Role of cyclooxygenases in colon carcinogenesis

ROLE OF CYCLOOXYGENASES IN COLONCARCINOGENESISDr. NEV N TOPAKSUMMARYColorectal cancer is the second most common cancer and the second leading cause ofcancer death in the United States. Most colorectal cancers arise from preexisting adenomas.Such potentially premalignant lesions should be distinguished from juvenile polyps,hamartomas, and inflammatory polyps, which are not thought to progress to colorectal cancer.Recent evidence suggests that serrated adenomas, hyperplastic polyps, and admixed polypsmay arise through a pathway different from that of conventional adenomatous polyps throughabnormalities in mismatch repair. Regardless of histologic class, polyps larger than 1.0 cm indiameter are more likely to contain carcinoma.Most epidemiologic studies have reported reductions in the incidence of colorectaladenomas, colorectal cancer, and colon cancer mortality associated with the use ofnonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin Several medications mayreduce colorectal cancer risk in FAP. Sulindac reduces the size and number of adenomas.Non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase (COX: prostaglandinendoperoxide synthase) and the synthesis of prostaglandins (PGs), can reduce the formationof colon cancers in experimental animals given carcinogens. Mammalian cells contain tworelated, but unique, isoforms of COX, referred to as COX 1 and COX 2. These two proteinsare encoded by separate genes. The most dramatic difference between these two isozymes isobserved in their patterns of expression. COX-1 is present in most tissues and is involved inthe physiological production of PGs for maintaining normal homeostasis, whereas COX 2,which is induced by mitogens, cytokines and growth factors, is primarily responsible for PGsproduced in inflammatory sites . Recent studies have demonstrated that COX 2 could affectcarcinogenesis via several different mechanisms, including cell proliferation, apoptosis,modulation of the immune system, angiogenesis and adhesion to the extracellular matrix.The purpose of the present study was to analyze proportions of COX 2 and COX 1immunoreactivity in 32 resected specimens of colorectal cancer and 35 colorectaladenomas, to investigate whether there was an association between COX 2 expression andapoptotic index with TUNEL, immunoreactivity of p53, bcl-2α, VEGF, MMP-7. A largeproportion (96.9%) of colorectal cancers expressed COX 2; MMP 7 and VEGF were alsodetected in 75% of tumors . p53 and cylinD1 immunorectivity were % 96,9 and %84.4respectively. COX 1 was only present in 31.2 % of tumors. The enhanced COX 2(97.1),VEGF(25.7), MMP-7(57.1), cyclin D1(85.7), p53(77.1) expression was also observed incolorectal adenomas. There was no staining p53 and cyclin D1 in normal mucosa.Colorectal carcinomas were showed significantly increased MMP-7 expression comparedwith adenomas and normal mucosa.COX 2 expression in colorectal cancers was significantly different from that in normalmucosa.There was no correlation between COX 2 expression and immunoreactivity of p53, bcl-2α,VEGF, MMP-7 in adenomas and colorectal cancers.The expression of VEGF in tumor tissues was inversely correlated with those of p53immunorectivity (r: -0,30 p: 0,05).These results and those of other investigators suggest that COX 2 may be related tothe development of colorectal cancer, but the precise role of COX 2 in colorectal cancer is notyet fully known .