Anna Sivula

Cyclooxygenase-2 and gastric carcinogenesis

Epidemiological studies have shown that the use of nonsteroid anti‐inflammatory drugs (NSAIDs) is associated with reduced risk of gastric cancer. The best‐known target of NSAIDs is the cyclooxygenase (Cox) enzyme. Two Cox genes have been cloned, of which Cox‐2 has been connected with gastric carcinogenesis. Expression of Cox‐2 is elevated in gastric adenocarcinomas, which correlates with several clinicopathological parameters, including depth of invasion and lymph node metastasis. This suggests that Cox‐2–derived prostanoids promote aggressive behavior of adenocarcinomas of the stomach. Cox‐2 expression is especially prominent in intestinal‐type gastric carcinoma and it is already present in dysplastic precursor lesions of this disease, which suggests that Cox‐2 contributes to gastric carcinogenesis already at the preinvasive stage. Our most recent data show that Cox‐2 is expressed in gastric adenomas of trefoil factor 1 deficient mice. Treatment of these mice with a Cox‐2 selective inhibitor, celecoxib, reduced the size of the adenomas. Taken together these data support efforts to initiate clinical studies to investigate the effect of Cox‐2 inhibitors as chemotherapeutic agents and as adjuvant treatment modalities against gastric neoplasias.

Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer.

SummaryExpression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) associates with reduced survival in human breast cancer. COX-2 may be directly involved with mammary carcinogenesis, since expression of COX-2 is sufficient for formation of breast tumors in transgenic mice, and COX-2 selective inhibitors can suppress tumorigenesis in rodent models of breast cancer. MMP-2 is an extracellular matrix degrading proteolytic enzyme that bas been linked to invasion and metastasis. A direct link between COX-2 and MMP-2 may exist, since inhibition of COX-2 activity can result in reduction of MMP-2 expression and activity. In this study we analyzed protein expression of COX-2 and MMP-2 in tissue array specimens of 278 invasive breast cancers by immunohistochemistry. Immunopositivity of these two markers was correlated with each other and with various clinicopathological parameters including survival. We found high COX-2 expression in 30% and high MMP-2 expression in 83% of the breast cancer specimens, and there was a positive association between the expression of these two factors (p=0.003). It was especially evident that whenever COX-2 expression was high, MMP-2 expression was almost invariably high (95%). Furthermore, high expression of either COX-2 or MMP-2 associated with decreased disease specific survival when compared with the COX-2 or MPP-2 low group (p=0.026 and p=0.021, respectively). Taken together, our results indicate that expression of COX-2 protein is associated with expression of MMP-2 protein in human breast cancer and that both COX-2 and MMP-2 are markers of poor prognosis in breast cancer.

Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines

Gastrointestinal carcinomas synthesize elevated levels of prostaglandin E2 (PGE2), which has been mechanistically linked to carcinogenesis. Recently, microsomal prostaglandin E synthase‐1 (mPGES‐1) was cloned, which seems to be inducible and linked to cyclooxygenase‐2 (Cox‐2) in the biosynthesis of PGE2. We examined expression of mPGES‐1 in intestinal type gastric adenocarcinomas and in gastric cancer cell lines. The transcript for mPGES‐1 was elevated in 57% (4/7) of gastric carcinomas as detected by Northern blot analysis. Moderate to strong mPGES‐1 immunoreactivity was observed in 56% (5/9) of the carcinomas as detected by immunohistochemistry. Furthermore, mPGES‐1 mRNA, protein and microsomal PGES activity were detected in gastric adenocarcinoma cell lines that originated from intestinal type tumors (MKN‐7 and MKN‐28). In contrast to Cox‐2, however, expression of mPGES‐1 mRNA or protein were not induced by phorbol 12‐myristate 13‐acetate (PMA) or interleukin‐1β (IL‐1β) in any of the gastric cancer cell lines tested (MKN‐1, ‐7, ‐28, ‐45 and ‐74). Two gastric cancer cell lines (MKN‐45 and MKN‐74) did not express mPGES‐1 and lacked microsomal PGES activity, but were still able to synthesize PGE2. Because all gastric cell lines expressed cPGES as detected by immunoblotting, it is possible that Cox‐2 can interact with cPGES or with some other yet unidentified PGES in gastric cancer cells. Furthermore, our data show that regulatory mechanisms that drive expression of mPGES‐1 and Cox‐2 dissociate in gastric cancer cell lines.

Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus.

Background: Adenocarcinomas of the gastric cardia and distal oesophagus are at present often considered as one clinical entity because of their comparable increasing incidence, prognosis, and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Aims: The aim of this study was to analyse expression of cyclooxygenase 2 (COX-2) in cardia carcinomas, and correlate this expression with clinicopathological parameters and survival. The results were compared with the prognostic value of COX-2 found for Barrett carcinomas. Methods: Tumour sections of 134 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the gastric cardia and substantially invading the distal oesophagus were immunohistochemically stained using a COX-2 monoclonal antibody. Specimens were blindly scored based on intensity and extent of COX-2 immunopositivity. Results: COX-2 expression was negative to weak in 59% (“COX-2 low”) and moderate to strong in 41% (“COX-2 high”) of tumours. This was significantly lower than in Barrett carcinomas (p<0.0001). COX-2 expression was not correlated with any clinicopathological parameter. A correlation between elevated COX-2 expression and reduced survival, as described for Barrett carcinomas, was not identified for cardiac carcinomas. Conclusions: There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.

Prognostic role of cyclooxygenase-2 in neoadjuvant-treated patients with squamous cell carcinoma of the esophagus

Based on our previous demonstration that elevated cyclooxygenase‐2 (COX‐2) expression is a prognostic factor for reduced survival in patients with adenocarcinoma of the esophagus, the aim of our study was to analyze the role of COX‐2 expression in esophageal squamous cell carcinoma. We analyzed COX‐2 protein expression from 117 consecutive patients by immunohistochemistry using a COX‐2 specific monoclonal antibody. Eighty‐one patients had not received any therapy before surgery whereas 36 patients received neoadjuvant chemotherapy as part of a randomized controlled trial. In the patients who received no chemotherapy, COX‐2 expression was low in 75% and high in 25% of the specimens. In this patient group, high COX‐2 expression associated with distal location of the tumor (p = 0.02), but did not correlate with any other clinicopathological parameter tested, including overall survival. In the patient group who received neoadjuvant chemotherapy, postoperative COX‐2 expression was low in 69% and high in 31%. Interestingly, in this patient group low COX‐2 expression correlated with development of distant metastases (p = 0.03) and to reduced overall survival (p = 0.02). Our results show that the prognostic significance of COX‐2 depends on the histological type of esophageal carcinoma and preoperative treatment of the patient. In conclusion, COX‐2 is not a prognostic marker in squamous cell carcinoma of the esophagus, but low COX‐2 expression is associated with poor prognosis in the neoadjuvant‐treated patients.

COX-2 in cancer

Multiple epidemiological studies indicate that the use of aspirin and other NSAIDs are associated with reduced risk of malignancies especially in the digestive tract. In addition, another NSAID sulindac causes regression of colorectal adenomatous polyps in patients with familial adenomatous polyposis (FAP) [1, 2]. Recent studies suggest that COX-2 is a rational target of NSAIDs in prevention of colorectal cancer. First, elevated levels of COX-2 mRNA and protein, but not those of COX-1, were found in colorectal adenocarcinomas and in their adenomatous precursors [3–5]. Second, selective COX-2 inhibitors suppress neoplasia formation in rodent models of colorectal cancer [6–10]. Importantly, genetic disruption of COX-2 suppresses the polyp formation in ApcΔ716-knockout and in Min mice, which are models for FAP [6, 11]. However, it should be noted that disruption of COX-1 gene also reduced the polyp burden in the Min mouse model [11]. Finally, elevated COX-2 expression was shown to associate with poor prognosis in colorectal carcinoma [12].