TMPRSS2, a novel membrane-anchored mediator in cancer pain.
More than half of all cancer patients have significant pain during the course of their disease. The strategic localization of TMPRSS2, a membrane-bound serine protease, on the cancer cell surface may allow it to mediate signal transduction between the cancer cell and its extracellular environment. We show that TMPRSS2 expression is not only dramatically increased in the primary cancers of patients but TMPRSS2 immunopositivity is also directly correlated with cancer pain severity in these patients. TMPRSS2 induced proteolytic activity, activated trigeminal neurons, and produced marked mechanical hyperalgesia when administered into the hind paw of wild-type mice but not PAR2-deficient mice. Coculture of human cancer cells with murine trigeminal neurons demonstrated colocalization of TMPRSS2 with PAR2. These results point to a novel role for a cell membrane-anchored mediator in cancer pain, as well as pain in general.
Discipline of Oral and Maxillofacial Surgery, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA Bluestone Center for Clinical Research, New York University, New York, NY, USA Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA.
David K
DK
Lam
Dongmin
D
Dang
Andrea N
AN
Flynn
Markus
M
Hardt
Brian L
BL
Schmidt
D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D059748:Proteolysis / Q000187:drug effects; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D014279:Trigeminal Nucleus, Spinal / Q000187:drug effects / Q000378:metabolism
D044464:Receptor, PAR-2; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human