title: Tumour-Derived Glutamate: Linking Aberrant Cancer Cell Metabolism to Peripheral Sensory Pain Pathways.
abstract: BACKGROUND
  Chronic pain is a major symptom that develops in cancer patients, most commonly emerging during advanced stages of the disease. The nature of cancer-induced pain is complex, and the efficacy of current therapeutic interventions is restricted by the dose-limiting sideeffects that accompany common centrally targeted analgesics.
  
  
  METHODS
  This review focuses on how up-regulated glutamate production and export by the tumour converge at peripheral afferent nerve terminals to transmit nociceptive signals through the transient receptor cation channel, TRPV1, thereby initiating central sensitization in response to peripheral disease-mediated stimuli.
  
  
  RESULTS
  Cancer cells undergo numerous metabolic changes that include increased glutamine catabolism and over-expression of enzymes involved in glutaminolysis, including glutaminase. This mitochondrial enzyme mediates glutaminolysis, producing large pools of intracellular glutamate. Upregulation of the plasma membrane cystine/glutamate antiporter, system xc -, promotes aberrant glutamate release from cancer cells. Increased levels of extracellular glutamate have been associated with the progression of cancer-induced pain and we discuss how this can be mediated by activation of TRPV1.
  
  
  CONCLUSIONS
  With a growing population of patients receiving inadequate treatment for intractable pain, new targets need to be considered to better address this largely unmet clinical need for improving their quality of life. A better understanding of the mechanisms that underlie the unique qualities of cancer pain will help to identify novel targets that are able to limit the initiation of pain from a peripheral source-the tumour.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fazzari
authors.forename: Katja
authors.initials: K
authors.lastname: Linher-Melville
authors.affiliation: Department of Pathology and Molecular Medicine; Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON. Canada.
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
mesh_terms: D000344:Afferent Pathways / Q000378:metabolism; D000818:Animals; D000072716:Cancer Pain / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; D018698:Glutamic Acid
keywords: Cancer pain; TRPV1; glutamate; glutaminase; system xc