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Falconer et al. MT-MMPs in prostate cancer

mice. After an interval of 4 weeks, PC3 cells were then Sabbota et al. [62] subsequently followed up their initial
injected directly into some of the implants, with/without findings and provided further evidence for a link
initiation of daily treatment with broad-spectrum MMP between RANKL shedding and MT1-MMP protein
inhibitor batimastat for 2 weeks. MT1-MMP expression expression, summarised in Figure 2. In this study,
was subsequently identified in PC3 bone tumors, conditioned media from LNCaP cells expressing both
localised primarily to tumor cells, with some stromal RANKL and MT1-MMP was shown to enhance cell
expression noted. The PC3 bone tumors were mostly migration of LNCaP-C4-2b cells, which are MT1-MMP
osteolytic in nature, and MMP inhibition by batimastat deficient. This was inhibited by osteoprotegerin (soluble
reduced the number of osteoclasts per millimetre in decoy receptor of RANKL) and selective MT1-MMP
these implants. The authors concluded that MT1-MMP inhibitor MIK-G2. The authors hypothesised that these
activity in prostate cancer cells appears to be crucial findings indicated that MT1-MMP enhances tumor
in bone matrix turnover. This, together with metastatic cell migration through initiation of an autocrine loop
tumor growth, appeared to be linked in cycle that is requiring RANKL shedding in prostate cancer cells.
disrupted by MMP inhibition [60] . Evidence was also provided for a role for Src as a
downstream mediator of RANKL [62] .
A further correlation between MT1-MMP expression in
prostate cancer cells and bone metastasis was also The importance of cadherin-11 in prostate cancer
reported by Bonfil et al. [61] . MT1-MMP expression was bone metastasis was considered by Huang et al. [63] .
abundant and consistent in tumor cells identified in Cadherin-11 is an osteoblast cadherin, identified as
paraffin sections of bone metastases from 20 prostate being aberrantly expressed in prostate cancer cells
[64]
cancer patients (androgen independent disease). derived from bone metastases . LNCaP-C4-2B4 cells
It should be noted that MT1-MMP expression was in which expression of cadherin-11 had been engineered
noted in endothelial cells, osteocytes, osteoblasts and demonstrated increased spread and intercalation into
stroma in matched normal bone samples, consistent an osteoblast layer in vitro and exhibited enhanced
with a role in bone development, albeit at expression migration and invasion. Downregulation of cadherin-11
levels which appear significantly lower than those in PC3 cells, which naturally express cadherin-11,
exhibited by the tumor cells. Preclinical models were decreased cell migration and invasion. A possible role
utilised to examine the role of MT1-MMP in metastatic for MT2-MMP was suggested, following gene array
bone colonisation of prostate cancer cells. MT1- analysis of the LNCaP-C4-2B4 cells. Several genes
MMP was introduced into LNCaP cells, while it was related to invasion and metastasis were identified as
silenced (using siRNA for MT1-MMP) in DU145 cells. upregulated, among which MT2-MMP was a prominent
[63]
MT1-MMP over-expression enhanced bone tumor finding . Interestingly, IGF-1 gene expression was also
growth (via intra-tibial injection) and associated reported as upregulated, which supports the evidence
[25]
osteolysis, while not affecting cell proliferation in vitro provided by Sroka et al. relating to a role for IGF-
or subcutaneous tumor growth in vivo. This led the 1R in MT-MMP expression and activity, as discussed
authors to conclude that MT1-MMP contributes a earlier.
unique stimulatory effect on tumor growth in the bone
microenvironment. Further studies utilising orthotopic MT-MMPs clearly play important roles in the
models which better replicate the normal disease development of metastatic bone deposits. Given
dissemination process are required to confirm these that most patients with prostate cancer ultimately
findings, but the authors nevertheless suggest the succumb to metastasis, a strategy to specifically target
possibility that MT1-MMP activity may be worthy of MT1-MMP-expression on tumor cells may prove an
pursuing as a therapeutic target for prostate cancer attractive means by which to address prostate cancer
bone metastases. Furthermore, a role for RANKL metastasis to bone.
was suggested: RANKL (receptor activator of NF-
κB ligand) is a regulator of osteoclastogenesis, and OPPORTUNITIES FOR DRUG TARGETING
its release in the bone microenvironment was linked
to MT1-MMP activity. siRNA knockdown of MT1- The expression of MT-MMPs in prostate cancer
MMP inhibited bone tumor growth of DU145 cells and and associated bone metastases suggests an
simultaneously led to osteogenesis, a phenomenon opportunity for targeted therapy. As an example, the
for which mechanistic information was not obtained. Bonfil group focused on MT1-MMP expression in
It was suggested that MT1-MMP inhibition may have prostate cancer bone metastases, and suggested
shifted the balance toward bone formation simply by that the increased MT1-MMP activity was worthy of
inhibition of osteolysis/osteoclastogenesis [61] . pursuing as a therapeutic strategy. The group later

322 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017