Scientists Discover Why Bowel Cancer Sometimes Outsmarts Treatment

A new study that challenges the prevailing view of how bowel cancer develops in the large intestine is published today in Nature Medicine.

Cancer Research UK scientists have discovered that bowel cancer may not be restricted to starting its journey in the stem cells in the lining of the intestines as previously thought.

The researchers, based in Oxford at the Welcome Trust Centre for Human Genetics, studied a hereditary faulty gene which can cause bowel cancer in middle age. The faulty gene causes normal cells to behave like immortal stem cells and develop tumours of their own– challenging the theory that normal cells have a fixed fate and limited lifespan.

The cells lining the bowel are continuously replaced – new ‘daughter’ cells are produced by immortal stem cells to replace those that have worn out.

Many types of cancer are caused when chemical messaging goes wrong. Scientists analysed polyp samples from hereditary bowel cancer patients and found disruption of a key signalling pathway involved in stem cell control. They found the same problem in a wider selection of bowel cancer tumours. When they altered the key signalling molecule in the lab it caused daughter cells that had moved out of the stem cell zone to behave like stem cells and develop into tumours.

This could ultimately explain how some cancers become resistant to chemotherapy, as stem cells killed by the treatment may be continually replaced by cancerous daughter cells.

Simon Leedham, CRUK funded researcher at the Welcome Trust Centre for Human Genetics and CRUK Oxford Centre member, 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. ”

Professor Tim Maughan, Professor of Clinical Oncology and CRUK Oxford Centre Networking Lead, commented: “This new insight into the way bowel cancer develops is critically important. People with the type of cancer described may respond to different types of therapy and we can now test that in our sample sets from previous patients. Understanding the mechanism will help us design new approaches to treating this subgroup of patients to improve their outcome”

Read the more about the study, Aberrant epithelial GREM1 expression initiates colonic tumourigenesis from cells outside the crypt base stem cell niche, Davis et Al, here.