Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain

Juan M. Jimenez-Andrade, Aaron P. Bloom, James I. Stake, William G. Mantyh, Reid N. Taylor, Katie T. Freeman, Joseph R. Ghilardi, Michael A. Kuskowski, Patrick W Mantyh

Research output: Contribution to journalArticle

102 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)14649-14656
Number of pages8
JournalJournal of Neuroscience
Volume30
Issue number44
DOIs
StatePublished - Nov 3 2010

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Bone Neoplasms
Nociceptors
Nerve Fibers
Prostatic Neoplasms
Pain
Nerve Growth Factor
Neoplasms
Stromal Cells
Bone and Bones
Chronic Pain
Disease Progression
Calcitonin Gene-Related Peptide
Bone Remodeling
Reverse Transcription
Canidae
Prostate
Pathology
Polymerase Chain Reaction
Messenger RNA
Injections

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Jimenez-Andrade, J. M., Bloom, A. P., Stake, J. I., Mantyh, W. G., Taylor, R. N., Freeman, K. T., ... Mantyh, P. W. (2010). Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. Journal of Neuroscience, 30(44), 14649-14656. https://doi.org/10.1523/JNEUROSCI.3300-10.2010

Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. / Jimenez-Andrade, Juan M.; Bloom, Aaron P.; Stake, James I.; Mantyh, William G.; Taylor, Reid N.; Freeman, Katie T.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.

In: Journal of Neuroscience, Vol. 30, No. 44, 03.11.2010, p. 14649-14656.

Research output: Contribution to journalArticle

Jimenez-Andrade, JM, Bloom, AP, Stake, JI, Mantyh, WG, Taylor, RN, Freeman, KT, Ghilardi, JR, Kuskowski, MA & Mantyh, PW 2010, 'Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain', Journal of Neuroscience, vol. 30, no. 44, pp. 14649-14656. https://doi.org/10.1523/JNEUROSCI.3300-10.2010
Jimenez-Andrade JM, Bloom AP, Stake JI, Mantyh WG, Taylor RN, Freeman KT et al. Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. Journal of Neuroscience. 2010 Nov 3;30(44):14649-14656. https://doi.org/10.1523/JNEUROSCI.3300-10.2010
Jimenez-Andrade, Juan M. ; Bloom, Aaron P. ; Stake, James I. ; Mantyh, William G. ; Taylor, Reid N. ; Freeman, Katie T. ; Ghilardi, Joseph R. ; Kuskowski, Michael A. ; Mantyh, Patrick W. / Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 44. pp. 14649-14656.
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