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of E-cadherin by MMP-3 has been shown to directly mediate EMT in renal tubular
epithelial cells (Zheng et al.
2009
).
EMT also could be induced by overexpression of MMP-9 and MMP-28 (epily-
sin). In SCp2 mammary cells, MMP-9-induced EMT was associated with the loss of
cytokeratin and acquisition of vimentin in a subset of scattering, motile cells
(Orlichenko and Radisky
2008
). Stable and irreversible EMT was shown to be
triggered by the overexpression of proteolytically active MMP-28 in lung A549
adenocarcinoma cells (Illman et al.
2006
). Coordinately, MMP-28-stimulated EMT
was accompanied by the loss of cell surface E-cadherin, increased levels of bioactive
TGF
complexes, upregulation of
MT1-MMP and MMP-9, and increased cell invasion of collagen matrices. Interest-
ingly, the onset of EMT was sensitive to a general MMP inhibitor GM6001, but once
TGF
b
-dependent EMT had occurred, the cell mesenchymal-like phenotype became
MMP-independent (Illman et al.
2006
). In a similar fashion, once initiated, the
progression of invasive mammary carcinomas in transgenic MMP-3 mice becomes
independent of continuous MMP-3 expression (Sternlicht et al.
1999
).
Therefore, select MMPs can be induced during EMT or directly trigger EMT or
EMT-related processes (Fig.
7.1
). Regardless of the ambiguous causality in
EMT-MMP relations, EMT-associated MMPs are likely to proteolytically degrade
cell-cell junction proteins and catalytically modify ECM at the tumor/stroma
border, thereby assisting invasion of malignant cells at the leading edge of infiltrat-
ing carcinomas.
b
due to proteolytic processing of latent TFG
b
7.3 Escape from the Primary Tumor: Breaking the Integrity
of the Epithelium and Its Basement Membrane
The detachment of aggressive tumor cells from the primary tumor is regarded as an
early step in the metastatic cascade and often as a prerequisite to metastatic
dissemination via hematogenous or lymphatic routes. For this reason, it is plausible
to expect that the MMPs induced during EMT would be capable of proteolytic
degradation of tight cell-cell contacts involving E-cadherin and the BM underlying
the epithelium. Indeed, constitutive shedding of E-cadherin ectodomain by proteo-
lytically active MMP-3 and MMP-7 was demonstrated from the surface of MCF-7
and MDCK in vitro (Noe et al.
2001
) and injured lung epithelium in vivo (McGuire
et al.
2003
). Inhibition of E-cadherin-mediated cell aggregation and induction
of collagen invasion by the released cadherin ectodomain strongly suggested that
select MMPs can proteolytically regulate cell invasion in vivo. In addition to
MMPs, E-cadherin can be proteolytically shed by other proteases, including
ADAM10 (Maretzky et al.
2005
) and kallikrein 6 (Klucky et al.
2007
).
Another mechanism of tumor disaggregation in vivo involves shedding of
3 integrin ectodomain by MT1-MMP, recently demonstrated for the ovarian
carcinoma cells (Moss et al.
2009
). MT1-MMP-mediated spontaneous release of
a
