Lung cancer cell. Credit: LRI EM Unit
Our Science Surgery series answers your cancer science questions.
Chris asked: ‘How do cancer cells remain dormant for many years?’
It’s an unfortunate fact that, despite apparently successful treatment, cancer can sometimes come back many years after diagnosis. And this could be because some cancer cells enter into a hibernation-like state, called ‘dormancy’.
“What it means for a cell to be dormant is essentially that it’s not dividing,” says Dr Simon Buczacki, a bowel cancer expert who specialises in dormancy.
Buczacki says it can be strange to think of cancer cells behaving in this way, because they’re mostly known for their ability to rapidly grow and divide. But these sleeping cancer cells could help to explain why some cancers come back after treatment.
“Breast cancer is a very good example of where dormancy could be at play,” says Buczacki. Although many people are successfully treated by their initial surgery and chemotherapy, for an unfortunate few cancer can come back many years later. And Buczacki says this is likely due to dormant cells.
“If cells had departed the tumour and were continuing to divide somewhere in the body, even if they were dividing really slowly, they would grow into a tumour in the years following treatment,” he explains.
“But when someone’s cancer recurs five or 10 years after surgery, the most feasible explanation is that these cells have lain dormant, sitting for years without dividing before being coaxed out of their slumber.”
Dormant cancer cells can avoid being killed by the vast majority of cancer treatments, which target dividing cells. Scientists like Buczacki want to learn more about these elusive cells, including how to kill them.
How do cancer cells become dormant?
Buczacki says there are several explanations for why a cell might stop dividing, the first being it simply runs out of divisions.Thanks to years of evolution, normal cells have inbuilt checks that count and control the number of times they can multiply. It’s a safety mechanism that’s often disrupted in cancer cells but, if present, it can trigger a cell to become dormant.
Cancer cells can also be pushed into becoming more specialised cells – like breast or bowel cells – and become stuck in that state (a process known as terminal differentiation), stopping them from dividing.
Finally, cancer cells can also stop dividing for what Buczacki describes as “unknown mechanisms”. “It may be that the cell isn’t receiving specific cues from surrounding cells or the environment, which could affect its ability to divide,” he adds.
But however a cell becomes dormant, it doesn’t always stay that way. “Cancer cells can sometimes sit for many years somewhere in the body, not dividing and then, for sometimes unknown reasons, they can start to divide again, regenerating the tumour in distant sites.”
Buczacki says it’s these dormant cells that scientists are aiming to understand. But they’re proving to be a fairly elusive bunch.
Studying sleeping cells
To understand cell behaviour, scientists rely on tools that measure some sort of activity in the cells they’re studying. For cancer cells, that’s mainly been studying how they grow and divide.
The big question for researchers studying dormancy has been “how do you study cells if they’re not dividing?”
This conundrum has made it difficult for researchers to get to know dormant cancer cells, leaving some key questions unanswered.
“We still don’t know what drives cancer cells to become dormant and what makes this behaviour reversible,” says Buczacki.
Scientists also don’t have a clear idea of where dormant cells could be hiding in the body.
“Because the cells will have left the original tumour and they won’t be dividing, they’re very difficult to find,” he adds.
Scientists have two main ideas for where dormant cells may be hiding:
- They could be sitting in parts of the body where the immune system can’t target them, like in the bone marrow. Then, when they’re triggered to start dividing again, they could move to a different organ and begin to develop into a tumour.
- Or they could be hiding out in organ where they will eventually become a tumour, sitting in a dormant state until something happens to make them start dividing again.
“Studies have shown both events happen – but which is happening in which tumours and what’s driving these different behaviours, we don’t know.”
Buczacki said it’s key for scientists to develop better tools to study dormancy, which could mean a combination of studying cells in a dish, animal models and altering the behaviour of cells by manipulating their DNA. All of which will be vital to help scientists reach their ultimate goal – killing dormant cells.
When it comes to targeting dormant cells, scientists are investigating a few different options. The first is to kill them while they sleep, by targeting something unique on the surface of dormant cancer cells.
The other option is to wake the cancer cells up. Buczacki says scientists have been trying to force dormant cells to divide again, which would mean they’d respond to traditional drugs like chemotherapy.
But although it’s a compelling idea, there’s a long way to go – and much more to learn – before this approach could be trialled in people with cancer. As Buczacki explains: “The danger of waking them up is that if your drug doesn’t work or you don’t eradicate all of them when you’ve woken them up, the patient is going to develop recurrent disease more rapidly.”
In other words, scientists have got to be sure they can kill all the cells once they start dividing for this strategy to work.
However you do it, dealing with dormancy is “absolutely fundamental” for Buczacki. He’s particularly excited about the potential impact for patients whose early stage cancer seems to be cured by treatment, but whose disease eventually comes back.
“If we can understand the routes to dormancy and how we can target dormancy, then the possibility of making significant improvements to those patient outcomes is huge.”
And it’s not just Buczacki whose focusing on this. We recently brought researchers together to share ideas about how best to tackle dormancy and map out a path for future research. Dormancy is a fundamental challenge for researchers in their quest for new ways to improve survival for people with cancer – but it’s a challenge they’re more than eager to accept.
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