Glutamate transporters in the biology of malignant gliomas

Abstract

Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters system x c (-) and excitatory amino acid transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat.

Figures

Fig. 1

Glutamate transporters in the non-pathological brain. Two glutamate transporters, System xc− (SXC) and the Excitatory Amino Acid Transporters (EAAT) function in concert to support normal brain function and glutamate (Glu) homeostasis. SXC is a Na+-independent, Cl−-dependent, cystine (Cys-Cys)/glutamate exchanger. SXC provides intracellular cysteine (Cys) for synthesis of glutathione (GSH). EAAT removes glutamate released into the extracellular space from SXC and other sources, maintaining extracellular glutamate homeostasis. EAAT also provides intracellular glutamate, which combines with cysteine (from SXC) and glycine (Gly) to form GSH, an important molecule for intracellular redox control and cellular protection. EAAT is a family of Na+-dependent transporters that exchange a proton and K+ along with uptake of glutamate. In the non-pathological brain, SXC and EAAT complement each other by providing a glutamate gradient for SXC-mediated cystine uptake and prevention of glutamate toxicity in the surrounding brain.

Fig. 2

Glutamate transporter and receptor expression and function in the non-pathological brain and in glioma. a In the non-pathological brain, astrocytes are in close proximity to the synaptic cleft of glutamatergic neurons. Glutamate (Glu) is released vesicularly from presynaptic neurons during synaptic transmission; Glu diffuses across the synaptic cleft, binds postsynaptic neuronal glutamate receptors (NMDAR, AMPAR, mGluR), and is then removed from the extracellular space by Excitatory Amino Acid Transporter (EAAT) glutamate transporters located on astrocytes (EAAT 1, 2) and neurons (EAAT 2). EAAT also balance the glutamate released through System xc− (SXC) in exchange for cystine (Cys2) uptake. b The replacement of normal brain tissue by glioma cells disrupts the normal synaptic arrangement, which alters glutamate homeostasis. Glioma cells have increased SXC activity but lack EAAT function, greatly increasing peritumoral glutamate concentrations. Increased SXC benefits cells by providing increased cystine uptake, which after intracellular reduction to cysteine (Cys), is used for glutathione (GSH) synthesis. GSH, an intracellular antioxidant, is especially important in malignant cells as they neutralize reactive oxygen species (ROS) produced. Additionally, elevated extracellular glutamate interacts with glioma glutamate receptors (AMPAR & mGluR) to stimulate cell proliferation, migration, and invasion. With the loss of glutamate homeostasis, neurons become susceptible to glutamate-mediated excitotoxicity and death as a result of overstimulation of neuronal glutamate receptors, which leads to uncontrolled intracellular Ca2+ rises, aberrant neuronal signaling, and ultimately excitotoxic neuronal death. Additionally, we hypothesize that glioma cells alter peritumoral astrocyte EAAT function, preventing them from being able to re-establish glutamate homeostasis, as they would in the non-pathological brain. (Image is not drawn to scale)

Fig. 3

Glutamate transporters confer biological advantages to malignant gliomas. The upregulation of System xc− (SXC) and loss of Excitatory Amino Acid Transporter (EAAT) glutamate transporters in glioma cells alter glutamate homeostasis in the brain. SXC-mediated cystine (Cys) uptake provides substrate for synthesis of glutathione (GSH), an important intracellular antioxidant that promotes cell survival. Glutamate (Glu) released in exchange for cystine uptake increases extracellular glutamate concentrations. Excess glutamate works in an autocrine/paracrine manner by activating glutamate receptors on glioma cells to promote tumor growth and invasion. Similarly, glutamate overstimulates glutamate receptors on surrounding neurons, causing excitotoxic neuronal death, which creates space for further tumor growth. Tumor growth and neuronal excitotoxicity lead to tumor-associated seizures and epilepsy in patients with malignant glioma.