Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion.
The cell surface hyaluronan receptor CD44 promotes tumor growth and metastasis by mechanisms that remain poorly understood. We show here that CD44 associates with a proteolytic form of the matrix metalloproteinase-9 (MMP-9) on the surface of mouse mammary carcinoma and human melanoma cells. CD44-associated cell surface MMP-9 promotes cell-mediated collagen IV degradation in vitro and mediates tumor cell invasion of G8 myoblast monolayers. Several distinct CD44 isoforms coprecipitate with MMP-9 and CD44/MMP-9 coclustering is observed to be dependent on the ability of CD44 to form hyaluronan-induced aggregates. Disruption of CD44/MMP-9 cluster formation, by overexpression of soluble or truncated cell surface CD44, is shown to inhibit tumor invasiveness in vivo. Our observations indicate that CD44 serves to anchor MMP-9 on the cell surface and define a mechanism for CD44-mediated tumor invasion.
Yu
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Molecular Pathology Unit and MGH Cancer Center, Massachusetts General Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02129, USA.
Stamenkovic
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D000818:Animals; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D006820:Hyaluronic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9; D008545:Melanoma / Q000201:enzymology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D006820:Hyaluronic Acid; D003094:Collagen; D017364:Collagenases; D020780:Matrix Metalloproteinase 9