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However, it is still unclear which MMPs might be differentially produced by
functional CSCs to specifically support their extravasation during metastasis
in vivo. Since trafficking and homing of CSCs is governed by the CXCR4/SDF-1
axis, it is possible that MMPs directly induced by SDF-1 or delivered by SDF-1-
responsive, CXCR4-positive cells could be those MMPs mechanistically assisting
in invasion/intravasation and extravasation/colonization of noncancerous stem cells
(Lapidot et al. 2005 ; Li and Neaves 2006 ). In this regard, MMP-9 is induced in HSC
niches in bone marrow (Heissig et al. 2002 ) or in premetastatic niches at the
secondary site (Kaplan et al. 2005 ) in an SDF-1-dependent fashion.
7.15 Selective Inhibition of Specific MMPs vs. Overall
Inhibition of MMP Functions in Metastasis
The pleiotropic nature of MMPs in cancer, reflected in the promoting or inhibiting
activities of different MMPs or by the dual functionality of individual MMPs, might
lead to uncertain outcomes when MMPs are blocked with broad-range, indiscrimi-
natory inhibitors (Kruger et al. 2009 ). Therefore, the development of inhibitors,
which would target the MMP of interest with high selectivity and potency, has
become a priority in pharmacological intervention into metastatic disease (Ra and
Parks 2007 ; Morrison et al. 2009 ). In addition, inhibitors specifically targeting
proteolytic functions of MMPs involved in a particular physiological process (e.g.,
inflammation) or produced by particular types of cells (e.g., inflammatory cells) have
become a focus of recent therapeutic approaches (Hu et al. 2007 ).
To determine which individual steps of the metastatic cascade are specifically
affected by MMP blocking, a complex, spatiotemporal analysis of inhibitory effects
in several independent in vivo models is required. Recently, such analysis was
performed during validation of a highly selective, fully human recombinant MT1-
MMP inhibitory antibody DX-2400 that specifically blocks the catalytic activity of
MT1-MMP (Devy et al. 2009 ). Discriminatory blockage of MT1-MMP by DX-
2400 significantly slowed tumor growth and angiogenesis and significantly reduced
the levels of gelatinolytic activity in the MDA-MB-231 s.c. xenografts. Blocking
MT-MMP also retarded the formation of metastatic lesions in the lungs and liver
when MDA-MB-231 cells were implanted orthotopically, suggesting that the early
steps of metastatic dissemination were targeted by DX-2400. In addition, examina-
tion of lung colonization after inoculation of B16F1 murine melanoma cells
indicated that the late steps of metastatic cascade were also susceptible to the
inhibitory effects of DX-2400 antibody. Most alarming, however, was the demon-
stration that the gelatinolytic activity in xenografts of mice that received a combi-
nation of DX-2400 and the anti-VEGF blocking antibody bevacizumab was not
inhibited. Such lack of inhibition was due to an unexpected fourfold increase in
gelatinase activity in the xenografts caused by VEGF blocking (Devy et al. 2009 ),
emphasizing that the inhibition of MMP functions amidst complex anticancer
therapy should be implemented with extreme caution.
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