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Murakami and Simons 2008 ), inflammatory cell MMP-9 becomes a major trigger of
the angiogenic switch during tumor progression.
The expression of MMP-9 was validated in a variety of cancers, including breast,
pancreatic, lung, bladder, colorectal, ovarian, prostate, and brain cancers, making
this MMP one of the most consistent MMP biomarkers (Aggarwal and Gehlot 2009 ;
Roy et al. 2009 ). Nevertheless, the role of MMP-9 in tumor progression remains
controversial, as in different settings the overexpression or downregulation of
MMP-9 might result in the retardation or acceleration of metastasis. Thus, the
genetic ablation of MMP-9 in the multistage mammary MMTV-PyVT tumor
model was associated with 80% decrease in lung metastases (Martin et al. 2008 ),
while the delivery of MMP-9 adenovirus to the estradiol-induced mammary xeno-
grafts in nude mice resulted in increased MMP activity in vivo, but decreased
tumorigenesis and angiogenesis (Bendrik et al. 2008 ). The overall inhibitory effects
of MMP9 gene therapy were attributed to the MMP-9-mediated release of endo-
statin, a potent inhibitor of angiogenesis in vivo (Nilsson and Dabrosin 2006 ) but
might also be attributed to the MMP-9-mediated generation of tumstatin, another
inhibitor of tumor angiogenesis (Hamano et al. 2003 ).
7.7.3 MMP-Governed Angiogenesis
Following the initial MMP-9-mediated switch, the formation of the angiogenic
network in vivo would require disaggregation of the endothelial cell layer, induc-
tion of endothelial cell migration and invasion, and finally lumen and tubule
formation. Collectively, these processes were consistently shown to depend on
the expression and matrix-remodeling activity of MT1-MMP within various
in vitro settings employing collagen and fibrin gels (Lafleur et al. 2002 ; Chun
et al. 2004 ; Davis and Senger 2005 ; van Hinsbergh and Koolwijk 2008 ; Iruela-
Arispe and Davis 2009 ). More detailed analyses employing ex vivo angiogenesis
models demonstrated that MT1-MMP expression is largely confined to the sprout-
ing tip of the developing vasculature and that this site-specific expression of MT1-
MMP depends on a cross talk between endothelial cells and mural, vascular smooth
muscle cells (Yana et al. 2007 ). Furthermore, MT1-MMP expressed in the endo-
thelial cells is required for initial proteolytic generation of vascular guidance
tunnels in 3D collagen matrices to allow for subsequent lumen and tube network
formation (Stratman et al. 2009 ). These findings highlight a previously unrecog-
nized step in vascular morphogenesis, i.e., creation of physical ECM spaces via
MT1-MMP proteolysis, and also reinforce the previously demonstrated dependence
of collagenous matrix remodeling on MT1-MMP during directional migration and
invasion of tumor cells (Wolf et al. 2007 ; Sabeh et al. 2009 ). An important aspect
of MT1-MMP expression during neovascularization in vitro is that its de novo
expression in endothelial cells can directly be triggered by different cytokines, e.g.,
GM-CSF (Krubasik et al. 2008 ), and therefore MT1-MMP can be a downstream
effector molecule within cytokine regulatory pathways.
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