Neuropilin-1 mediates nerve growth factor signaling of oral cancer pain.

Oral cancer is one of the most painful malignancies, with pain driven primarily by algogenic mediators in the tumor microenvironment, including nerve growth factor (NGF). Although NGF monoclonal antibodies alleviate cancer pain in patients, clinical development was halted because of adverse effects, highlighting the need for safer alternatives. Neuropilin-1 (NRP1), a nonenzymatic NGF coreceptor, mediates NGF and tropomyosin receptor kinase A (TrkA) signaling, yet its role in cancer pain is unknown. We found that NRP1 is robustly coexpressed with TrkA in peptidergic nociceptors of mouse trigeminal ganglia. NRP1 antagonists inhibited NGF-induced sensitization of transient receptor potential vanilloid 1 in isolated trigeminal nociceptors and reduced NGF-induced periorbital mechanical allodynia in mice. Conditioned medium from human tongue squamous carcinoma HSC-3 cells contained NGF and sensitized transient receptor potential vanilloid 1 in trigeminal nociceptors and induced periorbital mechanical allodynia. Immunoneutralization of NGF and NRP1 blockade inhibited these effects. Our results show that NRP1 is a necessary coreceptor for the pronociceptive effects of NGF/TrkA signaling in the trigeminal system and implicate NGF and NRP1 in oral cancer pain. Current oral cancer pain management strategies, including opioids, are inadequate and are burdened by unacceptable side effects. By abrogating the actions of growth factors, including NGF, NRP1-targeted therapies represent an alternative approach to mitigate cancer pain and possibly slow tumor growth.