Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis

We have uncovered a novel functional relationship between the hyaluronan re ceptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-beta in the control of tumor-associated tissue remodeling. CD 44 provides a cell surface docking receptor for proteolytically active MMP- 9 and we show here that localization of MMP-9 to cell surface is required f or its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-beta, providing a novel and potentially important mechanism for TGF-be ta activation. In addition, we show that MMP-9, localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-beta . These observations suggest that coordinated CD44, MMP-9, and TGF-beta fun ction may provide a physiological mechanism of tissue remodeling that can b e adopted by malignant cells to promote tumor growth and invasion.