Monday, January 01, 2007

Merlo et al: Cancer as an evolutionary and ecological process.

L. Merlo, J. Pepper, B. Reid and C. Maley. Cancer as an evolutionary and ecological process. Nature reviews cancer, Vol 6, pp 924-935, December 2006.

New year and (maybe not so) old traditions: the review of a paper. Nature reviews cancer is one of the world's top scientific journal in terms of impact factor for a reason: they publish very interesting and comprehensive reviews in a field of such importance and as crowded as cancer research. Review papers are comparatively more likely to be cited than the ones about one group's research, review papers in cancer research are normally highly cited since there are so many researchers working in the field. Review papers in a prestigious journal like Nature reviews cancer are thus bound to be cited once and once again and one would expect that only very good scientists would be invited to write for them (I believe that is only by invitation that you get to publish in these journals).

This review covers a topic that is very close to my interests: cancer from an evolutionary and ecological point of view. This view sees a neoplasm, a tumour, as a population of cells with a diversity of inheritable features. This means that evolution will happen and the fitter phenotypes will tend to be more abundant in the tumour population. Questions that might arise are how to alter the mutation rates, clone expansion and how does this expansion happen. Furthermore, given that in many cancers we can find mutations in vast areas of DNA, how do these cells retain enough genetic material to even function? The authors put forward the idea that this could be because most of the human genome is devoted to the development and homeostasis of a multicellular body and thus has no effect on the survival of the single cell in a tumour.

Having a diverse range of individuals whose uniqueness is inheritable is only one of the requirements of evolution. The other one is selection. In a tumour we have two sources of selection. Natural selection is the one that takes place in any tumour when there is scarcity of resources (oxygen, glucose, space). Under these circumstances some phenotypes are bound to be better at surviving and dividing than others. Additionally there is artificial selection which is the result of a therapy applied to a patient with a tumour. Artificial selection changes the fitness landscape, hopefully in such a way as to make survival impossible to every tumour cell. Unfortunately that is somewhat difficult so in many situations is worth altering the fitness landscape in ways that promote the survival of the least aggressive (that is, less likely to be able to invade and metastasise) tumour cells. In any case, altering the fitness landscape in favour of the patient is significantly easier when the tumour did not have much time to evolve.

Evolution in a tumour is not entirely the same as the one in organismal populations. That is to be expected given that tumour evolution lacks something of great importance: time. That is why during chemotherapy, surviving tumour cells are not the ones that develop mechanisms to resist but the ones that due to other reasons (genetic drift for example) already had the capability to resist before the therapy was used. Other differences include the reliance on stem cells for population diversity or that reproduction is asexual (which, incidentally, makes mathematical treatment much easier).

If a tumour resembles an ecosystem we should expect things such as cooperation, competition or parasitism. It seems that you get some of that. Like in an ecosystem individuals compete for the available resources (there is some speculation about that in the paper from Tomlinson reviewed the 10th of October of last year). There are predators if we understand as predation the behaviour of the cells from the immune system when they meet tumour cells. There should be parasitism, mutualism and commensalism (although the authors provide no evidence for that).

I found this a very nice and readable paper. I think it will make a good introduction to any cancer researcher that wants to study the evolutionary aspects of it. My only criticism of a paper that claims to deal with cancer as an evolutionary and ecological process is that the ecological part is significantly weaker than the evolutionary one.

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