Cancer clone evolution, just like evolutionary speciation, is characterised by an extraordinary diversity of descendants derived from a common ancestor. Yet, paradoxically, some evolutionary trajectories are convergent on a common phenotype.
The classical examples of convergency from evolutionary biology include eyes, wings, big brains and social structures, all of which have been ‘invented’ multiple times, independently. We find that their genetic, developmental and biochemical details are often distinct but in the end, the functional result is very similar 1.
As might be expected, convergent evolution of specialised phenotypes does occasionally involve co-option of the same or related genes – referred to as molecular convergence. So, although eyes have been invented many times with different light capturing structures and embryologies, they all rely on the photon capturing capacity of the photo-pigment, rhodopsin and the eye generating capacity of PAX6 genes 2.
Another remarkable example of molecular convergence is the exploitation of the same ‘hearing’ gene – prestin, in echo-locating bats and marine cetaceans 3.
The standard interpretation for evolutionary convergence is twofold. First, that having eyes and wings, for example, brings such big fitness advantages, sight and flight, that they are very likely to evolve more than once. And, second, that there are always constraints on what options or adaptations are available to solve life’s challenges and so different species are likely to come up with similar solutions, independently 1.
Cancer evolution is, in a very general sense, convergent, in so far as there is selective pressure favouring metastatic spread to secondary sites. But could it be more than that?
In a recent paper 4, Han Chen and Xionglei He have suggested that cancer clone evolution is highly convergent in terms of the type of cell associated with progression of disease. The authors used genome-wide expression profiles on some 18 types of solid tumours (around 3000 cancers altogether) in comparison with data from equivalent normal tissue controls.
They used a method called Jensen-Shannon divergence to measure the difference (or distance) between individual cancers, both with each other and their normal tissue counterparts.
They found that most cancer types share a common convergence (away from their normal counterparts) towards an embryonic stem cell (ESC) signature. This held for several cancers (lung, sarcoma, myeloma and breast) but not for all those they looked at. Interestingly, they found that colon cancer did not show this convergence, lending support for the notion that colon cancer has an explosive or ‘big bang’ origin and may be ‘born to be bad’ 5. Additionally, Chen and He found that a strong ESC signal was associated with poor clinical outcome.
The authors conclude that, despite the different tissue sites involved in primary growth and secondary, metastatic seeding, tumours evolve a consistent – or convergent – cellular phenotype, possibly reflecting some shared selective pressures in different tissues.
The study is elegant and the data is persuasive but I wonder if the apparent ‘reversion’ to an ESC-like state is quite what it seems. Let me suggest another explanation.
Cancer clones can expand indefinitely because some cells self-renew instead of differentiating. Acquired mutations unlock this potential, which is a characteristic of normal stem or progenitor cells. In the cancer clone, cells with the stem cell-like property of self-renewal provide the focus, or ‘unit’, of evolutionary selection, spawning progression of disease, metastases and drug resistance 6. It is to be expected that the frequency of these stem-like cells will increase as the disease progresses.
Evidence supporting this contention derives from observations that higher quantitative stem cell activity (transplantability or expression profiles) is associated with both progression of the disease and poor clinical outcomes in several cancer types that have been evaluated, including AML, colon and breast cancer 6.
If this interpretation is correct, then Han Chen and Xionglei He’s data could be interpreted somewhat differently – convergence in cancer evolution is towards enrichment of the unit of evolutionary selection – the cells with enhanced self-renewal capacity. This would not then be a ‘reversion’ to an embryonic state but a stabilisation of a tissue stem cell-like state in which the cancer originates.
But the main conclusion of Han Chen and Xionglei He would not be changed. There does appear to be significant phenotypic convergence reflecting, we assume, shared evolutionary pressures. Other data in the recent cancer literature, including examples of molecular convergence 7, are compatible with these findings.
Perhaps the main importance of these findings relates to the prospects for targeted therapy in the current climate of personalised medicine. An alternative to drugs tailored to the genotype of individual patients might be to target the fitness attribute most commonly used, irrespective of cancer subtype and genetics. That target would be the self-renewal phenotypes. In this regard, there have been some recent and encouraging therapeutic developments 8-10.
- Conway Morris S (2003) Life’s solution. Cambridge University Press.
Fisher R, Horswell S, Rowan A, Salm MP, de Bruin EC, Gulati S, McGranahan N, Stares M, Gerlinger M, Varela I, Crockford A, Favero F, Quidville V, André F, Navas C, Grönroos E, Nicol D, Hazell S, Hrouda D, O’Brien T, Matthews N, Phillimore B, Begum S, Rabinowitz A, Biggs J, Bates PA, McDonald NQ, Stamp G, Spencer-Dene B, Hsieh JJ, Xu J, Pickering L, Gore M, Larkin J, Swanton C (2014) Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome Biol, 14(8): 433.
Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, Leggett D, Li W, Pardee AB, Li CJ (2015) Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA, 112: 1839-1844.
Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, Moon YC, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorgyi E, Gallinger S, Dick JE, O’Brien CA (2014) Self-renewal as a therapeutic target in human colorectal cancer. Nat Med, 20: 29-36.
Zhu Z, Khan MA, Weiler M, Blaes J, Jestaedt L, Geibert M, Zou P, Gronych J, Bernhardt O, Korshunov A, Bugner V, Lichter P, Radlwimmer B, Heiland S, Bendszus M, Wick W, Liu HK (2014) Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival. Cell Stem Cell, 15: 185-198.