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Aine McCarthy, Cancer Research UK´s Scie

This article was originally published at Cancer Research UK´s Science Blog. Republished with permission.

Author: Aine McCarthy

Áine studied genetics at University College Cork, Ireland before making the move to London in 2010 and completing a PhD in cancer biology at Barts Cancer Institute. She joined the science communications team at Cancer Research UK in 2014 where she works to communicate the charity’s research to the public.

Every January, people across the UK make New Year’s resolutions. And cutting down on alcohol often appears on the list.

That’s because despite being engrained in the social culture of millions of people in the UK and across the world, alcohol is bad for our health.

It can damage the liver, cause pancreatitis and increase the risk of developing 7 different types of cancer.


But it hasn’t been clear exactly how alcohol causes cancer.


There are theories, which we’ve written about before. And now, thanks to new research published in the journal Nature and part-funded by Cancer Research UK, we’re a step closer to an answer that’s tied to one of these theories.


A spotlight on stem cells

When we talk about alcohol increasing the risk of cancer, there’s a little more to it than that. That’s because, as the latest research highlights, it’s one of the chemicals alcohol gets broken down into that seems to be one of the main culprits.


Alcohol is broken down via a strict process and converted into energy. And it’s acetaldehyde, at the centre of this chain, that’s the weakest link. If acetaldehyde isn’t broken down further it builds up in cells, where it damages DNA in a way that could cause cancer.

Professor Ketan Patel, and his team of Cancer Research UK-funded scientists at the MRC Laboratory of Molecular Biology in Cambridge, have now uncovered the kind of damage acetaldehyde causes to DNA – the blueprint of life that resides within cells. And in doing so, they’ve shown the way cells prevent this damage and how the damage is fixed if it happens.


Their work focuses on stem cells, a type of cell that supplies the many different specialised cells our bodies are made of. It’s important to understand how the DNA code in stem cells is damaged, because this damage can give rise to different types of cancer.


Specifically, the team studied blood stem cells in mice, because as Patel explains: “They’re a good way of monitoring changes and damage to DNA in a way that’s more informative than looking at cells in a dish.”


The team studied these stem cells to see if external factors such as alcohol can damage DNA in a way that can increase the risk of cancer.


Their focus on stem cells is also important for another reason. In recent years, there has been speculation that it’s the rate at which stem cells divide and create new cells that increases the risk of different cancers in different parts of the body.


We can’t control this process. But research looking at this idea sparked headlines around the world saying that cancer is just ‘bad luck’ (it’s more complicated than that), and that there’s nothing people can do to reduce their risk of developing different types of cancer (there is).


Patel says he and his team wanted to “see if this is really the case”.


‘The results were remarkable’

Scientists already know cells can protect their DNA from acetaldehyde by using a group of enzymes called acetaldehyde dehydrogenases (ALDH for short).


“When they’re working properly, the ALDH enzymes stop acetaldehyde building up by converting it into acetate, which cells can use as a source of energy,” says Patel.


To see the damage acetaldehyde might cause to stem cells’ DNA, Patel and his team had to look at cells that didn’t have these enzymes.


To do this, they used lab-based genetic engineering to create mice whose blood stem cells didn’t produce the enzyme ALDH2, meaning they couldn’t break down acetaldehyde.


They then gave these mice diluted ethanol, the purest form of alcohol, and used techniques to see the DNA inside the cells and read its code.


According to Patel, the results were striking and remarkable.


They found that in bone marrow samples carrying blood cells lacking the ALDH2 enzyme, just one dose of ethanol caused a build-up of acetaldehyde that seriously damaged the DNA.


“We saw huge amounts of DNA damage in these cells. Bits of DNA were deleted, bits were broken and we even saw parts of chromosomes being moved about and rearranged,” he says.


In fact, the researchers found that mice lacking the ALDH2 enzyme had 4 times the DNA damage in their blood cells compared to mice with a fully functioning ALDH2 enzyme.


To see if this damage occurred in the all-important stem cells, which are rare in the bone marrow, Patel’s team read the complete DNA code from carefully extracted stem cells. It carried a tell-tale sign that the DNA had been broken in two by acetaldehyde. And this pattern of DNA damage has the potential to turn cells cancerous.


“Our work definitively shows that external factors, like drinking alcohol, can damage DNA in blood stem cells, meaning it could also damage DNA in other types of stem cells,” says Patel.


“While we didn’t look at whether these mice got cancer or not, previous studies have shown that the type of DNA damage we saw in these mice can considerably increase the risk of cancer.”


A two-tier system

Patel’s team next turned their attention to understanding how cells try and repair the damage caused by acetaldehyde.


Through a series of experiments, including more lab-based genetic engineering, they discovered that cells take a coordinated approach to repairing their DNA.


“There are lots of ways cells can fix DNA damage,” says Patel. “What we’ve shown is that when damage happens as a result of breaking down alcohol, there’s a hierarchy when selecting the best way to carry out repairs.”


The team found the main way acetaldehyde-related damage is fixed is through the Fanconi anaemia repair pathway.


But some people have faults in the molecules that carry out these repairs, meaning their cells need to use others.


Patel’s team found that there are two other repair options for blood stem cells to fix alcohol-induced DNA damage (the non-homologous end-joining repair pathway and the homologous recombination pathway).


Patel describes it as a ‘two-tier system’.


“The first line of defence is the ALDH enzymes. But if these are faulty or missing, stem cells use different repair pathways in a coordinated way to fix any damage caused by acetaldehyde and prevent it being passed on to the cells they produce.”


The message remains the same

By showing that alcohol can damage DNA in stem cells, this research sheds new light on how it can cause cancer.


And it confirms that stem cells can be damaged and affected by external factors – it’s not all just bad luck.


What it doesn’t do is change the take-home message when it comes to alcohol and cancer: the less alcohol you drink, the lower your risk of developing cancer.


So this year, why not consider including ‘drinking less alcohol’ in your New Year’s resolutions?

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