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Falconer et al. MT-MMPs in prostate cancer

expression, but intriguingly inhibition by rapamycin factor receptor (EGFR) plays an important role in
(an mTOR inhibitor) actually upregulated MT1-MMP regulating cancer cell growth and function, not least
protein expression in PTEN null cells further, an in prostate cancer, and is therapeutically important [54] .
effect that was reversed by Akt inhibition. The authors More recently, a much wider study by the same group
discuss this potential side effect of rapamycin, and using the prostate cancer PRACTICAL consortium
note that similar observations have been reported data with approximately 21,000 patients, identified four
elsewhere [50] . key SNP-SNP interactions found to be associated with
prostate cancer aggressiveness. Of relevance here,
As was the case with expression data, information this study again linked MT3-MMP and EGFR [55] .
regarding the roles of the other members of the MT-
MMP family is somewhat limited. Delassus et al. [12] In addition, several studies point to an important role
identified a series of prostate cancer progression for MT-MMPs, and MT1-MMP in particular, in the
modulators and engineered overexpression in processes associated with metastatic spread to bone
prostate cancer cells (PC3) and others. Changes in in prostate cancer. This data will be considered in the
gene expression of MT1-, MT3- and MT6-MMP were following section.
then evaluated. Over-expression of activator protein-
2α, interleukin 4 and p16 INK4α had no effect on MT- EXPRESSION AND ROLES OF MT-MMPs IN
MMP expression. Fibulin1D led to down-regulation PROSTATE CANCER BONE METASTASIS
of MT1- and MT3-MMP (no reliable data for MT6-
MMP). Supporting the work of Wang et al. [36] , p53 over- It is suggested that more than 80% of patients with
expression led to reduced MT1-MMP expression (no disseminated prostate cancer will present with
reliable data for the other MT-MMPs evaluated). Over- metastasis to the bone [56,57] . Skeletal complications
expression of PTEN produced no change in MT1- are thus one of the leading causes of morbidity and
MMP expression, which is at odds with the data of mortality in prostate cancer patients. The normal
Kim et al. [50] , with the caveat that cells in that study equilibrium between osteoblastic and osteolytic
were mouse prostate cancer cells. Upregulation of activity in bone is disturbed in prostate cancer, leading
MT3-MMP was observed, however. Furthermore, to changes that are likely to provide a favourable
raf kinase inhibitor protein over-expression led to microenvironment for metastatic colonisation. Given
increased MT1-MMP, with no change detected for the established roles for MMPs in normal bone
the others. Finally, over-expression of E-cadherin led remodelling, a role for MMPs in prostate cancer
to reduced expression of all three MT-MMPs. This bone metastasis has long been proposed [58] . With
finding thus reinforces the observations discussed this in mind, it is perhaps surprising that relatively
earlier regarding the role of MT-MMPs in EMT (i.e. a little research has been directed to the MT-MMPs in
phenotypic shift from E- to N-cadherin expression) [14,30,36] . this area to-date. MT1-MMP knock-out mice exhibit
severe skeletal abnormalities, confirming a role in
Lin et al. [52] undertook genomic association studies normal bone maintenance and development [59] . Given
to identify genetic variants, i.e. SNPs utilising data these roles in normal bone health, the expression of
from the Cancer Genetic Markers of Susceptibility MT-MMPs in prostate cancer cells and tissues led
dataset, which includes data from 1,151 prostate Bonfil et al. [58] to speculate as to the existence of a
cancer patients. The authors explain how SNP-SNP selective process in which prostate cancer cells may
interactions, rather than studying individual SNPs, have a greater propensity to metastasise to bone, or
potentially have greater impact on unravelling the whether the microenvironment within the bone itself
underlying mechanisms of complex disease [52] . Three may induce MMP expression in prostate cancer cells,
important SNP-SNP interactions were identified, linking after their arrival at the bone.
MT3-MMP to ROBO1, CSF-1 and EGFR. ROBO1
is a member of the roundabout immunoglobulin Nemeth et al. [60] evaluated MT-MMP expression
superfamily, and has been identified as playing key in clinical samples and the role of MMP activity in
roles in prostate cancer progression [53] . It is cleaved prostate cancer that had metastasised to the bone,
by MMPs and translocates into the nucleus of cancer using a preclinical mouse model of bone metastasis
cells, which perhaps suggests a signalling role. The employing PC3 xenografts. MT1-MMP protein
authors suggest that as no specific MMP has to-date expression (as identified by immunohistochemical
been linked to ROBO1 cleavage, these data may have staining) was consistently observed in the 18 core
uncovered the potential for such a role for MT3-MMP. bone biopsy samples from prostate cancer patients. In
Colony stimulating factor-1 has been associated with preclinical studies, single human foetal bone fragments
increased tumor angiogenesis [52] . Epidermal growth were implanted subcutaneously in immunodeficient
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017 321