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Vol. 14, No. 2, pp. 163-176, January 15, 2000
and promotes tumor invasion and angiogenesis
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-
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-, providing a
novel and potentially important mechanism for TGF- activation. In
addition, we show that MMP-9 localization to the surface of normal
keratinocytes is CD44 dependent and can activate latent TGF-. These
observations suggest that coordinated CD44, MMP-9, and TGF- function
may provide a physiological mechanism of tissue remodeling that can be
adopted by malignant cells to promote tumor growth and invasion.
[Key Words:
MMP-9; CD44; TGF-; tumor angiogenesis; tumor invasion]
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