Evolution is change over time, and it is well-accepted that cancers evolve through the stepwise accumulation of somatic mutations. Logically, mutations ‘cause’ cancer, and therefore, simplistically, the key to preventing cancer could be to avoid mutations. However, epithelium, like the skin and intestines, divide and shed millions of cells every day, and could accumulate many mutations because DNA replication is imperfect.
One potential safeguard against ‘replication’ errors is a stem cell hierarchy, where long-lived stem cells divide infrequently. However, studies in mice indicate that both skin1 and intestinal stem cells2 are not quiescent but rather are actively dividing. Such tissues are primed for evolution because many more cells are produced than can survive.
Think for a moment about a young girl, four years old, diagnosed with acute lymphoblastic leukaemia (ALL). This is not so unusual, and in fact, ALL is the most commonly diagnosed childhood cancer. However, only two years earlier, this young girl was also diagnosed with a grade II glioma in her brain, treated by surgical resection with no chemotherapy or radiation exposure. Moreover, her father and her father’s brother both recently died of aggressive glioblastoma multiforme (GBM) brain tumours. This young girl and her family have Li-Fraumeni Syndrome, an inherited defect in one of the TP53 genes leading to a nearly 100% lifetime risk of cancer1.
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.
In the second of our guest blog posts, Dr Andrea Sottoriva describes how a comparison between the expanding universe and the growth of cancers led him to formulate his “Big Bang” theory of tumour growth – a model with novel treatment implications.
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In 1929 Edward Hubble, sitting at the top of Mount Wilson, observed that stars and galaxies are moving away from each other. He reasoned that, if stars are continuously moving apart, they must have been closer together at earlier times, to the point that at the very beginning the entire cosmos would have been compressed into a tiny space. This led to the hypothesis that our universe could have originated from a cosmic explosion, “the Big Bang”. But where are the remnants of such an enormous blast? Surely such a phenomenon must have left its mark in today’s universe? In fact, it did. Radio astronomers, Arno Penzias and Robert Wilson, detected the Cosmic Microwave Background radiation in 1964. This is the glow of the Big Bang explosion, it permeates the whole universe at an almost uniform -270 degrees Celsius.
So, what does all of this have to do with cancer? Tumours are large collections of cancer cells that grow out of control and invade healthy tissue, thus becoming life-threatening. Like the universe, cancers expand from something tiny, a single tiny cell. By sequencing the DNA of tumours we discovered that each cancer is unique to a single patient, in the same way that the universe is unique, as far as we can tell.
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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.
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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.
In the first of our guest blog posts, Dr. Marco Gerlinger highlights some of the remarkable developments being made in ctDNA analysis, a powerful new technology with the potential to transform tumour predictions and treatment outcomes.
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Cancer cells are masters in adapting to changing environments. This allows them to colonise other organs, to form metastases and also to acquire drug resistance. Darwinian evolution is thought to be a key driver of this adaptability. Randomly acquired mutations encode for novel phenotypes and some of these phenotypes may allow individual cells to survive changes in the environment1.
This adaptability is a key reason for the high rates of mortality from metastatic cancers. Treating a cancer that cannot evolve would probably be an easy task – maybe as straightforward as eradicating a bacterial infection with antibiotics. Thus, there is great need to understand how and why cancers readily evolve and to use this information to design more effective treatment approaches for ever-changing cancers.
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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
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