Annals of Anatomy 192 (2010) 309–313 Contents lists available at ScienceDirect Annals of Anatomy journal homepage: www.elsevier.de/aanat Invited review xCT modulation in gliomas: Relevance to energy metabolism and tumor microenvironment normalization  Nic E. Savaskan a,∗ , Ilker Y. Eyüpoglu b a Institute of Cell Biology and Neurobiology, Center for Anatomy, CCM2, Charité–Medical School Berlin, D-10117 Berlin, Germany b Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany article info Article history: Received 28 June 2010 Accepted 8 July 2010 Keywords: Glutamate Lactate Peritumoral edema Tumor microenvironment Glutamate/cystine transporter Neurotoxicity Apoptotic cell death abstract 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 X c - , 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 lead- ing 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 develop- ment 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. © 2010 Elsevier GmbH. All rights reserved. Contents 1. Introduction .......................................................................................................................................... 309 2. Cytotoxic approaches meet the tumor microenvironment ......................................................................................... 310 3. Brain edema in gliomas .............................................................................................................................. 310 4. xCT modulation and the tumor microenvironment ................................................................................................. 311 4.1. What can be expected as an outcome when blocking the xCT transporter in cancer? ...................................................... 312 Conflict of interest ......................................................................................................................................... 312 Acknowledgements ....................................................................................................................................... 312 References ................................................................................................................................................. 312 1. Introduction Current knowledge on nutrient transporters in cancer points out the fact that cancer cells have to adjust their increased demand for nutrients due to their excessive glucose metabolism via anaerobic glycolysis rather than oxidative phosphorylation (called Warburg effect; Warburg, 1956; Ganapathy et al., 2009). To keep up with increased energy demand due to this permanent respiratory defect  This contribution presents the Wolfgang Bargmann Preis 2009 lecture held at the annual meeting of the Anatomische Gesellschaft in Antwerp, Belgium. Dr. Nic Savaskan was the recipient of the 2009 Wolfgang Bargmann Award of the Anatomis- che Gesellschaft (AG). ∗ Corresponding author. Tel.: +49 1577 386 53 80. E-mail address: savaskan@gmx.net (N.E. Savaskan). that bypasses the Pasteur effect, cancer cells express nutrient transporters for lactate and amino acids, which in particular are primarily related to the augmentation of reactive oxygen species (ROS) and redox cycle regulation (Kroemer and Pouyssegur, 2008; Semenza, 2003; Vafa et al., 2002). In this respect, system x c - , aka xCT (human gene nomenclature for xCT: SLC7a11) takes cen- ter stage due to its level regulation of the rate-limiting substrate cysteine required for glutathione biosynthesis (Fig. 1). Indeed, there is ample evidence for the expression of cystine/glutamate antiporter xCT in various malignant tumors such as leukemias, lym- phomas, Karposi’s sarkoma, pancreatic cancer (Huang et al., 2005; Lo et al., 2008) as well as brain cancer (Ye and Sontheimer, 1999; Savaskan et al., 2008). There, the heterodimeric cystine/glutamate antiporter system x c - composed of xCT/SLC7a11 and its chaperone CD98/4F2hc (SLC3A2) function as a Na-independent electroneutral 0940-9602/$ – see front matter © 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.aanat.2010.07.003