Biology Reference
In-Depth Information
invasion. The expression of a secreted collagenase, MMP-1, at both the gene and
protein levels, was repeatedly associated with the propensity of MDA-MB-231 cell
variants to specifically metastasize to lung, brain, and bone (Kang et al.
2003
; Minn
et al.
2005a
,
b
; Bos et al.
2009
). Since these cell variants were originally derived
following experimental metastasis, thereby bypassing early steps of the metastatic
cascade, the requirement of MMP-1 expression in the selected breast carcinoma
cells capable of distant metastasis likely indicated the involvement of this MMP
either during extravasation at distant sites or during reseeding of primary tumors (as
discussed in the previous section) or during establishment of the micrometastatic
foci. By RNA interference, MMP-1 in conjunction with other factors was demon-
strated to functionally mediate tumor angiogenesis and extravasation of circulating
tumor cells from the lung capillaries (Nguyen and Massague
2007
). In the case of
the bone-homing variant of the breast carcinoma MDA-MB-231 cell line, MMP-1
also was shown to orchestrate a paracrine signaling cascade modulating bone
microenvironment
to favor osteoclastogenesis and breast cancer metastasis
(Lu et al.
2009
).
The search for genetic determinants of cancer metastasis in patients recon-
firmed the presence of
MMP1
gene in the 18-gene signature associated with breast
cancer metastatic disease.
MMP1
expression was also validated in the set of 63
genes associated with the progression and metastasis of advanced cervical cancers
(Harima et al.
2009
). On the other hand, extensive gene expression profiling of
primary carcinomas of diverse types vs. metastases, performed in search of
universal genetic differences predictive of metastases in patients, did not identify
any genes encoding for MMPs within the refined gene-expression signature
associated with metastasis and poor clinical outcome (Ramaswamy et al.
2003
).
Profiling of genes differentially expressed between human bladder cancer cell
lines sequentially selected for increased ability to colonize mouse lungs after
i.v. inoculations did not identify any MMP genes which would individually be
associated with increased metastatic potential (Nicholson et al.
2004
). Once
again, it has to be considered that gene expression profiling may not yet be
optimal for characterizing relationships between primary tumors and metastasis
(Klein
2009
). In the case of MMP gene signatures, this indeed has to be taken into
account.
In the microenvironment of the secondary organ, individual MMPs can actually
suppress the development of metastases. Thus, MMP-11 (stromelysin 3) was shown
to function as a repressor of distal invasion of spontaneously disseminating breast
cancer cells from mammary tumors developing in the MMP-11 deficient transgenic
MMTV-ras mice (Andarawewa et al.
2003
). Remarkably, the same MMP-11
functions as an inducer of local invasion in the primary tumors, suggesting the
contribution of other metastasis mechanisms leading to cancer progression in this
model system. In addition, in an experimental metastasis model, the elimination of
MMP-12-mediated production of the antiangiogenic peptide, angiostatin, in MMP-
12-deficient mice was implicated in elevated angiogenesis and increased size of
tumor colonies developing from extravasated Lewis lung carcinoma cells (Acuff
et al.
2006b
).
