gms | German Medical Science

Objective: Glutamate is a serum derived factor that promotes cell growth and proliferation in various cancer entities. Moreover, in the CNS glutamate also evokes neuronal cell death at high concentrations. A hallmark of malignant brain tumors is their possibility to induce a peritumoral edema or brain swelling and subsequently neurodegeneration. A major factor contributing to glioma-induced cell death has recently been identified as glutamate. Although glutamate signaling at the receptor and its downstream effectors has been understood at the molecular level, it remained unclear how glutamate is exported into the tumor microenvironment. Surprisingly, system Xc- appeared to take center stage in this process, mediating glutamate secretion in exchange for cystine to the extracellular space.

Methods: Glutamate transporters and receptors were disrupted by pharmacological and genetic approaches. Neurodegeneration was identified using a living organtypic brain slice culture model. Results were confirmed by in vivo experiments. Tumor growth was monitored in vivo using a 3 Tesla MRI.

Results: Here, we dissected glutamate and glutamate receptor signaling in gliomas demonstrating by pharmacological or genetic disruption that glutamate is not essential for proliferation. Hence, AMPA receptor signaling did not foster glioma proliferation in vitro. However, inhibition of system Xc- or AMPA receptors in vivo mitigated brain swelling and peritumoral alterations. Moreover, the ability of glutamate to promote glioma progression was mediated contrariwise indirectly via tumor microenvironment modulation and angiogenesis.

Conclusions: In particular, we shed light on the role of system Xc- in gliomas supporting the conceptual challenge that xCT transporter disruption goes beyond cytotoxicity towards microenvironmental normalization. Thus, system Xc- takes center stage in forming the basis of a metabolic equilibration approach.