Expression Of Cyclooxygenase-2 In Colorectal Cancer And Its Clinical Significance

Colorectal cancer is a major cause of morbidity and mortality accounting for an estimated 550,000 deaths annually worldwide. Colonic neoplasia develops in a stepwise fashion progressing from normal mucosa to adenomatous polyps to carcinoma, a process that takes years, thereby providing a prime opportunity for intervention. Although early detection by fecal occult blood testing and sigmoidoscopy can decrease the risk of cancer-related death by 20-30%, most persons never undergo appropriate screening.Epidemiological studies have previously determined that long-term ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) leads to a 40-50% reduction in mortality from colorectal cancer. One of the first observations that NSAID use may be beneficial in the treatment of colon cancer was detailed in a report from Waddell and Loughry who observed a reduction in polyp burden in patients with FAP following ingestion of NSAIDs on a regular basis for pain relief. Cyclooxygenase (COX) is believed to be one of the most important enzymes related to colon cancer. Numerous independent lines of research have supported the concept that NSAIDs alter the biologic processes of colon carcinogenesis.COX is the rate-limiting enzyme in the synthesis of prostaglandins. COX exists in at least two different isoforms COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and relevant to normal physiologic functions. On the other hand, COX-2 is an inducible form and is inducibly expressed in many human tissues by cytokines, pro-inflammatory cytokines, and tumor promoters.Numerous studies found COX-2 overexpressed in many cancers,which suggested that COX-2 maybe play an important role in the pathogenesis of these cancers. But the detailed molecular mechanisms through which COX-2 might be involved in colorectal tumourigenesis are yet not clearly understood. However, recent studies have proposed that COX-2 contributes to tumorigenesis and the malignant phenotype of tumour cells through inhibition of apoptosis, increased angiogenesis, increased invasiveness, modulation of inflammation/immuno-suppression, and conversion of procarcinogens to carcinogens.Following are the possible mechanisms that are being studied.1,. Inhibition of apoptosis of tumor cellsTsujii et al. demonstrated that over-expression of COX-2 in rat intestinal epithelial cells makes them resistant to butyrate-induced apoptosis and elevates Bcl-2 protein expression (which prolongs cell survival). Sheng et al. have shown that over-expression of COX-2 leads to inhibition of programmed cell death in intestinal epithelial cells. Further studies have shown that COX-2 selective inhibitors induce apoptosis in colon cancer cell lines .2 , Altered extracellular matrix adhesionOver-expression of COX-2 may confer a survival advantage on tumour cells by a change in cellular adhesion to the extracellular matrix .3 , Increased invasiveness of tumor cellsIncreased invasiveness of tumor cells has been suggested to be the result of matrix metalloproteinase production. Tsujii et al. attributed this increased invasiveness to the activation of membrane metalloproteinase (MMP) 2.4, Inhibiting immune surveillanceCOX-2 may play an indirect role in the regulation of immunosurveillance against the growth and metastases of cancer.5 -. Enhancing angiogenesis of the tumor cellsCOX-2 is related to tumor angiogenesis in colorectal cancer as COX-2 modulates production of angiogenic factors by colon cancer cells. It is likely that VEGF is one of the most important mediators of the COX-2 angiogenic pathway. Studies have found that the expression of both COX-2 and VEGF is significantly correlated with microvessel density.Numerous experiments including in vitro and animal studies have demonstrated a significant efficacy of selective COX-2 inhibitors for the treatment or prevention of colorectal tumors. So their use for the treatment or prevention of colorectal tumors seems very promising.In this study, we investigated forty-three patients with colorectal cancer were operated from Augest to november 2004 in the third hospital jilin University. The specimens containing 14 normal mucosas and 43 tumor tissues were selected for this study. The immunohistochemistry was used to determine the expression of COX-2. Briefly, slides were deparaffinized, rehydrated, and treated with 3%H2O2 to quench endogenous peroxidase activity. After washing the slides in phosphate buffer saline (PBS) for 5 min, the slides were then microwaved in 10 mmol/L citrate buffer (pH6.0) for 10 min for antigen retrieval. After three washes in PBS, nonspecific bindings were blocked by treating slides with 10% goat serum.The slides were incubated overnight with rabbit antihuman COX-2 monoclonal antibody (dilution, 1:100) at 4 °C. Next, after three washes in PBS, slides were incubated with goat biotinylated antirabbit immunoglobulin G for 15 min at...