Inhibition of melanoma brain metastasis by targeting melanotransferrin at the cell surface.
Brain metastases are a common feature of malignant melanoma and are associated with poor prognosis. Melanotransferrin (MTf), one of several antigens associated with the surface of melanoma cells, has been demonstrated to promote cell invasion. In this study, we investigated the role of membrane-bound MTf in several of the steps leading to the development of melanoma brain metastasis. Our results indicated that MTf-positive cells were detected in the brains of nude mice injected intravenously with human melanoma SK-Mel 28 cells. Moreover, administration of a single dose of a monoclonal antibody (L235) directed against human MTf significantly reduced the development of human melanoma brain metastases in nude mice. The ability of melanoma cells to cross the blood-brain barrier (BBB) in vitro is correlated with their MTf expression levels at the cell surface. Overall, our results indicated that membrane-bound MTf is a key element in melanoma cell transmigration across the BBB and subsequent brain metastasis. Thus, these data suggest MTf as an attractive target and demonstrate the therapeutic potential of an anti-MTf mAb for preventing metastatic melanoma.
Rolland
Yannève
Y
Molecular Medicine Laboratory, Département d'Hémato-Oncologie, Hôpital Ste-Justine, Université du Québec à Montréal, Montréal, Quebec, Canada.
Demeule
Michel
M
Fenart
Laurence
L
Béliveau
Richard
R
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000378:metabolism; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D016466:CHO Cells; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D058950:Melanoma-Specific Antigens; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases