Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis.
Cyclooxygenase-2 (COX-2) was recently reported (M. Tsujii and R. N. DuBois, Cell, 83: 493-501, 1995) to affect the metastatic potential of cells. Previous studies (M. Fukuda, Cancer Res., 56: 2237-2244, 1996) indicated that sialyl Lewis antigen expression is correlated with hematogenous metastasis of colon cancer. In the present study, we investigated the interaction between COX-2 activity, expression of sialyl Lewis antigens, in vitro cancer cell adhesion to endothelial cells, and in vivo metastatic potential. Effects of COX-2 activity and prostaglandin E(2) on cell adhesion, expression of sialyl Lewis antigens, and glycosyltransferase genes were determined in Caco-2-m (COX-2 low level), Caco-2-COX-2 (programmed to overexpress COX-2), and HT-29 (COX-2 high level) cells. Metastatic spread of these cells to the liver was also investigated. Caco-2-COX-2 cells had increased SPan-1 levels and increased adherence to endothelial cells via SPan-1 compared with Caco-2-m cells. HT-29 cells expressed sialyl Lewis a and adhered to endothelial cells via sialyl Lewis a. Treatment with a COX-2 inhibitor, celecoxib, decreased SPan-1 and sialyl Lewis a expression and adherence to endothelial cells. beta 3Gal-T5 and ST3Gal III and IV expression was inhibited by celecoxib and was enhanced by prostaglandin E(2) treatment. Caco-2-COX-2 and HT-29 cells metastasized to the liver, whereas Caco-2-m cells did not. Pretreatment with celecoxib reduced the metastatic potential as well as anti-sialyl Lewis antibodies. Our results indicate a direct link between COX-2 and enhanced adhesion of carcinoma cells to endothelial cells, and enhanced liver metastatic potential via accelerated production of sialyl Lewis antigens. COX-2 inhibitors may suppress metastasis.
Kakiuchi
Yoshimi
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. kakiuchi@medone.osaka-u.ac.jp
Tsuji
Shingo
S
Tsujii
Masahiko
M
Murata
Hiroaki
H
Kawai
Naoki
N
Yasumaru
Masakazu
M
Kimura
Arata
A
Komori
Masato
M
Irie
Takanobu
T
Miyoshi
Eiji
E
Sasaki
Yutaka
Y
Hayashi
Norio
N
Kawano
Sunao
S
Hori
Masatsugu
M
D000818:Animals; D018938:Caco-2 Cells; D002448:Cell Adhesion; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D016695:Glycosyltransferases / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009844:Oligosaccharides / Q000032:analysis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D000080506:Sialyl Lewis X Antigen
D007527:Isoenzymes; D008565:Membrane Proteins; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D016695:Glycosyltransferases; D015232:Dinoprostone