Biology Reference
In-Depth Information
systems. Thus, proteolytic degradation of vascular BMs in the premetastatic sites
was demonstrated in the lungs of mice orthotopically implanted with human breast
cancer cells (Erler et al.
2009
). Specifically, lysyl oxidase secreted by primary
tumor cells was shown to accumulate at premetastatic sites and cross-link type IV
collagen, facilitating the recruitment of BMDC and their production of MMP-2.
Myeloid cell-derived MMP-2 in turn cleaves collagen, thereby enhancing homing
of spontaneously metastasizing tumor cells to prepared metastatic sites (Erler et al.
2009
). In a separate model, it was another gelatinase, i.e., MMP-9 produced by a
subpopulation of CCR5-positive mesenchymal cells, that was shown to cause
changes in the stroma of premetastatic lung and functionally contribute to mela-
noma B16/F10 engraftment (van Deventer et al.
2008
). It has also been reported
that the primary B16/F10 melanoma tumor upregulates MMP-3 and MMP-10 and
angiopoetin 2 in the lung at the premetastatic stage, leading to the increased
permeability of pulmonary vasculature and subsequent extravasation of circulating
tumor cells (Huang et al.
2009
). In an orthotopic model of breast cancer, knocking
down of MMP-3, MMP-10, and angiopoetin 2 significantly inhibited spontaneous
lung metastasis of an MDA-MB-231 cell variant in nude mice (Huang et al.
2009
).
Therefore, MMP-mediated vascular destabilization is likely to constitute an impor-
tant mechanism in the formation of premetastatic niches, where extravasation of
tumor cells is specifically promoted to facilitate the establishment of metastatic
lesions.
7.14
Involvement of MMPs in Cancer Stem Cell
Mobilization and Homing
With the recognition of CSCs and their role in tumor progression, many of the
questions posed for the roles of MMPs in tumor cell invasion and metastatic
dissemination have been applied to CSC biology. It has also been suggested that
some aspects of CSC physiology could be similar to those demonstrated for normal
stem cells and therefore might involve already established cellular mechanisms,
including MMP-mediated stem cell release, trafficking, and homing (Kucia et al.
2005
; Li and Neaves
2006
).
Mobilization of BMDCs and hematopoietic stem cells (HSCs) from their
quiescent niches in bone marrow has been shown to critically depend on the
enzymatic activity of MMP-9. It was demonstrated that MMP-9 proteolytically
releases soluble Kit ligand, thereby promoting the recruitment of c-Kit-positive
stem/BMDCs in mice (Heissig et al.
2002
). During bone marrow ablation, MMP-
9-mediated release of Kit ligand has been shown to be dependent on activation
of proMMP-9 by tissue-type plasminogen activator, indicating that MMP-9 can
be a downstream target molecule in the plasminogen activation cascade (Heissig
et al.
2007
).
The physiology of HSCs is critically dependent on their interaction with stromal
matrix and stromal cells, including multipotent stromal cells (MSCs), frequently
