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collagen matrices, and this invasive behavior required exclusive expression and
proteolytic activity of only one MMP, i.e., MT1-MMP (Sabeh et al.
2004
; Zhang
et al.
2006
; Rowe et al.
2009
).
The role of fibroblast-derived MT1-MMP in complex in vitro and in vivo settings
appears to be less exclusive and the contribution of other MMPs can be demon-
strated. Thus, the invasion into type I collagen gels of human head and neck
squamous cell carcinoma tumor cells, triggered by cocultured wild-type murine
fibroblasts, was abrogated when the fibroblasts were deficient in MT1-MMP, but
was also reduced by 50% if the fibroblasts were lacking MMP-2 (Zhang et al.
2006
).
Moreover, in an orthotopic model where tumor cells were coinjected with wild-type
or MMP-deficient fibroblasts, tumor growth was significantly diminished not only
when fibroblasts did not express MT1-MMP, but also if they lacked MMP-2 and
MMP-9 (Zhang et al.
2006
).
The importance of matrix remodeling by MT1-MMP expressed in TAFs has
been recently extended to metastatic spread from the primary tumor. To assess the
ability of MT1-MMP-deficient tumor cells to proliferate and metastasize in vivo,
MT1-MMP knockout mice were crossed to MMTV-PyMT mice (Szabova et al.
2009
). When mammary glands from MT1-MMP-deficient/MMTV-PyMT or their
wild-type MMTV-PyMT littermates were orthotopically transplanted into cleared
mammary fat pads of wild-type recipients, tumorigenesis was significantly accel-
erated in the absence of MT1-MMP, a finding which is in apparent contrast with
the previously demonstrated cell proliferation controlling function of tumor
MT1-MMP in 3D collagen (Hotary et al.
2003
) and the reported defects of collagen
remodeling in MT1-MMP-deficient mice (Holmbeck et al.
1999
). Surprisingly, the
levels of lung colonization in the recipients bearing orthotopic MT1-MMP-deficient
tumors were 50% lower compared with wild-type tumors, indicating that MT1-
MMP expression is essential for full metastatic spread in this model. Since in
MMTV-PyMT-driven mammary carcinomas, MT1-MMP is exclusively expressed
in the stromal fibroblasts, the findings suggest that the lack of stromal collagen
remodeling in primary tumors by MT1-MMP-deficient TAFs is responsible for the
reduction of metastatic spread (Szabova et al.
2009
). These findings provide an
excellent example of how stromal MMPs can profoundly influence metastasis and
how the lack of proper matrix remodeling in the primary tumor can inhibit dissemi-
nation of actively proliferating tumor cells.
Critical importance of CAFs in cancer progression has been demonstrated by
their ability to influence the development and progression of carcinomas via
fibroblast-derived growth factors and cytokines and MMPs (Bhowmick et al.
2004
; Orimo and Weinberg
2006
). Thus, a number of studies show that CAFs
promote tumor growth and angiogenesis through secretion of SDF-1, which
directly stimulates growth of CXCR4-expressing carcinoma cells and attracts
endothelial progenitor cells (Orimo et al.
2005
) or mesenchymal stem cells
(Karnoub et al.
2007
). In mouse models of skin, mammary, and pancreatic
cancer,CAFsweredemonstratedtopromotetumorgrowthbyorchestrating
the recruitment of inflammatory cells and stimulating angiogenesis (Erez et al.
2010
). Importantly, activated CAFs expressing proinflammatory gene signatures,
