Run-away stem cell proliferation may play role in bowel cancer, study finds

Scientists at the University of Cambridge have identified a key mechanism which they believe is involved in the development of bowel cancers. In a study published today in the journal Nature Cell Biology, the researchers speculate that a failure to properly regulate stem cells could lead to the development of tumours.

Stem cells are the body’s ‘master cells’, which have the ability to divide and make copies of themselves numerous times and are able to mature into one of the many specialised cell types found in the body, such as muscle cells and nerve cells.

The research team recently showed that proliferation of stem cells in the epidermis – the outermost layers of cells in our skin – is controlled by a molecule known as Lrig1. This molecule acts like a volume switch, ensuring that the stem cells do not grow unchecked.

In this new study, funded by the Wellcome Trust and the Medical Research Council, the researchers developed mice genetically manipulated so that they were unable to produce Lrig1. They found that the Lrig1 ‘knockout mice’ developed benign growths along the inside lining of their small intestine, produced by excessive proliferation of stem cells. This suggests that Lrig1 is essential for the regulation of stem cells in the bowel; without this protein, the number of stem cells expand rapidly in a process reminiscent of the early stages of bowel cancer.

Until now, the onset of bowel cancer was thought be caused by excessive activation of the protein beta-catenin. This new study demonstrates that in fact there may be multiple causes. In this case, it appears that Lrig1 acts to counter the effect of the growth factors that are acting to generate the stem cells. It does this by binding to a receptor normally reserved for the growth factors. The receptor is analogous to a car ignition, with the growth factor acting as a key. When the key is inserted into the ignition and turned, the car starts – so when the growth factor binds to the receptor, it triggers the generation of stem cells. But if a dummy key is inserted into the ignition, the car is prevented from starting – in this case, Lrig1 binds to the receptor and prevents it working.

The growth factor in question, known as EGFR, is known to be involved in the early stages of colorectal cancer, so the researchers now speculate that the cause of tumour initiation and progression may be caused by aberrant stem cell regulation.

Interestingly, numerous therapeutic compounds such as Cetuximab and Panitumumab, which inhibit EGFR activation, are successfully used in the treatment of bowel cancer. The researchers speculate based on their results that the effect of these therapeutics is partly to eliminate tumour cells with stem cell properties and thereby reduces risk of cancer recurrence.

Senior author of the study Dr Kim Jensen from the Wellcome Trust Centre for Stem Cell Research at the University of Cambridge says: “Our findings identify a new mechanism which we believe can trigger tumour formation. This is supported by our understanding of how some of the drugs used to treat this type of cancer work. Together they suggest that run-away proliferation of stem cells can cause the development of tumours.”

Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, adds: “Last year, almost 16,000 people in the UK died from bowel cancer. This study provides a piece in the jigsaw of our understanding of how bowel cancer develops, Understanding its underlying causes will be important to developing better drugs to treat the disease.”

The article is available online at Nature Cell Biology.

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