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into blood vessels in orthotopic and transgenic breast cancer models (Wyckoff et al.
2007
). In a Transwell model in vitro, transendothelial migration of breast carci-
noma MDA-MB-231 cells was shown to be facilitated by neutrophils (Wu et al.
2001
). Unfortunately, the role of MMPs released by macrophages or neutrophils,
known producers of MMP-9 and other MMPs that could function catalytically
in mediating the intravasation events, has not been addressed in these studies.
Therefore, it is still largely unknown precisely where and exactly how tumor cells
intravasate and even less clear which MMPs with regard to their cell origin or
biochemical nature are likely involved in the degradation of vascular BM during
intravasation.
In the chick embryo CAM model, where intravasation could be significantly
diminished by broad-range MMP inhibitors but not by inhibition of tumor-derived
MMPs (Deryugina et al.
2005
; Partridge et al.
2007
), our preliminary data indicate
that MMPs delivered by inflammatory cells could be positively linked to the
intravasation event. Thus, there are strong positive correlations between the levels
of spontaneous intravasation with the levels of MMP-9-delivering neutrophils and
MMP-13-positive macrophages infiltrating the stroma of primary tumors derived
either from HT-1080 fibrosarcoma or PC-3 prostate carcinoma cells. Inhibition of
such inflammatory cell influx into primary carcinoma or fibrosarcoma tumors with
anti-inflammatory agents, such as anti IL-8 blocking antibody or specific antibodies
blocking CXCR2-ligand interactions, results in significant and concomitant
decrease of tumor angiogenesis, intravasation, and metastasis without having any
significant effect on primary tumor size (Fig.
7.6
). Although formally not proved,
the angiogenic vessels are generally regarded as conduits for tumor cell intravasa-
tion. In our CAM studies, the strong positive correlations between the levels of
tumor angiogenesis and tumor cell intravasation and dissemination provide addi-
tional evidence that angiogenic vessels are indeed those exploited by escaping
tumor cells as conduits for vascular dissemination.
7.9 MMP-Mediated Proteolysis During Late Steps
of Tumor Progression
Following successful intravasation, cancer cells are believed to circulate in the
blood or lymphatic system. This stage might be considered a period between the
early and late events of metastasis. Intravasated cells must survive the hostile nature
of the circulation, avoid clearance, and also avoid the onslaught of apoptotic and
anoikis signals that target unanchored tumor cells in the circulation. It is uncertain
how long it takes for
spontaneously
intravasated tumor cells to get arrested in the
capillary bed of the secondary organ. In contrast, the arrest of tumor cells inoculated
as a single cell suspension intravenously or intracardially appears to be a relatively
rapid process, taking possibly only a few minutes. In the chick embryo, tumor cells
injected into the allantoic vein are trapped in the terminal arterioles of the CAM
