Science

Evolution in cancer: Yes! Darwin: No?


Series on Tumor Evolution

ResearchBlogging.org
Evolution is a fancy word for gradual change. In this general sense, all kinds of things evolve. The universe evolves, societies evolve, finches evolve.

The mechanisms and principles of these three evolutions are all different. For example, the finches change by Darwinian evolution, which is one particular type of evolution based on natural selection: There is diversity in traits between individuals in a population; because of their traits some individuals have more offspring than others; the traits are heritable and can be passed on to offspring. Over time the favorable traits will become dominant in the population – and with them the genotypes underlying them.

This is how it works for finches. How about cancer? Is that developing by Darwinian evolution too? Not so fast, say Sidow and Spies:

The forced application of terms and concepts from organismal population genetics can distract from the fundamental simplicity of cancer evolution,

write Sidow and Spies in their review ‘Concepts in solid tumor evolution‘ (TiG 2015) and they plan to set the record straight.

What a feisty little paper! Just look at the first paragraph, which already drips with irony:

Everybody knows what evolution is. Right? One hundred and fifty-six years after the first modern treatment of evolution, and 53 years after discovery of ‘the’ molecular clock, most biologists have an intuitive feel for evolution. [M]entioning it in scientific papers is de rigueur even if the study has nothing to do with evolution. After all, (i) every single biological process is the product of evolution and, therefore, (ii) nothing in biology makes sense except in the light of evolution.

It looks like the authors have been frustrated by one unmotivated Dobzhansky quote too many. As a response, they have chosen a two-part approach:

  1. In the first part of their paper they argue that population genetics of tumor cells needs to be different from population genetics of humans.
  2. In the second part they develop their own two-parameter model of tumor development. As the authors acknowledge, it is a variation of the models that come out of Martin Nowak’s group and I found this part less novel and less thought-provoking.

Why cancers are special

So let’s hear more about the first bit. I found it a very engaging read, because Sidow and Spies list a good number of differences between cancer evolution and organismal evolution. For example this striking (and well known) one:

Cancer repeats, the tree of life does not. [L]ife on earth is the realization of a single experiment that will never repeat. By contrast, each type of human cancer is an experiment that is repeated over and over with similar initial conditions among the trials and a limited range of possible evolutionary trajectories.

They put particular emphasis on ‘cell autonomy’:

Driver mutations act cell-autonomously, that is, they confer a growth advantage on the cell in which they arose. (…) [N]on-cell-autonomous mechanisms exist and play a role in cancer, but it is cell-autonomy that make cancer the disease of relentless cell proliferation.

Cell autonomy, say Sidow and Spies, is what makes cancers really special. For example:

[T]here is no reason to think that the cells of earlier clones stop growing and dividing merely because new clones arise.

Exactly right. This is what we discussed in the beginning of this series and it is one of the reasons why my lab’s methods have populated inner nodes in the clonal evolution tree.

It’s not warfare, it’s evolution!

But Sidow and Spies go even further than that. Because of cell autonomy, they argue, there is no natural selection:

[I]nvoking ‘natural selection’ instead of clonal proliferation can lead to unnecessary conceptual complications.

No natural selection means no Darwinian evolution. There is no competition between clones. They all just happily proliferate independently of each other. Sidow and Spies write:

Much cancer literature implies or asserts that clones compete with one another – as if cells within a clone behave concertedly and ‘gang up’ on all the cells of another clone.

This is really where it starts to get fuzzy for me: Why does competition imply concerted action and ganging up? It’s not warfare, it’s evolution! Finches with bigger beaks evolve not by ganging up on other finches with less pronounced beaks, but because they are better adapted to whatever environment one of these Galapagos islands offers.

Sidow and Spies dismiss the influence of the microenvironment and surrounding tissue:

Concerted behavior, such as slowing of growth rates in larger tumors due to reduced nutrient availability and the accumulation of toxic byproducts, is likely due to the microenvironment and not due to common ancestry.

For SnS this is the end of the story: if something is due to the microenvironment and not to the genetic makeup of the cancer cell, then it is not important.

Indeed, with infinite resources and no space constraints all cells might survive. In this case Sidow and Spies’ arguments might be correct and instead of selection (which requires that some offspring does not survive) we should only talk about proliferation. For colon cancer, some evidence pointing this way exists (see the Big Bang paper). But I do not believe this is generally true.

Even if the cancer cells grow autonomously (i.e. without needing any further external stimulation), they are part of a tissue and this generally means (i) space constraints, (ii) constraints on blood supply, (iii) anti-tumor activity of immune cells and many other things limiting cancer growth. Bissell and Hines wrote a review with the provocative title Why don’t we get more cancer? to describe how the microenvironment can restrain tumor progression. Further experimental evidence for clonal competition under environmental constraints can be found in a paper from Kornelia Polyak’s group called “Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity”:

We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse.

These environmental constraints bring us back into the classical model of Darwinian evolution. I have kept on comparing cancer to finches (an idea Sidow and Spies abhor), because I think it can actually be useful. Just like finches competing for food, the cancer cells compete for space, blood and immune-evasion. Just like finches, they do not all survive. Just like finches, they develop according to Darwinian principles.

Florian

References:
Sidow, A., & Spies, N. (2015). Concepts in solid tumor evolution Trends in Genetics DOI: 10.1016/j.tig.2015.02.001

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One thought on “Evolution in cancer: Yes! Darwin: No?

  1. Great article. I just don’t get why ancestral populations that keep growing and proliferating should lead to populating internal nodes on the tree. It’s not like phylogenetics claims the second a new species (whatever that is) arises all members of the ancestors simultaneously suffer cardiac arrest. They also keep proliferating, that’s *why* the internal node remains typically unobserved.

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