree with Cath, it would be difficult to enroll people in that clinical study – “we are going to do everything we can to make your tumor happy”…
Hi Cath and Anna, thanks for your comments. I agree that a therapy of containment would be a hard sell but I am not sure anybody is suggesting anything like that just yet: a few unwilling mice will have to experience that first. An entirely different matter though is whether the public should be educated about ‘a cure for cancer’ looking increasingly similar to a quest for ‘El Dorado’…which is not to say that there’s no gold out here if you look for it.
Anna, about the primary and secondary metastases. This is certainly an intriguing concept but I can’t see what mechanisms could be used for the primary to control secondaries and what would be the evolutionary advantage for tumour cells to acquire the capability to respond to remote signals from a distant site.
Very informative, David.
… but I can’t see … what would be the evolutionary advantage for tumour cells to acquire the capability to respond to remote signals from a distant site.
If cells can respond in such a fashion during normal development – eg, migration from the neural crest; and migration of primordial germ cells via the gut mesentery to the gonadal ridge (there’s certainly evidence for an attractive mechanism here) – then wouldn’t it be likely that tumour cells could readily exploit this to their advantage? This is not my bag, but is metastasis solely an outcome of primary tumour cells entering the circulation, with secondaries tending to(?) arise in sites characteristic to the particular cancer, because those are the sites where they first get caught in the cellular mesh? Or is there something else going on, such as an endocrine-type response?
…with secondaries tending to(?) arise in sites characteristic to the particular cancer, because those are the sites where they first get caught in the cellular mesh?…
I am not an expert on this either, but as I understand it there is a “seed and soil” principle where cells from the primary tumor are being shed in rather large numbers and end up a bit all over, but can only start to grow at certain sites where they fit with the micro-environment – where the right sort of growth factors can be found, and so on. There is an introduction to the theory in a nature milestones cancer paper. Still, this doesn’t explain why or how the primary tumor would prevent the metastasis from growing, if indeed it does. Speculating completely wildly, inspired by the topic of evolution, one could imagine that it would be bad for the “life” of the primary tumor if the patient died from metastasis, so for that reason it would be better for the primary tumor to keep metastasis from growing. But as to how that would happen, I have no idea.
Hormones? Cytokines? Immunoregulation?
All just completely unfounded ideas ;)
I’ve seen studies that try to characterise which primary breast tumours will metastasise to which sites. There are some correlations between biomarkers present in the primary tumour and site of metastasis, but no hard-and-fast rules have emerged yet.