Breast Cancer-Induced Bone Remodeling, Skeletal Pain, and Sprouting of Sensory Nerve Fibers

Abstract

Breast cancer metastasis to bone is frequently accompanied by pain. What remains unclear is why this pain tends to become more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression sensory nerve fibers that innervate the breast cancer bearing bone undergo a pathological sprouting and reorganization, which in other nonmalignant pathologies has been shown to generate and maintain chronic pain. Injection of human breast cancer cells (MDA-MB-231-BO) into the femoral intramedullary space of female athymic nude mice induces sprouting of calcitonin gene-related peptide (CGRP + ) sensory nerve fibers. Nearly all CGRP + nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA + ) and growth associated protein-43 (GAP43 + ). This ectopic sprouting occurs in periosteal sensory nerve fibers that are in close proximity to breast cancer cells, tumor-associated stromal cells and remodeled cortical bone. Therapeutic 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. The present data suggest that the breast cancer cells and tumor-associated stromal cells express and release NGF, which drives bone pain and the pathological reorganization of nearby CGRP + / TrkA + / GAP43 + sensory nerve fibers.

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

“…Brain-derived neurotrophic factor and NT-4/5 exhibit a different type of activity on breast cancer cells as they were found to stimulate tumor cell survival. In addition, the impact of neurotrophins could go beyond the stimulation of breast tumor cells themselves as recent studies suggest an effect of NGF on angiogenesis (36) as well as on the sprouting of sensory nerve fibers participating in cancer-induced pain (37). In addition to other studies reporting neurotrophin intervention in other pathologies, the present work integrates with the emerging concept that proNGF is a biologically active molecule that can function outside the nervous system.…”

Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain

“…Cancer-induced bone pain not only is associated with an initial tumor-induced nerve injury of distal processes of sensory fibers but also with sprouting and formation of neuroma-like structures by sensory and sympathetic fibers innervating the tumor-bearing site. 3,22 The current view is that nerve growth factor (NGF) released by endogenous stromal, immune, and inflammatory cells drives the sensory fiber ectopic sprouting as this is significantly decreased by early anti-NGF treatment without any effect on bone destruction or tumor growth. 27 Consistent with the possibility that nerve fiber sprouting contributes to skeletal pain, pre-emptive and sustained anti-NGF treatment attenuates cancer-induced pain behavior, whereas late and acute treatment exerts limited effect.…”

“…5 Accordingly, there is a significant cancer-induced sprouting of CGRP-expressing fibers that is matched by higher numbers of CGRP-positive neuronal cell bodies in dorsal root ganglia (DRG) ipsilateral to the cancer-bearing bone. 3,22,33 Such upregulation of CGRP in the DRG is the likely product of increased translation promoted by retrogradely transported NGF in TrkA-expressing sensory neurons. 35 Current evidence suggests that although more CGRP is shuttled to the peripheral terminals of sensory neurons, no changes in CGRP expression can be observed in the ipsilateral dorsal horn.…”

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 .…”