Biology Reference
In-Depth Information
of the original tumor, enhance tumor angiogenesis, and induce recruitment of
neutrophils and macrophages through “seed-derived” factors such as CXCL1, a
mediator of leukocyte influx into sites of inflammation (Kim et al.
2009
).
An important implication of the above-described findings is that MMP-1-expres-
sing breast cancer cells might be a part of the mechanism for local recurrence
following tumor excision (Kim et al.
2009
). It would imply that enhanced MMP-1
expression might be part of a signature in primary tumors from patients that will
develop local recurrence. However, a recently published analysis of MMP/TIMP
expression in breast cancer patients who have undergone mastectomy demonstrated
lower expression levels of several MMPs, including MMP-1, MMP-7, and MMP-9,
in primary tumors from those patients who developed local recurrence compared
with those without local recurrence (Del Casar et al.
2010
). These data may indicate
that a subset of aggressive MMP-expressing tumor cells responsible for recurrence
could be very small and would not show up in a straightforward signature of
primary tumors in patients. The patient data might also indicate that MMP/TIMP
signatures in the primary tumors may not be predictive of mechanisms or events
that occur later in the metastatic cascade.
7.12
Involvement of MMPs in the Establishment
of Metastases at the Secondary Site
The fact that millions of cells could be shed from primary tumors but only a few are
capable of establishing metastases led to the notion that spontaneous metastasis via
hematogenous route could be a very inefficient process (Bockhorn et al.
2007
). This
inefficiency is attributed in part to the low rate of cell survival in the circulation and
the possibility that extravasated cells enter a dormant state in the unfavorable
environment of the secondary organ (Suzuki et al.
2006
). Based on the failure of
approximately 98% of solitary tumor cells to initiate growth in secondary sites and
the failure of a majority of micrometastases to give rise to secondary tumors, there
is a notion that the transition of micrometastases to macrometastases and the
maintenance of metastatic growth into clinically relevant metastases are the only
principal rate limiting steps in the whole metastatic cascade (Croker and Allan
2008
). If the dormancy is overcome and spontaneously metastasized cells initiate
proliferation, MMPs could be active players in communications between metastatic
tumor cells and the stroma of the secondary site (Cairns et al.
2003
). The impor-
tance of stromal MMPs in influencing the fate of extravasated cells was initially
demonstrated in an experimental metastasis model, where colonization of intrave-
nously injected melanoma and lung carcinoma cells was significantly inhibited in
MMP-2 knock-out mice (Itoh et al.
1998
).
During spontaneous metastasis, however, the proteolytic functions of tumor
MMPs in organ-specific homing and the establishment of secondary lesions remain
poorly defined despite their well-appreciated role in matrix degradation and tumor
