Reciprocal interactions between osteoclasts and nociceptive sensory neurons in bone cancer pain

Abstract

Many common cancers such as breast, prostate, and lung cancer metastasize to bones at advanced stages, producing severe pain and functional impairment. At present, the current pharmacotherapies available for bone cancer pain are insufficient to provide safe and efficacious pain relief. In this narrative review, we discuss the mechanisms used by cancer cells within the bone tumor microenvironment (TME) to drive bone cancer pain. In particular, we highlight the reciprocal interactions between tumor cells, bone-resorbing osteoclasts, and pain-sensing sensory neurons (nociceptors), which drive bone cancer pain. We discuss how tumor cells present within the bone TME accelerate osteoclast differentiation (osteoclastogenesis) and alter osteoclast activity and function. Furthermore, we highlight how this perturbed state of osteoclast overactivation contributes to bone cancer pain through (1) direct mechanisms, through their production of pronociceptive factors that act directly on sensory afferents; and (2) by indirect mechanisms, wherein osteoclasts drive bone resorption that weakens tumor-bearing bones and predisposes them to skeletal-related events, thereby driving bone cancer pain and functional impairment. Finally, we discuss some potential therapeutic agents, such as denosumab, bisphosphonates, and nivolumab, and discuss their respective effects on bone cancer pain, osteoclast overactivation, and tumor growth within the bone TME.

Keywords: Nociceptor; bone cancer; cancer pain; neuroimmune interactions; osteoclast.

Figure 1.

Direct and indirect mechanisms of osteoclasts underlying the pathogenesis of cancer pain. (A) Direct mechanisms by which OCLs produce pain include the induction of local acidosis, mediated by the action of V-ATPase, which activates acid-sensing receptors on peripheral nociceptor terminals in the bone tumor microenvironment, including TRPV1, ASIC1b, and ASIC3. OCLs also release chemokines, such as CCL2, at the absorption lacuna, which activate CCR2 receptors on local nociceptor terminals. OCLs' sustained activation of nociceptors leads to peripheral sensitization, central sensitization, spinal glia activation, and severe pain. In addition to factors released by osteoclasts, tumor cells release a host of factors that contribute directly to nociceptor sensitization and nerve sprouting, including cytokines (IL-1β and tumor necrosis factor), VEGF ligands, NGF, G-CSF, and GM-CSG (not shown). Tumor cells also increase the acidity of the extracellular environment, further activating proton-sensing nociceptors. (B) Indirect mechanisms by which OCLs produce bone cancer pain include tumor-induced induction of osteoclastogenesis, osteoclast hypertrophy, and accelerated osteoclast absorption of bone. This leads to decreased bone mass, enabling further tumor invasion of the bone tissue, and increased likelihood for skeletal-related events such as bone fracture and nerve compression, leading indirectly to bone cancer-related pain. NGF, nerve growth factor; VEGF, vascular endothelial growth factor.