People often talk about ‘the big C’ as a single disease. But cancer is actually a group of more than 200 distinct diseases, each with their own unique set of causes.
The reason we broadly group them together is that all cancers share some common traits. For example, whichever type it is, cancer happens when cells escape their natural programming to stop dividing when they ought to. Instead they become renegade ‘immortal’ cells, dividing without limit and – if left untreated – spreading around the body.
Or at least that’s what was thought.
But new research by our scientists is beginning to challenge this idea, showing that the situation may not be as simple as was first thought. Immortality, it seems, may not be quite the hallmark of cancer we think it is.
A useful model
The thought-provoking discovery is the work of Professor Dorothy Bennett and her colleagues, funded in part by Cancer Research UK. The team, based at the University of London, are looking for ways to beat malignant melanoma, the most serious form of skin cancer.
Melanomas – in the form of cancerous moles – are relatively easy to remove from the body and compare with healthy skin tissue in the lab. For this reason, Professor Bennett’s team knew it could be a particularly good cancer to study the chain of events that lead healthy cells to transform into cancer cells.
Questioning a longstanding view
The researchers also knew that many studies had already looked at the behaviour of ‘late-stage’ skin cancer cells – ones that are capable of invading surrounding tissues and spreading around the body.
In fact, lab studies stretching back to the 1950s have consistently shown that such late-stage disease is made up of cells that can divide indefinitely.
Somehow these cancer cells are able to bypass the natural aging process our cells go through, known as ‘senescence’.
All cells in our body have a pre-programmed limit to how many times they divide – for example, normal skin pigment cells from newborn babies divide around 50 times. After this, they stop dividing and go into a senescent ‘sleeping’ state. This safety system is one of our inbuilt cancer prevention mechanisms, although – as we know only too well – it’s not foolproof.
If you were to look at the cell division in a healthy mole on your skin, you would see that most of the cells are in this sleeping state – they are not dividing. But cells in an aggressive melanoma have ‘woken up’ and divide out of control.
So conventional scientific thinking says that healthy cells have an inborn ‘rule’ that tells them to stop dividing at some point, whereas cancer cells can divide limitlessly. And if this is the case in aggressive, spreading cancers then surely it must be true in early-stage tumours too?
But Professor Bennett realised that nobody had ever actually proved the existence of ‘immortal’ cells in early-stage cancers, which haven’t yet acquired the ability to spread.
It took 4 years of painstaking work to find out whether this was true. And the results were rather unexpected.
A surprising result – cancer without immortality
To discover whether early tumours contained immortal cells or not, the researchers took cells from moles that had been removed because of suspected cancer and grew them in the lab. The samples ranged from healthy (benign) moles to early melanomas that had not yet spread, known as primary tumours.
As expected, cells taken from healthy moles had stopped dividing, and none of them were immortal.
But the scientists were shocked to discover that very few of the cells taken from primary tumours were immortal. In fact, the majority spontaneously stopped growing after a relatively short time.
These cells did at first seem to go beyond the normal limit of cell division though – continuing to divide beyond their natural limits for a while – but they couldn’t keep it up indefinitely.
It was as if they’d side-stepped the first barrier – cell senescence – but then come up against a second barrier that stopped them becoming truly immortal.
Cells in crisis
Millions of years of evolution have given our cells a range of tools to prevent them from dividing limitlessly, protecting us from cancer.
For instance, there’s an in-built ‘countdown timer’ in our cells – protective caps called telomeres that are found at the ends of chromosomes and shorten every time a cell divides. Once the telomeres get too short, this normally permanently stops cells from dividing.
The researchers found that the primary tumour samples showed signs of ‘telomeric crisis’, meaning that they had continued to divide beyond normal limits until their telomeres became dangerously short. This makes chromosomes prone to fusing together, causing catastrophic DNA faults.
In this scenario, the only way for cancer cells to become truly immortal is by switching on an enzyme called telomerase, which is able to re-build the protective telomeres and ‘re-set the timer’.
Professor Bennett’s team found that only a handful of the primary skin cancers they looked at had made this crucial leap towards immortality, which then allows individual cells that spread around the body to go on dividing to form new cancer masses.
The rest of the samples contained something new and unexpected – ‘mortal’ cancer cells.
Clues to curbing cancer’s immortality
These new results call into question a longstanding dogma of cancer – that immortality is a hallmark of cancer.
Professor Bennett’s work refines this view (at least for melanoma), showing that immortality is potentially only a feature of later-stage disease that is more likely to spread.
It’s a bleak irony that by gaining immortality, cancer cells might evolve into a state most likely to kill – around nine in ten deaths from cancer are down to the disease spreading.
But thanks to this work, we now have several clues for how to improve treatment. For example, Professor Bennett believes that we now need to explore ways to detect whether telomerase is ‘switched on’, or look for other indicators of immortality in primary tumours. This could help predict which are most likely to spread, and determine the best treatment to give different patients.
And in related work, we recently announced that a group of Cancer Research UK experts, including Professor Bennett, are working with drug company AstraZeneca to identify chemicals that trigger senescence – literally putting cancer cells back to sleep – which they hope could lead to new cancer treatments in years to come.
From bench to bedside
It’s important to stress that this research only looks at how cells grow under laboratory conditions – a long way from a cancer patient.
But it’s still vital for helping scientists understand cancers’ inner secrets, and provides key intelligence on how to tackle the disease. Lab discoveries can – and do – lead to new treatments. For example, the discovery of a common genetic fault in chronic myeloid leukaemia ultimately led to the drug imatinib (Glivec), which has saved the lives of thousands of people with the disease.
Only time will tell if Professor Bennett’s work will affect how patients with melanoma are treated, but without this kind of research, we’d never make the progress we need to beat cancer.
Oliver Childs, Senior Science Information Officer
Soo, J. et al. (2011). Malignancy without immortality? Evidence for cellular immortalization as a late event in melanoma progression Pigment Cell & Melanoma Research DOI: 10.1111/j.1755-148X.2011.00850.x