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

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.

Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma

“…However, we could not establish statistically significant differences upon transplantation with auto-BM ex vivo loaded with either of the described virus constructs, suggesting the therapeutic effects emanate from the virus backbone, not the TNF transgene tested. These in vivo results although were unpredicted based on our in vitro results and the fact that we had expected higher therapeutic effects of the armed MYXV construct with a pro-inflammatory cytokine like TNF, as had been observed in a syngeneic lung metastatic osteosarcoma model [13]; however our in vivo results were not entirely surprising since TNF has been reported by others to promote IL-6, a propagating factor for MM [30,31] that suppresses apoptosis of MM by activating the NF-κBpathway [32]. This is in contrast of recently published meta-analysis demonstrating the protective effect of TNF against MM risk in the dominant model and allele analysis [33].…”

Myeloma and marrow adiposity: Unanswered questions and future directions

“…Furthermore, adiponectin was found to inhibit osteoclast differentiation and maturation via the mTOR pathway [37], thereby contributing to MM associated bone disease. In addition, decreased adiponectin expression increased bone pain sensitivity through the regulation of nerve growth factor (NGF), suggesting that adiponectin could also have analgesic properties [38]. Targeting adiponectin is complex as it works in concert with other important hormones including insulin, leptin, and various cytokines making its pharmacological exploitation more challenging.…”

The role of bone marrow microenvironment in the progression of multiple myeloma from monoclonal gammopathy of undetermined significance

“…Под воздействием опухолевых клеток стромаль ные клетки костного мозга секретируют IL6, IL17, онкостатин М, сосудистый эндотелиальный фактор роста (VEGF), фактор роста нервов и др. [7,16]. Вы деление ФНОα, IL6, трансформирующего фактора роста β (TGFβ) коррелирует с количеством опухоле вых плазматических клеток в костном мозге [17].…”

“…Однако адипоциты могут продуцировать и проти вовоспалительные факторы, например адипонектин, ингибирующий сигнальный путь NFκB, а также ак тивирующий апоптоз ММклеток через киназу AMPK. С прогрессией ММ ассоциирована гипоадипонекти немия, которую может обеспечивать секреция ММ клетками ФНОα [16,40,41].…”