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AI endoscopy enables 3D surface measurements of pre-cancerous conditions in oesophagus

Clinicians and engineers in Oxford have begun using artificial intelligence alongside endoscopy to get more accurate readings of the pre-cancerous condition Barrett’s oesophagus and so determine patients most at risk of developing cancer.

In a research paper published in the journal Gastroenterology, the researchers said the new AI-driven 3D reconstruction of Barrett’s oesophagus achieved 97.2 % accuracy in measuring the extent of this pre-cancerous condition in the oesophagus in real time, which would enable clinicians to assess the risk, the best surveillance interval and the response to treatment more quickly and confidently.

Barrett’s is a pre-malignant condition that develops in the lower oesophagus in response to acid reflux. There is a less than 0.1-0.4% risk per year of developing cancer with normal Barrett’s oesophagus – or one in 200 patients. However, that risk increases with the extent of Barrett’s lining.

Clinicians use a system called the Prague C&M criteria to give a standardised measure of Barrett’s oesophagus. This uses the circumferential length of the Barrett’s section and the maximum extent of the affected area. This score roughly determines the level of risk of developing cancer and how often the patient needs to be surveyed by an endoscopist, usually every five years for low-risk cases and two to three years for longer Barrett’s segments.

Oxford University Hospitals (OUH) NHS Foundation Trust has a cohort of around 800 patients with Barrett’s who have periodic endoscopic surveillance.

OUH Consultant Gastroenterologist Professor Barbara Braden, together with Dr Adam Bailey, oversees a large endoscopic surveillance programme for Barrett’s patients at OUH. She says the quality of the endoscopy is very dependent on the skill and expertise of the person carrying out the procedure.

“Until now, we have not had any accurate ways of measuring and quantifying the Barrett’s oesophagus. Currently, we insert the scope and then we estimate the length by pulling it back,” said Prof Braden.

“We asked colleagues from the Department of Engineering Science – Prof Jens Rittscher and Dr Sharib Ali – whether they could find a way to measure distances and areas from endoscopic videos to give us a more accurate picture of the Barrett’s area and they came up with the brilliant idea of three-dimensional surface reconstruction.”

Prof Braden, of the University of Oxford’s Translational Gastroenterology Unit, based at the John Radcliffe Hospital, added:

“Currently, you have to have a great deal of experience to know how to spot the subtle changes which indicate early neoplastic alterations in Barrett’s oesophagus. Most endoscopists don’t encounter an early Barrett’s cancer that often. So, instead of teaching thousands of endoscopists, by applying deep learning techniques to endoscopic videos you can teach a programme.”

The Oxford study is using technology to reconstruct the surface of the Barrett’s area in 3D from the endoscopy video, giving a C&M score automatically. This 3D reconstruction allows the clinician to quantify precisely the Barrett’s area including patches or ‘islands’ not connected to the main Barrett’s area.

Dr Sharib Ali, the first author of the paper and the main contributor of this innovative technology, is part of the team working on AI solutions for endoscopy at the University of Oxford’s Department of Engineering Science. He said:

“Automated segmentation of these Barrett’s areas and projecting them in 3D allows the clinician to not only report very accurately the extent of the Barrett’s area, but to pinpoint precisely the location of any dysplasia or tumour, which has not been possible up to now.”

The technique was tested on a purpose-built 3D printed oesophagus phantom and high-definition videos from 131 patients scored by expert endoscopists. The endoscopic phantom video data demonstrated a 97.2 % accuracy for the C&M score measuring the length, while the measurements for the whole Barrett’s oesophagus area achieved nearly 98.4 % accuracy. On patient data, the automated C&M measurements corresponded with the endoscopy expert scores.

“With this new AI technology, the reporting system will be much more rigorous and accurate than before. It makes it much easier when the clinician sees the patient again – they know exactly where to target biopsies or therapy. And the quicker and more efficient it is, the better the experience for the patient,” Dr Sharib Ali explained.

The research was supported by the NIHR Oxford Biomedical Research Centre (BRC), through its cancer and imaging themes.

New prostate cancer risk tool

Each year in the UK around 48,500 men are diagnosed with prostate cancer and 11,900 die from the disease. To improve survival, Professor Julia Hippisley-Cox (Nuffield Department of Primary Care and Health Sciences) and Professor Carol Coupland (University of Nottingham) have developed a tool to calculate personalised risk of prostate cancer using the health records of 1.45 million men in the QResearch database. The new risk prediction algorithm aims to diagnose more tumours earlier when they are easier to treat.

The tool is designed to be used for asymptomatic individuals and combines the prostate specific antigen (PSA) blood test result with factors such as age, ethnicity, body mass index, smoking status, social deprivation and family history. Compared to using the PSA test alone, the new algorithm is more accurate at predicting prostate cancer cases (68.2% compared to 43.9% using PSA-only), high-grade aggressive tumours (49.2 % versus 40.3%) and prostate cancer deaths (67% versus 31.5%).

The decision in most primary care practices to refer men who are asymptomatic is based on binary PSA thresholds, although this can lead to too many false-negative and false-positive results. Furthermore, a binary threshold does not give any indication for the patient as to their absolute risk of developing prostate cancer and/or clinically significant disease requiring immediate intervention. The results show that the risk equation provides a valid measure of absolute risk and is more efficient at identifying incident cases of prostate cancer, high-grade cancers and prostate cancer deaths than an approach based on a PSA threshold. The intended use is to provide a better evidence base for the GP and patient to improve decision-making regarding the most appropriate action, for example, reassurance, repetition of PSA test, referral for MRI, regular monitoring, referral to a urologist, or use of preventative interventions should any become available.

 – Professor Julia Hippisley-Cox (Nuffield Department of Primary Care and Health Sciences)

More research is now required to assess the best way to implement the algorithm and evaluate the health economics and the impact on prostate cancer diagnosis and subsequent survival.

Read the full publication in the British Journal of General Practice.

Read the feature in the Daily Mail

New study investigates how growth factors in our gut could initiate cancer

The cells that make up our tissues are strictly organised, and various differentiated cell types do different jobs in specific locations. The cell composition of tissues and the way the cells are organised is often different in pre-cancerous conditions, or even severely disrupted when they progress to tumours.

Understanding the molecular signals that cause cell differentiation and prompt the cells to find their location within the tissue, may explain the morphological changes observed in patients with pre-cancerous conditions. Ultimately, the alteration of these signals might be a driving force in tumour development and progression.

A recent paper from the Boccellato Lab at the Ludwig Institute for Cancer Research, University of Oxford, has investigated how the epithelial cell lining of our gastrointestinal tract differentiates based on different growth factors, and how this could ultimately determine how a patient progresses to precancerous conditions that could lead to stomach cancer.

Image: A picture from the published paper showing how normal gastric pits can change shape and functionality if EGF levels are altered, and eventually lead to the pre-cancerous condition Atrophic Gastritis

The team exposed healthy human gut tissue (the mucosoid cultures, patented) to a variety of growth factors, including EGF, BMP and NOGGIN. What they found is that different combinations of these factors help to determine which cells differentiate to form the gastric glands. These glands line the stomach, and contain a variety of different cells that produce digestive enzymes and gastric acid to help to digest our food, or mucus to protect the stomach lining.

For example, exposure to growth factors including EGF and BMP formed the foveolar cells that produce the mucus to line our gut, whereas inhibition of EGF induces the differentiation of cells producing gastric acid and digestive enzymes.

Patient with the pre-cancerous condition called Atrophic Gastritis have a problem with digestion due to the lack of digestive enzymes and gastric acid producing cells. In the biopsies of this pre-cancerous condition, the team have found elevated levels of EGF, which correlated with the lack of those gastric acid producing cells and with a flattened shape of the stomach tissue.

What this study has shown is that specific localisation of growth factors in the tissue microenvironment may be responsible for the differentiation process. So changing the relative quantities or localisation of these growth factors could trigger a change in the epithelium structure and cellular composition over time, potentially leading to cancer.

Building a high-resolution, dynamic map of the growth factors during cancer progression is the next step in this research. The team will also be investigating causes for these growth factor level changes. For example, long-term infection with  Helicobacter pylori bacteria is associated with increased risk of gastric cancer. Investigating how infection alters the growth factor microenvironment is essential to understand the response of the tissue and its potential aberration leading to cancer.

Dr Francesco Boccellato says:

“By better understanding the role of growth factors underlying the epithelial structures in pre-cancerous conditions, we can detect when cancers may appear and thus treat them earlier.

“This study has allowed us to draw up a new, detailed map of the signalling microenvironment in the healthy human gastric glands, which we can now draw upon in future studies as we investigate how growth factors influence cancer occurrence.”

About the Boccellato lab

The Boccellato lab is investigating oncogenic pathogens and how they contribute to cancer.  Patients infected with those pathogens have a higher chance of developing cancer, but the malignancy arises many years after the initial infection event. Cancer may develop as a result of a long battle between the pathogen that persists, hides and damages the tissue, and the host that attacks the pathogen and continuously repairs the damage caused by the infection.

Oxford success at the early detection sandpit on pancreatic cancer

Pancreatic cancer is a devastating disease with low survival rates that have hardly improved in the last 40 years. These cancers are very challenging to treat, in part due to their frequently late diagnosis when the cancer is already advanced.

To address this need for earlier detection, Cancer Research UK, Pancreatic Cancer UK and the Engineering and Physical Sciences Research Council convened a 3-day virtual workshop in November 2020. Multidisciplinary teams worked together to generate innovative research ideas for detecting pancreatic cancer earlier. At the end of the workshop, the teams pitched their ideas to receive seed funding for feasibility testing from a Cancer Research UK Early Detection Innovation Award. Two successful teams involved Oxford researchers.

Team ReTHOMS: Real-time high-sensitivity optrode metabolic sensor for pancreatic cyst fluids

Team ‘ReTHOMS’ includes Oxford’s Professor Eric O’Neill (Department of Oncology) who is working with Dr Paolo Bertoncello (Swansea University), Dr David Chang (University of Glasgow) and Dr George Gordon (University of Nottingham). The team aims to develop a new sensor device to detect malignant transformation in people with pancreatic cysts, a condition that puts them at higher risk of pancreatic cancer.

Pancreatic cysts are fluid-filled sacs on or in the pancreas that are mostly benign. However, 2-3% are precancerous and can develop into pancreatic cancer. Cysts are often identified incidentally and are then monitored for malignant transformation using either clinical imaging or analysis of the cyst fluid for cancer biomarkers such as mucins. Despite this surveillance regime, early cancers are still being missed since these methods have limited sensitivity and specificity.

To improve the early detection of malignant cyst transformation, the team aims to develop real-time and highly sensitive detection of an expanded range of cancer biomarkers. In addition to mucin, raised cellular levels of the chemical hydrogen peroxide are associated with cancer. So-called optrode technology will be used to detect hydrogen peroxide and mucin in cyst fluid. Optrodes are optical sensor devices that detect light emitted as a result of an electrochemical reaction with the biomarkers being analysed.

During this short project, the team will build the optrode device for measuring hydrogen peroxide and mucin, and undertake technical and biological validation. The longer-term aim of this research is to detect pancreatic cancer earlier by screening pancreatic cyst fluid at the point-of-care and determining further action based on the risk of cancer.

Team EDPAN: Earlier detection of pancreatic cancer through personalised assessment of risk combined with non-invasive infrared spectroscopy

Oxford’s Dr Pui San Tan (Nuffield Department of Primary Care Health Sciences) will work as part of team EDPAN with Dr Pilar Acedo Nunez (University College London), Dr Aida Santaolalla (King’s College London), Dr Paul Brennan (University of Edinburgh), Dr Lucy Oldfield (University of Liverpool), Dr Andrew Kunzmann (Queen’s University Belfast) and Dr Mohammad Golbabaee (University of Bath). This team aims to identify individuals at higher risk of pancreatic cancer for further diagnostic screening.

One of the reasons that pancreatic cancer is often diagnosed late is that symptoms are non-specific and cannot discriminate those that require investigation for pancreatic cancer. Team EDPAN will develop an approach for personalised risk stratification to identify individuals at higher risk that would benefit from more in-depth screening for pancreatic cancer.

During the project, the team will make use of existing cohorts for pancreatic cancer (ADEPTS (UCL) and PanDIA (Liverpool)) and larger cohorts for epidemiology research (UK Biobank, AMORIS). They will combine clinical and demographic information with analysis of serum and urine samples using a technique called infrared spectroscopy. They will also evaluate changes in immune components. These approaches aim to identify individuals at high-risk of pancreatic cancer and investigate whether addition of infrared spectroscopy data and immune analysis improves the accuracy of the risk prediction model.

New clinical prediction tools for myeloma

Myeloma is a cancer of the bone marrow that caused 117,077 deaths worldwide in 2020 (International Agency for Research on Cancer). Earlier diagnosis improves the rate of survival but unfortunately, delays in myeloma diagnosis are common and result in poorer patient outcomes.

One of the reasons for the diagnostic delay is that myeloma symptoms are non-specific and relatively common in people without cancer. For example, back pain is associated with myeloma yet there are many other non-myeloma causes of this symptom. Additional measures are therefore needed to highlight the possibility of myeloma in patients where GPs do not originally suspect this disease.

GPs frequently order simple laboratory tests, such as the full blood count, to investigate patients presenting with non-specific symptoms. Previous work by Dr Constantinos Koshiaris, Dr Jason Oke, Dr Brian Nicholson and colleagues from Oxford’s Nuffield Department of Primary Care Health Sciences and the University of Exeter identified certain abnormalities in blood test results that indicate a higher risk of myeloma, such as low haemoglobin which can be observed up to 2 years before a myeloma diagnosis.

In this paper published recently in the British Journal of General Practice, the Oxford researchers have developed new clinical prediction models for myeloma that incorporate both symptoms and blood test results. Using the Clinical Practice Research Datalink (GOLD version), a primary care database containing electronic health records for more than 11 million patients in the UK, the team identified the most common symptoms and full blood count results recorded for patients with myeloma. The most predictive of these were included in the models they developed and the new tools were validated against a set of test data. Decisions made using their prediction models resulted in fewer false positives and more true positives when compared to single tests or symptoms alone.

By identifying patients at highest risk of myeloma in primary care, these new prediction rules have the potential to reduce diagnostic delays by a substantial amount. Further research is now needed to understand more about the feasibility and implementation of this tool in the primary care setting and the impact it will have on the diagnostic pathway and patient outcomes.

Early Detection Award for research into the clinical application of single cell genomics

Myelodysplastic syndromes (MDS) are a group of blood cancers in which the bone marrow fails to make normal levels of blood cells. MDS can be broadly classified into two major groups: high-risk MDS, in which patients progress to acute myeloid leukaemia with a very poor survival rate; and low-risk MDS, in which the disease is less aggressive but patients still suffer from a huge burden of symptoms, often the result of anaemia.

There are a number of exciting new targeted treatment options for low-risk MDS. However, these do not work in all patients and, particularly given the high economic cost of newer treatments, current biomarkers are not sufficiently predictive of treatment response. There is a need to more precisely categorise MDS to predict the disease trajectory and the response to therapy so that the most effective treatment can be given to each patient.

Large investments in sequencing technology in clinical laboratory services are enabling precision medicine in certain cancers and revolutionising patient care. Dr Onima Chowdhury, MRC Clinical Academic Research Fellow and Consultant Haematologist (MRC Weatherall Institute of Molecular Medicine and Oxford University Hospitals) is working with Professor Adam Mead, Dr Supat Thongjuea and Dr Lynn Quek at the MRC WIMM to explore the use of single-cell genomics in the clinical diagnosis and management of MDS. Funded by a Cancer Research UK Early Detection and Diagnosis Primer Award, the team will seek to develop a simple, clinically applicable processing and analysis pipeline, as well as identifying biomarkers that correlate and can perhaps supersede current diagnostic modalities.

Long-term, the team hope that this approach will be able to improve outcomes of patients through improved diagnosis, risk prediction and targeted treatment in MDS and other haematological malignancies.

New funding for early diagnosis research using platelets

It is known that the earlier a cancer is detected, the more likely a cancer patient is to have better outcomes. One of the challenges for achieving early detection is to develop a minimally invasive test to detect the signs of early cancer in the body.

Because blood tests are simple to carry out in the clinic, a lot of effort has been focused on detecting molecules released from cancer cells in blood samples – so-called ‘liquid biopsies’. However, the majority of techniques that are used currently have a low sensitivity for early-stage cancers, due to low levels of cancer cell-derived molecules being present in blood plasma.

Dr Bethan Psaila, Cancer Research UK (CRUK) Advanced Clinician Scientist, Group Leader at the Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM) and principal investigator at the Radcliffe Department of Medicine at Oxford University, is pioneering an approach that might be able to enrich for cancer-derived molecules in the blood. Working with Professor Chris Gregory (University of Edinburgh), Professor Paul Rees (University of Swansea) and Dr Henkjan Gersen (University of Bristol), Beth is leading a multi-disciplinary team that brings together cancer cell biologists, and imaging and engineering expertise to explore the use of platelets for early cancer diagnosis.

Platelets perfuse tumours and take up cancer cell-derived biomolecules. Isolating platelets from the blood and analysing their contents will hopefully be a more sensitive method for detecting cancer-specific molecules in the blood.

In this newly funded project, the team will use state-of-the-art pre-clinical models as well as samples from patients with colorectal cancer, pancreatic cancer and oesophageal cancer as exemplar cancers to assess the utility of ‘tumour-educated’ platelets (TEPs) for early cancer diagnosis. They will use detailed imaging and biomechanical techniques to assess whether TEPs can be reliably distinguished from platelets in healthy people or those with non-malignant disorders.

This multi-institutional project is funded by a Cancer Research UK Early Detection and Diagnosis Project Award and builds on a successful CRUK Innovation Award the team received after a workshop on liquid biopsy technologies in 2018. The ~£650,000 award will run for four years and will support two DPhil studentships, a postdoctoral research scientist and a research assistant.

Drinking alcohol regularly increases cancer risk in Chinese populations

A new study demonstrates that reducing alcohol consumption in China could be an important cancer prevention strategy. Full story on the NDPH website.

For Western populations, there is a well-established association between regular alcohol consumption and a greater risk of various types of cancer. However, it was unknown whether these increased risks were the same for Eastern populations, which have very different drinking patterns and alcohol tolerance. Cancer rates are rising rapidly in China, and this may be partly due to more frequent alcohol consumption as citizens become more affluent. A new study led by NDPH on the large China Kadoorie Biobank has investigated this, with the findings published today in the International Journal of Cancer.

The study assessed over half a million adults recruited across ten diverse regions in China between 2004 and 2008. Each participant was questioned about their drinking habits, then followed up for a median period of 10 years. By the end of the study, almost 27,000 individuals had developed cancer (13,342 men, 13,619 women).

About a third of the men in the study drank regularly (at least once every week). Compared with those who abstained from alcohol, regular drinkers had a 26% higher risk for cancers previously associated with alcohol (ie, mouth/throat, oesophagus, colon-rectum and liver) and a 7% higher risk for all types of cancer. The risks were greater in those who drank daily or drank outside of meals.

For most of the cancers investigated, there was a clear dose-response relationship. Each 280 g/week higher alcohol intake was associated with an increased risk of 98% for oesophageal cancer; 74% for mouth/throat cancer; 52% for liver cancer and 19% for colon-rectum cancer. The study also found that each 280 g/week higher alcohol intake increased the risk of lung cancer (25%) and gallbladder cancer (60%), even though these cancers had not previously been clearly linked with alcohol.

In East Asia, many people cannot metabolise alcohol effectively due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2. This causes the carcinogenic compound acetaldehyde to accumulate, which can lead to facial flushing. In this study, those who experienced flushing after drinking had stronger associations between alcohol intake and cancer risk, particularly for oesophageal and lung cancer. This suggests that the risk of developing cancer is greater for those with low alcohol tolerability.

The associations remained strong when the researchers controlled for potential confounding variables including age, region, education, income, body mass index, physical activity, and fresh fruit intake. The association between alcohol and lung cancer was similar for regular smokers and those who had never smoked regularly. Nevertheless, large-scale genetic studies are needed to determine if the associations between alcohol and cancer are likely to be causal.

Very few women in the study drank alcohol regularly, hence the study was unable to assess whether the association between alcohol and cancer risk was the same for women.

Lead author Dr Pek Kei Im said: ‘Our study has clearly shown that among Chinese men, alcohol consumption is associated with increased risks of several types of cancer, including some that were less clearly established to be alcohol-related previously. This suggests that lowering population levels of alcohol consumption is an important strategy for cancer prevention in China.’

Detecting for multiple cancers in one simple test

Biomarkers – or biological markers – are used in many areas of health and disease as measures of a biological or clinical state. In the context of cancer, identifying biomarkers of early stage cancer is crucial for being able to detect disease earlier and improving the outcomes of patients with cancer. However, biomarkers alone are not sufficient for earlier detection. We also need to develop cost-effective, non-invasive, simple-to-use technologies that can be used in the clinic to detect these biomarkers with high sensitivity, specificity and accuracy.

Professor Jason Davis in the Department of Chemistry at the University of Oxford is working on just that. Professor Davis’ research has focused on developing portable, handheld diagnostic tests that use a range of electroanalytical methods for biomarker detection. This includes recent work on using novel electrochemical impedance-based sensing technology to detect C-reactive protein, a marker of inflammation in the body.

These methods are advantageous for use in diagnostics since they generate results in a few minutes and are more sensitive than other commonly used techniques such as ELISA (enzyme-linked immunosorbent assay). They also do not require the sample to be processed before testing, meaning that a single drop of blood can be analysed directly, without needing further reagents or equipment. Multiple different biomarkers can be analysed simultaneously, potentially allowing multi-cancer blood tests in the future.

To further develop this technology into a clinically implementable assay, five years ago, Osler Diagnostics was spun out of Professor Davis’ lab. The ultimate aim is that this assay could be applied in GP surgeries to test for disease in asymptomatic individuals.

Professor Davis is currently looking at clinical applications within cardiac, cancer and neurological diseases and welcomes interest from researchers who would like to contribute their biomarker ideas and clinical problems.

About the researchers

The Davis Group runs an interdisciplinary research programme within the Department of Chemistry that develops and applies methods for the fabrication of advanced functional interfaces, and are actively engaged in the development of molecular detection, diagnostic, theranostic, and imaging methodologies.

Understanding how cancer arises from infected tissue

Whilst rates in the UK are relatively low, stomach cancer is still the third highest cause of cancer mortalities worldwide. The largest risk factor for stomach cancer is a chronic infection of the H. pylori bacteria. The contributions of other factors like diets high in salt, smoked foods, smoking and obesity are also important.

H. pylori can be found in the gut, and some strains cause gastritis & stomach ulcers. Long term colonisation can result in persistent cellular and tissue damage. Over time, the damaged gut lining can lose its structure and eventually become so undefined that the patient develops atrophic gastritis – a precancerous condition that could eventually lead to cancer.

A to F shows the increasing change of structure to existing gastric epithelium, as a result of prolonged H. pylori infections. (A) The normal gastric epithelium is organised in invaginations called glands. (B) A remarkable increase in size is observed in the inflamed stomach after H.pylori infection, a condition called chronic gastritis. (C) Atrophic gastritis, a precancerous condition with a higher chance of leading to cancer: the glandular structure is lost. (D) The emergence of a new type of gland with different features: a condition known as intestinal metaplasia to cancer. (E-F) The progression from dysplasia to cancer. Credit: Correa & Piazuelo, 2013

 

Understanding how persistent infection can result in increased risk of cancer is the focus of Dr Francesco Boccellato, Ludwig Institute, and his lab. Improving the knowledge of underlying mechanisms in early cancer biology may help us to understand how cancers originate in various parts of the body, and thus giving doctors more insight to detect cancer earlier in patients with precancerous conditions.

Francesco’s most recent project is investigating the role of growth factors in the determination of gut epithelial cells. The cellular lining of the gut, known as the epithelium, is where most stomach cancers originate. The epithelium is made up of a variety of different types of cells, responsible for different things such as mucus secretion, production of gastric acid and digestive enzymes.

Cross section of the stomach lining showing a gastric gland with different cell types that make up the epithelium. What causes stem cells to differentiate into these different cells is the focus of the Boccellato lab. Credit: Boccellato lab

The team are investigating what it is that activates stem cells to differentiate into different epithelial cells, in the hope of identifying new ways that the cells can become cancerous.

It is Francesco’s hypothesis that the specific localisation of growth factors in the tissue microenvironment may be responsible for the differentiation process. If this is the case, then it may be that a change in the relative quantities or localisation of these growth factors triggers a change in the epithelium structure and cellular composition over time.

The team are investigating this through in vitro models known as mucosoid cultures – growing human epithelial cells outside of the body and exposing them to different conditions to see how the cells regenerate and differentiate. Mucosoids are an innovative stem cell based cultivation system developed by the Boccellato lab, which enables an exceptional long term regeneration and maintenance of epithelial cells. The cells form a polarised monolayer producing mucus on the top side similar to the epithelium in a patient.

Top: example of a mucosoid with cells (the plasma membrane is labelled in green) producing protective mucins (MUC5AC) labelled in red (the yellow is where the two labels overlap creating the mucus layer). Bottom: example of a mucosoid with cells (the plasma membrane is labelled in red and the nuclei in blue) showing one cells producing Pepsinogen (in green) the precursor of pepsin, the main digestive enzyme. Source: Boccellato et al., GUT 2019

The results of Francesco’s investigation into the role of growth factors in determining gut cell differentiation and progression into atrophic gastritis are expected in Spring 2021. It is hoped that by better understanding the role of growth factors underlying the epithelial structures in pre-cancerous conditions, we can detect when cancers may appear and thus treat them earlier. Further studies will elucidate the role of bacterial infections (like H.pylori) in this process of re-shaping the tissue.

The H. pylori-cancer relationship is a great model for understanding other infection-based cancers. Colon cancer, gallbladder cancer, cervical cancer, stomach cancer and lymphoma are all examples of cancers that can be caused by bacterial infection. By better understanding how gut tissues work and progress to pre-cancerous conditions, we can apply this to other cancer models to see if the same is true.

A final line of investigation by the team will be into how H. pylori bacteria access gut cells to cause damage. The epithelium is usually protected by a mucus barrier, on which our natural and harmless microflora grow. Healthy gut bacteria cannot perforate this mucus barrier to reach epithelial cells, but H. pylori appears to be able to. Francesco is investigating what makes this possible, so that we may be able to develop drugs that prevent H. pylori infections from reaching the epithelium and causing damage.

About the Boccellato lab

The Boccellato lab is investigating oncogenic pathogens and how they contribute to cancer. Patients infected with those pathogens have a higher chance of developing cancer, but the malignancy arises many years after the initial infection event. Cancer may develop as a result of a long battle between the pathogen that persists, hides and damages the tissue, and the host that attacks the pathogen and continuously repairs the damage caused by the infection.

The team use innovative tissue culture systems of human primary cells to re-build the infection niche in vitro and to understand the long term effect of infection on epithelial cells.  

References

Boccellato F.  GUT. 2019 Mar;68(3):400-413. doi: 10.1136/gutjnl-2017-314540. Epub 2018 Feb 21.

Sepe LP, Hartl., mBio. 2020 Sep 22;11(5):e01911-20.doi: 10.1128/mBio.01911-20.

Boccellato F, Meyer F. Cell Host Microbe. 2015 Jun 10;17(6):728-30.doi: 10.1016/j.chom.2015.05.016.

Piazuelo MB, Correa P. Gastric cáncer: Overview. Colomb Med (Cali). 2013;44(3):192-201. Published 2013 Sep 30.