Biology Reference
In-Depth Information
surface proteases and collagenases capable of localizing matrix degrading activity
to the pericellular space (Seiki
2002
; Holmbeck et al.
2004
; Sounni and Noel
2005
;
Itoh and Seiki
2006
). Additional information was accumulated following the
clinical trials, which indicated that the early events of tumor progression such as
tumor-induced angiogenesis were closely linked to MMP functions (Folgueras et al.
2004
; van Hinsbergh et al.
2006
; van Hinsbergh and Koolwijk
2008
; Deryugina and
Quigley
2010
). Also, it became apparent that some MMPs can have protective roles
in cancer progression (Fingleton
2006
; Lopez-Otin and Matrisian
2007
; Martin and
Matrisian
2007
), and if they are mistakenly targeted for inhibition, tumor metastasis
might inadvertently be promoted (Overall and Kleifeld
2006
; Fingleton
2008
).
Finally, specific roles of MMPs during formation of metastatic and vascular niches
(Lapidot et al.
2005
; Psaila and Lyden
2009
;Butleretal.
2010
)aswellasproteolytic
functions of MMPs in tumor self-seeding (Norton and Massague
2006
; Kim et al.
2009
) and cancer stem cell (CSC) physiology (Kucia et al.
2005
;Nethetal.
2007
;
Laird et al.
2008
;Zhouetal.
2009
) are now in a spotlight of intensive investigations.
This review will be centered mainly on the evidence directly linking proteolytic
functions of MMPs with matrix invasion of tumor cells during distinct steps of the
metastatic cascade.
7.2 The Onset of Matrix Invasion in Tumor Progression:
Epithelial-Mesenchymal Transitions
The conversion of early stage adenomas into invasive carcinomas involves
epithelial-mesenchymal transitions (EMT), ultimately resulting in tumor cells accu-
mulating the ability to invade the stroma, reach the circulation, and develop second-
ary foci (Kang and Massague
2004
; Polyak and Weinberg
2009
). This concept of
conversion of epithelial cells into distinct mesenchymal cell lineages has been
persuasively challenged as lacking convincing in vivo histopathological evidence
in clinical samples of human and animal tumors (Tarin et al.
2005
). Nevertheless,
EMT with an emphasis on gene expression transitional changes rather than true cell
lineage conversions is still generally regarded as one of the earliest and critical steps
in tumor progression required for efficient dissemination of tumor cells.
One of the major hallmarks of EMT contributing to malignant phenotype in
experimental model systems is the loss of E-cadherin, the molecule responsible for
adherens junctions between epithelial cells and thus tight intercellular organization
of carcinomas (Thiery and Sleeman
2006
; Yilmaz and Christofori
2009
). Repres-
sion of E-cadherin occurs under control of several transcriptional factors, such
as Twist, Snail and SlP1, overexpression of which triggers EMT in a subset of
premalignant epithelial cells (Yang et al.
2006
). Concomitant with the repression of
E-cadherin and other epithelial markers is the induction of the mesenchymal
markers, e.g., vimentin, fibronectin, smooth muscle actin, and N-cadherin in carci-
noma cells undergoing EMT (Yang et al.
2004
). The mesenchymal phenotype of
