Adenosine triphosphate drives head and neck cancer pain through P2X2/3 heterotrimers

Yi Ye, Kentaro Ono, Daniel G. Bernabé, Chi T. Viet, Victoria Pickering, John C. Dolan, Markus Hardt, Anthony P. Ford, Brian Schmidt

Research output: Contribution to journalArticle

Abstract

INTRODUCTION: 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.

Original languageEnglish (US)
Pages (from-to)62
Number of pages1
JournalActa neuropathologica communications
Volume2
DOIs
StatePublished - 2014

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Neck Pain
Head and Neck Neoplasms
Adenosine Triphosphate
Purinergic P2X2 Receptors
Purinergic P2X3 Receptors
Animal Models
Cellular Microenvironment
Pain
Trigeminal Ganglion
Nociceptors
Pain Perception
Tumor Microenvironment
Neurobiology
Nerve Growth Factor
Cancer Pain
Drive
Nerve Fibers
Neoplasms
Hypersensitivity
Quality of Life

ASJC Scopus subject areas

  • Medicine(all)

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Adenosine triphosphate drives head and neck cancer pain through P2X2/3 heterotrimers. / Ye, Yi; Ono, Kentaro; Bernabé, Daniel G.; Viet, Chi T.; Pickering, Victoria; Dolan, John C.; Hardt, Markus; Ford, Anthony P.; Schmidt, Brian.

In: Acta neuropathologica communications, Vol. 2, 2014, p. 62.

Research output: Contribution to journalArticle

Ye, Yi ; Ono, Kentaro ; Bernabé, Daniel G. ; Viet, Chi T. ; Pickering, Victoria ; Dolan, John C. ; Hardt, Markus ; Ford, Anthony P. ; Schmidt, Brian. / Adenosine triphosphate drives head and neck cancer pain through P2X2/3 heterotrimers. In: Acta neuropathologica communications. 2014 ; Vol. 2. pp. 62.
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