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 metasta sis by mechanisms that remain poorly understood. We show here that CD44 ass ociates with a proteolytic form of the matrix metalloproteinase-9 (MMP-9) o n the surface of mouse mammary carcinoma and human melanoma cells. CD44-ass ociated cell surface MMP-9 promotes cell-mediated collagen IV degradation i n vitro and mediates tumor cell invasion of G8 myoblast monolayers. Several distinct CD44 isoforms coprecipitate with MMP-9 and CD44/MMP-9 coclusterin g is observed to be dependent on the ability of CD44 to form hyaluronan-ind uced aggregates. Disruption of CD44/MMP-9 cluster formation, by overexpress ion of soluble or truncated cell surface CD44, is shown to inhibit tumor in vasiveness in vivo. Our observations indicate that CD44 serves to anchor MM P-9 on the cell surface and define a mechanism for CD44-mediated tumor inva sion.