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

dependent decrease in MT1-MMP and MMP-2 expression was observed following exposure to Dz13 in
SJSA-1 OS cells, and this is in line with previous studies that have also demonstrated that MMP-2 and
MMP-9 expression is regulated by c-Jun [58,59] .

Bisphosphonates have been shown to reduce invasion and metastasis and potentiate the effects of
conventional chemotherapy in OS [14,60,61] . Heikkilä et al. investigated the effect of clodronate on MT1-
[62]
MMP mediated activation of MMP-2 and showed that increasing the concentration of this bisphosphonate
reduced MT1-MMP and MMP-2 mRNA and protein expression in MG-63 cells. Previously, it has been
shown that alendronate reduced the secretion of MMP-2 and is able to induce apoptosis in OS, while
risedronate reduces mRNA and protein levels of MMP-2 and MMP-9 in U2OS and Saos-2 cell lines [63,64] .
Unfortunately, the effect of alendronate and risedronate on MT1-MMP levels were not assessed in these
studies.

In summary, MT1-MMP plays multiple roles in OS, many of which go beyond the roles associated with
tumour migration and invasion, which can be directly attributed to its proteolytic capacity and extracellular
matrix degradation (see Table 1). There is still much to be learnt, but as we have discussed, MT1-MMP has
a significant impact on multiple intracellular signalling pathways, all of which adds to its importance as a
key player in OS progression. The potential for targeting MT1-MMP as a therapeutic strategy, and the
challenges associated with it will now be considered.

CHALLENGES AND FUTURE PROSPECTS
There is considerable evidence (both clinical and experimental) to support the role of MT1-MMP in
metastasis in several cancers (notably breast and prostate cancers), but this is not the case in OS [9,65,66] . This
could be attributed to the rarity of OS, which makes accessing tissue samples for gene mapping and
experimentation very difficult. Therefore, utilising the metastatic potential of HOS-MNNG and HOS-143B
cell lines could provide a better model by which to study the involvement of MT1-MMP in OS metastasis.
In the UK, the ICONIC project, funded by the Bone Cancer Research Trust, aims to create an OS patient
registry, providing clinicians and researchers with better access to patient data and samples, thereby helping
[67]
them to better understand the disease and develop novel treatments . Similar registries also exist in the
USA [68,69] .

The MAP chemotherapy regime remains the standard of care for localised OS [1,70] . It has long been
understood that significant side effects are associated with the use of chemotherapeutic agents; this is
especially true for HD-MTX. HD-MTX has many adverse side effects resulting from its toxicity, and so
[71]
requires the administration of a rescue dose of leucovorin following its infusion . In addition to this,
studies have shown that in OS, the transport of MTX across the cell membrane is impaired, therefore
[72]
necessitating the larger doses required to achieve a therapeutic effect .
There is a pressing need for novel therapeutics for OS patients, especially for those with metastatic disease
or tumour recurrence, both of which correlate with an unfavourable prognosis, and MT1-MMP is clearly a
target worthy of attention. One approach has been the development of synthetic MMP inhibitors (MMPIs),
but unfortunately, no molecule has successfully made it to the clinic. Many MMPIs failed to progress
beyond Phase III clinical trials due to poor specificity, deregulation of TIMPs and the off-target toxicity that
has resulted in suboptimal dosing recommendations. Novel molecular biology techniques have been utilised
to rapidly detect the expression profiles of MMP genes in each patient, determine the potential efficacy of
MMPIs and therefore take an individualised approach to treatment . The recent advances in MMPIs have
[73]
[74]
been extensively reviewed by Gregg Fields , who highlighted that despite previous failures in clinical trials,