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Falconer et al. MT-MMPs in prostate cancer

Table 1: MT-MMP nomenclature reported in the androgen-insensitive, more metastatic
[8]
cell lines PC3 (and sublines PC3-M and PC3-MM2 )
Gene Protein
MMP-14 MT1-MMP and DU145. Expression has also been reported
MMP-15 MT2-MMP in TSU-Pr1 cells [9,10] , also androgen-insensitive.
MMP-16 MT3-MMP Meanwhile, the less aggressive androgen-sensitive
MMP-17 MT4-MMP cell line LNCaP (and sublines LNCaP-C4 and
[8]
MMP-24 MT5-MMP LNCaP-C4-2 ) exhibit low or an absence of MT1-
MMP-25 MT6-MMP MMP gene expression [8,10-13] . Daja et al. explain that
[8]
MT-MMP: membrane-type matrix metalloproteinases despite these differences in gene expression, active
MT1-MMP protein expression was identified in both
The MMP family of proteolytic enzymes comprises LNCaP and PC3 cells and their sublines. Furthermore,
over 26 structurally similar zinc-dependent Jennbacken et al. [14] demonstrated that transformation
endoproteases. The wider family comprises two major of LNCaP into an androgen-independent cell line
subgroups: (1) the soluble or secreted MMPs and (i.e. LNCaP-19 [15] ) was accompanied by increased
(2) the membrane-type MMPs (MT-MMPs). The MT- aggressiveness (growth and migratory capacity)
MMPs are further sub-classified by their cell surface and by upregulation of both MT1-MMP gene and
association, either by a transmembrane domain (as is protein expression. The influence of the tumor
the case for MT1-, MT2-, MT3-, and MT5-MMP) or by microenvironment, specifically fibroblasts (WPF5),
a glycophosphatidylinositol anchor (in MT4- and MT6- was investigated on PC3 and DU145 cells in a study
MMP). The nomenclature for the MT-MMPs is outlined by Coulson-Thomas et al. [16] . An increase in MT1-
in Table 1: the gene and protein names are generally MMP gene and protein expression was reported in co-
used interchangeably. The structures of the MT-MMP cultures of WPF5 and PC3 or DU145 cells. Protein
[6]
family have been well described . They are each was localised at the cellular projections of all cell
synthesised as inactive pre-pro enzymes in the Golgi lines. When considered together with changes in
apparatus, with cleavage of the signal peptide and pro- vimentin distribution and an up-regulation of integrin
domain required before transport to the cell surface. α5β1 expression, this is indicative of a more invasive
phenotype.
The roles played by many MMPs in wider cancer
initiation, progression and metastasis have been Information regarding the remaining members of
extensively explored, with pivotal roles described in the MT-MMP family is more scarce. Interestingly, in
[7]
prostate cancer in particular . Expression and the contrast to the picture observed with MT1-MMP, MT2-
roles played by the MT-MMP family in prostate cancer MMP gene expression has been reported as more
are less well studied, however, and it is this area that significant in LNCaP cells and sublines than in PC3
is the focus of this review. The available evidence cells. The pattern of MT3-MMP gene expression is the
for expression of MT-MMPs in prostate cancer cells opposite to this, and thus similar to that observed for
and clinical tissues will be examined first, followed by MT1-MMP . Protein levels were similar in both cell
[8]
consideration of their roles in prostate cancer function lines, however. Processed MT-MMPs, indicative of
and in metastasis to the bone. latent MMP activation, were observed to be increased
in the more aggressive sublines. Jung et al. [11]
EXPRESSION OF MT-MMPs IN PROSTATE described significant gene expression of MT2-
CANCER CELL LINES MMP and MT5-MMP in both cell types. MT3-MMP
expression was observed in LNCaP cells with negligible
A significant body of literature exists concerning expression in PC3 or DU145 cells. Meanwhile, MT4-
the expression of MT1-MMP in prostate cancer MMP expression was observed in PC3 and DU145,
cell lines, albeit limited almost exclusively to the with negligible expression in LNCaP cells.
widely studied PC3, DU145 and LNCaP cell lines.
Prostatic adenocarcinoma cells PC3 (derived from a EXPRESSION OF MT-MMPs IN PROSTATE
bone metastasis) and DU145 (derived from a brain CANCER CLINICAL TISSUES
metastasis) are androgen-insensitive and metastatic
(PC3 being the more aggressive of the two), while The clinical expression of secreted MMPs in prostate
[7]
LNCaP cells (prostatic adenocarcinoma cells derived cancer has been well reviewed by Gong et al. , with
from a lymph node metastasis) are androgen-sensitive expression of MMP-2, -3, -7, -9 and -13 gene and
[8]
cells and non-metastatic . protein each identified in serum and tumor tissue of
patients with prostate cancer, and correlation with
MT1-MMP gene expression has been consistently progression and metastasis observed. Interestingly,

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