Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells.
Up-regulation of cyclooxygenase-2 (COX-2) and overproduction of prostaglandins have been implicated in the initiation and/or progression of colon cancer. However, it is uncertain in which cells and how COX-2 is induced initially in the tumor microenvironment. We found that a conditioned medium of the colon cancer cell line, LS 180, contained a factor to induce COX-2 in human peripheral blood mononuclear cells. This factor was purified biochemically and revealed to be mucins. A small amount of mucins (approximately 100 ng of protein per ml) could elevate prostaglandin E2 production by monocytes. The mucins induced COX-2 mRNA and protein levels of monocytes in a dose- and time-dependent manner, indicating a COX-2-mediated pathway. We also have examined immunohistochemically the localization of COX-2 protein and mucins in human colorectal cancer tissues. It is noteworthy that COX-2-expressing macrophages were located around the region in which mucins were detectable, suggesting that COX-2 also was induced by mucins in vivo. These results suggest that mucins produced by colon cancer cells play a critical role in the initial induction of COX-2 in the tumor microenvironment.
Inaba
Takaaki
T
Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
Sano
Hajime
H
Kawahito
Yutaka
Y
Hla
Timothy
T
Akita
Kaoru
K
Toda
Munetoyo
M
Yamashina
Ikuo
I
Inoue
Mizue
M
Nakada
Hiroshi
H
D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism; D017077:Culture Media, Conditioned; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008954:Models, Biological; D009000:Monocytes / Q000201:enzymology* / Q000378:metabolism; D009077:Mucins / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017077:Culture Media, Conditioned; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007527:Isoenzymes; D008565:Membrane Proteins; D009077:Mucins; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human