Keynote Conference - Interevent

Symp#29 MMPs and TIMPs
Chairs Ruy Jaeger
Membrane Type I- Matrix Metalloproteinase (MMP14): A Multifaceted Cell Surface Protease in Cancer
Stanley Zucker
Stony Brook University, USA
MMP14, an intrinsic plasma membrane proteinase, plays a critical role in digesting basement membrane and
extracellular matrices and in inducing cancer cell migration, thereby promoting cancer invasion and metastasis. We
and others have demonstrated that MMP14 is highly expressed in most human cancers and correlates with poor
clinical outcome. We have evaluated the role of MMP14 in converting quiescent tumor initiating cells (TICs) to
metastatic cancer cells. Our studies of the hemopexin (PEX) domain of MMP14 have shown that of the 4 outermost
blades, strands I and IV are essential fo cell migration. Peptides mimicking these outermost strands reduced cancer
cell migration and angiogenesis in vitro and lung metastasis in vivo. We next examined the effect of cellular hypoxia on
MMP14 function in TICs. SK-3rd TICs, isolated by passage of human breast cancer cells in immunodeficient mice,
display enhanced lung metastases. Surprisingly, under normoxic conditions, SK-3rd cells displayed minimal increase in
cancer invasion. However, when cultured under hypoxic conditions, a dramatic increase in cell invasiveness in 3D
collagen gels was demonstrated, which coincided with increased localization of MMP14 at the cell surface. These data
suggest that induction of TIC invasion during hypoxia is caused by enhanced trafficking of MMP14 from the trans Golgi
network to the plasma membrane. MMP14 also induces the generation of reactive oxygen species in cancer cells,
leading to enhanced cancer aggressiveness. Our most recent studies incriminated tumor growth factor-beta as a key
intermediary in MMP14 cell signaling in cancer progression.
Rama Khokha
University Western Ontario, Toronto, Canada
Role of matrix metalloproteinases and inflammasome pathway in the development of airway inflammation and
fibrosis
Vincent Lagente
UMR991 INSERM/Université de Rennes 1, Faculté de Pharmacie,
2 avenue du Prof Léon Bernard, 35043 Rennes cedex, France
Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turn-over of extracellular
matrix and so they are suggested to be important in the process of lung disease associated with tissue remodelling.
Pulmonary fibrosis has an aggressive course and is usually fatal for an average of three to six years after the onset of
symptoms. Pulmonary fibrosis is associated with deposition of extracellular matrix (ECM) components mainly collagen
in the lung interstitium. The excessive airway remodeling as a result of an imbalance in the equilibrium of the normal
processes of synthesis and degradation of extracellular matrix components could be in favor of anti-protease
treatments. We previously demonstrated a significant inhibition of bleomycin-induced pulmonary fibrosis in mice by
the MMP inhibitor batimastat. We also reported a correlation of the differences in collagen deposition in the lungs of
bleomycin-treated mice with a reduced molar pro-MMP-9/TIMP-1 ratio in broncholaveolar lavage fluid, beginning as
early as the inflammatory events at day 1 after bleomycin administration. The differences in TIMP-1 level, particularly
at early events after bleomycin administration, suggest that early altered regulation of matrix turnover may be
involved in the further development of bleomycin-induced pulmonary fibrosis. We also demonstrated that
Inflammasome-NLRP3 pathway associated with the IL-1R/MyD88 signaling is required in the bleomycin-induced
increased TIMP-1 level and pulmonary fibrosis in mice. Finally, these observations emphasize those effective therapies
for these disorders must be given early in the natural history of the disease, prior to the development of tissue
remodeling and fibrosis.
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