Biology Reference
In-Depth Information
At the metastatic site, tumor cells are believed to undergo mesenchymal-epithe-
lial transition (MET), which is regarded as an important event in the metastatic
cascade (Chaffer et al.
2007
; Hugo et al.
2007
). Along with the overall reversal
nature of MET features such as reversal toward reexpression of E-cadherin
(Auersperg et al.
1999
; Wells et al.
2008
), it is plausible to suggest that MMPs,
which have been initially induced during EMT at the primary tumor and over-
expressed during early invasion steps, would be downregulated during the estab-
lishment of metastases as the colonizing cells undergo MET. In agreement with this
view, a comprehensive comparative analysis performed to identify molecular sig-
natures associated with nodal metastasis in breast cancer demonstrated significant
downregulation of MMP-10 (stromelysin 2), MMP-13, and MT3-MMP in lymph
node tumors vs. corresponding primary breast tumors. Furthermore, genes
expressed at higher levels in metastases were mainly those involved in transcription,
signal transduction, and immune response, providing metastasized cells with prolif-
eration and survival potential (Ellsworth et al.
2009
).
7.13 MMPs and Formation of the Premetastatic Niche
The mechanisms by which MMPs assist the arrival, survival, and proliferation of
disseminating tumor cells to the secondary site involve the formation of premeta-
static niches at distant organs. The original niche model has postulated the existence
of a specific microenvironment locale that maintains and regulates stem cells
(Morrison and Spradling
2008
). A relatively novel model for metastatic niches
suggests the existence of a suitable conducive microenvironment that allows for
tumor cell engraftment and micrometastatic-to-macrometastatic transition (Psaila
and Lyden
2009
). The induction of new niches or the adaptation of preexisting
niches is now regarded as a central mechanism of tumor cell metastasis to distant
organs.
Despite considerable progress in elucidating the underlying mechanisms of
niche formation, the knowledge of functional contribution of specific MMPs in
this process is mainly limited to the initial findings demonstrating the involvement
of MMP-9 (Kaplan et al.
2005
). In the premetastatic lung, VEGFA specifically
induces MMP-9 expression in endothelial cells and also attracts MMP-9-producing
MAC1-positive and VEGFR1-positive myeloid cells (Hiratsuka et al.
2002
; Kaplan
et al.
2005
). The proteolytic activity of MMP-9 in turn is believed to release growth
factors and cytokines, including soluble Kit ligand, which recruits tumor cells and
additional BMDCs that express c-Kit, the soluble Kit receptor. The central role
played by MMP-9 in these processes was demonstrated by a genetic approach
whereby the suppression of MMP-9 induction by using MMP-9 null mice signifi-
cantly impaired niche formation and tumor engraftment (Hiratsuka et al.
2002
;
Kaplan et al.
2005
).
Priming of premetastatic niches for tumor engraftment should involve local
MMP-mediated tissue remodeling which has been confirmed in several model
