05.07.2024 Regenerative stem cells as the origin of inflammation-associated intestinal tumours

Medical research group finds trigger points for bowel cancer at a young age

Group photo of the research team
Photo: Bhargavi Sundaresan
The Schmitt research group from the Institute of Pharmacology of the Department of Medicine.

If you ask a cell biologist how cancer develops, the answer is: through a mutation in a stem cell. In a new publication in the journal "Nature Genetics", scientists from the Erasmus Medical Centre (Erasmus MC) in Rotterdam and Philipps-Universität Marburg, Germany, break this dogma. They show that intestinal tumours can also develop from a differentiated, specialised secretory cell type that actually has the task of producing mucus or antibacterial molecules.

The researchers came to this discovery because of a contradiction. The main risk factors for colon cancer, namely chronic inflammation and western dietary habits, the so-called Western-style diet, strongly suppressed normal intestinal stem cells. However, if this is the case, they cannot be the origin of the colon tumours. Hence, the question arises: which other cell types can give rise to intestinal cancer instead? Earlier studies by Dr. Mark Schmitt, principal investigator at the Institute of Pharmacology at Philipps-Universität Marburg, show that differentiated secretory intestinal cells that are actually specialised in other tasks, revert to stem-like cells in response to inflammation-induced tissue damage in order to take over the function of the suppressed bona fide stem cells. Could these secretory intestinal cells be the origin of intestinal tumours in an inflammatory context?

This hypothesis proved to be correct. In mice with a genetic predisposition to cancer specifically in these secretory intestinal cells, tumours developed as soon as the intestine became inflamed. The origin of these intestinal tumours was not a stem cell, but the usually differentiated, specialised intestinal cell, as the researchers showed. 

Then the scientists noticed something else: the intestinal tumours of the mice not only resemble the tumours that occur in people with chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. With the help of machine learning and artificial intelligence, the scientists were able to show that also around 40 per cent of human intestinal tumours that do not develop in the context of inflammatory bowel disease originate from normally differentiated secretory intestinal cells.

This number is much higher than the researchers had expected and is probably due to a mild but persistent chronic inflammation that can be caused by western dietary habits in the intestine. As Dr. Schmitt's research group was able to show, the consumption of a Western-style diet, very similar to intestinal inflammation, leads to a loss of normal stem cells, followed by the activation of stem cell features in secretory cells, which could then grow into a tumour. This happens not only in the relatively small group of colorectal cancer patients with inflammatory bowel disease, but in many more people.

The researchers link their findings to a worrying trend: Colorectal cancer, by definition a disease associated with age, is increasingly being diagnosed in young people. The results now confirm the researchers' suspicion that there is a link between Western lifestyle, chronic inflammation and the development of bowel cancer at a young age, possibly related to the switch to alternative cells-of-origin of the tumours.

The research was funded by the Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International (WCRF) grant programme. Dr. Julia Panina, Head of Research Funding at WCRF, said: “These groundbreaking findings challenge current scientific knowledge on where colorectal cancer originates, which will inform new ways of how it can be prevented, diagnosed and treated. Thanks to this research, we can now identify another type of cell that causes colorectal cancer, and one of the factors for the inflammation that leads to this change – namely, a Western-style diet high in fat, sugar and starch. This risk factor can be reduced by following World Cancer Research Fund’s recommendations to make wholegrains, vegetables, fruit, and pulses (legumes) such as beans and lentils a major part of your usual daily diet, avoid red and processed meat, and limit alcohol intake. This research shows yet another reason why this advice is so vital.”

The outcomes of the study are moreover important as they could lead to a new classification of colon cancer, the researchers argue: colon tumours that arise from secretory cells have a poorer prognosis than tumours that arise from intestinal stem cells. The researchers hope that the updated classification will lead to a better prediction of disease progression and personalised treatments.

Original publication: Nature Genetics, https://www.nature.com/articles/s41588-024-01801-y doi: 10.1038/s41588-024-01801-y

 Press release of the Erasmus Medical Centre: https://amazingerasmusmc.com/biomedical/researchers-break-dogma-intestinal-tumor-does-not-always-arise-from-stem-cell/