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Let's beat cancer sooner

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

Comments

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Meg September 8, 2016

How do NETS fit into this?

Bill September 6, 2016

It is another ten years before this could be applied in treating cancer, that is the usual lead time. Forgive my unconvinced attitude but this is one of 100’s of proteins that are involved in cancer. Like Mike Broom my wife has lived healthily but has been fighting 3c ovarian since 2011. How about researchers stop dangling carrots and throw off the shackles of NICE and start curing people. Oh sorry! there is too much money involved not to mention careers that would suffer if a substantial step forward was made in beating cancer.

Aine McCarthy September 5, 2016

Hi Matthew,

That’s a really good question. When an adult stem cell divides it becomes two new ‘adult’ cells – a replacement stem cell and a cell that turns into a specialist cell, like a bowel wall cell. But any mistakes in the stem cell’s DNA are also copied into the two new cells. That’s why cancer is more common as we get older – the DNA mistakes build up increasing the chances that a cancer-linked gene becomes damaged. And the researchers found intriguing evidence that stem cells are protected from the immune system, but this also means that cancers can develop under the radar.

While things we do that damage our DNA, such as smoking, increase the risk of developing cancer, there’s no evidence that stress plays a role. You can read more about that here: http://scienceblog.cancerresearchuk.org/2016/06/10/stress-cancer-and-electromagnetic-therapy-what-does-the-evidence-say/

Emma

Elizabeth Longland September 4, 2016

What exciting results, which furthers the understanding of cancers’ development and will eventually lead to better treatments or even prevention in some cases.

Charlie September 3, 2016

Is this research applicable to Neuroendocrine Tumours?

Liz September 3, 2016

An interesting article explaining the research in an understandable way for everyone.
Has any research ever been done on how stress/traumatic life events can trigger DNA mistakes in stem cells ?

John Galvin September 3, 2016

This was really interesting information. No one really worries about getting cancer until they or a loved one has it. Living a healthier life is not only better for us but it increases our chances of avoiding cancer. Having faulty DNA stem cells which are replicating at the wrong place and time is just part of the lottery of life. As we now know cancer has been around for millions of years so we can’t entirely stop it, can we? Can our stem cells ever be error free? I don’t think so, I hope I’m wrong.

Mike Broom September 3, 2016

I never smoked, drank very little alcohol, led an active sporting life and was not overweight. However I have still ended up with a multi myeloma cancer. Please advise me how this situation is not down to bad luck!

Taiwo September 3, 2016

Thank you for letting me know about the research, it’s useful for me. I wish you more successful research.

Annalisa Deavall September 2, 2016

Really interesting/ informative read.

Danny Connaughton September 2, 2016

It’s interesting science, for sure. The key is to convert it into cures…..but I guess we all know that. I will do my bit by continuing to donate each month.

Carole Bonney September 2, 2016

I found this article most helpful thank you. I like to hear of upcoming developments since having breast cancer in 2014. At that time I was a Practice Manager in a busy large GP surgery. I endured a lot of stress over 20 years in that post. I honestly feel that this contributed along with HRT to my cancer as I am the only member of my family to have ever had cancer. Stress lowers the immune system leaving our bodies weaker & susceptible in my humble opinion. Good luck to all who have been affected & keep up the excellent research.

Colette Rogers September 2, 2016

Thank you for your unrelenting ongoing work in this area. Cancer is cruel, but by understanding how it functions we are more likely to choose a lifestyle that prevents in the future.

Mark September 2, 2016

A very concise, interesting article

Kathryn Davenport Dunn FRSA September 2, 2016

I thank all the scientists for the super discoveries regarding cancer and treatments. How wonderful to hear news on a regular basis about the break throughs they have found to help us all in prevention and cure of many cancers. Thank you to every one of you.

Joyce Hull September 2, 2016

I have noticed in a long life that cancer often follows divorce or bereavement. Trauma would seem to play a part in damaged stem cells increasing?

Matthew addicott September 1, 2016

Fantastic bit of research! Kudos to you and your team! I unfortunately don’t have a clue about this, but wondered if when a adult and a cell is copied, wether the cell that is produced is that of a young person, or that of a adult person? Would the “information” for that cell then compatible with the older person if it’s a young persons cell? Or does the body realise this cell is wrong and cannot perfectly replicate the cell it requires so then continuously produces cells? Is this why we age cause cell replication is never as good?Can’t see the bodies immune system wanting to attack “regenerating” cells. I could well have the wrong end of the stick so please be polite.

Liz Brown September 1, 2016

After surgery for bowel cancer in February my surgeon definitely put the tumour down to ‘just bad luck’. I am reasonably fit and healthy, I exercise, eat well and am rarely ill. I do have a lot of stress in my life and would really like to know if this adds to the bad luck. I would be interested in assisting with your research.

Diane Humphries September 1, 2016

Very interesting if prom 1 could be bottled like a yearly flu jab.It seems that getting older you are unable to maintain your prom1 so finding something to replicate and renew is perhaps the hardest part as cells die keep up the good research

Lindsay September 1, 2016

A really good article – accessible and understandable. The odds can increase by engaging in some of the items on the list of risk factors but even if one didn’t there is still ‘bad luck’ and cancer may develop. Of course people who engage in the risks do not necessarily develop cancer. Is that ‘good luck’?

Viv September 1, 2016

A very interesting read and approach to cancers. The diagrams explain very clearly and simply the basics of how cancer can form.

Kay Anthony September 1, 2016

Really interesting – thanks!

Emma Smith September 1, 2016

Thanks for spotting that mistake David, corrected.
Emma

Martin September 1, 2016

4/10 could be prevented means 6/10 couldn’t, this suggests a large amount could be related to bad luck. While suggesting ways to improve behaviour to lower risk is admirable, please be careful to avoid this turning into people with cancer being somehow at fault, it’s a fine line and you’re treading dangerously close.

David September 1, 2016

Interesting article explained well, though some proof reading would have picked up the occurrence of “back luck” in the first paragraph that should have been “bad luck”.