Increased Colorectal Epithelial Cell Proliferation and Crypt Fission Associated with Obesity and Roux-en-Y Gastric Bypass Anita Sainsbury, 1 Robert A. Goodlad, 3 Sarah L. Perry, 1 Stephen G. Pollard, 2 Gerard G. Robins, 1 and Mark A. Hull 1 1 Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, University of Leeds, St. James’s University Hospital; 2 Department of Obesity Surgery, St. James’s University Hospital, Leeds, United Kingdom; and 3 Histopathology Unit, London Research Institute, Cancer Research UK, London, United Kingdom Abstract Background and Aims: The relationship between obesity, weight reduction, and future risk of colorectal cancer is not well understood. Therefore, we compared mucosal biomarkers in normal weight individuals [body mass index (BMI), 18.5-24.9 kg/m 2 ] with those in morbidly obese patients (BMI >40 kg/m 2 ) before and 6 months after Roux-en-Y gastric bypass (RYGB). Methods: Rectal epithelial cell mitosis, crypt area, and crypt branching were measured following whole crypt microdissection. Apoptosis was measured by immuno- histochemistry for neo-cytokeratin 18 on fixed tissue sections. Serum levels of C-reactive protein and cytokines were assayed in combination with quantifi- cation of mucosal proinflammatory gene expression by real-time RT-PCR. Results: Twenty-six morbidly obese patients (mean BMI, 54.4 kg/m 2 ) had significantly increased mitosis, crypt area, and crypt branching (all P < 0.01) compared with 21 age- and sex-matched normal weight individuals (mean BMI, 22.5 kg/m 2 ). Morbidly obese patients underwent a mean excess weight loss of 41.7% at a mean of 26 weeks after RYGB. Surprisingly, this was associated with a further increase in mitosis and decreased apoptosis of epithelial cells. At the same time, lower levels of serum C-reactive protein and interleukin-6 following RYGB were accompanied by a reduction in mucosal IL-6 protein content but elevated mucosal expression of other proinflammatory genes such as cyclooxyge- nase-1 and cyclooxygenase-2. Conclusions: Mucosal biomarkers, accepted as indica- tors of future colorectal cancer risk, are increased in morbidly obese patients compared with normal weight controls. The hyperproliferative state that exists 6 months after RYGB may have important implications for long-term colorectal cancer risk in bariatric surgery patients. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1401–10) Introduction Multiple epidemiologic studies have described excess body weight as an independent risk factor for develop- ment of colorectal cancer (1, 2). In general, the relative risk of colorectal cancer increases with excess body weight from overweight [defined as body mass index (BMI; weight/height 2 ) 25-29.9 kg/m 2 ] to obesity (BMI >30 kg/m 2 ), compared with normal weight individuals (BMI, 18.5-24.9 kg/m 2 ). The relative risk of colorectal cancer in subjects in the highest BMI group (usually stratified as BMI >28-30 kg/m 2 ) has been reported to vary between 1.5 and 2.0 compared with normal weight controls, with the association being stronger for colonic than rectal cancer, and for men rather than women (1, 2). It has been estimated that 69,000 colorectal cancer–related deaths per year (based on WHO mortality rates for the year 2001) worldwide can be attributed to being overweight and obesity (3). The burden of excess body weight–related colorectal cancer is likely to increase significantly in the future with the continuing ‘‘obesity epidemic’’ (4). Elevated BMI is also associated with increased risk of colorectal adenoma (1, 2), which suggests that body size influences the premalignant stages of colorectal carcino- genesis during tumor initiation and adenoma growth. A relationship between excess body weight and early stages of colorectal carcinogenesis implies that weight loss in overweight/obese individuals could lead to reduced future risk of colorectal cancer. However, the hypothesis that weight loss reduces subsequent colorec- tal cancer risk has not been addressed directly by any long-term cohort epidemiologic study, apart from the Iowa Women’s Health Study, which showed a nonsig- nificant 18% decrease in colorectal cancer incidence in those postmenopausal women who had at least one previous episode of intentional weight loss of >20 pounds (5). An alternative experimental strategy is to quantify colorectal epithelial cell and crypt biomarkers as surrogate measures of future neoplastic risk (6). Cancer Epidemiol Biomarkers Prev 2008;17(6). June 2008 Received 12/7/07; revised 3/4/08; accepted 3/31/08. Grant support: World Cancer Research Fund International. M.A. Hull is a Medical Research Council (UK) Senior Clinical Fellow. Note: Supplementary data for this article are available at Cancer Epidemiology Biomarkers and Prevention Online (http://cebp.aacrjournals.org/). Requests for reprints: Mark Hull, Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, University of Leeds, St. James’s University Hospital, Leeds LS9 7TF, United Kingdom. Phone: 44-113-343-8650; Fax: 44-113-343-8702. E-mail: M.A.Hull@leeds.ac.uk Copyright D 2008 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-2874 1401 Downloaded from http://aacrjournals.org/cebp/article-pdf/17/6/1401/2267580/1401.pdf by guest on 14 June 2022