Changes in Stem Cells of the Colon in Response to Increased Risk of Colorectal Cancer

Colorectal cancer is a common disease worldwide. Increasing evidence is demonstrating that colorectal cancers arise from 'cancer stem cells.' Stem cells in the colon reside at the bottom of thousands of microscopic crypts throughout the wall of the colon. They create all the cells lining the bowel wall. These cells are created in the base of the crypt and ascend to the top acquiring the characteristics of mature cells of the bowel wall as they ascend.

It is now thought that colorectal cancer cells arise from stem cells where the genetic material regulating growth and division of the stem cell has become defective. This leads to unregulated production of cells which in turn have defective genetic information and cancer formation.

Prior studies have demonstrated that the earliest changes before a cancer develops are changes in cellular proliferation. Now that reliable markers to identify stem cells have been found, the researchers aim to investigate stem cell numbers and changes in distribution in those at normal risk of colorectal cancer and those at higher risk. The researchers hypothesise that changes in cellular proliferation at the top of the crypt in individuals at higher risk of colorectal cancer are due to a change in the number of stem cells in the crypt base.

All patients referred for lower gastrointestinal (GI) endoscopy at a participating centre will be considered for inclusion. Patients with a previous adenomatous polyp resection under surveillance will be considered for inclusion to the polyp group. Patients with ulcerative colitis under surveillance will be considered for inclusion to the ulcerative colitis group.

• Adenomatous polyp
  Patients who have begun the polyp-cancer sequence (ie. are in polyp surveillance after excision of a prior adenomatous polyp) will be used to test those patients at higher risk of colorectal.
• Patients at normal risk of cancer
  Patients found to have endoscopically and histological normal mucosa.
• Ulcerative colitis
  Patients who are under surveillance for known ulcerative colitis will be used to test those patients at higher risk of colorectal.

• Dronamraju SS, Coxhead JM, Kelly SB, Burn J, Mathers JC. Cell kinetics and gene expression changes in colorectal cancer patients given resistant starch: a randomised controlled trial. Gut. 2009 Mar;58(3):413-20. Epub 2008 Oct 31.
• Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007 Oct 25;449(7165):1003-7. Epub 2007 Oct 14.

Inclusion Criteria:

• Referred for endoscopy at participating centre

Exclusion Criteria:

• Age <16 or >85
• Familial polyposis syndrome
• Lynch syndrome
• Known colorectal tumour
• Previous colorectal resection
• Pregnancy
• Chemotherapy in last 6 months
• Therapy with aspirin/other nonsteroidal anti-inflammatory drug (NSAID)
• Other immunosuppressive medication
• Incomplete left sided examination
• Colorectal carcinoma found at endoscopy
• Iatrogenic perforation at endoscopy
• Colorectal cancer on histology
• Microscopic colitis on histology

For the colitis group

• Simple clinical colitis activity index (SCCAI) score > 5