Prostaglandins as mediators of COX-2 derived carcinogenesis in gastrointestinal tract.
This review was designed to show the role of expression of cyclooxygenase (COX)-1 and COX-2 in the cancerogenesis of esophagus, stomach and colon. Unlike COX-1, which is expressed in the normal esophago-gastro-colonic mucosa, COX-2 was found to be expressed mainly in the pre-cancer changes in the mucosa including Barrett's esophagus, Helicobacter pylori (H. pylori)-induced gastritis and inflammatory changes in colonic mucosa. In Barrett's esophagus, prostaglandins (PGs) derived from upregulated COX-2 contribute to the progression of low-grade to high-grade dysplasia and finally to cancer. In chronic gastritis induced by chronic H. pylori infection, overexpression of COX-2 is probably induced by inflammatory cytokines, growth factors, especially gastrin and reactive oxygen species leading to mutagenesis and subsequent metaplasia, dysplasia and cancer formation. The imbalance between cell proliferation and apoptosis caused mainly by products of COX-2 leads to cancerogenesis. Similarly, in colorectal cancer the overexpression of COX-2, possibly induced by the action of growth promoting factors including progastrin and gastrin and overexpression of survivin contribute to the colorectal cancerogenesis that could be, at least in part, amended by the treatment with specific COX-2 inhibitors. We conclude that: 1) COX-2-derived PGs play a key role in the tumorigenesis in the gastrointestinal tract; 2) The tumor-promoting effect of PGs may be attributed to their ability to stimulate cell proliferation and migration, to inhibit the apoptosis and to increase angiogenesis and invasiveness; 3) In accordance to the proposed major role of COX-2 in cancerogenesis, selective COX-2 inhibitors have been shown in numerous studies to exhibit strong chemopreventive effect on the development of gastrointestinal cancers.
Konturek
P C
PC
Department of Medicine, University Erlangen-Nuremberg, Germany. peter.konturek@med1.imed.uni-erlangen.de
Kania
J
J
Burnat
G
G
Hahn
E G
EG
Konturek
S J
SJ
D000818:Animals; D002471:Cell Transformation, Neoplastic; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D011230:Precancerous Conditions / Q000503:physiopathology; D011453:Prostaglandins / Q000502:physiology*
D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2