HEALTH NEWS

Study Title:

Colon Cancer and GI Inflammation

Study Abstract

P-cadherin is normally expressed in the basal layer of squamous epithelia and absent from the healthy intestine and colon. We have previously shown it to be expressed in all inflamed, hyperplastic, and dysplastic intestinal and colonic mucosa. This study aimed to better understand the mechanisms controlling the expression of P-cadherin and the biological effects of its ectopic presence in the intestine and colon. We investigated the CpG methylation status of the P-cadherin (CDH3) promoter and P-cadherin mRNA and protein expression in cases of familial and sporadic colorectal cancer (CRC). The CDH3 promoter was hypomethylated in colonic aberrant crypt foci, in CRC, and, occasionally, in the normal epithelium adjacent to cancer, demonstrating a potential "field effect" of cancerization. The hypomethylation was also associated with induction of P-cadherin expression in the neoplastic colon (P < 0.0001). We then created transgenic mice that overexpressed P-cadherin specifically in the intestinal and colonic epithelium under the liver fatty acid binding protein promoter. Forced ectopic expression of P-cadherin accompanied by indomethacin-induced inflammation resulted in a 3-fold higher crypt fission rate within the small and large intestines in the homozygous mice compared with the wild-type animals (P < 0.02). We conclude that epigenetic demethylation of the P-cadherin promoter in the human intestine permits its ectopic expression very early in the colorectal adenoma-carcinoma sequence and persists during invasive cancer. Induced P-cadherin expression, especially in mucosal damage, leads to an increased rate of crypt fission, a common feature of clonal expansion in gastrointestinal dysplasia.

From press release:

Scientists investigating a molecule known to play a key role in causing colon cancer have made a series of ground-breaking discoveries that could have major implications for future treatment of the disease, responsible for 655,000 deaths worldwide per year. Their findings are published in the journal Cancer Research, today (Wednesday 1 October 2008).

Led by Professor Janusz Jankowski the Sir James Black Professor of Gastrointestinal Biology and Trials at Barts and The London School of Medicine and Dentistry, researchers examined the cell adhesion molecule P-Cadherin. Having shown previously that this molecule is expressed in the mucous membrane of an inflamed intestine and colon, they wanted to better understand the mechanisms controlling its expression, and the biological effects of its unnatural presence in the intestine and colon. The P-Cadherin gene is important during early development, including in the formation of the foetus, but its actions are suppressed in the normal mature colon in adults. The repression of this gene in inflamed mucosa is lessened however, especially in stem cells, allowing the pockets of gut cells to form buds, enabling the damaged, inflamed mucosa to spread.

Now this latest research has revealed how the bowel becomes abnormal long before obvious changes are observable beneath the microscope, and how early pre cancer (10-15 years before it develops) expands within the bowel. The team have also highlighted the genetic and molecular mechanisms that switch on the gene, causing these processes to occur, and - in a model system - revealed how they are more likely to happen in an inflamed bowel than a non inflamed bowel. Their findings are a dramatic step forward in this field of cancer research and hold promise for future discoveries and therapies.

Colorectal cancer is the third most common form of cancer, and second only to lung cancer as the leading cause of cancer-related death in the Western world. Around 35,000 people a year are diagnosed with the disease in the UK, resulting in around 16,000 deaths.

Professor Jankowski said: "Understanding how a cancer develops so early in the disease gives great hope. If the changes in cell adhesion are understood and can then be identified so early in the disease then patients can be offered preventative therapy or even change of lifestyle to avert cancer developing at all."

Study Information

Anita Milicic, Lea-Anne Harrison, Robert A. Goodlad, Robert G. Hardy, Anna M. Nicholson, Michal Presz, Oliver Sieber, Sonia Santander, James H. Pringle, Nikki Mandir, Philip East, Jolanta Obszynska, Scott Sanders, Elena Piazuelo, Jacqui Shaw
Ectopic Expression of P-Cadherin Correlates with Promoter Hypomethylation Early in Colorectal Carcinogenesis and Enhanced Intestinal Crypt Fission In vivo.
Cancer Research
2008 October
Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom