Peripheral Mechanism of Cancer-Induced Bone Pain

Abstract

Cancer-induced bone pain (CIBP) is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis. CIBP constitutes a specific pain state with distinct characteristics; however, it shares similarities with inflammatory and neuropathic pain. At present, although various therapies have been developed for this condition, complete relief from CIBP in patients with cancer is yet to be achieved. Hence, it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs. Herein, we focused on the peripheral mechanism associated with the initiation of CIBP, which involves tissue injury in the bone and changes in the tumor microenvironment (TME) and dorsal root ganglion. The nerve-cancer and cancer-immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis, ultimately leading to CIBP. The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.

Keywords: Cancer-induced bone pain; Immunocytes; Peripheral mechanism; Sensory nerve; Tumor microenvironment.

Fig. 1

Changes in sensory nerves and dorsal root ganglion in a CIBP mouse model. A Sensory neurons express various receptors and channels, such as ASIC3, TRPA1, TRPV1, P2X₃, Na_v1.7, Na_v1.8, and Na_v1.9, which are activated by corresponding endogenous agonists to mediate CIBP. B Axonogenesis occurs in cancers and mediates CIBP. Several growth factors and cytokines, such as NGF, Wnt5a, and MaR1, promote axonogenesis following nerve injury. The expression of RAGs following nerve injury was upregulated, including atf3, sox11, and gap43. Abbreviations: ROS, reactive oxygen species; RNS, reactive nitrogen species; RCS, reactive carbonyl species; NO, nitric oxide; RAGs, regeneration-associated genes. The figure is created with BioRender.com

Fig. 2

Cancer cell-derived factors facilitate CIBP. RANKL binds to RANK to regulate bone homeostasis by regulating the osteoclast differentiation/activation. Melatonin prevents cancer cells from secreting RANKL and inhibits osteoclast differentiation. An effective component of the traditional Chinese medicine turmeric powder, DMC, inhibits breast cancer cell invasion and migration as well as RANKL-mediated osteoclast maturation and activation. PD-1 inhibition suppresses osteoclast formation and sustains cancer pain relief. HMGB1 binds to the RAGE expressed on peripherin⁺ sensory nerves that innervate the bone, inducing the activation of DRG neurons and eliciting CIBP. Release of glutamate from cancer cells via the cystine/glutamate antitransporter system xC (−) contributes to CIBP, while the system xC (−) inhibitor SSZ blocks glutamate release. Abbreviations: RANK, receptor activator of nuclear factor-κB; RANKL, ligand for receptor activator of nuclear factor-κB; DMC, demethoxycurcumin; PD-1, programmed cell death–1; HMGB1, high mobility group box 1; RAGE, receptor for advanced glycation end products; SSZ, sulfasalazine. The figure is created with BioRender.com

Fig. 3

Immune cells in the tumor microenvironment contribute to CIBP. The CCL2 inhibitor Bindarit suppresses cancer development and cancer-related inflammation and pain and inhibits in vitro M2 macrophage polarization. Myeloid immune cell-derived osteoclasts induce osteolytic bone lesions. Cancer-induced osteoclast differentiation can be inhibited by STING agonists via IFN-I signaling, thus contributing to the prevention of bone destruction and relief of CIBP. Abbreviations: STING, stimulators of interferon genes; IFN-I, type-I IFN. The figure is created with BioRender.com