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.