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Fluorescently labelled bowel cells, Image © Dow et al/Cell 2015

Bowel cancer’s origins can often be traced back to just a single faulty gene: APC – short for adenomatous polyposis coli.

The potent effects of damage to this critical stretch of our DNA were first uncovered back in the 1980s, when our scientists helped track it down and link it to bowel cancer.

The gene turned out to be what’s known as a ‘tumour suppressor’, which normally (as the name suggests) protects our cells from becoming cancerous.

This crucial role is reflected in the fact that it’s the first domino to fall in an estimated eight out of 10 cases of bowel cancer. Faults in the gene switch it off, leaving once-healthy cells exposed to a relentless barrage of signals telling them to keep growing – ultimately leading to the formation of a tumour.

Since APC’s discovery, scientists have been trying to decode these signals. The ultimate goal is to find ways to target them with treatments, tackling bowel cancer at its very root.

Today, things took a big step forwards: an international team of scientists – writing in the journal Cell – has offered the first answers to a question that has been on scientists’ minds for some time: what happens if you switch APC back on again?

And, tantalisingly, their answers point to potential new ways to develop treatments for bowel cancer.

Off or on?

Picking apart exactly how the loss of APC leads to bowel cancer has been no easy task, according to Professor Owen Sansom, whose team at the Cancer Research UK Beatson Institute is also studying these signals.

“Scientists across the globe have spent a lot of time removing APC from cells in the lab and in animal models to study how bowel cancer develops,” he says.

This painstaking work has revealed a critical role for APC in controlling a second molecule, called β-catenin, which can be found inside our cells.

Without APC, a cell produces too much β-catenin, and can’t control where the molecule should be held inside the cell. This leaves the β-catenin free to enter the cell’s nucleus, where it switches on other genes that trigger rapid cell growth.

This relay of events is known as the Wnt signalling pathway, and it plays a crucial role in the early stages of bowel cancer development.

Because the misfiring Wnt pathway appears to be so important, a global research effort has homed in on finding ways to target these signals for treatment.

But there have been a few questions left unanswered.

As a tumour develops, its cells acquire more and more genetic damage, further fuelling their growth and helping them survive. In the case of bowel cancer there are two genetic ‘dominos’ that usually fall soon after APC: KRAS and p53.

Until now, it’s been unclear if it’s these additional faults that keep the cancer cells growing, or whether the initial inactivation of APC still has a role to play later in the disease’s development.

“An important question we haven’t been able to answer is whether or not bowel cancer cells retain their dependency on APC loss to keep growing,” says Sansom.

And, according to him, this has largely been down to a technical challenge. “We’re really good at removing these genes and proteins, but not so good at putting them back into cells afterwards,” he says.

But the latest study has addressed this question for the first time – with striking results.

Deciphering dependency

Lab-grown

Lab-grown bowel ‘organoids’, A) at the start, showing the characteristic structure of bowel tissue; B) after APC is switched off, lacking organisation; C) after APC is switched back on, returning to normal structure. Image © Dow et al/Cell 2015

The researchers, based at the Memorial Sloan Kettering Cancer Center in New York, developed genetically engineered mice in which they could carefully control the activity of APC in cells lining the bowel. The mice were also genetically tagged with fluorescent markers, allowing the researchers to follow the development of their bowel cells in different circumstances.

They also carried out similar experiments in tiny lab-grown pockets of bowel tissue called ‘organoids’ (see image, right).

Similar experiments have been done before; that’s how we know these faults, in this order, are so important in bowel cancer development. But what’s special about this new study is that the researchers found a way to switch APC back on again – something that hasn’t been possible before.

When they did this they saw a very striking response: the tumours shrank, and then disappeared.

And, even 30 weeks later, the disease hadn’t come back. It was as if the disease had been simply switched off.

Science fact or science fiction?

On the surface, these results allude to a really powerful way of making these bowel tumours shrink and disappear: just switch APC back on again.

Unfortunately it’s not that simple. Almost all drugs in use today – from aspirin to Zytiga – work by switching overactive biological processes off, rather than switching on new or missing ones. The ability to re-engineer a working form of the APC gene into cells in a cancer patient is – currently – more in the realm of science fiction than clinical reality. And it’s likely to remain so for some time.

But, as Sansom points out, what these results do show us is that research is heading in the right direction – especially in the development of potential new drugs for bowel cancer.

Because when APC is switched off, other things do get switched on: β-catenin levels rise and Wnt signals fire. And this means there might be targets for drugs somewhere among these processes.

“These are really exciting results,” says Sansom. “What they show is that, at least in the case of this new lab model, later stages of bowel cancer are still dependent on APC being switched off.”

“This reinforces the idea that targeting the Wnt pathway, which gets activated when cells lose APC, could be a really powerful way of tackling the disease.”

The researchers themselves suggest a particular type of drug that can trigger the destruction of β-catenin even when APC isn’t around. There are plenty of researchers trying to develop these drugs – called Tankyrase inhibitors – and they are just one example of potential targets that hit the Wnt pathway.

From one gene to many

The next steps are to better understand how this dependency on APC loss plays out in people with bowel cancer, rather than in the lab.

But these findings, plus the addition of a new laboratory model with which to study bowel cancer, could prove crucial in tracking down the best targets to shut off the Wnt pathway in patients.

But there’s a wider point here. Nearly three decades ago, scientists discovered a single gene with the potential to fuel the development of bowel cancer, and beating the disease seemed – suddenly – a much simpler task. But the intervening years have shown us that even a single type of cancer can be viewed as multiple diseases when the layers of genetic complexity stack up.

The sometimes-baffling ways that new gene faults appear, accumulate and diversify as a tumour develops is one of the biggest challenges facing researchers. And in the context of this so-called ‘tumour heterogeneity’, searching for and exploiting the underlying, original faults causing the disease has never seemed so urgent.

Today, the legacy of that 80s research comes into stark focus. The APC gene not only lies at the origins of bowel cancer, but beyond that too – exposing a crucial, fundamental weakness, and a new way to find out how to target it.

Nick

Reference

Dow, L., O’Rourke, K., Simon, J., Tschaharganeh, D., van Es, J., Clevers, H., & Lowe, S. (2015). Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer Cell, 161 (7), 1539-1552 DOI: 10.1016/j.cell.2015.05.033

Comments

Nick Peel June 22, 2015

Hi Ronny,
Thanks for your comment. The researchers looked at the genes and cellular signals controlling how bowel (colorectal) cancer develops, so the study didn’t include neuroendocrine tumours.
Best wishes,
Nick, Cancer Research UK

Ronny Allan June 19, 2015

Nick – is this purely focussed on bowel cancer as in colon/large intestine or does it cover less and uncommon cancers of the small intestine such as Neuroendocrine Tumours ?

JOANNA VLASSOPULOS June 19, 2015

Interesting and educational article. Sounds promising, I enjoyed reading and learning..