Cancers are life threatening because they migrate within the body, spreading far from their point of origin. This process – metastasis – hijacks tissues and compromises their critical functions. When they reach this stage, most cancer clones will be robust and resistant to treatment, whether that be radiotherapy, chemotherapy or immunotherapy. So, in a sense, it is resistance that is the major stumbling block to successful treatment. Those exceptional cancers that are curable, even when disseminated (childhood acute lymphoblastic leukaemia, testicular cancer and choriocarcinoma) retain sensitivity.
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.
We are seeing a renaissance of optimism about immunotherapy for cancer – after many years of disappointment. Patients with advanced and clinically intransigent lung cancers and melanomas, treated in early clinical trials with antibodies to immune checkpoint inhibitors PD-1 and CTLA-4, have been surviving longer than would previously have been expected 1,2. And other studies have demonstrated that patients whose tumours were infiltrated with lymphocytes show better outcomes 3.
Putting these observations together, the inference is that some tumours present neoantigens that are recognised by the immune system and that this reactivity can be boosted by releasing the checkpoint brakes on the immune system.
One of the striking achievements of cancer genomics and its allied bioinformatics has been to construct phylogenetic trees depicting the trajectories of sub-clones in cancers and their ancestral relationships. It’s like taking a peek back in time at the origin and prior evolutionary history of the malignancy.
But what about the converse? Is it possible to infer, from features of cancer cells, what their future potential or ability to evolve into more malignant, metastatic or drug-resistant phenotypes may be? There’s no doubt this would be extremely useful, particularly in the context of early diagnosis and intervention.
Genome sequencing has revealed that a plethora of gene mutations can co-exist in individual cancers: thousands in some cases 1,2. Based on Darwinian theory, we assume that whilst most are irrelevant, buried in the background is a modest number of mutations (perhaps counted in single figures) that are functionally active in a way that contributes to cancer clonal development. The ‘offspring’ of the cells with these mutations will be more successful than the cells that surround them. Continue reading
At the 2015 NCRI Conference Professor Mel Greaves, our founding author, was given the Lifetime Achievement Award by CRUK
This post is a synopsis of the lecture I gave at the National Cancer Research Institute (NCRI) conference in Liverpool on the 2nd November 2015 – minus some anecdotes about mentors and colleagues – you needed to be there to hear those. It’s my personal, historical narrative of tackling the challenge involved in unravelling the biology and causes of childhood leukaemia. Continue reading
For some time before we had the benefit of cancer genomics, it was generally believed that for a cancer to disseminate and become potentially lethal, it would have had to accrue several mutations that, collectively, would provide a kind of ‘full house’ for malignancy.
It was further assumed that, in the absence of rampant genetic instability, the critical set of mutations would arise one at a time and that it would, therefore, take time to assemble a ‘full house’ set. The linear relationship of cancer incidence to age (in log-log plots) was taken to indicate that four to six rate-limiting mutational events might be involved 1,2. However this inference rested on some questionable biological assumptions 3. Continue reading
Since the turn of this century, cancer genomics has strongly endorsed the Darwinian view of cancer biology 1,2. Interrogation of the genomes of single cancer cells and multi-regional small biopsies of tumours have allowed us to construct evolutionary histories, or phylogenies, of cancer clones – revealing genetic and cellular architectures very reminiscent of Darwin’s iconic drawing of evolution or speciation 2. Continue reading
Charles Darwin had it right, despite knowing nothing of genetics or the basis of inheritable variation. This illustration shows us how evolution and speciation works for microbes, fungi, plants, animals, and, essentially, it is also how cancer works. Continue reading
‘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. Continue reading