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Page 2 of 15 Spencer et al. J Cancer Metastasis Treat 2022;8:2 https://dx.doi.org/10.20517/2394-4722.2021.174

develop OS, especially for those who have developed metastases, has not significantly improved over the
past 30 years, with only 55% of patients surviving for more than 10 years. This is primarily attributed to the
[1,2]
lack of novel therapeutics .

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play key roles in
angiogenesis, cancer progression and metastasis. These proteases are classified based on their structural
characteristics and are often subdivided into two major groups; secreted MMPs and membrane-type MMPs
(MT-MMPs) . In normal tissues, MMPs are involved in a variety of physiological processes, including
[3]
mediation of inflammation and tissue remodelling. However, the overexpression of MMPs in cancer has
been associated with poor prognosis, and they have been considered as potential diagnostic and prognostic
biomarkers in several cancer types, including OS, as exemplified by MT1-MMP (see Figure 1). Technically
speaking, MT1-MMP is the name for the protein, whereas MMP-14 refers to the gene, but these terms are
often used interchangeably in the literature.

The activation of MT-MMPs, achieved through cleavage of a single protein and pro-peptide domain,
promotes their transport to the cell surface where they degrade components of the extracellular matrix and
basement membranes - either directly or indirectly through the recruitment of other MMPs - thereby
facilitating invasion and metastasis . In a variety of carcinomas, the dysregulation of MT1-MMP has been
[8]
extensively studied, yet the molecular mechanisms underlying OS disease progression are unclear, but MT1-
MMP may play a key role . Initially, this review will examine the expression of MT1-MMP in OS clinical
[9]
tumour samples and cell lines, followed by a discussion as to the potential role of MT1-MMP in OS
progression and metastasis, before finally considering opportunities for therapeutic targeting for the benefit
of OS patients.

EXPRESSION OF MT1-MMP IN OSTEOSARCOMA
In OS clinical samples
The clinical expression of secreted MMPs, especially MMP-2 and MMP-9, has been the subject of many
reviews. Both proteinases have been identified in tumour samples resected from patients with OS [10,11] . The
differential expression of MT1-MMP in tumour tissue samples, when compared to normal tissues, has been
widely researched; the data available for the expression of MT1-MMP in OS clinical tissues are summarised
in this section.

Uchibori et al. examined 47 patient samples, all of which were taken prior to patients undergoing
[12]
treatment who presented with no distant metastasis. MT1-MMP, MMP-2, -9, and tissue inhibitor of
metalloproteinases 2 (TIMP-2) protein expression and their correlation with prognosis were examined
immunohistochemically and by gelatin zymography. Strong expression (positive cell ratio > 50%) of MT1-
MMP in 21 (45%) samples was noted, 18 (38%) of which were also positive for MMP-2 expression. The
overall survival rate (OAS) for the 18 patients exhibiting strong expression of both MT1-MMP and MMP-2
was 57%, whereas, for the other patients, OAS was 87%. Although many patients within this study remained
disease-free up until the follow-up (after 5 years), 15 patients developed metastasis, and 11 patients died of
the disease. Localisation of MT1-MMP, MMP-2 and TIMP-2 to the cytoplasm and cell membrane was
observed, with a significant association between the strong expression of MT1-MMP, but not MMP-2, and a
reduction in patient survival when compared to tumour samples that exhibited weak expression. The event-
free survival rate (EFS) was determined for the surviving 36 patients, all of whom were in remission
following neoadjuvant and adjuvant chemotherapy and surgical resection. The EFS at 5 years for those with
tumours exhibiting strong MT1-MMP expression and for those with tumours exhibiting weak expression
was 60% and 81%, respectively. Of the 36 patients, 13 had tumours that exhibited strong expression of both