Biology Reference
In-Depth Information
the final gene expression signature associated with cell motility and invasion when
breast carcinoma cells were collected directly from live animals using an in vivo
invasion assay and subjected to gene expression analysis in comparison to the
general population of tumor cells (Wang et al.
2004b
,
2005
). Although MT1-
MMP was initially identified as a part of a 24 gene signature predicting the
invasiveness of human breast cancer cell lines (Zajchowski et al.
2001
), more recent
gene profiling of 51 breast carcinoma cell lines did not identify MT1-MMP or other
MMP genes as associated with the invasive behavior or mesenchymal appearance
of tumor cells in culture (Neve et al.
2006
). In cancer patients, the expression of
MT1-MMP in primary tumors was also not validated as a potential biomarker,
either diagnostic or prognostic, in a variety of cancer types (Roy et al.
2009
), with
the exception of one recent study of clear cell ovarian carcinoma (Adley et al.
2009
).
In addition to the demonstrated necessity for the proteolytic activity of MT1-
MMP and a few other tumor MMPs in directional matrix proteolysis by tumor and
endothelial cells, an overwhelming body of evidence has accumulated also pointing
to the functional contribution to tumor invasion and metastasis of another class of
matrix-degrading MMPs, i.e., MMPs associated with the tumor microenvironment.
These MMPs are produced by different types of cells comprising tumor stroma,
including fibroblasts and inflammatory cells. Some of the genes for stromal cell
MMPs might not show up in the gene signatures of select tumor variants or tumors
from patients. Mutual induction of MMP expression in juxtapositioned tumor and
stromal cells is well documented in numerous in vitro and in vivo studies and
summarized in a number of comprehensive reviews (Elenbaas and Weinberg
2001
;
Egeblad and Werb
2002
; Lynch and Matrisian
2002
; Almholt and Johnsen
2003
;
Mueller and Fusenig
2004
; Deryugina and Quigley
2006
,
2010
; Jodele et al.
2006
).
7.7.1 Tumor-Associated Fibroblasts and Their
MMP-Mediated Functions
Tumor-associated fibroblasts (TAFs) or cancer-associated fibroblasts (CAFs) rep-
resent a particular stromal cell type because these cells can function both as the
active ECM producers and as the active modifiers of the deposited ECM. In vivo,
fibroblasts are regarded as slow or nonmigratory cells responsible for the structural
organization and stability of connective tissues. Nevertheless, if exposed to hapto-
tactic factors and/or chemoattractants, fibroblasts exhibit remarkable migration and
invasion activities in experimental in vitro or in vivo settings and often exhibit traits
of myofibroblasts in development. Thus, soluble factors secreted by breast carci-
noma SUM102 cells stimulate the expression of MMP-1 in normal human mam-
mary fibroblasts and induce their migration and invasion (Eck et al.
2009
).
However, when cultured in vitro alone, without any associated tumor cells, isolated
mouse fibroblasts were surprisingly shown to be capable of invasion into type I
