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

Nature Medicine volume 15, pages 802–807 (2009)Cite this article

Abstract

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer1,2. 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 nerves2. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood2. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells3 and tumor cells4. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF)3 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.

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Figure 1: Evidence for release of G-CSF and GM-CSF from tumor-affected tissues and expression of their receptors (G-CSFR and GM-CSFRα) on sensory nerve fibers and cell bodies.
Figure 2: Evidence for mouse G-CSF- and GM-CSF-evoked functions in sensory neurons with respect to molecular signaling, gene expression, CGRP release and nerve activity.
Figure 3: Functional role of G-CSF and GM-CSF signaling in nociceptive sensitization, tumor-induced hyperalgesia and hypertrophy of cutaneous nerve fibers in vivo.
Figure 4: Effects of RNA interference-induced knockdown of GM-CSFRα specifically in sensory neurons on tumor growth and tumor-induced hyperalgesia and nerve remodeling.

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Acknowledgements

The authors thank H.-J. Wrede, C. Harding-Rose and D. Baumgartl-Ahlert for technical assistance and R. LeFaucheur for secretarial help. This work was supported by grants from the Association of International Cancer Research and the Landesstiftung Baden-Württemberg (Program RNAi) to R.K. and by US National Institutes of Health grants DA11471 and CA91007 to D.A.S.

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Author notes

  1. Christoph W Michalski & Stefan Brugger

    Present address: Present addresses: Surgery Clinic, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany (C.W.M.); Anesthesiology and Intensive Medicine, University Clinic of Basel, Basel, Switzerland (S.B.).,

  2. Sebastian Stösser, Martina Kurejova and Christian Njoo: These authors contributed equally to this work.

Authors and Affiliations

  1. Pharmacology Institute, University of Heidelberg, Heidelberg, Germany

    Matthias Schweizerhof, Sebastian Stösser, Martina Kurejova, Christian Njoo, Vijayan Gangadharan, Nitin Agarwal, Kiran Kumar Bali, Christoph W Michalski, Stefan Brugger & Rohini Kuner

  2. Department of Anesthesiology and Intensive Care Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    Martin Schmelz

  3. Department of General Surgery, University of Heidelberg, Heidelberg, Germany

    Christoph W Michalski

  4. Department of Pharmacology, University College London, London, UK

    Anthony Dickenson

  5. Department of Diagnostic & Biological Sciences, University of Minnesota, School of Dentistry, Minneapolis, Minnesota, USA

    Donald A Simone

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Contributions

M. Schweizerhof performed the largest portion of the experiments and analyzed data; S.S., M.K. and C.N. performed several experiments and analyzed data; V.G., N.A., M. Schmelz, C.W.M., K.K.B. and S.B. performed some experiments and analyzed data; A.D. contributed knowledge of mouse models; D.A.S. contributed knowledge of mouse models and helped with some experiments and with the writing of the manuscript; R.K. designed and supervised the study, analyzed data and wrote the manuscript.

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Correspondence to Rohini Kuner.

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Schweizerhof, M., Stösser, S., Kurejova, M. et al. Hematopoietic colony–stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat Med 15, 802–807 (2009). https://doi.org/10.1038/nm.1976

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