Biology Reference
In-Depth Information
7.16 Emerging Perspectives
Rapidly emerging concepts of cancer progression have illuminated new, unex-
pected mechanisms, which might govern metastatic disease along different path-
ways, thereby challenging the conventional views. One such notion is based on
findings demonstrating the presence of cancer cells in distant organs at very early
stages of cancer progression or even in the absence of detectable primary tumors
(Pantel and Brakenhoff
2004
; Dalerba et al.
2007
; Husemann et al.
2008
). This
point of view challenges the widely accepted prevailing scenario postulating that
dissemination of metastatic cells occurs from well-established, invasive primary
tumors, where aggressive tumor cells and engaged stromal cells are endowed over
time with the traits necessary for ensuing metastasis, including disregulated MMPs.
New studies might validate functional, proteolytic roles of MMPs in the very early
dissemination of metastatic cancer cells from those primary sites which even lack
visual signs of EMT, invasive fronts or angiogenesis.
A special emphasis may also be placed on addressing whether individual MMPs
other than MMP-9 contribute to the formation of premetastatic niches especially if
the size of the primary tumor is negligible or too small to induce cytokines and other
factors at systemic levels necessary for recruitment of MMP-9 delivering BMDCs
to distant sites. Clearly, the establishment of a niche in a premetastatic site will
require tissue or matrix remodeling and likely some proteolytic activity of yet-to-
be-defined enzymes. In addition, validation of functional roles of specific MMPs
in the important transition of micrometastases into macrometastases could con-
stitute a focus of studies aimed to elucidate this rate-limiting, final step of the
metastatic cascade (Croker and Allan
2008
). These roles might include MMP-
triggered neovascularization and matrix remodeling at the secondary site probably
by MMP-delivering or MMP-producing BMDCs that influx into metastatic foci and
facilitating their sustained growth.
Tumor self-seeding (Kim et al.
2009
) is another recent notion in cancer progres-
sion, which could represent a general phenomenon during metastasis. This model
illuminates the possibility that aggressive CTCs that had escaped from a fairly
developed tumor can reseed the primary site and establish therein a selected subset
of highly aggressive tumor cells responsible for overt metastases and local recur-
rence. This model also points to reseeding CTCs as a possible source of those
heretofore undefined cells that could actually be responsible for recruitment of bone
marrow-derived progenitor cells to developing primary tumors. In addition, this
model also raises the possibility that CTCs might reenter their original and familiar
microenvironment and therefore not slip into dormancy, but on the contrary,
actively proliferate and induce MMP-dependent stroma remodeling through either
their own MMPs, such as MMP-1 [already identified in the reseeding signature
(Kim et al.
2009
)] and MT1-MMP (one of the important cell surface tethered tumor
MMPs), or stroma-engaged MMPs, such as MMP-9 produced by newly recruited
inflammatory neutrophils and macrophages. The functional contribution of both
tumor and stromal MMPs in granting the aggressive CTCs access back to the
