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News Room > Press Releases 2008
Research Into Colorectal Cancer Uncovers Early Clue October 3, 2008 - Two new studies provide further understanding of some of the genetic variations and molecular changes that might affect the development of colorectal cancer, according to the authors of the research. In a study appearing in the October 1 issue of Cancer Research, British researchers reveal how early precancer might expand within the bowel and, in an animal-model study, show how the related changes are more likely to happen in an inflamed bowel than in a noninflamed bowel. In previous pioneering research, the British team, lead by Janusz A.Z. Jankowski, MD, PhD, from the Digestive Diseases Center at the University of Leicester, in the United Kingdom, observed that the P-cadherin molecule is expressed in the mucous membrane of an inflamed intestine and colon. "P-cadherin is increased in many inflammatory conditions in the bowel - Crohn's disease, colitis, ulcers, radiation damage, dysplasia, and cancer," he told Medscape Oncology. P-cadherin is normally expressed in the basal layer of squamous epithelia and is absent from the healthy intestine and colon. The cadherins are a family of cell-adhesion molecules involved in organ development and morphogenesis. They display tissue-specific distribution and are identified as epithelial, neuronal, or placental. Altered expression of cadherins has been linked to changes in cellular behavior and the development of tumors, the authors explain. In colorectal cancer, P-cadherin is abnormally present in the earliest morphologically recognized neoplastic lesion, known as the aberrant crypt focus, write the authors. "Understanding why [P-cadherin] was expressed so early in all these conditions, [such as Crohn's disease, colitis, and cancer], in the bowel could explain the future development of cancer [in an individual]," said Dr. Jankowski about the impetus for the research. The importance of P-cadherin is in part related to its accelerating effect on abnormal tissue in the colon, he explained. "P-cadherin causes the crypts in the colon to divide - not just individual cells. This accelerates the chance that subsequent mutations [associated with cancer] will be carried in the new crypts. As a consequence, the number of colon cells with mutations that cause cancer increases very quickly. And, when subsequent mutations develop, they have a greater chance of occurring in the larger patch of cells already expressing P-cadherin and the initial mutation," he noted. In the study, samples of normal colon were collected from patients with gastrointestinal complaints undergoing colonoscopy. Also, samples of colon mucosa containing aberrant crypt foci, phenotypically normal colon (from outside the tumor margins), and colorectal cancer were collected when colorectal cancer patients underwent colectomy. Genetic material was extracted from the tissue and subsequently implanted into mice. The methodology allowed researchers to measure the genetic and phenotypic effects of induced P-cadherin expression in the mouse intestine in vivo. The results "strongly suggest" that ectopic or abnormal expression of P-cadherin in the intestine, exacerbated by mucosal damage, can lead to increased crypt fission or the spread of neoplasia, write the authors about the animal models. The next step for the research team is to run clinical trials to suppress P-cadherin, said Dr. Jankowski. First-Ever Genetic Link Between Obesity and Cancer Revealed "Finding genetic mutations associated with cancer means that you can find high-risk people. The goal of this kind of research is to eventually have a gene-predicting model, with a panel of 5 to 10 genes, that gives you a good prognostic tool," Dr. Kaklamani told Medscape Oncology. The findings are published in the October 1 issue of the Journal of the American Medical Association. Several epidemiologic studies have shown an association between obesity and colorectal cancer risk, note the authors. The association between related adiposity, or fatty tissue, and this risk led researchers to focus on adiponectin, a protein secreted by adipose tissue, said Dr. Kaklamani. "Fat people have lower levels of adiponectin and skinny people have higher levels. It is beneficial to have, as far as cancer is concerned," she noted. The new research focuses on a gene called ADIPOQ, which leads to the formation of adiponectin. The study results show that people who inherit a common genetic variant of ADIPOQ carry up to a 30% lower risk for colon cancer than those without the genetic variant. In effect, those without the gene variant and those who have unhealthy blood levels of adiponectin might benefit from early colorectal testing. More studies are needed to confirm whether those without the variant benefit from cancer-prevention lifestyle changes, such as diet and exercise. The study actually consisted of 2 case-control studies: 1 in the New York City metropolitan area looked at Ashkenazi Jews, an ethnic group known to have a high incidence of colorectal cancer; and 1 looked at a more ethnically and geographically diverse population. The second study confirmed the finding that a variant of the ADIPOQ gene was associated with decreased colorectal cancer risk, explained Dr. Kaklamani. Dr. Jankowski reports the following support: an employment and commercial research grant from AstraZeneca; a commercial research grant from Cancer Research UK; commercial research support from Pfizer and AstraZeneca; and speakers bureau honoraria from Ferring and AstraZeneca. He is also an member of the consultant/advisory board for Proctor & Gamble. The authors of the JAMA study have disclosed no relevant financial relationships. Cancer Res. 2008;68:776-7768. |
