title: Adenosine triphosphate drives head and neck cancer pain through P2X2/3 heterotrimers.
abstract: BACKGROUND
  Cancer pain creates a poor quality of life and decreases survival. The basic neurobiology of cancer pain is poorly understood. Adenosine triphosphate (ATP) and the ATP ionotropic receptor subunits, P2X2 and P2X3, mediate cancer pain in animal models; however, it is unknown whether this mechanism operates in human, and if so, what the relative contribution of P2X2- and P2X3-containing trimeric channels to cancer pain is. Here, we studied head and neck squamous cell carcinoma (HNSCC), which causes the highest level of function-induced pain relative to other types of cancer.
  
  
  RESULTS
  We show that the human HNSCC tissues contain significantly increased levels of ATP compared to the matched normal tissues. The high levels of ATP are secreted by the cancer and positively correlate with self-reported function-induced pain in patients. The human HNSCC microenvironment is densely innervated by nerve fibers expressing both P2X2 and P2X3 subunits. In animal models of HNSCC we showed that ATP in the cancer microenvironment likely heightens pain perception through the P2X2/3 trimeric receptors. Nerve growth factor (NGF), another cancer-derived pain mediator found in both human and mouse HNSCC, induces P2X2 and P2X3 hypersensitivity and increases subunit expression in murine trigeminal ganglion (TG) neurons.
  
  
  CONCLUSIONS
  These data identify a key peripheral mechanism in cancer pain and highlight the clinical potential of specifically targeting nociceptors expressing both P2X2 and P2X3 subunits (e.g., P2X2/3 heterotrimers) to alleviate cancer pain.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ye
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ono
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bernabé
authors.forename: Chi T
authors.initials: CT
authors.lastname: Viet
authors.forename: Victoria
authors.initials: V
authors.lastname: Pickering
authors.forename: John C
authors.initials: JC
authors.lastname: Dolan
authors.forename: Markus
authors.initials: M
authors.lastname: Hardt
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Ford
authors.affiliation: Bluestone Center for Clinical Research, New York University, 421 First Avenue, 233 W, New York, NY 10010, USA. bls322@nyu.edu.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Schmidt
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002277:Carcinoma / Q000150:complications* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000150:complications* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000209:etiology* / Q000378:metabolism*; D010147:Pain Measurement; D058476:Receptors, Purinergic P2X2 / Q000502:physiology*; D058477:Receptors, Purinergic P2X3 / Q000502:physiology*
chemical_list: D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate