Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion.
Mesothelin is a glycosylphosphatidylinositol-linked cell surface molecule expressed in the mesothelial lining of the body cavities and in many tumor cells. Based on the finding that a soluble form of mesothelin specifically binds to ovarian carcinoma cell line OVCAR-3, we isolated cDNAs encoding a mesothelin-binding protein by expression cloning. The polypeptides encoded by the two cloned cDNA fragments matched to portions of CA125, an ovarian cancer antigen and a giant mucin-like glycoprotein present at the surface of tumor cells. By flow cytometric analysis and immunoprecipitation, we demonstrate that CA125 binds to mesothelin in a specific manner. Binding of CA125 to membrane-bound mesothelin mediates heterotypic cell adhesion as anti-mesothelin antibody blocks binding of OVCAR-3 cells expressing CA125 to an endothelial-like cell line expressing mesothelin. Finally, we show that CA125 and mesothelin are co-expressed in advanced grade ovarian adenocarcinoma. Taken together, our data indicate that mesothelin is a novel CA125-binding protein and that CA125 might contribute to the metastasis of ovarian cancer to the peritoneum by initiating cell attachment to the mesothelial epithelium via binding to mesothelin.
Rump
Armin
A
Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-Ku, Tokyo 113-0032, Japan.
Morikawa
Yoshihiro
Y
Tanaka
Minoru
M
Minami
Sawako
S
Umesaki
Naohiko
N
Takeuchi
Masaki
M
Miyajima
Atsushi
A
D000818:Animals; D018394:CA-125 Antigen / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins; D000090204:Mesothelin; D051379:Mice; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding
D018394:CA-125 Antigen; D058851:GPI-Linked Proteins; C451759:MUC16 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C000715528:Msln protein, mouse; D000090204:Mesothelin