Elsevier

European Journal of Cancer

Volume 37, Issue 12, August 2001, Pages 1469-1474
European Journal of Cancer

Expression of cyclooxygenase-2 (COX-2) mRNA in human colorectal adenomas

https://doi.org/10.1016/S0959-8049(01)00137-XGet rights and content

Abstract

Cyclooxygenase-2 (COX-2) is an important target for the suppression of colorectal tumorigenesis by non-steroidal anti-inflammatory drugs (NSAIDs). To evaluate the role of COX-2 in human sporadic colorectal adenomas, COX-2 mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in 63 adenomas. COX-2 mRNA was detected in all the adenomas at higher levels than in normal colorectal mucosa (P<0.001). Levels of expression in the adenomas were correlated with their size (P=0.019), but no relationships were demonstrable between COX-2 expression and adenoma location, macroscopically observed configuration or microscopic degree of dysplasia. These findings suggest that COX-2 plays an important role in the growth of sporadic colorectal adenomas.

Introduction

Much interest has focused on the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) suppress the development certain gastrointestinal tumours, particularly colorectal carcinomas [1]. Epidemiological evidence indicates an inverse relationship between the use of NSAIDs and colorectal cancer [2]. A decrease in the mean number of polyps and in their mean diameter was demonstrated in patients with familial adenomatous polyposis (FAP) treated with NSAIDs [3]; not only polyps in FAP and colorectal cancers, but also sporadic adenomas have been shown to be less likely among patients who consumed NSAIDs 4, 5. The precise mechanism underlying these effects remains to be clarified, but appears to depend on the blockade of COX-2 [1].

COX is a key regulatory enzyme in prostaglandin biosynthesis. Two isoenzymes have been identified [6]. While COX-1 is apparently expressed constitutively in virtually all mammalian tissues, COX-2 expression is almost undetectable under physiological conditions in most tissues, but can be induced by proinflammatory agents, growth factors and mitogens 6, 7. A high level of COX-2 expression is present in human colorectal cancers 8, 9, 10, 11, 12, 13. Studies using in vitro model systems showed cells overexpressing COX-2 to produce prostaglandins that stimulate angiogenesis, inhibit apoptosis, and increase the metastatic potential 6, 14.

Colorectal adenomas are currently considered the precursor lesions for most colorectal cancers. The finding in the National Polyp Study that after removal of polyps there was a lower incidence of colorectal cancers than expected, supports this hypothesis [15]. In animal models, COX-2 expression is detected in 80–90% of colorectal adenocarcinomas and in 40–50% of adenomas [16]; induction of COX-2 is a very early event in the sequence of polyp formation and development [17]. Specific inhibition of COX-2 caused a greater reduction in polyp number than sulindac, which inhibits both COX-1 and -2 [17]. Since expression of COX-2 in sporadic human colorectal adenomas has been incompletely investigated, we analysed the relationship of COX-2 expression in these adenomas to various clinicopathological features.

Section snippets

Patients and methods

We studied a total of 63 randomly chosen polyp specimens that had been removed from patients treated at our institution between January and October 1999. Fifty-eight polyps from 38 patients (mean polyp number 1.5 per patient; range 1–6) were excised completely by endoscopic polypectomy; five other polyps from 4 patients were obtained from surgically-resected specimens. No patient had a history of regular use of NSAID. The maximum diameter of a polyp was measured immediately after removal, prior

Results

Clinicopathological findings for the 63 adenomas are listed in Table 1. Sizes of adenomas varied from 3 to 25 mm in maximum diameter (mean 10 mm). Adenoma size was significantly correlated with the degree of dysplasia (P=0.025, Table 2). COX-1 mRNA was detected in all adenomas and normal mucosal samples. COX-2 mRNA expression was expressed relative to that of COX-1 (COX-2 index, representing the COX-2/COX-1 band density ratio). COX-2 mRNA was detected in only 35% of normal mucosal samples, and

Discussion

In the present study, we demonstrated that COX-2 mRNA expression was markedly increased in sporadic colorectal adenomas compared with normal colorectal mucosa. Moreover, COX-2 mRNA expression was significantly greater in adenomas with larger diameters.

Other recent studies have also examined COX-2 mRNA expression in human sporadic colorectal adenomas; Eberhart and colleagues [10] found a marked excess in COX-2 mRNA expression in six of 14 adenomas compared with paired normal mucosal samples.

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