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Falconer et al. MT-MMPs in prostate cancer

luminal cells in PIN and prostate cancer cells, though potential regulatory pathways. Some of the molecular
less intense in the basolateral regions of benign events associated with MT-MMP expression and
tissues. IGF-1R was expressed primarily in the basal function in tumor cell migration, angiogenesis and
cells of normal glands and highly expressed in prostate vascular signalling are summarised in Figure 1 [28] .
cancer tissues [25] .
MT1-MMP plays a role in epithelial-to-mesenchymal
As is the case with studies on cell lines, the majority of transition (EMT). EMT is an important process in the
clinical reports focus on expression of MT1-MMP. Both metastatic cascade, involving multiple oncogenic
Jung et al. [11] and Riddick et al. [26] compared a wider drivers [29] . Cao et al. [30] initially used DNA microarray
range of MT-MMP family member gene expression database mining to reveal upregulation of MT1-MMP
in paired tissue samples from non-malignant and in human primary and metastatic prostate cancer
malignant parts of the same prostate cancer patient samples. Using 3D cell culture models, the study
biopsies, using real-time polymerase chain reaction additionally demonstrated that transformation of
(PCR). Interestingly, Jung et al. [11] identified a LNCaP cells with MT1-MMP induced morphological
significant down-regulation for all investigated MT- changes and modulation of epithelial and
MMPs except for MT2-MMP in malignant tissue mesenchymal markers consistent with EMT, and
and did not detect a correlation between tumor thus metastatic transformation. Further experiments
[26]
classification and MT-MMP expression. Riddick et al. demonstrated that these MT1-MMP-induced
investigated MT-MMP gene expression in 44 prostate phenotypic changes were linked to Wnt5a, also
[31]
cancer cases and 23 benign prostate hyperplasia associated with EMT . These findings are supported
[14]
specimens, also by real-time PCR. This study by the aforementioned study by Jennbacken et al. ,
additionally found increased gene expression of MT2- which similarly described E-cadherin downregulation
MMP, MT5-MMP and MT6-MMP in malignant tissue and N-cadherin upregulation (both consistent with
compared to benign prostate tissue, and suggested EMT) in the androgen-independent LNCaP-19 cell
that these proteases are likely to participate directly line, accompanied by increased MT1-MMP.
in prostate tumor invasion. It is important to note that
MT6-MMP was primarily expressed by the epithelial Degradation of the extracellular matrix (ECM), and
cancer cells rather than stromal cells. The lack of specifically laminin-10 (Ln-10), was explored by
[32]
difference in MT1-MMP expression between malignant Bair et al. . Laminins are key glycoprotein components
and local non-malignant tissue perhaps provides of the ECM: providing structural support to the basal
further evidence for the conclusions previously lamina in both normal prostate and malignant tissue.
The authors point to evidence previously published
discussed [17,18,20] .
describing upregulation of Ln-10 as prostate cancer
progresses from normal to PIN through to invasive
The evidence for MT-MMP expression, and particularly cancer, suggesting a role for MT1-MMP in the invasion
MT1-MMP expression, in prostate cancer cells and of prostate cancer [33] . Here, recombinant MT1-MMP
tumors from patients is compelling. The picture (and MT1-MMP-expressing cells and tissues) was
is complicated by the involvement of the tumor shown to cleave the α5 chain of purified human Ln-
microenvironment, in which MT-MMP expression is 10 from its 350-kDa form into specific fragments.
influenced, perhaps initiated, by the development of This cleavage was shown to decrease cell adhesion
cancer. In the following section, the roles of individual to purified Ln-10, and to increase transmigration of
MMPs are considered, along with links to other DU-145 cells through cleaved Ln-10 and thus the
pathways known to be important in prostate cancer basal lamina. Increased invasion mediated by MT1-
progression and metastasis. MMP was also observed by Wang et al. [34] . Using
cells engineered to overexpress MT1-MMP (namely
FUNCTIONS OF MT-MMPs IN PROSTATE PC3-LN4), invasion into type-I collagen gels in vitro
CANCER PROGRESSION AND METASTASIS was observed, through activation of pro-MMP2. PC3-
LN4 cells additionally proliferated at a faster rate
It is widely accepted that MT-MMPs play key roles than mock-transfected control cells when grown
in the metastatic process [27] . With regards prostate subcutaneously in nude mice.
cancer, MT-MMPs have been identified as contributing
towards apoptosis, angiogenesis, proliferation and Endo180 (uPARAP, urokinase-type plasminogen
[7]
metastasis . MT-MMPs have been shown to be activator receptor-associated protein) regulates
involved in various molecular processes in prostate collagen remodelling and chemotactic cell migration
cancer progression and metastasis, which will now be through cooperation with MT1-MMP. A study
considered here, together with information regarding by Kogianni et al. [35] describes how Endo180 is
318 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 12, 2017