ONCOLOGY: RESEARCH ARTICLE
Membrane-type 1 matrix metalloproteinase as predictor of survival and candidate therapeutic target in Ewing sarcoma
Marcus J. Brookes,
Elizabeth A. Roundhill,
Lee Jeys,
Michael Parry,
Susan A. Burchill,
Kenneth S. Rankin,
Corresponding Author
Marcus J. Brookes
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Correspondence
Marcus J. Brookes, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Email: [email protected]
Search for more papers by this authorElizabeth A. Roundhill
Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK
Search for more papers by this authorLee Jeys
Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK
Search for more papers by this authorMichael Parry
Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK
Search for more papers by this authorSusan A. Burchill
Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK
Search for more papers by this authorKenneth S. Rankin
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Search for more papers by this authorMarcus J. Brookes,
Elizabeth A. Roundhill,
Lee Jeys,
Michael Parry,
Susan A. Burchill,
Kenneth S. Rankin,
Corresponding Author
Marcus J. Brookes
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Correspondence
Marcus J. Brookes, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Email: [email protected]
Search for more papers by this authorElizabeth A. Roundhill
Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK
Search for more papers by this authorLee Jeys
Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK
Search for more papers by this authorMichael Parry
Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK
Search for more papers by this authorSusan A. Burchill
Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK
Search for more papers by this authorKenneth S. Rankin
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Search for more papers by this authorAbstract
Background
Ewing sarcoma (ES) is the second most common primary bone malignancy, with an urgent need for new treatments. ES is associated with high rates of progression and relapse, driven by drug-resistant cells capable of migration, self-renewal and single-cell tumorigenesis, termed cancer stem-like cells (CSCs). Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-bound proteolytic enzyme, which, via direct and indirect mechanisms, digests four of the main types of collagen. This can be hijacked in malignancy for invasion and metastasis, with high expression predicting decreased survival in multiple cancers. In this study, we have examined the hypothesis that MT1-MMP is expressed by ES cells and explored the relationship between expression and outcomes.
Procedure
MT1-MMP expression in ES established cell lines, primary patient-derived cultures and daughter ES-CSCs was characterised by RNA sequencing, Western blotting, immunocytochemistry and flow cytometry. Immunohistochemistry was used to detect MT1-MMP in tumour biopsies, and the relationship between expression, event-free and overall survival examined.
Results
MT1-MMP was detected at both RNA and protein levels in five of six established cell lines, all primary cultures (n = 25) and all daughter ES-CSCs (n = 7). Immunohistochemistry of treatment-naïve biopsy tissue demonstrated that high MT1-MMP expression predicted decreased event-free and overall survival (p = .017 and .036, respectively; n = 47); this was not significant in multivariate analysis.
Conclusions
MT1-MMP is expressed by ES cells, including ES-CSCs, making it a candidate therapeutic target. The level of MT1-MMP expression at diagnosis may be considered as a prognostic biomarker if validated by retrospective analysis of a larger cohort of clinical trial samples.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| pbc29959-sup-0001-tableS1.docx36.5 KB | Supporting Table S1 Patient clinical details with the percentage of cells with intensity scores of 0, +1, +2 or +3 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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