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 nonmalignant 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 coexpress
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, reverse transcription 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.