Biology Reference
In-Depth Information
Invadopodia-mediated matrix proteolysis involves close coordination of MT1-
MMP with actin and cortactin to recruit MT1-MMP to cell-ECM contacts
(Artym et al.
2006
) and also with caveolin-1 to traffic MT1-MMP to lipids rafts
(Yamaguchi et al.
2009
). When invadopodial localization of MT1-MMP was
disrupted, overexpression of MT1-MMP in melanoma cells did not facilitate
ECM degradation or cell invasiveness (Nakahara et al.
1997
), further emphasizing
that both structural and enzymatic coordinations are required during invadopodia
function. However, the structural organization of invadopodia per se appears to be
MT1-MMP-independent. Thus, the invadopodial actin-cortactin structures were
formed in MDA-MB-231 breast carcinoma cells upon inhibition or depletion of
MT1-MMP, but were unable to degrade matrix and assist tumor cell invasion
(Artym et al.
2006
). Initially, MT1-MMP and also its direct target, MMP-2, were
found to be the major MMPs responsible for mediating matrix degradation by the
proteolytically active invadopodia of breast carcinoma cells (Kelly et al.
1998
). The
active form of MMP-9, closely associated with CD44, was also implicated in the
invadopodia-associated matrix degradation and tumor cell migration during breast
cancer progression (Bourguignon et al.
1998
). Recently, the functional proteolytic
activity of invadopodia has started to be attributed exclusively to MT1-MMP
(Rowe and Weiss
2008
). Nevertheless, in addition to MT1-MMP, both MMP-2
and MMP-9 have been repeatedly found central to invadopodia-mediated matrix
degradation (Linder
2009
).
Spatial control of MT1-MMP distribution and pericellular proteolysis at the
leading edge of an individual cell has been shown to create a complex sensor axis,
actually guiding cell migration in a certain direction (Packard et al.
2009
). Although
it is still not completely clear which proteases and substrate molecules are responsi-
ble for the very
initial
induction of a unidirectional proteolysis and chemoattractive
cell migration, it has become clear that MT1-MMP and native and denatured
collagens play a critical role in mediating these processes (Friedl and Wolf
2009
).
The recent insights gained by reexamining collective cell cancer invasion and the
evocation of directed pericellular proteolysis of matrix components at the leading
edge provide a new look at the original pathway-clearing aspects of tumor-derived
MMPs and bring these early simplistic in vitro notions to the very complex multi-
molecular and multicellular aspects of in vivo malignant invasion.
7.7 The Cross Talk Between Tumor and Stromal MMPs
During Tumor Invasion and Angiogenesis
The apparent sufficiency of MT1-MMP to govern most of the critical programs
exploited by tumor cells to invade the surrounding stroma (Hotary et al.
2006
;
Rowe and Weiss
2008
) would imply that highly invasive tumor cells should express
this MMP in vivo within the confinements of the developing primary tumor.
However, MT1-MMP (or any other MMP for that matter) was not identified in
