Abstract
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.
Highlights
Multiple Myeloma (MM) is a haematological disease where malignant plasma cells interact with the bone marrow (BM) constituents to promote tumour proliferation and bone destruction
To determine if nerve growth factor (NGF) is induced in MM, serum was obtained from 5TGM1-MM bearing C57Bl6/KaLwRij or Rag2−/− mice, which showed that levels of NGF were significantly increased in myeloma-bearing animals (Fig. 1a)
KaLwRij-strain mice are immunocompetent, but Rag2−/− mice lack mature B and T cells, and we considered whether this difference contributed to the variance in baseline serum NGF levels between the mouse strains
Summary
Multiple Myeloma (MM) is a haematological disease where malignant plasma cells interact with the bone marrow (BM) constituents to promote tumour proliferation and bone destruction. NGF signalling occurs through two cell-surface receptors, the high-affinity TrkA (encoded by NTRK1) and the low-affinity p75NTR (encoded by NGFR), and has diverse effects including cell growth, sprouting, differentiation and survival, depending on the target cell type and receptor expression. This signalling pathway is known to be broadly involved in pain sensitisation in humans, as naturally occurring NGF and NTRK1 mutations have been found to cause congenital insensitivity to pain[16,17]. These central glial responses appear to occur in some other models of cancer-related pain[21,22], and suggest a mechanism of pain that may be shared by many bone-borne diseases
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