Angiogenic markers, neovascularization and malignant deformation of Barrett's esophagus.
The molecular events underlying progression of Barrett's esophagus to adenocarcinoma remain an area of active investigation. Neovascularization and angiogenesis have been studied in esophageal adenocarcinomas by counting of microvessels after staining with vascular markers, and by immunohistochemistry for vascular endothelial growth factor. Angiogenesis appears to be increased early in the neoplastic process, but has poor prognostic value. We have demonstrated that expression levels of two important genes that regulate cell growth, namely inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, are frequently upregulated in Barrett's esophagus and associated adenocarcinomas. COX-2 expression may be related to reflux of bile salts, which induce COX-2 expression in Barrett's tissues and esophageal adenocarcinoma cells in vitro. COX-2 inhibition induces apoptosis and blocks proliferation in COX-2-expressing esophageal adenocarcinoma cells in vitro, and blocks angiogenesis in both in vivo and in vitro models. Although controversial, recent evidence suggest that iNOS-derived NO can inhibit angiogenesis in some model systems. In conclusion, both iNOS and COX-2 appear to be involved in Barrett's-associated neoplastic progression, but COX-2 inhibition is more promising as a chemopreventive strategy. COX-2 inhibition may exert beneficial effects by decreasing angiogenesis and epithelial proliferation, and by facilitating apoptosis of epithelial cells that have undergone DNA damage.
Wilson
K T
KT
Department of Medicine, Division of Gastroenterology, and Greenebaum Cancer Center, University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore 21201, USA. kwilson@umaryland.edu
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D004947:Esophagus / Q000098:blood supply; D006801:Humans; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012680:Sensitivity and Specificity
D043925:Angiogenesis Inducing Agents; D014408:Biomarkers, Tumor; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases