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When defences attack: the hidden cause of cancer hiding in our cells

by Emma Smith | Analysis

12 May 2015

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Riot police

Last month, we wrote about Cancer Research UK-funded scientists at The Francis Crick Institute, whose research is tracing the origins of the genetic diversity within tumours.

Their recent findings pointed the finger of suspicion at the actions of a family of molecules in our cells, called APOBECs (pronounced AY-poh-becks), in causing certain types of genetic damage that can drive tumour growth.

But this isn’t the first time that APOBECs’ characteristic fingerprints have been found to cause cancer – so we thought we’d take a closer look at these fascinating biological double-agents, which start out as a friend, but somehow morph into a deadly enemy as cancers develop.

What are APOBECs?

Scientists stumbled across the first member of the APOBEC family in 1993, while studying how our bodies transport fat around the bloodstream. They were trying to work out how a fat-carrying protein called apolipoprotein B existed in two different-sized versions. Eventually they discovered that something seemed to be ‘editing’ the instructions (called messenger RNA) that tell cells how to make the protein.

They gave this editing tool the name ‘Apolipoprotein B mRNA Editing Enzyme, Catalytic polypeptide-like’ – which, thankfully, got shortened to ‘APOBEC’.

Over the following years, while studying human genes, researchers discovered APOBEC’s genetic cousins dotted around our DNA. And it transpired that, as well as editing the RNA messages that our cells copy from DNA in order to make proteins, APOBECs can change the underlying DNA code too.

This turns out to be essential for our health. One member of the APOBEC family is vital for creating the enormous diversity we need to adapt to infections, by creating a multitude of ‘tweaks’ in crucial immune molecules called antibodies.

Other APOBECs attack viruses trying to smuggle their genes into our own DNA, neutralising the threat by scrambling their genetic code.

So that’s the good side of APOBECs. But what happens if they start behaving badly?

APOBECs and cancer

The first hint that APOBECs might play a role in cancer came in 1995, when a group of researchers from the US engineered mice to produce high levels of APOBEC in their liver in order to study their fat levels.

Unexpectedly, all the animals developed liver cancer.

The next clue came from scientists studying an APOBEC called AID, which is made exclusively in a type of white blood cell called a B cell. When they compared cancerous B cells to normal ones, they noticed levels of AID were higher in the cancer cells. What’s more, they found genetic mistakes had been sprinkled throughout the immune cells’ DNA, with AID as the chief culprit causing these errors.

Gradually more and more evidence began to stack up that AID was playing a key role in several types of white blood cell cancers (such as leukaemia and lymphoma).

So let’s get down to the nitty gritty – what are APOBECs doing to our DNA that can cause cancer?

How do APOBECs alter DNA?

Our DNA is made up of long strings of four chemicals called adenine, thymine, cytosine and guanine, which are usually referred to by the letters A, T, C, and G. The order of these chemicals contains the information our cells need to grow and divide.

And, as shown in the diagram below, they’re tightly wound into a twisted ladder – the iconic double helix – made up of two paired strands that precisely match A with T, and C with G.

The structure of DNA

The structure of DNA

APOBECs are tiny machines inside our cells, that can change these DNA instructions (as well as altering the related molecule RNA, but we’re going to focus on DNA here).

They do this by chopping off a small bit of the chemical cytosine (‘C’), converting it into a different chemical – U (uracil).

But APOBECs can only chop up the C letters in DNA when it’s present as a single strand. This means that – most of the time – our own DNA is protected, because it’s tightly wound into the double helix. (Viruses trying to sneak into our cells often contain single stranded DNA – which is how APOBECs protect us).

But there are occasions when our own DNA gets separated into single strands and becomes more vulnerable to APOBECs (which are shown as a pink dot in the diagram below):

How APOBECs work

How APOBECs work

One instance is, ironically, during our cells’ natural DNA repair processes, which kick in following damage by certain chemicals or ultraviolet radiation.

While it’s being repaired, broken DNA can end up temporarily single-stranded at the ends, creating a target for APOBECs.

Another single-stranded situation occurs when cells unwind their DNA as part of the process of making new proteins. But because cancer cells often have other mistakes in their DNA, this reading process can become jerky, get stuck or even cause DNA breaks – increasing the opportunities for APOBECs to attack.

One small mistake can be costly

APOBECs are normally kept under tight control and any accidental damage they cause is repaired: our cells have a repair kit that spots ‘U’s building up in our DNA, snipping them out and correcting them before they become a problem.

But this isn’t fool-proof. If there are too many errors, the system can get overwhelmed and they go unrepaired, causing problems when cells try to read or copy their DNA.

Changing one letter doesn’t sound catastrophic, but the instructions encoded in our DNA often depend on a precise sequence of letters in order to work properly. Just one small spelling mistake in a crucial gene involved in controlling how cells multiply or die can have disastrous consequences. In some cases this causes cells to grow out of control.

And these mistakes can also be passed on as our cells divide, contributing to the development of cancer.

The APOBEC footprint: more vital clues


Researchers have found fingerprints of the processes that cause cancer

Researchers have known for more than 30 years that certain DNA damaging agents, such as tobacco smoke and ultraviolet rays, leave distinctive patterns of mistakes in our genetic code, called a ‘footprint’ or ‘signature’.

Now advances in DNA-reading technology have allowed researchers to look in ever-greater detail at the signatures of all kinds of damage left in the DNA of cancer cells. And it turns out that almost everywhere they look, APOBECs have left their mark.

For example, in 2012 – as we blogged about at the time – an international group of scientists catalogued all the DNA mistakes in 21 breast cancer samples. Within the data they spotted distinct clusters of mistakes matching the characteristic DNA changes caused by APOBECs. The researchers named these clusters “kataegis” (from the Greek for thunderstorm).

More recently, Professor Charles Swanton and his team at the Francis Crick Institute discovered that many of the genetic mistakes happening late in the evolution of several cancers bear the hallmark of APOBECs.

Crucially, they found that the genetic diversity of the cancer exploded at the same point when APOBECs started introducing DNA errors.

The smoking gun

All the evidence points to APOBECs playing a role in cancer, but there’s still a question mark over whether they cause cancer to develop in the first place, or become active once a tumour is growing. Professor Swanton’s data suggest that in some cancers at least, it’s the latter, but further research may uncover different roles.

There are other intriguing clues linking cancer and APOBECs.

For example, higher levels of the female hormone oestrogen can increase the rate at which errors accumulate in DNA – this seems to be due to oestrogen switching on an APOBEC family member called AID.

And results from various studies have found unexpectedly high levels of APOBEC ‘signatures’ in tumours linked with certain bacterial and viral infections – including stomach, cervical and head and neck cancers. This suggests that these infections might lead to over-exuberant APOBEC activity, that might eventually trigger cancer to develop.

Whether APOBECs trigger cancer to start or drive the genetic diversity frequently seen in difficult to treat forms of the disease – or, indeed, play roles in both – these discoveries raise two important questions:

Firstly, what is making these normally useful molecules attack our DNA? Is it due to a high level of DNA repair following damage? Alternatively, might it be it driven by the rapid growth of cancer cells, continually unravelling their DNA to read genes or copying it as tumour cells divide out of control?

Another reason could be other mistakes in cancer cells’ DNA causing the DNA-reading machinery to stutter, leaving DNA vulnerable. This is called ‘replication stress’ (we’ve written more about it here).

“Replication stress is likely to be a major factor leading to the activation of APOBECs in tumours,” says Professor Swanton.

“This is a double blow to our cells – replication stress itself leads to our DNA becoming unstable and breaking, then APOBECs deliver a follow up punch by introducing errors as the DNA is repaired,”

Working out what switches APOBECs from friend to foe is a crucial piece in the puzzle of understanding what drives cancer to grow and spread.

And crucially, this could offer a potential way of developing entirely new ways to stop cancer in its tracks. For example, can we put a stop to the damage APOBECs cause to our DNA by developing drugs that could block them? And could preventing the rapid evolution caused by APOBECs make the treatments we already have more effective?

And Professor Swanton is excited by this prospect.

“We’re reaching a very exciting point in cancer biology where studying the DNA code of tumours is revealing why a person’s cancer is so genetically diverse,” he says.

“This knowledge is paving the way to a new approach to treat cancer – drugs that are specifically designed to prevent cancer evolving and adapting. This may help to overcome the biggest challenge we face in treating cancer: drug resistance.”

There are many questions still to answer and more to discover about these fascinating molecules. Clearly, the tale of APOBECs and their role in cancer is far from over, and we can’t wait for our researchers to help paint the full picture.