Top-to-bottom changes in colorectal cancer

SimonLeedham
Dr Simon Leedham

Researchers at the WTCHG have discovered a new mechanism that triggers the development of tumours in the large intestine. The work could have major implications for the design of therapeutic strategies against colorectal cancers.

The cells that line the intestine are all descended from stem cells in the base of pits in the lining known as crypts. Once cells move out of the crypt base and adopt one of a number of specialised identities, they usually last only a few days before being sloughed off into the gut and destroyed. Until recently cancer researchers assumed that colorectal tumours must therefore originate from the stem cells in the crypts – the ‘bottom-up’ hypothesis.

Now Simon Leedham and his colleagues have published evidence that changes in the levels of key signalling molecules can cause cells that have already left the crypt base to develop into tumours. Their paper, published in a recent issue of Nature Medicine, presents evidence for this alternative ‘top-down’ model of tumour formation.

The researchers studied a mouse model of a human condition called hereditary mixed polyposis syndrome, a rare genetic abnormality that causes bowel cancer in middle age. The defective gene causes overproduction of a signalling molecule called Grem-1. In mice with this condition, the researchers found that excessive Grem-1 changed the fate of cells that had already moved out of the crypt base, reverting these cells to a more stem-like form that could reproduce.

These proliferating cells formed ‘ectopic crypts’, small, budding structures that could then develop into tumours. The same ectopic crypt structures are also found in non-hereditary colonic tumours called traditional serrated adenomas (TSA), which account for 2 per cent of all polyps removed by gastroenterologists. Leedham and his colleagues found that gut tissue removed from TSA patients also expressed very high levels of Grem-1, helping to identify the hitherto unknown mechanism underlying these polyps.

Simon Leedham, Cancer Research UK funded researcher at the Welcome Trust Centre for Human Genetics, said: ‘This study has implications for drug development and tumour treatment. If these signalling pathways are disrupted in tumours then daughter cells could revert back to behaving like stem cells and then replace any cancer stem cells killed by chemotherapy.’

‘This may be one of the mechanisms behind tumour resistance to chemotherapy but could also represent a potential drug target. If we can restore the disrupted signalling balance in tumours then we may be able to stop daughter cells from replacing cancer-causing stem cells and increase the effectiveness of our current therapies.’

 

Hayley Davis, Shazia Irshad, Mukesh Bansalet al, Aberrant epithelial GREM1 expression initiates colonic tumourigenesis from cells outside the crypt base stem cell niche, Nature Medicine 2014