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suggesting the involvement of specific tumor cell-endothelial cell interactions
(Wang et al.
2004a
; Schluter et al.
2006
). Lewis lung carcinoma cells injected
intra-arterially into the heart were visualized in hepatic sinusoids by fluorescence
intravital microscopy within 30 min following inoculation (McDonald et al.
2009
).
Interestingly, this initial arrest of tumor cells on liver sinusoidal endothelium was
enhanced by inflammation and facilitated by adherent neutrophils in the inflamed
sinusoids.
It is still unclear whether any specific MMP directly assists tumor cell arrest on
the vascular endothelium, but interactions between tumor cells and platelets facili-
tate the formation of tumor cell/platelet emboli, which is believed to enhance
intravasation via induced expression of tumor cell MMP-9 (Lindenmeyer et al.
1997
). The interactions of arrested tumor cells with platelets and fibrinogen in the
lung capillaries have long indicated that coagulation facilitates tumor spreading
in the pulmonary vasculature (Im et al.
2004
). Therefore, both coagulation and
fibrin proteolysis appear to be essential for tumor cells to efficiently interact
with the endothelial cell layer and initiate extravasation, which is considered the
beginning of the late steps in the metastatic cascade. The biochemistry of fibrin
proteolysis would mainly indicate the involvement of the tPA/uPA/plasminogen
activation cascade and plasmin-mediated degradation. Since MT-MMPs
expressed on the endothelial cells were shown to be capable of degrading fibrin-
rich matrices both in vitro and in vivo (Hiraoka et al.
1998
; Ratel et al.
2007
), it is
possible that dissolution of fibrin clots containing tumor cells might at times be
actually performed by the MT1-MMP expressed on the surface of tumor cells or
endothelial cells at the site of tumor cell transmigration. It should be kept in mind,
however, that dissolution of the fibrin clot by MT1-MMP would likely not be as
efficient as the well-established, natural fibrinolytic protease, plasmin.
Endothelium-attached tumor cells can also proliferate within the capillaries of the
secondary organs, thereby providing an intravascular source of metastasis (Al-Mehdi
et al.
2000
). In an orthotopic model of human prostate cancer, in vivo imaging in live
mice allowed for the real-time characterization of cancer cell-endothelium
interactions during spontaneous metastatic colonization. Prior to detection of extra-
vascular metastases, GFP-tagged PC-3 carcinoma cells were observed residing inside
the blood vessels of the liver and the lung, where they proliferated and exhibited
MMP proteolytic activity, detected by an MMPSense probe sensitive to MMP-
mediated cleavage. These results demonstrate that the intravascular microenviron-
ment could provide a critical staging area for the development of spontaneous
metastasis (Zhang et al.
2010
). It would be of interest to identify whether expression
of tumor MMPs in such intravascular metastases would have specific spatiotemporal
regulation, i.e., be attenuated at the early phases of tumor foci development and
intensified at the later stages to assist in tumor cell shedding into the vascular
circulation. In general, however, it is accepted that if survived in the circulation,
arrested tumor cells cross the endothelial cell-BM barrier, i.e., extravasate into the
parenchyma of the distant organ.
