Cyclooxygenase 2 expression in nasopharyngeal carcinoma: immunohistochemical findings and potential implications.

BACKGROUND: Cyclooxygenase 2 (COX-2), an inducible prostaglandin synthase, participates in inflammatory and neoplastic processes. It is expressed by various tumours and contributes to carcinogenesis. Notably, COX-2 inhibitors appear to have tumour suppressor effects and are being evaluated in clinical trials. AIMS: To investigate COX-2 expression in nasopharyngeal carcinoma (NPC), a common tumour in parts of Asia, and to discuss potential implications. METHODS: Eighty five cases of NPC were reviewed. COX-2 immunohistochemistry and semiquantitative assessment of expression in nasopharyngeal biopsies were performed. Because COX-2 is proangiogenic, tumour microvessel density was also assessed with the use of CD31 immunohistochemistry. RESULTS: Histologically, 78 NPCs were undifferentiated, six were non-keratinising, and one was keratinising. Thirty nine NPCs had adjacent dysplastic epithelium. COX-2 expression was noted in 60 NPCs, 14 of 39 samples of dysplastic epithelium, and only one of 25 samples of normal epithelium (p < 0.01). Microvessel density was not significantly different between COX-2 positive and COX-2 negative tumours (p = 0.774). Tumour COX-2 positivity was not associated with higher tumour stage (p = 0.423). CONCLUSION: COX-2 expression is more frequently seen as nasopharyngeal epithelium progresses from normal to dysplastic to carcinoma. This suggests that COX-2 contributes to the multistep process of NPC carcinogenesis. COX-2 represents a therapeutic target for COX-2 inhibitors, and there is thus a basis for the further investigation of this adjuvant treatment modality for NPC. COX-2 inhibitors are known to potentiate the antitumour effects of radiotherapy, which is the primary treatment for NPC.

TNP-470 inhibits 7,12-dimethylbenz[a]anthracene-induced mammary tumor formation when administered before the formation of carcinoma in situ but is not additive with tamoxifen.

In many women pathologic lesions, such as hyperplasia and carcinoma in situ, precede invasive breast cancer. We have shown that tissue vascularity increases with histologic progression to invasive disease. Similarly, in the well-characterized 7,12-dimethylbenz[a]anthracene (DMBA) model of mammary tumorigenesis, preinvasive lesions exhibit increased vascularity with progression. Using this model we asked whether inhibition of angiogenesis would block progression and if so, at which stage. We treated rats with DMBA followed by the potent angiogenic inhibitor, TNP-470, and/or tamoxifen starting 1 day or 6 weeks later. Histopathology and in vitro angiogenic potential of mammary organoids were evaluated 3 months after DMBA. All statistical tests were two-sided. Early TNP-470 and tamoxifen treatment inhibited the formation of carcinoma in situ (p < 0.001) and invasive disease (p < 0.001). However, their effects were not additive, despite their unique mechanisms of action. TNP-470 administration begun at the time of microscopic carcinoma in situ formation was unable to prevent the further development of carcinoma in situ or invasive breast cancer, whereas tamoxifen was highly effective (p = 0.001). There was no added benefit of combining TNP-470 and tamoxifen. TNP-470 therapy, unlike tamoxifen, did not inhibit the angiogenic potential of DMBA-treated normal mammary organoids, supporting its lack of a direct effect on the epithelium. These data provide proof-in-principle that inhibition of angiogenesis early in mammary tumorigenesis prevents mammary tumor formation in a hormone-sensitive model, indicating that angiogenesis is a potential target for cancer chemoprevention. Interactions with other chemopreventive strategies and the timing of administration must be thoroughly examined in vivo.