Title:Tumour-Derived Glutamate: Linking Aberrant Cancer Cell Metabolism to Peripheral Sensory Pain Pathways
Volume: 15
Issue: 4
Author(s): Jennifer Fazzari, Katja Linher-Melville and Gurmit Singh*
Affiliation:
- Department of Pathology and Molecular Medicine; Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON,Canada
Keywords:
Cancer pain, glutamate, glutaminase, system xc
-, TRPV1.
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.
Conclusion: 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.
