Background & Aims
Bone cancer pain (BCP) is one of the most common symptoms presented by patients with primary bone sarcomas and pre-dominantly occurs as distant metastases of non-bone primary tumors, notably those in breast, prostate, and lung. BCP treatment possess a major clinical challenge and the underlying mechanisms of BCP remain elusive. We have reported that the Wnt signaling in the spinal cord involves in the development of BCP. However, the role of peripheral Wnt signaling in BCP remains unknown. This study aimed to investigate the role of peripheral Wnt5a/Ryk signaling in the pathogenesis of BCP.
Methods
Experiments were performed in adult, female Sprague-Dawley rats. BCP was induced by tibia bone cavity tumor-cell implantation (TCI), which produced bone cancer-related thermal hyperalgesia, spontaneous and movement-evoked painful behaviors. Tumor cells were extracted from the ascitic fluid of rats that had previously received Walker256 mammary gland carcinoma cells. The tumor cells (1 x 105 cells/ ?L, 5 ?L) were injected into the intramedullary space of the left tibia to induce bone cancer pain in rats. The combination of behavioral tests, western blot analysis, Immunohistochemistry, ELISA immunoassay, Primary DRG neuron culture, Calcium imaging, and Quantitive reverse transcription-polymerase chain reaction (qRT-PCR) were used.
Results
TCI treatment produced bone cancer-related thermal hyperalgesia, mechanical allodynia, spontaneous and movement-evoked painful behaviors. TCI also induced ectopic sprouting of Wnt5a/Ryk signaling in the DRG somata and peripheral terminals and in the tumor-affected bone tissues. Peripheral intraplanar or intratibial injection or spinal administration of Wnt5a/Ryk signaling blockers significantly suppressed the painful syndromes in TCI rats. The TCI-DRG neurons became more sensitive to Wnt5a and Wnt5a/Ryk signaling activation, which increased intracellular calcium activity and expression of TRPV1 and regulated capsaicin-induced intracellular calcium activity. Blocking Ryk receptor activation prevented or reduced Wnt5a-induced mechanical allodynia and thermal hyperalgesia. Further, Wnt5a facilitation of TRPV1 sensitization was blocked by inhibiting JNK activation.
Conclusions
This study indicates that Wnt5a/Ryk signaling is a critical peripheral mechanism underlying the pathogenesis of BCP and suggests that targeting Wnt5a/Ryk in the primary sensory neurons and in the tumor-invasive tissues can be an effective approach for the prevention and treatment of BCP.
References
Liu S, Liu WT, Liu YP, Dong HL, Henkemeyer M, Xiong LZ, Song XJ. Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents. Cancer Res 2011;71(13):4392-4402.
Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ. WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 2013;123(5):2268-2286.
Simonetti M, Agarwal N, Stosser S, Bali KK, Karaulanov E, Kamble R, Pospisilova B, Kurejova M, Birchmeier W, Niehrs C, Heppenstall P, Kuner R. Wnt-Fzd signaling sensitizes peripheral sensory neurons via distinct noncanonical pathways. Neuron 2014;83(1):104-121.
Presenting Author
Xue-Jun Song
Poster Authors
Topics
- Specific Pain Conditions/Pain in Specific Populations: Cancer Pain & Palliative Care