S1957 Potential Role of Biological Ageing in Colorectal Cancer: How Many Miles on the Clock?

Abstract

Patients with Inflammatory Bowel Disease (IBD) are at increased risk of developing colorectal cancer. The use of biomarkers to aid in the early detection and diagnosis of colorectal cancer is of interest due to their potential to improve treatment preventing further progression. Calprotectin (S100A8/S100A9) has been identified previously as a potential marker for colorectal cancer, but few studies have looked at its possible role in secondary prevention. Aim: To evaluate the potential for calprotectin in screening for, and early detection of, the transition from inflammation to dysplasia. Methods: Chronic colitis was induced in male Sprague Dawley rats by the administration of trinitrobenzene sulfonic acid (TNBS; 30 mg in 50% ethanol ic), followed six weeks later by reactivation with TNBS (5 mg/kg iv) for three days. To induce colitis-associated dysplasia the rats then received TNBS (iv) twice a week for ten weeks. A group of age-matched normal untreated animals were also included as controls. After sacrifice the colons were removed and analyzed for damage, pathology, and expression of S100A8 and S100A9were measured by real time RT-PCR. Tissue distribution of the S100 proteins was measured by immunohistochemistry. Results: Administration of TNBS caused ulceration and damage as expected, which correlated with the pathological diagnosis. Animals diagnosed with dysplasia had the highest macroscopic damage (p<0.05 vs. normal). Using the ΔΔCt method the fold expression of S100A8 was found to be upregulated and similar in both IBD and dysplasia compared to non specific inflammation (NSI) or untreated, whereas expression of S100A9 was more than 2-fold higher in dysplasia than in IBD. The IHC score for S100A8 showed the highest intensity of staining among the samples diagnosed with IBD and low grade dysplasia. In each case this was significantly higher than the staining intensity found in areas of NSI or high grade dysplasia. When the protein expression for the heterodimer S100A8 & S100A9 was examined the intensity of staining in areas of low grade dysplasia was high, with no difference in the intensity of staining between the other diagnoses. These all showed comparable but lower intensity values compared to low grade dysplasia. In each case there appeared to be a shift from weaker staining in NSI to increased staining during the transition to dysplasia. Interestingly, as the pathologyworsens the expression once again decreases.Conclusion:There is a potential role for S100A8 and S100A9 in secondary prevention via early disease detection of low grade dysplasia or active IBD. Supported in by 1U56 CA126379, RR003050 & 1F31DK077584