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

TLDR

CD44 serves as a cell‑surface docking receptor for active MMP‑9, and surface localization of MMP‑9 is required for its promotion of tumor invasion and angiogenesis. The study shows that CD44‑dependent surface localization of MMP‑9 activates latent TGF‑β, linking CD44, MMP‑9, and TGF‑β to promote tumor invasion, angiogenesis, and tissue remodeling.

Abstract

We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-β in the control of tumor-associated tissue remodeling. CD44 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 for its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-β, providing a novel and potentially important mechanism for TGF-β activation. In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-β. These observations suggest that coordinated CD44, MMP-9, and TGF-β function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.