Myeloma Microenvironmental TIMP1 Induces the Invasive Phenotype in Fibroblasts to Modulate Disease Progression
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- Rei Ishihara
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Tsukasa Oda
- Laboratory of Mucosal Ecosystem Design, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8510, Japan
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- Yuki Murakami
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Ikuko Matsumura
- Department of Haematology, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
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- Saki Watanabe
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Yuta Asao
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Yuta Masuda
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Nanami Gotoh
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Tetsuhiro Kasamatsu
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Hisashi Takei
- Department of Haematology, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
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- Nobuhiko Kobayashi
- Department of Haematology, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
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- Nobuo Sasaki
- Laboratory of Mucosal Ecosystem Design, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8510, Japan
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- Takayuki Saitoh
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan
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- Hirokazu Murakami
- Faculty of Medical Technology and Clinical Engineering, Gunma University of Health and Welfare, Maebashi 371-0823, Japan
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- Hiroshi Handa
- Department of Haematology, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
抄録
<jats:p>Tissue inhibitors of metalloproteinases (TIMPs) are endogenous matrix metalloproteinase inhibitors. TIMP1 is produced by cancer cells and has pleiotropic activities. However, its role and source in multiple myeloma (MM) are unclear. Here, we evaluated TIMP1 protein and mRNA levels in bone marrow (BM) plasma cells and assessed the effects of TIMP1 expression on fibroblast invasive capacity using three-dimensional spheroid cell invasion assays. TIMP1 mRNA and protein levels were elevated when patients progressed from monoclonal gammopathy of undetermined significance or smouldering myeloma to MM. Furthermore, TIMP1 levels decreased at complete response and TIMP1 protein levels increased with higher international staging. TIMP1 mRNA levels were markedly higher in extramedullary plasmacytoma and MM with t(4;14). Overall survival and post-progression survival were significantly lower in MM patients with high TIMP1 protein. Recombinant TIMP1 did not directly affect MM cells but enhanced the invasive capacity of fibroblasts; this effect was suppressed by treatment with anti-TIMP1 antibodies. Fibroblasts supported myeloma cell invasion and expansion in extracellular matrix. Overall, these results suggested that MM-derived TIMP1 induces the invasive phenotype in fibroblasts and is involved in disease progression. Further studies are required to elucidate the specific roles of TIMP1 in MM and facilitate the development of novel therapies targeting the TIMP1 pathway.</jats:p>
収録刊行物
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- International Journal of Molecular Sciences
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International Journal of Molecular Sciences 24 (3), 2216-, 2023-01-22
MDPI AG