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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.

 

Bowel cancer patients going undiagnosed due to COVID distruption

A new study led by the University of Oxford has found that since the first coronavirus lockdown the number of people diagnosed with bowel cancer in England has fallen sharply, with a deficit persisting up to October 2020.

Between April and October 2020, over 3,500 fewer patients than expected were diagnosed with bowel cancer in England. Since bowel cancer is more likely to be curable if it is detected at an early stage, these results suggest that many patients, whose diagnosis has yet to be made, may die unnecessarily. The results are published today in The Lancet Gastroenterology & Hepatology.

The research was carried out by a team of clinicians and academic researchers from across the UK, including from the University of Leeds and the University of Newcastle.

For this study, the researchers assessed the patterns of referral for bowel cancer investigation, diagnosis and treatment within the English NHS from 1 January 2019 to 31 October 2020.

The results showed that, compared with an average month in 2019, during April 2020 at the peak of the first wave of coronavirus:

  • the monthly number of referrals by GPs to hospital clinics for investigation of possible bowel cancer reduced by 63% (from 36,274 to 13,440);
  • the number of colonoscopies performed fell by 92% (from 46,441 to 3,484); and
  • the monthly number of people with confirmed bowel cancer referred for treatment fell by 22% (from 2,781 to 2,158), and the number of operations performed fell by 31% from (2,003 to 1,378).

This is the first study to assess the impact of the COVID-19 pandemic on the diagnosis and management of bowel cancer across England.

Full story available on the Nuffield Department of Population Health website.

Bioengineering the human gut

The ability to grow human tissue in the lab has progressed rapidly over recent years, promising a new frontier for regenerative medicine and experimental modelling of human diseases, including for early detection research. The in vitro culture of the gastrointestinal (GI) tract is particularly attractive due to the prevalence of disorders of this tissue, including irritable bowel disease and cancer, and the need for replacement tissue for transplantation. However, the number of different cell types and the precise arrangement required to form a functional tubular GI tract makes this tissue challenging to grow in the lab.

A common strategy for constructing GI tracts is to use a scaffold material to establish the tissue structure, which is then seeded with human cells that stick to the structure and grow. Various different scaffold materials have been tested but there is still room for improvement.

To generate GI tracts that are representative of those in the body, Dr Linna Zhou and Dr Carlos Ruiz Puig from Professor Xin Lu’s (Ludwig Institute for Cancer Research) and Professor Hagan Bayley’s (Department of Chemistry) labs have researched the use of collagen protein as a scaffold. In their paper published in the journal Advanced Functional Materials, the researchers developed a new and simple method to construct tubular GI tracts from collagen without some of the additional steps that have been used by others previously.

Their method uses precise 3D printing of droplets containing cells and collagen, which then form into continuous tubes. Importantly, the complex tubular shape was produced by controlling the density of the fibroblasts – cells that produce the structural framework for animal tissues – seeded at different sections of the GI tracts.

They generated different types of GI tract (intestine and stomach) by seeding the collagen structures with human cells from different tissues and were able to demonstrate the important layered structural features found in the natural GI tract. The engineered stomach tissues were susceptible to infection with the cancer-associated bacteria Helicobacter pylori, providing a valuable early disease model.

These advanced bioengineered GI tracts therefore show great potential both for use as a disease model in biological research and for regenerative medicine. Future plans include using these engineered GI tracts to study GI cancer development and progression. Understanding more about the biology of early cancer will assist with strategies for early detection. This model will also be used to test therapeutic agents.

Full article on the OxCODE website.

Using AI to improve the quality of endoscopy videos

Cancers detected at an earlier stage have a much higher chance of being treated successfully. The main method for diagnosing cancers of the gastrointestinal tract is endoscopy, when a long flexible tube with a camera at the end is inserted into the body, such as the oesophagus, stomach or colon, to observe any changes in the organ lining. Endoscopic methods such as radiofrequency ablation can also be used to prevent pre-cancerous regions from progressing to cancer if they are detected in time.

Unfortunately, during conventional endoscopy, the more easily treated pre-cancerous conditions and early stage cancers are harder to spot and often missed, especially by less experienced endoscopists. Cancer detection is made even more challenging by artefacts in the endoscopy video such as bubbles, debris, overexposure, light reflection and blurring, which can obscure key features and hinder efforts to automatically analyse endoscopy videos.

In an effort to improve the quality of video endoscopy, a team of researchers from the Institute for Biomedical Engineering (Sharib Ali and Jens Rittscher), the Translational Gastroenterology Unit (Barbara Braden, Adam Bailey and James East) and the Ludwig Institute for Cancer Research (Felix Zhou and Xin Lu) have developed a deep-learning framework for quality assessment of endoscopy videos in near real-time. This framework, published in the journal Medical Image Analysis, is able to reliably identify six different types of artefacts in the video, generate a quality score for each frame and restore mildly corrupted frames. Frame restoration can help in building visually coherent 2D or 3D maps for further analysis. In addition, providing quality scores can help trainees to assess and improve their endoscopy screening performance.

Future work aims to employ real-time computer algorithm-aided analysis of endoscopic images and videos, which will enable earlier identification of potentially cancerous changes automatically during endoscopy.

This work was supported by the NIHR Oxford Biomedical Research Centre, the EPSRC, the Ludwig Institute for Cancer Research and Health Data Research UK.

(1)Real-time detection of artefacts of different types including specularity, saturation, artefact, blur, contrast, bubbles, each indicated with different coloured boxes on the image. Artefact statistics and quality score are generated. Frames suitable for restoration of blur, artefact and saturation are identified. (2) Fast and realistic frames restoration. Discriminator-generator networks are used. (3) Restoration of the entire video. Before restoration, many more frames were corrupted and fewer frames were of good quality compared to after restoration when over 50% of frames had been restored.

Graphical abstract summarising the main messages of the publication. © The Authors CC-BY-NC-ND 4.0

How chemotherapy impacts the body

Current standard cancer treatments, such as chemotherapy and radiotherapy, can have lasting effects on the body. Chemotherapy for example is associated with many side effects, such as nausea and anaemia, due to the impact of the toxins on healthy tissue as well as the tumour.

Neoadjuvant therapy, whereby therapies are administered before the main treatment, to help reduce the size of a tumor or kill cancer cells that have spread, has previously been suggested to contribute to changes in the composition of a patient’s body. This includes reduction in muscle mass (or ‘sarcopenia’) which is a natural result of aging, but in those with cancer it can lead to some post-operative complications and other diseases further down the line.

A new study from Mr Nick Maynard, Oxford University Hospitals Trust, has assessed the changes in muscle mass in gastro-oesophageal cancer patients, to better understand the long-lasting impact therapies have on the body and if it can be used to predict the risk of post-op complications. From a sample of 199 patients, they observed a decrease in skeletal mass in all individuals, with 91 participants losing more than 5% of their original skeletal mass. Those with a high rate of muscle mass depletion were generally male and significantly older, i.e. over the age of 67 years old.

50% of patients in the study experienced post-operative complications, such as pneumonia, with 13% having severe complications. However, Nick and the team observed that this was not related to the patient’s loss of skeletal mass.

Fortunately, this means that patients undergoing surgery for oesophageal cancer with large reductions in muscle mass are not necessarily at an increased risk of post-operative complications. Whilst these results do not produce any new method for predicting post-op complications, as sarcopenia did not determine the frequency of post-op complications in the sampled patients, they provide a deeper understanding of how neoadjuvant therapies can impact the body. This is important as post-operative loss of muscle mass has been previously associated with a lower survival rate for oesophageal cancer patients, so this will help to inform clinicians which patients may need to be more closely monitored.

First Huaxi SCU-Oxford Forum on Gastrointestinal Cancer

As part of the 110th Anniversary celebrations for the founding of Sichuan University (SCU), members of the Sichuan University (West China Hospital)-Oxford University Gastrointestinal Cancer Centre attended the first Centre Forum on Gastrointestinal Cancer at SCU. In attendance was an internationally known faculty of researchers who explored basic, translational and clinical aspects of colorectal, oesophageal and gastric cancer in a series of plenary lectures. See the full event agenda here.

The event built on the expertise of leading faculty members from Sichuan and Oxford University, complemented by international experts who are recognized leaders in their respective fields.

The lectures provided state of art updates on clinical management and insights into the biology of these tumour types and how this information can be exploited to identify new disease markers and therapeutic targets.

The forum attracted over 5,000 clinicians virtually from across China, representing all of the specialties involved in the management of GI cancer and basic scientists with an interest in translational and precision cancer medicine and is considered a great success.

Many thanks to the superb technical team who assured that all zoom delivered lectures were delivered with perfect clarity.

It gives the Centre great pleasure to announce that they will hold the second Huaxi  SCU-Oxford Forum on Gastrointestinal Cancer in Queens College Oxford in early September 2021, in partnership with collaborators from the University of Oslo, with whom they have formed the Colorectal Cancer Network.

Oxford University and Sichuan University form joint Centre for Gastrointestinal Cancer

The University of Oxford-Sichuan University Huaxi Joint Centre for Gastrointestinal Cancer is a new international collaboration that seeks to develop an integrated gastrointestinal cancer plan through the exchanging of ideas and resources.