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Neoplasia. 2019 Aug;21(8):777-787. doi: 10.1016/j.neo.2019.05.006. Epub 2019 Jun 24.

Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo.

Author information

1
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide, 5005; Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, 5001.
2
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, 5001.
3
Discipline of Surgery, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide, 5005; Basil Hetzel Institute, 37 Woodville Road, Woodville, 5011.
4
Bone Biology Laboratory, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010.
5
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide, 5005; Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, 5001; Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 2471, Adelaide, 5001. Electronic address: andrew.zannettino@adelaide.edu.au.

Abstract

Multiple myeloma is a fatal plasma cell malignancy that is reliant on the bone marrow microenvironment. The bone marrow is comprised of numerous cells of mesenchymal and hemopoietic origin. Of these, macrophages have been implicated to play a role in myeloma disease progression, angiogenesis, and drug resistance; however, the role of macrophages in myeloma disease establishment remains unknown. In this study, the antimyeloma efficacy of clodronate-liposome treatment, which globally and transiently depletes macrophages, was evaluated in the well-established C57BL/KaLwRijHsd murine model of myeloma. Our studies show, for the first time, that clodronate-liposome pretreatment abrogates myeloma tumor development in vivo. Clodronate-liposome administration resulted in depletion of CD169+ bone marrow-resident macrophages. Flow cytometric analysis revealed that clodronate-liposome pretreatment impaired myeloma plasma cell homing and retention within the bone marrow 24 hours postmyeloma plasma cell inoculation. This was attributed in part to decreased levels of macrophage-derived insulin-like growth factor 1. Moreover, a single dose of clodronate-liposome led to a significant reduction in myeloma tumor burden in KaLwRij mice with established disease. Collectively, these findings support a role for CD169-expressing bone marrow-resident macrophages in myeloma disease establishment and progression and demonstrate the potential of targeting macrophages as a therapy for myeloma patients.

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