Damn You Darwin! Pt 2. Resist & survive!

And now it’s time for the (very belated!) sequel to my last post. Evolution & cancer: part deux.

Back in Nae Trainers, I described one of the processes which can cause tumours to become resistant to therapy, namely the activation of Multidrug Resistance pathways.  These mechanisms, which tumour cells use to detect the effects of treatment, are switched on by cells as a consequence of drug treatment. The cancer cells use them to actively fight back to try and survive, so you can think of them as a type of “Direct Resistance”.

But that is not the only way that Therapy Resistance can emerge.  There are other processes which could be described as “Indirect Resistance”.  These processes do not involve active changes to tumour cell behaviour.  Instead, the cells don’t respond at all, but react passively to the treatment.  In this case, whether a tumour cell, or a population of tumour cells survive is down to chance.

…And this is where Darwin comes in! In my last post, I gave a simplified explanation of Darwinian Evolution.  So now, I’m going to explain how Darwin’s theory can be used to describe the emergence of this passive form of Therapy Resistance (so, if you haven’t already done so, I encourage you to go and read that previous post first before continuing, as it’ll make the following explanation clearer).

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That you up to speed now?  Excellent!  Off we go!

So, previously, in my example of the cats & mice, I explained how different Selective Pressures would affect both species and drive the evolution of different traits in each (camouflage in the mice, eyesight in the cats).  Now, an important thing to remember is that it is not every member of each population which changes.  Not every individual is the same.  The population is varied and the individuals most likely to survive and reproduce are the ones which have the trait being selected.  Therefore their offspring are more likely to have that trait, therefore it becomes more common. And so, for the example of the cats & mice, the Selective Pressures can be summarised as Cats: finding food; and Mice: escaping threats.

Now, here’s the thing.  You can say exactly  the same thing about a tumour.  as I’ve said before (see One Of The Crowd), a tumour is not a single, individual “thing”, it is made up of lots and lots of individual cells.  A POPULATION of cells.  And like the populations of cats & mice from the last post, the cells that make up the tumour are not all the same.  There is VARIATION within the tumour cell population.  So, a tumour is less like Figure A and more like Figure B.

Damn you darwin 2.1

And, again, just like the cats & mice, the different varieties of cells won’t necessarily respond in the same way to the same Selective Pressure.

…..But what type of Selective Pressure could affect tumour cells??   Well, for tumour cells, the Selective Pressures are actually exactly the same as for the cats and mice: finding food and escaping threats!  Which, for a cancer cell, means getting access to the bloodstream for nutrients and oxygen, and surviving therapy.

Cancer therapies work by killing tumour cells.  They may do this by targeting specific molecules that are vital for the cells (and as before, we’ll call these vital molecules “Bills” – see Kill “Bill”).  Or they may damage DNA.  But the point is, the treatment damages the tumour cell.  And, hopefully, damages it enough to kill it.

But! Because there is variation within the tumour cell population, this means that there might be a small number of them that, just by chance, are better able to cope with the therapy-induced damage and are more likely to survive.  And this is what you see in Figures C & D.  In Figure C, a cancer treatment (the red dots) is killing the cancer cells.   But a small number –  the purple coloured cells – are resistant and therefore survive (Figure D).  Therefore, they will begin to grow and divide, meaning the tumour grows back: Relapse!

Damn you darwin 2.2

And, since the newly formed cells are derived from cells which were resistant to the original treatment, the new tumour cells are more likely to be resistant too!  Therefore, the likelihood of that treatment working again is very, very low (Figure E).

Damn you darwin 2.3

And so, an alternative treatment needs to be used instead.  But! Again, because there is ALSO variation within the cell population Of the newly grown, relapsed tumour (as in Figure E), the second treatment, just like the first one, might ALSO be unable to kill all of the cells (Figures F & G – the pink cells are resistant). And, again, as the small population of pink cells in the tumour is better able to survive the second treatment, then the tumour will regrow AGAIN!

Damn you darwin 2.4

And this is how tumour growth and development is shaped by Darwinian evolution.  In an animal population, the individual are competing for resources in order to survive and reproduce.  And those individuals who have a selective advantage (eg. being harder to see in the case of the mice, having slightly better eyesight in the case of the cats), are more likely to survive and reproduce.

And individual tumour cells within a tumour population behave in EXACTLY the same way.  The individual tumour cells are competing for resources (oxygen & nutrients in the blood supply). And again, those individual cells that have a selective advantage (more resistant to therapy)  are more likely to survive.

Now, there are several things that can cause the variation which makes a tumour cell more resistant.

If the treatment damages the tumour cell’s DNA, then whether it can survive the treatment depends on how efficiently it can repair the DNA damage.  Within a cell population, there will be variability in how active repair mechanisms are, so any cell that has higher activation of DNA repair processes will be better able to  fix the damage and, therefore, survive….and when it grows and divides in two, both of these newly formed cells will have highly active DNA repair. Then two become four…become eight…..become sixteen….

Or, if the treatment targets a specific “Bill”, then there might be variation in how reliant the cells are to the “Bill”.  If the tumour cell depends on it completely for survival, then the “Bill”-targeting treatment is more likely to work.  But some cells may not be totally dependent on the “Bill”.  They might have another “Bill” they can use instead – a “Bob” if you will, so the drug that targets the “Bill” won’t affect the cells which can use the “Bob”. And then each “Bob”-using cell becomes two…then four…then eight…..then sixteen….

And so, you end up with a small number of cells surviving. And their descendant cells will also be able to survive subsequent treatments.  And so, a more resistant tumour will evolve….Just as new cat & mouse species evolved in the last post!  Through evolution!

So, if anyone ever asks you why tumour relapses happen, you’ll know who to blame.  Charles bloody Darwin!

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Greaves, M., & Maley, C. (2012). Clonal evolution in cancer Nature, 481 (7381), 306-313 DOI: 10.1038/nature10762