Pathological Sprouting of Adult Nociceptors in Chronic Prostate Cancer-Induced Bone Pain

Abstract

Pain frequently accompanies cancer. What remains unclear is why this pain frequently becomes more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression, sensory nerve fibers that innervate the tumor-bearing tissue undergo a pathological sprouting and reorganization, which in other non-malignant pathologies has been shown to generate and maintain chronic pain. Injection of canine prostate cancer cells into mouse bone induces a remarkable sprouting of calcitonin gene related peptide (CGRP+) and neurofilament 200 kDa (NF200+) sensory nerve fibers. Nearly all sensory nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA+). This ectopic sprouting occurs in sensory nerve fibers that are in close proximity to colonies of prostate cancer cells, tumor-associated stromal cells and newly formed woven bone, which together form sclerotic lesions that closely mirror the osteoblastic bone lesions induced by metastatic prostate tumors in humans. Preventive treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. Interestingly, RT-PCR analysis indicated that the prostate cancer cells themselves do not express detectable levels of mRNA coding for NGF. This suggests that the tumor-associated stromal cells express and release NGF, which drives the pathological reorganization of nearby TrkA+ sensory nerve fibers. Therapies that prevent this reorganization of sensory nerve fibers may provide insight into the evolving mechanisms that drive cancer pain and lead to more effective control of this chronic pain state.

Immunohistochemical investigation of nerve fiber presence and morphology in elderly cervical spine meniscoids

“…It must be considered that Inami et al investigated meniscoids excised from participants undergoing laminectomy for cervical myelopathy, removing the dorsal meniscoids at the affected spinal level. Sensory innervation may vary in the presence of pathology, as increased frequency of sensory nerve fibers has been observed in arthritic knee pain [39], breast pain [40], cancer-related pain [41], and non-healed fractures [42], and hypersensitivity of regenerating axonal sprouts is thought to contribute to the perpetuation of symptoms in chronic pain [39,43]. As all participants included in the study of Inami et al had sufficient pain to warrant surgical intervention, and as the neck pain statuses of the cadavers of the present study are unknown, it is plausible that the high nerve fiber frequency reported by Inami et al represents sprouting of sensory nerve fibers in the context of long-standing pain and inflammation.…”

Tissue Preparation and Immunostaining of Mouse Sensory Nerve Fibers Innervating Skin and Limb Bones

“…Furthermore, changes in the expression of neurotransmitters, receptors, ion channels or other phenotypic markers in normal developmental or pathological conditions can also be studied 3,[5][6][7][8][9][10] . Along with appropriate electrophysiological, biochemical and behavioral testing, such changes in peripheral sensory neuron staining patterns can be used to test hypotheses related to various pain states 6,9 , inflammation 11 and neuropathies 5,12 . In conclusion, these techniques provide an invaluable source of in vivo data that complements and reinforces other anatomical, structural and functional data acquired through additional approaches, furthering our understanding of the regulation and acquisition of plasticity in peripheral sensory nerve fibers in health and disease.…”

CXCR3: Latest evidence for the involvement of chemokine signaling in bone cancer pain

“…Neurotrophins could regulate the survival, development, and function of subsets of sensory and sympathetic neurons, and are essential to the generation and maintenance of pain Price et al, 2005). Tyrosine kinase receptor A is detectable in nociceptive sensory nerve fibers innervating the bone, and inhibiting nerve growth factor (NGF) expression could attenuate cancer-induced behavioral signs of pain in BCP mice (Bloom et al, 2011;Halvorson et al, 2005;Jimenez-Andrade et al, 2010;Jimenez-Andrade et al, 2011;Mantyh et al, 2010). Also, treatment against NGF could impact pain-driven peripheral changes in DRG and central changes in the spinal cord .…”