Discovery of origin of esophageal cancer cells highlights importance of screening for pre-cancerous Barrett's esophagus

Date:
August 12, 2021
Source:
University of Cambridge
Summary:
Abnormal cells that go on develop into esophageal cancer -- cancer
that affects the tube connecting the mouth and stomach -- start life
as cells of the stomach, according to scientists. The study found
that a particular subtype of esophageal cancer known as esophageal
adenocarcinoma is always preceded by Barrett's esophagus -- abnormal
cells of the esophagus -- even if these cells are no longer visible
at the time of cancer diagnosis. This confirms that screening for
Barrett's is an important approach to esophageal cancer control.



FULL STORY ========================================================================== Abnormal cells that go on develop into oesophageal cancer - cancer that
affects the tube connecting the mouth and stomach - start life as cells
of the stomach, according to scientists at the University of Cambridge.


==========================================================================
The study, published today in Science, found that a particular subtype
of oesophageal cancer known as oesophageal adenocarcinoma is always
preceded by Barrett's oesophagus - abnormal cells of the oesophagus
- even if these cells are no longer visible at the time of cancer
diagnosis. This confirms that screening for Barrett's is an important
approach to oesophageal cancer control.

Cancer of the oesophagus is the sixth most deadly cancer, and oesophageal adenocarcinoma is on the rise in western countries. Scientists and doctors
have known for some time that the development of this cancer is linked
with Barrett's oesophagus, which shows up in endoscopy as a pink 'patch'
in the surface of oesophagus and affects around one out of every 100 to
200 people in the United Kingdom - and between 3 and 13 people out of
100 with this condition will go on to develop oesophageal adenocarcinoma
in their lifetime. However, the question of where these abnormal cells
come from has been a mystery that has baffled scientists for decades.

A multidisciplinary group of scientists led by Professor Rebecca
Fitzgerald at the Medical Research Council Cancer Unit, University of Cambridge, today provides the most comprehensive explanation to date.

Dr Lizhe Zhuang, joint first author of the study, said: "It's intriguing
that, although Barrett's oesophagus predominately occurs in the lower part
of oesophagus close to stomach, it has so-called 'goblet cells' resembling
a much more distant organ, the small intestine. Over the past twenty
years there have been at least six different hypotheses about the origin
of Barrett's oesophagus. Using the latest techniques, we believe we have arrived at an answer to this mystery." The research team analysed tissue samples from patients with Barrett's oesophagus and from organ donors
who have never had the condition. The samples were collected as part of
the Cambridge Biorepository for Translational Medicine at Addenbrooke's Hospital, part of Cambridge University Hospitals NHS Foundation Trust.



==========================================================================
Lead authors Dr Karol Nowicki-Osuch and Dr Lizhe Zhuang established a
detailed 'atlas' of human cells and tissues from all possible origins
of Barrett's oesophagus, including oesophageal submucosal glands, an
elusive tissue structure that acts in a similar way to saliva glands
and has never before been isolated from fresh human tissue.

The researchers then compared the maps of cells from healthy tissues,
Barrett's oesophagus and oesophageal adenocarcinoma using a number of state-of-the-art molecular technologies. These included single cell RNA sequencing, a powerful technology that enables researchers to investigate
the functions of a large number of individual cells. They also looked
at methylation profiles -chemical modifications to the DNA of cells in
the tissue - and at genetic linage to trace back where a particular cell
type originated.

The results showed a striking similarity between stomach cells and
Barrett's oesophagus, suggesting that the cells at the very top of the
stomach can be reprogrammed to adopt a new tissue identity, becoming more
like intestine cells, and replace the oesophageal cells. Furthermore,
in this new study the team showed that two genes, MYC and HNF4A, are
the keys that switch the tissue identity from stomach to intestinal cells.

Dr Karol Nowicki-Osuch, joint first author of the study, said: "The
techniques we used have shown us the internal processes that happen in
the stomach cells when they become Barrett's. The big question now is:
what triggers these genes? It's likely to be a complex combination of
factors that include bile acid reflux (often felt as heartburn) and other
risk factors, such as obesity, age, male sex and Caucasian ethnicity." Importantly, the researchers found that all oesophageal adenocarcinoma
cells begin as stomach cells before transforming into Barrett's cells
and then into cancer cells.

Professor Fitzgerald added: "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. 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."
Michelle Mitchell, Chief Executive of Cancer Research UK, said, "Today's insights into the origin of oesophageal adenocarcinoma could help inform
future research efforts into how to diagnose this type of cancer early -
which is key for improving patient outcomes.

"This research goes hand in hand with other recent successes in early
detection such as Cytosponge, the sponge-on a-string test, which we funded
to detect Barrett's in patients with heartburn symptoms." The research
was largely funded by the Medical Research Council, Wellcome and Cancer Research UK.

========================================================================== Story Source: Materials provided by University_of_Cambridge. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Nowicki-Osuch, K & Zhuang, L et al. Molecular phenotyping reveals
the
identity of Barrett's esophagus and its malignant
transition. Science, 2021 DOI: 10.1126/science.abd1449 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210812145036.htm

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