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