xCT modulation in gliomas: Relevance to energy metabolism and tumor microenvironment normalization

Several nutrient transporters impacting the glutathione/redox cycle regulation and cell proliferation have been identified in cancer, which render these transporters potential prime targets for cytotoxic anticancer therapy. One promising transporter is system Xc−, also known as xCT (SLC7a11), which is expressed in various cancers including primary malignant brain tumors (gliomas). An important biological feature of these transporters, and in particular of xCT is its specific modulation of the tumor microenvironment leading to growth advantage for cancer. Thus, tumor microenvironment shaping by xCT inhibition revealed a so far neglected hallmark of gliomas, i.e. tumor-induced neurotoxicity and its impact on the development of peritumoral brain swelling. This review here discusses available pharmacological tools for the tumor microenvironment normalization, in the context of perifocal edema and the Warburg effect and highlights the implications of such metabolic normalization approach in the design of new therapies.