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referred as to mesenchymal stem cells. MSCs, originally isolated from bone
marrow as stromal progenitor cells with high proliferative and differential poten-
tials (Pittenger et al.
1999
), have no self-renewal capacity and therefore do not meet
stringent criteria for functional stem cells. Mobilized into the circulation, MSCs
were demonstrated to infiltrate numerous secondary sites, including primary tumors
and metastatic sites, where they integrate into tumor stroma and vasculature,
differentiate into cells of different lineages, and affect progression of carcinogene-
sis (Lazennec and Jorgensen
2008
).
Several MMPs have been implicated in different aspects of MSC physiology.
Inflammatory cytokines upregulate MMP-2, MT1-MMP, and MMP-9 production in
MSCs, thereby providing potential mechanism for MSC recruitment and extravasa-
tion (Ries et al.
2007
). Passage through BM may involve MT1-MMP and MMP-2,
individual knock-down of which substantially impaired MSC invasion through
Matrigel (Ries et al.
2007
). Differentiation of MSCs into osteoblasts is accompanied
by the upregulation of MMP-2, MMP-3, MMP-8 (neutrophil collagenase), MMP-13,
and MT1-MMP (Parikka et al.
2005
;Nethetal.
2006
;Kasperetal.
2007
), but
functional contribution was validated by RNA silencing for only MMP-13 (Kasper
et al.
2007
) and MT1-MMP (Lu et al.
2010
).
Considering that the expression and proteolytic activity of MMPs and especially
of MT1-MMP is required for highly invasive tumor cells, it has been expected that
MMPs would also regulate metastatic dissemination of CSCs as they traffic in vivo.
The majority of studies addressing physiology of CSCs, however, employ estab-
lished tumor cell lines exhibiting some levels of stem cell markers (such as CD133)
and the ability to form spheres in vitro. The efficiency of sphere formation and
sphere invasiveness in 3D matrices are used operationally as a measure of “stem-
ness” of such tumor cell lines. Thus, neurosphere formation by the medulloblas-
toma DAOY cell line was accompanied by increased gene expression of CD133,
MT1-MMP, and MMP-9 (Annabi et al.
2008
). Indicating the functional importance
of these two MMPs, gene silencing of either MT1-MMP or MMP-9 by siRNA
reduced the formation of neurospheres and concomitantly abrogated their invasion
in vitro, while overexpression of MT1-MMP triggered neurosphere formation and
concomitant activation of proMMP-2. In a similar fashion, neurospheres formed by
glioma U87 cells selected for high levels of CD133
+
had enhanced the expression of
MT1-MMP, which was functionally important for COX-2 or S1P signaling (Annabi
et al.
2009a
,
b
). These findings allowed for the suggestion that increased MT1-
MMP might promote brain tumor infiltration, whereas the increase in MMP-9 may
contribute to the opening of the blood-brain barrier (Annabi et al.
2008
), although it
is debatable how much the behavior of spheres generated by cells from established
tumor cell lines reflects the actual physiology of CSCs.
Circulating stem cells are believed to release MMPs that will enable them to
cross the endothelial barrier and home to distant organs (Kucia et al.
2005
). It has
been shown that human bone marrow and peripheral blood CD34
+
cells comprising
a subset of stem cells manifest a differential production of MMPs and TIMPs in
response to chemokines such as SDF-1, MIP-1
, and IL-8, driving their invasion
through the subendothelial BMs in vitro (Janowska-Wieczorek et al.
2000
).
a
