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

Schematic representation of the pathway that signals sustained pain-like responses in E0771 bone metastatic cancer pain (a) E0771 breast cancer cell inoculation in the fourth mammary gland induces bone metastasis in the femur head (b, c). IL-8 release from E0771 cells activates osteoclasts to release IGF-1. (d) Schwann cell IGF-1 receptor (IGF-1R), after IGF-1 stimulation, triggers an intracellular signaling cascade (IRS-1, Akt, and eNOS) that terminates with (e) nitric oxide (NO) dependent TRPA1 activation. (f) NOX1 Ca-dependent activation induces the release of H2O2 that targets neuronal TRPA1 to signal pain. [Display omitted] •Pain is a recurrent symptom of cancer more frequent in the presence of bone metastases.•IGF-1, an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain.•IGF-1 receptor signaling in Schwann cell sustains metastatic bone cancer. 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.