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At the beginning of 2015, headlines were filled with claims that cancer was ‘mainly down to bad luck’. But as we and several others explained at the time, the findings of the high-profile US study making the news had been misinterpreted, leaving people worried and confused.

The US team had linked what was already known about how often specialised cells divide in certain organs to the risk of cancer in those sites in the body. But the media coverage jumped from calculations around cell division to speculation about cancer rates in the overall population.

Misleading headlines aside, the researchers who published the paper were attempting to answer two important, long-standing riddles: why are some types of cancer much more common than others, and how much of cancer risk comes down to random chance?

Over the years, two areas of research have attempted to find an answer to this conundrum. On one side, scientists have focussed on the biology of the cells where many believe cancers start – so-called stem cells. On the other side, researchers have carried out large population studies to identify how things in our environment and the ways we live our lives affect our risk of cancer.

There’s evidence that both stem cell biology and our environment and behaviours affect our chances of developing cancer, but which plays the more important role? Until now, the two sides have failed to do one thing; look at the biology of how the two factors – DNA damage and stem cell division – combine in living cells.

Now a team of researchers, led by Cancer Research UK-funded Professor Richard Gilbertson, have published their findings in the journal Cell, and provided the first clear look at how the two work in combination.

And it’s an exciting glimpse into the process of how cancer begins.

What are stem cells?

Cells with faulty genes that divide out of control lie at the root of cancer. Yet over the years it’s become apparent that not all cells have the potential to become cancerous. It has long been suspected that the main cell types that can turn into a cancer are a special pool of cells, called stem cells.

If you’re unfamiliar with stem cells, we all begin our lives as a microscopic ball of them once a sperm fertilises an egg. As the graphic below shows, these amazing cells can change their shape and characteristics to become any kind of specialist cell in the body, such as a brain or skin cell.

Once we’re fully grown, organs keep small numbers of stem cells to repair damage, wear and tear and replace old cells that are past their sell-by date. Stem cells are extremely important, but their ability to copy themselves over and over means they can randomly pick up a genetic mistake (cells copy their DNA to divide, and the process isn’t 100% perfect) and turn into a cancer. And because random mistakes build up over time, we’re more likely to get cancer as we get older.

In the study from early 2015, researchers had looked at data on how often stem cells were dividing in different organs. They then used complex maths to conclude that the main reason some types of cancer are more common than others is because stem cells divide at different rates. This is something we have no control over – hence the oversimplified interpretation that cancer is ‘mainly bad luck’.

But research has also shown that in addition to random mistakes made during cell division, there are many other things that can damage our cells and affect cancer risk, including aspects of our environment and behaviours that are within our control.

Carcinogens that cells are exposed to, such as chemicals in cigarette smoke, damage cells’ DNA. This increases the chances that mistakes may crop up in crucial genes, causing cancer to form. And the evidence is clear – around 4 in 10 cases of cancer in the UK could be prevented, largely through adopting healthier behaviours.

But the biological evidence linking up these two ideas has, until now, eluded researchers.

Tracking stem cells

In their latest study Gilbertson and his team, then based at St Jude Children’s Research Hospital in the US, targeted cells that were marked with a protein called Prom1 on their surface. In order to study these cells in a living organism they needed a way to track them, so they genetically engineered mice to have Prom1 cells that produce a fluorescent green protein when switched on by a drug.

By turning the green protein on when the mice were different ages, the team could compare what Prom1 cells were doing in different organs in mice at an age equivalent to childhood and middle age.

“We could work out how quickly the Prom1 cells divide and make new specialist cells in each organ by looking at how many green cells there are,” Gilbertson explains. And it quickly became clear that Prom1 cells are stem cells in some organs, but not others.

“What’s interesting is that Prom1 cells behave differently in various organs, and at different ages,” he says.

“For example, these cells multiplied rapidly in the bowels of adult and young mice – nearly all the cells glowed green. But there were few green cells in the brain, pancreas, kidney, or salivary gland, telling us that in these organs, Prom1 cells aren’t acting as stem cells.”

The team also found that there were differences between adult and young mice too, particularly in the liver, where Prom1 cells are rapidly dividing in younger animals to form the organ, but are ‘sleeping’ in adults.

But tracing the stem cells is only half the picture. The team also wanted to test how damaging the cells’ DNA might affect the risk of developing cancer in different organs. To do this, they created green Prom1 cells with mistakes in genes known to play important roles in human cancer.

“We looked at six cancer genes in total,” says Gilbertson. “Some are over-active versions of genes driving cancer cell growth and others are broken genes that normally put the brakes on cancer cells.”

Now the team had a way to get the bottom of the mystery and test, at least in mice, whether rapidly dividing stem cells or faulty genes had the biggest role to play in cancer developing.

A ‘perfect storm’

“Unsurprisingly, both are important when it comes to cancer,” Gilbertson says. “But here, at last, we have the scientific evidence that this is true.”

The group looked at the tumours that develop in the mice, and these are their key findings:

  • Tumours only develop in organs where the Prom1 cells are stem cells, like the bowel. Prom1 cells that aren’t stem cells – including those in the brain, pancreas, kidney, or salivary gland – could not make cancer, despite the Prom1 cells harbouring genetic mistakes that could trigger the disease.
  • The behaviour of Prom1 cells changes throughout life. This was most clear in the liver, where Prom1 cells are active stem cells in young mice but ‘asleep’ in adults. Stem cells with faulty genes have no effect on adult mice, but in young mice they cause the same type of liver cancer that human children can develop (called hepatoblastoma).
  • ‘Sleeping’ stem cells in adult organs can be reawakened if the organ is damaged and needs repairing. When the team injured the liver in adult mice, the Prom1 cells kicked into action and began dividing rapidly. And because the cells contained faulty genes, tumours formed, just as they did in young mice where the cells were already active.

“The genetic mistake is vital in cancer developing, but only in the right context,” Gilbertson explains. “Only if the mistake happens in the wrong place at the wrong time will a tumour form”.

Stopping cancer before it starts?

As well as proving that cancer’s not just down to ‘bad luck’, understanding the way these stem cells act throughout life in mice could have implications for treating and preventing cancer in the future.

RichardGilbertson

Hopefully these findings will help us, and other scientists around the world, develop new ways to prevent and treat cancer – Professor Richard Gilbertson

Despite their rapid growth and rapidly dividing stem cells, cancer is relatively rare in children, and Gilbertson and his team made an interesting finding during their experiments as to why this might be.

“The Prom1 stem cells in young mice are more resistant to becoming cancerous than stem cells in adults,” he says. “We don’t know why this is yet, but if we figure this out, we might be able to change the behaviour of adult stem cells to reduce the risk of cancer.”

And in a last twist to the tale, the team found that Prom1 stem cells had high levels of molecules that cloak them from immune cells. Gilbertson thinks this reflects the importance of protecting these cells.

“Stem cells are vital for keeping us in working order,” he says. “But the downside of protecting them is that if they go wrong, they can escape detection and carry on dividing unchecked.”

This thorough research into the very beginnings of cancer has provided the evidence to back up what we already knew; of course there’s an element of bad luck to cancer, but at the same time things in our lives that increase the chance of the ‘perfect storm’ brewing.

We can still stack the odds in our favour, for example by stopping smoking, keeping a healthy weight, eating healthily, drinking less alcohol, keeping active and enjoying the sun safely.

“This has been a huge undertaking”, Gilbertson says. “We started this project 10 years ago. I set out with the intention of finding out why some types of cancer are more common than others, but also why children develop different types of cancer from adults.

“We’ve not only answered these questions, but made some really exciting discoveries about the characteristics of cells where cancer begins. Hopefully these findings will help us, and other scientists around the world, develop new ways to prevent and treat cancer.”

Emma

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NADER September 30, 2016

This way of doing business how much appreciated you significant and invaluable work is til a rookie approach to the problem. It need PRACTICAL national and better even international approach. I (orrect or wrong!) believe you need 1 pounds every day not every moth from all 70 million UK residencts and similarlly all USA and EU. To fond hundreds of more scientists, Dr and evaluate the patients throughly. I am senior Dr and scientist still we get a fraction of what we need. Call me naive! Wait tens of the years to pass a way that must have been passed in a year. Either way is not cheap unfortunately, you will pay but not prevention and cure only try and treat.