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Barrett's oesophagus under the microscope
“Over the past 20 years, there have been at least 6 different hypotheses about the origin of Barrett’s oesophagus,” says Dr John Lizhe Zhuang, whose research has focused on answering this question, which has remained a mystery for decades.
Barrett’s oesophagus, also known simply as ‘Barrett’s’, is a precancerous condition that affects around 1 in every 100 to 200 people in the UK. In this condition, some of the cells that line the oesophagus become abnormal. And, for a small number of people, it can eventually develop into a type of oesophageal cancer called oesophageal adenocarcinoma, which often has a very poor outcome.
Scientists and doctors have known about the link between Barrett’s and oesophageal cancer for some time, but there continues to be questions surrounding the condition, including where and how it actually starts.
You’d be forgiven for assuming that the answer should be obvious – if it’s found in the oesophagus, surely that’s where it starts?
We spoke to some of our researchers based at the University of Cambridge about why the origins of Barrett’s have been a mystery, and how they have managed to finally solve it.
A complicated condition to study
When looked at under a microscope, Barrett’s is like a mosaic. It’s uniquely made up of lots of different types of cells that resemble those from the oesophagus, the stomach and even the intestine.
This has naturally led to the idea that it could be due to cells taking on a new identity. But determining where exactly Barrett’s starts has remained out of reach.
“Until recently we’ve been limited in answering these questions for 2 main reasons: one is access to fresh patient material to actually study the problem, and two is the technology to really probe it in detail,” says Professor Rebecca Fitzgerald from the MRC Cancer Unit, who led the researchers investigating this question.
The nature of Barrett’s makes it very difficult to study.
Currently people are only ever diagnosed with Barrett’s when it has already formed, so doctors are unable to track how it has developed over time.
In scenarios like this, scientists will try to use alternative ways to find out what they need to know, usually by growing the cells they’re interested in in a dish or study how the condition develops in animals, such as mice.
Unfortunately, neither of these options work well for Barrett’s. Its complexity makes it difficult to grow the mosaic of cells in a dish, and Fitzgerald says that mouse models aren’t ideal because “mice don’t get heartburn and reflux”, which is thought to be a key driver of the condition.
The fact that we stand upright is a problem as well, as the junction between the oesophagus and the stomach is in a different place compared to mice. As the cells that line the oesophagus and those that line the stomach are different, the point at which the two meet is very important.
This left the team with one option: tissue samples from humans.
“The main access for those kinds of tissues is often at surgery,” says Fitzgerald. “But those patients will have cancer already so that’s no good, as we need to get samples from healthy people.”
To solve this problem, the researchers teamed up with Dr Kourosh Saeb-Parsy, a transplant surgeon at Addenbrooke’s Hospital. As the oesophagus and stomach aren’t used in transplantation, they were able to be removed from organ donors to be analysed in this study.
Thanks to this, the team were able to analyse tissue samples from patients with Barrett’s oesophagus and from organ donors who have never had the condition.
Arriving at an answer
Alongside colleague Dr Karol Nowicki-Osuch, the team used these samples to create a detailed ‘atlas’ of human cells and tissues from the potential starting places of Barrett’s.
Using a number of state-of-the-art molecular technologies, the team separated the tissue samples down to single cells, like disassembling a Lego model into its individual pieces, and mapped the different genes each cell was using.
The researchers then compared the maps of cells from healthy tissues, Barrett’s oesophagus and oesophageal adenocarcinoma, to see which were the most similar.
The results, published in the journal Science, showed that stomach cells and Barrett’s oesophagus are remarkably alike, suggesting that the cells at the very top of the stomach, in an area called the cardia, can change to look more like intestine cells and replace other cells in the oesophagus.
The team confirmed this answer by creating a 3D model from human cells to test their hypothesis, as well as constructing the genetic trees of the different tissue types – similar to how you can use DNA to build a family tree – to pinpoint cells in the cardia as Barrett’s ancestor.
Using the latest techniques, we believe we have arrived at an answer to this mystery.
– Dr John Lizhe Zhuang, Hutchison-MRC Research Centre and Cancer Research UK Cambridge Centre.
For Nowicki-Osuch, this elusive explanation makes sense.
“It only takes one step for stomach cells to become the mix of cells that make up Barrett’s, whereas the other options would need multiple steps. It makes sense to us that the simplest route is the one we’ve found to be the source of this disease.”
That’s not all they found. Their work to show that Barrett’s begins its life as cells at the top of the stomach allowed the team to answer another question as well: whether Barrett’s is a required step in the development of oesophageal adenocarcinoma.
A universal point of origin
Fitzgerald has been working on ways to screen for Barrett’s oesophagus for a long time now, but around half of patients with oesophageal adenocarcinoma have no evidence of Barrett’s oesophagus at the time of their diagnosis.
Does that mean that only half of oesophageal adenocarcinoma cases start as Barrett’s, with the other half developing differently? Or are they just diagnosed at a point when signs of Barrett’s are no longer visible?
By comparing the genetic maps the team had created to a large cancer database, they found that oesophageal adenocarcinoma always has indications that it developed from Barrett’s, even if the patients were diagnosed directly with cancer with no evidence of Barrett’s at the time.
“Even if the pre-cancerous Barrett’s is not visible at the time of cancer diagnosis, our data suggests the cancer cells will have been through this stage,” says Fitzgerald. “This has been debated for some time, but our conclusion is important as it means that screening for Barrett’s is an important approach to controlling oesophageal cancer.”
This research shows that diagnosing Barrett’s before it has the opportunity to develop into cancer is really important, but as only a small proportion will actually make that step, figuring out which cases will turn cancerous is vital, and something Fitzgerald continues to work on.
The quest continues
A combination of the ideal source of tissue samples and modern technology provided the perfect storm for the team to finally solve 2 key mysteries about Barrett’s, but Fitzgerald says some unanswered questions still remain.
“There’s more work to be done on this,” she says. “Can we actually point to these cells in the stomach and tell you that’s exactly where they are? No, we can’t. Can we actually work out what triggers these cells to become Barrett’s? We know it’s probably related to acid reflux, but we don’t link those two things together in this study. Can we actually understand how the gastric cells get to the lower oesophagus to become Barrett’s?”
Zhuang wonders why Barrett’s always happens in the oesophagus, despite starting off somewhere else. “Why it doesn’t happen elsewhere in the stomach?” he says, “I think that’s actually the big question for me now. Are there certain gastric cells that are more prone?”
As is often the way in science, answering questions will often be like finally unlocking one door just to find 5 more locked doors ahead of you, revealing questions you may never have considered before.
Fitzgerald and her team continue to work to answer these questions, unlocking as many doors as they can to help prevent as many deaths from oesophageal cancer as possible.