Hematopoietic colony|[ndash]|stimulating factors mediate tumor-nerve interactions and bone cancer pain

doi:doi:10.1038/nm.1976

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer^1,². 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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Hematopoietic colony–stimulating factors mediate tumor-nerve interactions and bone cancer pain

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