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This entry is part 26 of 26 in the series Our milestones

In this instalment, we go back to the 1990s to uncover the story of how an unexpected discovery by our scientists is now helping diagnose cervical cancer earlier and, decades on, is still bearing fruit for other cancers. 

In the mid-1990s most headlines about cloning were reserved for Dolly the sheep. But she wasn’t the only thing being cloned during that time. Professor Ron Laskey, a Cancer Research UK-funded scientist, was busy in his lab at Cambridge University carrying out cloning studies of his own. He wasn’t making identical copies of farm animals though; by his own admission, he was working on something rather more obscure.

“We were interested in a fairly precise detail of how new DNA is made in cells when they grow and copy themselves,” recalls Laskey.

“Particularly, how each time a cell divides it manages to make exactly 2 copies of its almost 2 metres of DNA.”

At the time, scientists thought this was controlled by something in the cell that acted like a ‘ticket’, allowing the DNA copying process to go ahead, but only when the time was right.

The identity of this mysterious controller was unknown, but Laskey’s team had a lead from previous studies: a family of molecules called minichromosome maintenance proteins (MCMs). These molecules bundle together, and earlier work had suggested that cells can only divide when MCMs are bound to their DNA.

Armed with this knowledge, Laskey wanted to know more about the possible role of these molecules in DNA replication, so his lab began studying them in fine detail. To do this, they made clones of one of the MCM molecules so that they could examine it in a variety of lab experiments on cells in dishes.

Laskey’s team looked at what happened if the cells divided with and without the MCM molecules bundled together. They soon found that the cells couldn’t copy their DNA if the complex wasn’t present. In fact, it was indispensable for this process – the team had found the ‘ticket’.

Not so black and white

Laskey and his team published this seminal discovery in 1995, and it opened an entirely new field of research. But the work that followed, including how it’s now being used to help diagnose cancer, wouldn’t have been possible without another key character: Professor Nick Coleman.

A fellow Cambridge-based researcher, Coleman was working as an academic pathologist at the time of Laskey’s discovery, specifically looking at cervical cancer and the cell changes that precede the disease.

The two scientists were introduced by Gareth Williams, a clinical researcher in Laskey’s group and together they wondered if the newfound role of MCMs in DNA replication could have potential uses in cancer diagnosis. Since tumours are masses of growing cells, could the ‘ticket’ from the MCMs help identify cells that are dividing when they shouldn’t be, perhaps indicating cancer?

We soon came up with evidence that these MCMs could be powerful markers for cancer

– Professor Nick Coleman, Cancer Research UK

“We joined forces and soon came up with evidence that these MCMs could be powerful markers for cancer,” says Coleman.

And it didn’t take long to prove they were onto something.

Looking at samples from patients, the scientists could see that there was a striking difference in the levels of MCMs in normal cervical tissue compared to tissue taken from cervical tumours and patients with precancerous changes. This suggested that detecting MCMs could be a way to help tell apart healthy cervical cells from abnormal cells in this tissue.

“It was an obvious question after that discovery: could we use what we’d seen in these tissues to help improve the analysis of cervical smear samples?” says Coleman.

Cervical smears are samples of cells taken from the cervix during cervical screening to look for abnormal cells using a microscope. While they can pick up early changes that could lead to cancer, smears aren’t a test for cervical cancer itself.

“These smears are notoriously difficult to interpret. Often in patients with cancer or precancerous changes the number of abnormal cells in the sample is very low, in the single figures,” Coleman says.

“On top of that, you’re looking for subtle differences between healthy and cancerous or precancerous cells. What we needed was some sort of system that could more easily allow us to tell the cancerous and precancerous cells apart from the healthy cells.”

They figured out that they could use the MCMs as a way to do this, and developed a test that could pick up these molecules inside the cells in cervical smear samples.

Colour vision

With an exciting new test ready to be put through its paces, the team began pilot studies on cervical screening samples in a hospital in Cambridge. Early results were encouraging, so they expanded their study into another hospital and over the next couple of years, they had managed to analyse some 1,500 samples.

In 1998, they published their initial findings: the new MCM test was remarkably accurate in distinguishing between abnormal and healthy cells in cervical tissue. On top of this, the team’s early results suggested that combining the MCM test with the traditional method for analysing screening samples could be a powerful new way to help detect early indicators of cervical cancer.

But they didn’t stop there.

With such a promising set of findings, they wondered whether MCMs could also be used to mark abnormal cells in other types of cancer. The team expanded their investigations and looked at a number of different tissues, including the lung, gut and bladder, and once again found marked differences in how detectable MCMs were inside cells.

In healthy cells that were dividing, the researchers could detect MCMs. But those that had lost the ability to divide, such as those forming the surface lining of an organ like the cervix, were lacking MCMs.

This was an important finding, because it’s these surface cells that are sampled in diagnostic tests for a number of different cancers, such as cervical, bladder and lung.

So, if you were to take a sample of these cells and see MCMs present, it would signal that the cells were dividing and potentially abnormal. And this is exactly what they found in samples from patients with precancerous changes or tumours.

According to Laskey, healthy surface cells break down their MCMs so that they can’t keep dividing and spread around the body, potentially forming tumours.

“But tumour and precancerous cells hold onto the MCMs so that they can divide again, even if they’re at the surface of a tissue,” he says.

“In a nutshell, that’s the critical reason why the MCM test works to detect cancer, and why we realised it could be applied quite broadly to cancers other than cervical cancer,” says Coleman.

And it was this lightbulb moment that sparked a research journey to bring these discoveries into the clinic, which still continues today.

Scouting for opportunities

With evidence stacking up that MCMs could help detect early signs of several cancers, Laskey, Coleman and Williams began working with our commercial arm, Cancer Research Technology (CRT), which brings together academics with industry to further develop Cancer Research UK discoveries for the benefit of cancer patients. CRT helped to patent the discoveries and set out to find new collaborations that could progress this research further.

Patents in hand, Laskey, Coleman and Williams made their way to the US to strike up conversations with various companies about ways to develop the test further so that it could potentially be used routinely in hospitals.

Over the following years, a number of organisations realised the potential of using MCMs in cancer diagnosis and were given licenses by CRT to explore the technology further. One of these companies is Becton Dickinson, who in 2007 developed a test for MCMs called ProExC.

Since 2008, this kit has been used in labs in more than 10 countries across the globe – including throughout Europe and the US – to help analyse cervical screening samples and tissue biopsies. Years of research has shown the test is particularly useful for samples that are tricky to interpret using traditional approaches, boosting the detection of precancerous changes in these patients.

It’s very gratifying to see our original findings being applied to other cancers

– Professor Ron Laskey, Cancer Research UK

The ongoing uses of MCM detection don’t end there, though. The MCM technology was used to help establish two new companies known as Cytosystems and Arquer, which are developing tests based on the detection of MCMs to improve the diagnosis of bladder and prostate cancers. On top of that, this year CRT and another collaborator, Varleigh Dx, announced the launch of a promising new test that could help diagnose pancreatic cancer, a hard-to-treat cancer that’s seen little improvement in survival in recent decades.

In a study published in the British Journal of Cancer, scientists from University College London showed that the test is better at detecting pancreatic cancer than the standard test being used to monitor patients who have a condition that could be caused by cancer, called a biliary stricture. Their results suggest that the new MCM test could be used alongside the standard test to improve the diagnosis of pancreatic cancer, which is usually diagnosed at a late stage.

“As one of the scientists involved in the early work looking at MCMs, it’s very gratifying to see our original findings being applied to other cancers, including those tricky to diagnose early like pancreatic cancer,” says Laskey.

“If this test can improve survival for pancreatic cancer, then that would be a terrific achievement,” adds Coleman. “It’s promising work.”

And with further tests in the pipeline, these decades-old discoveries could continue to aid the diagnosis of even more types of cancer.

“This is a fantastic example of how collaborations can help speed up bringing discoveries made in our scientists’ labs into the clinic, where they can benefit people,” says Dr Phil Elstob, head of commercial portfolio at Cancer Research Technology.

“MCM tests give us another tool to help beat cancer sooner, and it’s exciting to see what the future holds for these tests.”

Justine

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