Multiple myeloma increases nerve growth factor and other pain-related markers through interactions with the bone microenvironment

• Published in: Scientific reports 2019-10, Vol.9 (1), p.14189-11, Article 14189
• Main Authors: Olechnowicz, Sam W. Z., Weivoda, Megan M., Lwin, Seint T., Leung, Szi K., Gooding, Sarah, Nador, Guido, Javaid, Muhammed Kassim, Ramasamy, Karthik, Rao, Srinivasa R., Edwards, James R., Edwards, Claire M.
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 38/77; 631/67/1990/804; 631/67/70; 64/60; Adiponectin; Adiponectin - antagonists & inhibitors; Adiponectin - genetics; Analgesics; Animal models; Animals; Bone marrow; Bone Marrow - drug effects; Cell activation; Cell Proliferation - drug effects; Disease Models, Animal; Gene Expression Regulation, Neoplastic - drug effects; Growth factors; Humanities and Social Sciences; Humans; Imidazoles - pharmacology; Locomotion; Mice; multidisciplinary; Multiple myeloma; Multiple Myeloma - complications; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Nerve growth factor; Nerve Growth Factor - genetics; Neuroglia - metabolism; Neuroglia - pathology; NF-kappa B - antagonists & inhibitors; NF-κB protein; Osteoblasts; Osteoblasts - drug effects; Pain; Pain - complications; Pain - drug therapy; Pain - genetics; Pain - pathology; Peptides - pharmacology; Piperidines - pharmacology; Quinoxalines - pharmacology; Science; Science (multidisciplinary); Stromal cells; Stromal Cells - drug effects; Tumor Microenvironment - drug effects; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-α; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-50591-5

Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development.