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detected by a cryptic site-specific HU126 monoclonal antibody around blood
vessels in the colonized lungs at 24 h and 7 days after i.v. inoculation of melanoma
cells into the chick embryo (Roth et al.
2006
). The involvement of type IV collagen
degradation in extravasation in a mammalian system was demonstrated indirectly
by significant inhibition of lung colonization with the same HU126 during experi-
mental metastasis in mice (Roth et al.
2006
). The nature of the proteases degrading
collagen IV, unfortunately, was not identified in this study.
When colonization levels of target organs such as liver, brain, or bone marrow
are used as an end point of experimental metastasis, it is difficult to dissect the
extravasation process per se from the overall experimental metastasis process to
specifically address the putative contribution of specific MMPs. Therefore, it
could be the survival and proliferation capabilities of the extravasated tumor
cells which would determine the overall outcome of colonization. In this regard,
MMPs expressed by extravasated tumor cells might be more important in enhanc-
ing their survival, i.e., avoiding an apoptosis onslaught by mediating distinct
migratory-adhesive interactions in a new matrix microenvironment. In this case,
the invasive aspects of extravasation would be reflected in the ability of tumor
cells to degrade and remodel the ECM of the secondary site by possibly exploiting
their own MMPs or the stromal MMPs in their microenvironment. Thus, stromal
MMP-9 supplied by bone marrow derived cells, and most likely by neutrophils,
was implicated in the early survival and establishment of lung metastatic foci in
mice following i.v. inoculation of human lung carcinoma cells (Acuff et al.
2006a
).
7.11 Contribution of MMPs to Primary Tumor
Self-Seeding: Another Extravasation Event
Recent studies from Massague's laboratory provided experimental evidence for the
self-seeding concept in cancer progression (Kim et al.
2009
). In particular, this
concept accommodates the view that primary tumors can be reinfiltrated by circu-
lating tumor cells (CTCs), which extravasate back to the primary tumor bed after
their initial escape, intravasation, and circulation (Norton and Massague
2006
).
Self-seeding by aggressive breast cancer CTCs was demonstrated for several tumor
types, including breast and colon carcinomas and melanoma tumors developing in
mice (Kim et al.
2009
). Similar to the gene signatures associated with organ-
metastasis to the lungs, bone, and brain (Nguyen and Massague
2007
; Bos et al.
2009
; Nguyen et al.
2009
), the
MMP1
gene was identified in a gene signature
associated with the propensity of breast carcinoma CTCs to efficiently reenter their
primary tumors. Together, MMP-1 and fascin-1 expressed by breast cancer CTCs
act as mediators of transendothelial migration involved in tumor self-seeding. The
MMP-1/fascin-1-mediated extravasation of CTCs into the tumor of origin, in turn,
is driven by chemoattractants, such as IL-6 and IL-8, produced by the primary
tumor. Complementing this vicious cycle, the reinfiltrated CTS accelerate growth
