Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers

Aaron P. Bloom, Juan M. Jimenez-Andrade, Reid N. Taylor, Gabriela Castañeda-Corral, Magdalena J. Kaczmarska, Katie T. Freeman, Kathleen A. Coughlin, Joseph R. Ghilardi, Michael A. Kuskowski, Patrick W Mantyh

Research output: Contribution to journalArticle

84 Citations (Scopus)

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 coexpress 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. Perspective: Therapies that block breast cancer pain by reducing the tumor-induced pathological sprouting and reorganization of sensory nerve fibers may provide insight into the evolving mechanisms that drive breast cancer pain and lead to more effective therapies for attenuating this chronic pain state.

Original languageEnglish (US)
Pages (from-to)698-711
Number of pages14
JournalJournal of Pain
Volume12
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Bone Neoplasms
Bone Remodeling
Nerve Fibers
Breast Neoplasms
Pain
Mastodynia
Nerve Growth Factor
Stromal Cells
Nude Mice
Chronic Pain
Disease Progression
GAP-43 Protein
Bone and Bones
Calcitonin Gene-Related Peptide
Therapeutics
Thigh
Neoplasms
Pathology
Neoplasm Metastasis
Injections

Keywords

  • breakthrough pain
  • MDA-MB-231-BO
  • NGF
  • Periosteum
  • preventive analgesia

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Neurology
  • Clinical Neurology

Cite this

Bloom, A. P., Jimenez-Andrade, J. M., Taylor, R. N., Castañeda-Corral, G., Kaczmarska, M. J., Freeman, K. T., ... Mantyh, P. W. (2011). Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers. Journal of Pain, 12(6), 698-711. https://doi.org/10.1016/j.jpain.2010.12.016

Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers. / Bloom, Aaron P.; Jimenez-Andrade, Juan M.; Taylor, Reid N.; Castañeda-Corral, Gabriela; Kaczmarska, Magdalena J.; Freeman, Katie T.; Coughlin, Kathleen A.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.

In: Journal of Pain, Vol. 12, No. 6, 06.2011, p. 698-711.

Research output: Contribution to journalArticle

Bloom, AP, Jimenez-Andrade, JM, Taylor, RN, Castañeda-Corral, G, Kaczmarska, MJ, Freeman, KT, Coughlin, KA, Ghilardi, JR, Kuskowski, MA & Mantyh, PW 2011, 'Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers', Journal of Pain, vol. 12, no. 6, pp. 698-711. https://doi.org/10.1016/j.jpain.2010.12.016
Bloom AP, Jimenez-Andrade JM, Taylor RN, Castañeda-Corral G, Kaczmarska MJ, Freeman KT et al. Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers. Journal of Pain. 2011 Jun;12(6):698-711. https://doi.org/10.1016/j.jpain.2010.12.016
Bloom, Aaron P. ; Jimenez-Andrade, Juan M. ; Taylor, Reid N. ; Castañeda-Corral, Gabriela ; Kaczmarska, Magdalena J. ; Freeman, Katie T. ; Coughlin, Kathleen A. ; Ghilardi, Joseph R. ; Kuskowski, Michael A. ; Mantyh, Patrick W. / Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers. In: Journal of Pain. 2011 ; Vol. 12, No. 6. pp. 698-711.
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