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single-cell size microtracs. This ECM micropatterning assists further cell locomo-
tion and cell-mediated expansion of matrix platforms capable of accommodating
collective cell migration. This transition is controlled by multistep pericellular
proteolysis executed by cell surface proteases, particularly by MT1-MMP, in
tight coordination with
1 integrins and F-actin. In collagen-rich matrices, the
widening of the ECM tracks, i.e., macropatterning, and the induction of multicellu-
lar invasion also depend on MT1-MMP-mediated collagenolysis (Wolf et al.
2007
).
It appears from these models that individual MT1-MMP-expressing tumor cells that
have escaped from the edge of a solid tumor and infiltrated surrounding stroma would
govern the subsequent collective tumor cell invasion. This scenario, however, could be
attributed to the mesenchymal origin of the HT-1080 fibrosarcoma cells or upregula-
tion of mesenchymal markers by the MDA-MB-231 carcinoma cells. In conditions,
more closely mimicking the physiological situation, i.e., when tumor cells retain their
epithelial markers such as E-cadherin and p120 catenin in SCC12 and A431 squamous
cell carcinomas, the collective invasion in 3D collagen model system was shown to be
invariably led by stromal fibroblasts (Gaggioli et al.
2007
). Moreover, carcinoma cells
invading collagen gels as collective chains alsomaintained their epithelial markers and
were crucially dependent on close contacts with fibroblasts. The leading fibroblasts
were demonstrated to generate tracks in the matrix, suggesting the role for proteases
andMMPs in collective cancer cell invasion; however, the nature of these proteases or
the identity of the specific MMPs was not elucidated in this study (Gaggioli et al.
2007
),
but it is possible that some or all of these matrix-degrading MMPs may come from the
leading fibroblasts or tumor-activated fibroblasts.
b
7.5 Secreted vs. Cell Surface-Anchored MMPs
An important aspect of MMP-mediated cellular invasion is whether secreted MMPs,
which do not contain a transmembrane domain or membrane-anchoring sequence,
have any significant role during tumor invasion or whether cell surface MMPs are
the sole MMPs that execute pericellular proteolysis. Historically, the elevated expres-
sion of secreted MMPs has been demonstrated in metastatic carcinomas, especially at
the leading edge, resulting in the concept that secreted MMPs might indeed play a
substantial role in tumor spreading. However, cell surface bound MMPs are the only
proteases which logically accommodate the directionality of tumor invasion.
Given the ability of many secreted MMPs to bind to cell surface-docking
molecules, paradoxically, it might not matter whether MMPs are intrinsically
tethered to the plasma membrane (such as MT-MMPs) or initially secreted into
the intercellular space (such as MMP-2 or MMP-9) (Fig.
7.2
). Importantly, upon
binding to the cell surface, secreted MMPs frequently process and activate their
respective membrane receptors and also initiate signal transduction pathways
determining the survival of tumor cells or efficiency of their migration and invasion.
Secreted MMP-1 produced by stromal fibroblasts was shown to bind to and cleave
the protease-activated receptor 1 (PAR-1) on breast carcinoma cells, generating
