The role of glutamate receptors in the regulation of the tumor microenvironment

Abstract

Glutamate, as one of the most important carbon sources in the TCA cycle, is central in metabolic processes that will subsequently influence tumor progression. Several factors can affect the expression of glutamate receptors, playing either a tumor-promoting or tumor-suppressor role in cancer. Thus, the activation of glutamate receptors by the ligand could play a role in tumor development as ample studies have demonstrated the expression of glutamate receptors in a broad range of tumor cells. Glutamate and its receptors are involved in the regulation of different immune cells’ development and function, as suggested by the receptor expression in immune cells. The activation of glutamate receptors can enhance the effectiveness of the effector’s T cells, or decrease the cytokine production in immunosuppressive myeloid-derived suppressor cells, increasing the antitumor immune response. These receptors are essential for the interaction between tumor and immune cells within the tumor microenvironment (TME) and the regulation of antitumor immune responses. Although the role of glutamate in the TCA cycle has been well studied, few studies have deeply investigated the role of glutamate receptors in the regulation of cancer and immune cells within the TME. Here, by a systematic review of the available data, we will critically assess the physiopathological relevance of glutamate receptors in the regulation of cancer and immune cells in the TME and provide some unifying hypotheses for futures research on the role of glutamate receptors in the immune modulation of the tumor.

Controlling pericellular oxygen tension in cell culture reveals distinct breast cancer responses to low oxygen tensions

“…Expected metabolic changes in response to hypoxia include an increase in (i) glucose consumption due to increased uptake and glycolytic flux, (ii) extracellular lactate from decreased TCA cycle flux and increased lactate transport, (iii) glutamine uptake to replenish TCA cycle intermediates for lipid metabolism, and (iv) extracellular glutamate secretion, which promotes cancer cell proliferation. 39, 42, 45–48 MCF7 cells were cultured for 72 hours in 18.6%, 4%, and 1% O 2 incubators, resulting in supraphysiologic (10.8% O 2 ), hypoxic (1.2% O 2 ), and anoxic (0.0% O 2 ) pericellular tensions, respectively ( Figure 5A ). Consumption (glucose and glutamine) and production (lactate and glutamate) rates trended higher with decreasing pericellular O 2 tension over the 72 hour time course ( Figure 5B – 5E ).…”

Targeting glutamate metabolism in chronic lung diseases

“…Group III mGluRs (mGluR4, mGluR6, mGluR7 and mGluR8) participate in the regulation of neurotransmitter release, modulation of synaptic transmission and have effects on pain perception, addiction and motor coordination. 34,35 Glutamate metabolism is associated with the process of protein folding, de novo synthesis of nucleic acid and lipid synthesis (Figure 3). As a common neurotransmitter, glutamate is intricately involved in the pathogenesis of numerous neurological disorders, spanning from epileptic seizures and traumatic brain injuries to neurodegenerative diseases and psychiatric disorders.…”

“…Group II mGluRs (mGluR2 and mGluR3) are involved in the regulation of neurotransmitter release, modulation of synaptic transmission and influence processes such as anxiety and cognition. Group III mGluRs (mGluR4, mGluR6, mGluR7 and mGluR8) participate in the regulation of neurotransmitter release, modulation of synaptic transmission and have effects on pain perception, addiction and motor coordination 34,35 …”

Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers

“…Notably, we found that the understudied group III mGluR, mGluR8, also undergoes β-arr-mediated internalization. mGluR8, despite receiving less attention compared to other mGluR subtypes, is typically found presynaptically where it can serve as an inhibitory autoreceptor (1,(22)(23)(24)(25) and has been strongly implicated in the pathophysiology and potential treatment of pain, anxiety disorders, neurodegeneration, and cancer (26)(27)(28)(29)(30)(31)(32)(33).…”