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Dr Francesco Boccellato is investigating the mechanisms of tissue regulation in the healthy stomach and in a pre-cancerous condition known as atrophic gastritis. This may help to identify those who may have cancer, as well as find new ways to prevent cancer from progressing

Correa's cascade

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.

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 GastritisA 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.

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