Dysregulation of intestinal morphogen gradients leads to ectopic stem-cell properties in intestinal neoplasia and inflammation/restitution

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The human gut is made up of units called crypts, in which all cell types within it are derived from the stem cells housed at the crypt base. Control of these stem cells is thought to occur from the action of chemical messages secreted by cells that surround the stem cell. Derangement of these messages can lead to abnormal stem-cell growth leading to colorectal cancer formation which affects 39,000 people a year in the UK and is responsible for more than 16,000 deaths annually. Intestinal inflammation is common, with inflammatory bowel disease affecting up to 2% of the population. Longstanding (chronic) intestinal inflammation and repair is a significant risk factor for cancer development. We hypothesise that inherited or sporadic genetic mutations and chronic intestinal inflammation and repair can dysregulate the delicately balanced chemical messages that control the stem-cell and that this disruption can lead to loss of control of stem-cell division, initiating tumour formation.A team of clinicians and scientists intend to examine these functional mechanisms using biological models to mimic the changes seen in early tumourigenesis and in intestinal damage and repair. We believe that this work will lead to a better understanding of tumour development and growth, help to determine whether measurement of pathway disruption may predict patients' risk of cancer development and highlight potential target areas for anti-cancer treatment.