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

Yu Q, Stamenkovic I

Molecular Pathology Unit, Massachusetts General Hospital, and Department of Pathology, Harvard Medical School,
Boston, Massachusetts 02129 USA.

We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-beta 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-beta, providing a novel and potentially important mechanism for TGF-beta 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 function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.

MeSH Terms:

Animal
Antigens, CD44/physiology
Cell Membrane/enzymology
Culture Media, Conditioned/pharmacology
Endothelium, Vascular/pathology
Endothelium, Vascular/enzymology
Gelatinase B/metabolism*
Hydrolysis
Keratinocytes/metabolism
Keratinocytes/enzymology
Male
Mammary Neoplasms, Experimental/pathology
Mammary Neoplasms, Experimental/enzymology
Mammary Neoplasms, Experimental/blood supply*
Mice
Mice, Inbred A
Mice, Mutant Strains
Neoplasm Invasiveness
Neovascularization, Pathologic/pathology
Neovascularization, Pathologic/metabolism
Neovascularization, Pathologic/enzymology*
Peptide Hydrolases/metabolism*
Protein Isoforms/metabolism
Support, U.S. Gov't, P.H.S.
Transforming Growth Factor beta/metabolism*
Tumor Cells, Cultured

Substances:

Transforming Growth Factor beta
Protein Isoforms
Culture Media, Conditioned
Antigens, CD44
Gelatinase B
Peptide Hydrolases

Grant support:

CA09216/CA/NCI
GM48614/GM/NIGMS
CA55375/CA/NCI

PMID: 10652271, UI: 20119177