Biology Reference
In-Depth Information
7.1
Introduction
The complex process of metastasis includes very distinctive invasion steps where
proteolytic enzymes, especially matrix metalloproteinases (MMPs), have been
demonstrated to play critical roles. Multiple invasion events occur during both
early and late stages of tumor progression, including (1) initial escape of tumor cells
from the primary site where MMPs are believed to dissolute cell-cell contacts
between tightly adherent carcinoma cells, degrade the epithelial BM, and initiate
matrix proteolysis and remodeling; (2) directional invasion of individual or cohort
tumor cells into the surrounding stroma, which is specifically modified and remo-
deled by MMPs; (3) tumor angiogenesis during which endothelial cells, activated
by proangiogenic factors released and/or processed by MMPs, invade tumor stroma
and form a new vessel network; (4) intravasation and extravasation of tumor cells,
during which MMPs are thought to proteolytically degrade the basal membrane at
the abluminal surface of blood vessels; (5) establishment of secondary metastases,
including MMP-mediated preparation of metastatic niches; and (6) expansion of the
established micrometastatic foci, where MMPs can assist the onset of a new
invasive metastatic cycle.
Conceptually, the link of MMPs to the most early invasion steps of tumor
progression, i.e., escape from the primary tumor and invasion of surrounding
stroma, has been the most logical and comprehensible of all the linked associations
between proteases and malignancy. The need for proteolytic digestion of the
extracellular matrix (ECM) during transition from “carcinoma in situ” to “invasive
carcinoma” became the basis for evoking a contributory role for those MMP pro-
teases that can digest the components of BM. The same logic was imposed on the
concept that infiltrating cancer cells need to pass through the dense fibrillar network
of the ECM and thus specific ECM-degrading proteases, i.e., most members of the
MMP family, were linked to the invasive cancers.
In the 1980s and 1990s, the above concepts were fueled by the findings that
certain members of the MMP family were expressed at higher levels in the more
invasive tumors and more aggressive tumor cell lines. Substantial evidence
regarding the role of MMPs in cellular invasion had been accumulated by using
broad-range MMP inhibitors, which generally dampened tumor invasion within
many in vitro settings and tumor progression within a few in vivo model systems.
These studies justified the use of MMP inhibitors in clinical trials, the failure of
which, however, forced a substantial reevaluation of the role of MMPs in tumor
progression.
During and immediately after the clinical trials of MMP inhibitors, several
significant concepts had emerged in the MMP field. One notion has been founded
on experimental data indicating that host- or stroma-derived MMPs were function-
ally important in tumor progression, possibly more than tumor cell-derived MMPs
(Egeblad and Werb
2002
; Folgueras et al.
2004
; Deryugina and Quigley
2006
;
Jodele et al.
2006
). The second concept was the recognition that the cell membrane-
anchored MMPs, i.e., membrane-type MMPs, or MT-MMPs, were potent cell
