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Matrix Metalloproteinase-13 Is an Unfavorable Prognostic Factor in Chordoma by Digesting Growth Inhibitory Collagens
Yumiko Oishi1, Katsuhiro Kawaai2, Ryota Tamura1
1Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan.
Objective:
Chordomas are low-grade but invasive tumors with limited therapies. Some conventional chordomas exhibit cartilage-like extracellular matrix (ECM). This study examined the expression and clinical significance of collagenases in chordomas.
Methods:
Brachyury-positive primary chordoma tissues were analyzed by immunohistochemistry for matrix metalloproteinase (MMP)13, MMP9, and cathepsin K, and by immunofluorescence for MMP13 and MMP9. ECM phenotype was categorized using safranin-O staining, where safranin-O marks cartilage-like ECM. We compared MMP13 expression scores and progression-free survival (PFS) between safranin-O-negative and -positive groups. Collagenase gene expression and protein localization in JHC7 cells were analyzed by quantitative PCR and immunocytochemistry, respectively. Collagen digestion activity was evaluated using fluorescein isothiocyanate-labeled type II collagen (COL2) in the presence or absence of an MMP13-specific inhibitor. Cell growth was evaluated in the presence of type I collagen (COL1) or COL2.
Results:
Safranin-O negative chordomas had shorter PFS than safranin-O positive chordomas (p = 0.016). MMP13 was expressed in human chordoma tissues and JHC7 cells; the MMP13 expression score was higher in safranin-O-negative chordomas than in safranin-O-positive chordomas (p = 0.018). JHC7 cells digested COL2, and digestion was partially but significantly inhibited by an MMP13-specific inhibitor (p < 0.05). COL2 inhibited the growth of JHC7 cells more strongly than COL1 in a dose-dependent manner (p < 0.01).
Conclusions:
MMP13 may promote aggressive behavior in chordoma by degrading growth-inhibitory COL2-rich ECM. These data support MMP13 as a potential unfavorable prognostic marker and therapeutic target in chordoma.
Insights
Matrix metalloproteinase (MMP)13 may drive aggressive chordoma by degrading growth-inhibitory collagen type II (COL2). Higher MMP13 expression correlates with poorer outcomes, suggesting MMP13 as a prognostic marker and therapeutic target.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Chordomas are invasive tumors with limited treatment options.
- Some chordomas feature cartilage-like extracellular matrix (ECM).
- The role of collagenases in chordoma progression is not well understood.
Purpose of the Study:
- To investigate the expression and clinical significance of collagenases, specifically matrix metalloproteinase (MMP)13, in chordomas.
- To determine the relationship between MMP13 expression, ECM phenotype, and patient outcomes.
- To explore the functional role of MMP13 in chordoma cell behavior and extracellular matrix interaction.
Main Methods:
- Immunohistochemistry and immunofluorescence were used to analyze MMP13, MMP9, and cathepsin K expression in chordoma tissues.
- Safranin-O staining categorized ECM phenotype (cartilage-like vs. non-cartilage-like).
- Gene expression, protein localization, collagen digestion assays, and cell growth assays were performed using JHC7 chordoma cells and collagen types I (COL1) and II (COL2).
Main Results:
- Chordomas lacking safranin-O staining (non-cartilage-like ECM) showed significantly shorter progression-free survival (PFS).
- MMP13 expression was higher in safranin-O negative chordomas compared to safranin-O positive ones.
- JHC7 cells degraded COL2, an activity partially inhibited by an MMP13-specific inhibitor, and COL2 inhibited cell growth more effectively than COL1.
Conclusions:
- MMP13 may contribute to aggressive chordoma behavior by degrading growth-inhibitory COL2-rich ECM.
- MMP13 expression levels could serve as an unfavorable prognostic marker for chordoma patients.
- MMP13 represents a potential therapeutic target for chordoma treatment.
