‘No man, even under torture, can say exactly what a tumour is.’
J. Ewing, 1916
What exactly is cancer? Can we capture its biological essence in a few words or a phrase? For the ancient Greeks, it was a manifestation of black bile, or constitutional melancholy. The common understanding today is that it reflects renegade, mutant cells proliferating out of control, with a potentially lethal consequence: a territorial hijack of essential, normal tissue functions.
Around 100 years ago, Boveri 1,2 described chromosomal abnormalities in cancer and it has since come to be regarded as a ‘genetic’ disease or, in more recent parlance, ‘a disease of the genome’ 3.
These descriptions are more or less correct but they don’t reflect the uniqueness of cancer as a disease. Cystic fibrosis, Huntington’s disease and β-thalassaemia are clear-cut genetic diseases: a specific (predominantly inherited) gene variant with high penetrance for a specific set of symptoms. (meaning that if you inherit the ‘right’ gene you are very likely to get the disease) Cancer may well have an inherited component, but its development is driven by acquired mutational changes in somatic cells and has a complex and diverse biological character well beyond that.
During the 1960’s and 1970’s, scientists, especially those working in the more accessible leukaemias, first noticed that cancer cells diversify genetically at the chromosome level and ‘evolve’ over time. This led Peter Nowell 4 to propose a general model for cancer cell evolution. The idea was simple but persuasive: starting from a mutated single cell, a descendent clone is generated in which progeny cells further diversify, by mutation, and evolve progressively into more malignant and drug-resistant phenotypes.
Around the same time, John Cairns 5 suggested that as the DNA in proliferating tissue stem cells has an inherent risk of mutation, natural selection must be a real liability with respect to cancer.
There is indeed a fundamental, intrinsic liability, a liability that comes from more than three billion years of evolution, of replicating DNA, cells and multi-cellular animals 6. Evolution by natural selection will inevitably ensue if three simple conditions are met:
- random genetic diversity in replicating entities providing for phenotypic variation
- phenotypes that impact on relative fitness to survive and/or reproduce
- inheritability of phenotypic variation.
The winners in this evolutionary lottery are those individuals who, serendipitously, express the fitness traits that are best adapted to the prevailing challenges, whatever they be, for example, competition for resources, mates, predation, or even coping with climate change. Evolution, to quote the biologist George Williams ‘has no eyes to the future’. It is a short-term contingency or a ‘what works best today’ test. So it is that, as environmental circumstances change, winners can become losers.
This is how evolution and speciation works for microbes, fungi, plants and animals. Charles Darwin had it spot on, despite knowing nothing of genetics or the basis of inheritable variation. And this is also essentially how cancer works.