Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain

Matthias Schweizerhof, Sebastian Stösser, Martina Kurejova, Christian Njoo, Vijayan Gangadharan, Nitin Agarwal, Martin Schmelz, Kiran Kumar Bali, Christoph W. Michalski, Stefan Brugger, Anthony Dickenson, Donald A Simone, Rohini Kuner

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.

Original languageEnglish (US)
Pages (from-to)802-807
Number of pages6
JournalNature Medicine
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2009

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Colony-Stimulating Factors
Bone Neoplasms
Granulocyte-Macrophage Colony-Stimulating Factor
Tumors
Bone
Neoplasms
Granulocyte Colony-Stimulating Factor
Sensory Receptor Cells
Pain
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Cancer Pain
Bone and Bones
Bone Remodeling
Hyperalgesia
Myeloid Cells
Peripheral Nerves
Nerve Fibers
Granulocytes
Sarcoma
Neurons

Cite this

Schweizerhof, M., Stösser, S., Kurejova, M., Njoo, C., Gangadharan, V., Agarwal, N., ... Kuner, R. (2009). Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nature Medicine, 15(7), 802-807. https://doi.org/10.1038/nm.1976

Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. / Schweizerhof, Matthias; Stösser, Sebastian; Kurejova, Martina; Njoo, Christian; Gangadharan, Vijayan; Agarwal, Nitin; Schmelz, Martin; Bali, Kiran Kumar; Michalski, Christoph W.; Brugger, Stefan; Dickenson, Anthony; Simone, Donald A; Kuner, Rohini.

In: Nature Medicine, Vol. 15, No. 7, 01.07.2009, p. 802-807.

Research output: Contribution to journalArticle

Schweizerhof, M, Stösser, S, Kurejova, M, Njoo, C, Gangadharan, V, Agarwal, N, Schmelz, M, Bali, KK, Michalski, CW, Brugger, S, Dickenson, A, Simone, DA & Kuner, R 2009, 'Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain', Nature Medicine, vol. 15, no. 7, pp. 802-807. https://doi.org/10.1038/nm.1976
Schweizerhof M, Stösser S, Kurejova M, Njoo C, Gangadharan V, Agarwal N et al. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nature Medicine. 2009 Jul 1;15(7):802-807. https://doi.org/10.1038/nm.1976
Schweizerhof, Matthias ; Stösser, Sebastian ; Kurejova, Martina ; Njoo, Christian ; Gangadharan, Vijayan ; Agarwal, Nitin ; Schmelz, Martin ; Bali, Kiran Kumar ; Michalski, Christoph W. ; Brugger, Stefan ; Dickenson, Anthony ; Simone, Donald A ; Kuner, Rohini. / Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. In: Nature Medicine. 2009 ; Vol. 15, No. 7. pp. 802-807.
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