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. 2023 May:110:348-364.
doi: 10.1016/j.bbi.2023.03.013. Epub 2023 Mar 20.

Schwann cell insulin-like growth factor receptor type-1 mediates metastatic bone cancer pain in mice

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Free article

Schwann cell insulin-like growth factor receptor type-1 mediates metastatic bone cancer pain in mice

Lorenzo Landini et al. Brain Behav Immun. 2023 May.
Free article

Abstract

Insulin growth factor-1 (IGF-1), an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain (MBCP), but the underlying mechanism is poorly understood. In mice, the femur metastasis caused by intramammary inoculation of breast cancer cells resulted in IGF-1 increase in femur and sciatic nerve, and IGF-1-dependent stimulus/non-stimulus-evoked pain-like behaviors. Adeno-associated virus-based shRNA selective silencing of IGF-1 receptor (IGF-1R) in Schwann cells, but not in dorsal root ganglion (DRG) neurons, attenuated pain-like behaviors. Intraplantar IGF-1 evoked acute nociception and mechanical/cold allodynia, which were reduced by selective IGF-1R silencing in DRG neurons and Schwann cells, respectively. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated transient receptor potential ankyrin 1 (TRPA1) activation and release of reactive oxygen species that, via macrophage-colony stimulating factor-dependent endoneurial macrophage expansion, sustained pain-like behaviors. Osteoclast derived IGF-1 initiates a Schwann cell-dependent neuroinflammatory response that sustains a proalgesic pathway that provides new options for MBCP treatment.

Keywords: Bone cancer pain; Osteoclast derived IGF-1; Oxidative stress; Schwann cells; TRPA1.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FDL, PG, and RN are the founding scientists of FloNext Srl. PG has been in advisory boards and/or received fees for lectures from Novartis, Amgen, TEVA, AbbVie, Eli-Lilly, Lundbeck. The other authors have no conflicts of interest to declare.

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