Mutated cells 'hijack ageing gene' to initiate cancer

A gene associated with ageing may aid precancerous cells in outcompeting healthy stem cells, new research has shown.

Researchers looking at precancerous intestinal tumours called adenomas found that when a gene called Notum was removed, the number of adenomas was much lower.

'We found that mutated cells use this gene to block environmental factors critical to normal stem cells gaining advantage in competition' said study author Dr Nalle Pentinmikko from the University of Helsinki in Finland.

The Notum gene had already been discovered by Dr Pekka Katajisto (also from the University of Helsinki) and was known to be expressed as a normal part of ageing, where it inhibits stem cells' ability to repair tissue damage. The precancerous cells 'kind of hijack the ageing gene and use it against the healthy stem cells' he said.

Normally, competition between different groups of stem cells means that most mutated cells with the potential to become cancerous are outcompeted and never proliferate. However a mutation in the APC gene is associated with an increased risk of developing colorectal cancers, causing a human condition called Familial Adenomatous Polyposis.

The researchers compared organoid models of mouse intestines derived from healthy stem cells and stem cells with a mutation in the APC gene, By looking at gene expression in the tissues, the team were able to establish that APC is involved in the regulation of Notum, which itself inhibits the growth of healthy intestinal stem cells by interrupting the signalling pathway of their growth factor proteins, known as 'WNTs'. The mutant cells do not need WNTs to grow.

Understanding the role of Notum in the development of intestinal cancers could help many who inherit mutations in their APC gene. It is known that the Notum gene can be silenced pharmacologically, which may offer an avenue to develop treatment.

'This research demonstrates that by enhancing the natural mechanisms of how tissues remove damaged cells, we could also reduce cancer risk in other tissues' said Professor Katajisto.

In addition to treating early-stage cancers, the study's findings hold promise as part of treatment for Alzheimer's where 'Notum plays a similar WNT-inhibitory role in the brain, where a decline of WNT signalling is thought to be a major mediator of synaptic loss' according to Cancer Grand Challenges.

The paper, published in the journal Nature, was a joint investigation by scientists from the University of Helsinki and the Beatson Institute of Cancer Research in Glasgow.