Prostanoids, cyclooxygenases, inflammation and cancer

Erik Dülsner, Sarah Chiblak, Andrea-Pohl-Arnold, Karin Müller-Decker

Focussing especially on cancer, the long-term objective of our research is to substantially contribute to the understanding of the role of prostanoids in epithelial cancer development, particularly during early stages.

As autocoids, prostanoids perform important tasks in the coordination of the concerted activities of different cell types in normal and diseased tissues. The levels of biological active prostanoids are primarily determined by their biosynthesis via the key enzymes cyclooxygenase(COX)-1 and COX-2. Both isoforms are the molecular targets of non-steroidal anti-inflammatory drugs, while COXibs represent selective COX-2 inhibtors. The inactivation of prostanoids by metabolic clearance is catalyzed by 15-prostglandin dehydrogenase (15-PGDH).

Accordingly, the expression and activity of COX and 15-PGDH are strictly regulated under normal conditions. A transient up- or down-regulation of these enzymes, was found during irritation and tissue regeneration. A permanent deregulation of COX-2 and 15-PGDH was observed during carcinogenesis in both humans and mice.

Moreover, a cause-and-effect relationship exists between aberrant COX-2 expression/activity and the development of dysplastic and malignant lesions in various epithelia.

We previously reported that keratin 5 promoter-driven COX-2 overexpression and activity in basal cells of stratified epidermis and urinary bladder spontaneously caused hyperplasia and dysplasia. Moreover, transitional cell carcinomas were spontaneously induced in the urinary bladder, while mouse skin was sensitized for carcinogenesis.
Hyperproliferative and dysplastic lesions were also induced in a COX-2- and PG-dependent manner in mammary glands (fibrocystic changes like in humans) and in pancreas (pre-invasive duct-derived neoplasms resembling so called human IPMN and PanIN lesions). The cognate human diseases were consistently found to overexpress COX-2. Basic research aiming at a better understanding of COX-2- and PG-mediated effects on growth, angiogenesis, invasion, and immune surveillance is mantadory for an improvement of early diagnosis and treatment of epithelial cancers. By means of COX-2 transgenic mouse models and ex vivo epithelial cultures, a unique possibility is given to focus on the identification of molecular pathways leading to the formation and malignant progression of early-stage epithelial cancer lesions.




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