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

Pain is one of the many debilitating side effects of cancer. Now, Rohini Kuner and her colleagues show that blocking hematopoietic colony-stimulating factor signaling on neurons can inhibit pain caused by bone cancer. 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 nerves 2 . Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood 2 . Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells 3 and tumor cells 4 . 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.