Regulation angiogener Wachstumsfaktoren (VEGF-A und C) durch Cyclooxygenasen (COX-1 und 2) beim Barrett-Karzinom: Implikationen für Chemopräventionskonzepte

Abstract

Background: Prevention of esophageal adenocarcinomas within the precancerous Barrett’s esophagus by inhibition of the enzyme cyclooxygenase (COX) is recognized as a promising strategy. Regulation of angiogenesis is regarded as one major effect of COX. Materials and Methods: Expression of COX-1 and 2, as well as VEGF-A- and C mRNA was determined in 97 primary resected Barrett’s cancer cases, using RT-PCR. COX protein expression was analyzed using immunhistochemistry. Cell culture experiments using selective inhibitors of COX-1 (SC-560), COX-2 (rofecoxib) or non-selective COX-inhibitors (diclofenac) were assigned to substantiate a potential regulatory relationship between COX and angiogenesis. Results: All carcinomas were positive for COX-1 and COX-2 protein. mRNA expression levels varied between tumor tissues of different patients. The expression levels of both COX-isoforms were strongly correlated with each other as well as with VEGF-A and C. Exposition of esophageal cancer cell lines OE-33 and OSC-1 with COX-inhibiting drugs lead to a significantly reduced expression of VEGF-A and VEGF-C. Conclusions: The variable expression of both COX-isoforms and the strong significant correlation with the proangiogenetic factors VEGF-A and C suggests a pathogenetic role in Barrett’s carcinogenesis, via an effect on angiogenesis and lymphangiogenesis. The functional relationship was substantiated by cell cultural inhibition experiments. Thus, chemoprevention by COX-inhibition may be — at least in part — antiangiogenetic in nature.