Dear Colleagues,

Tumors possess a perturbed metabolism already acknowledged decades ago by Warburg, and known today as the Warburg effect. They also have a disturbed pH regulation pathway, being more acidic extracellularly than normal cells. Inadequate delivery of oxygen to tumor cells, i.e., hypoxia, is the main factor responsible for these phenomena and induces a plethora of adaptive cellular responses, including genetic instability, angiogenesis, invasiveness, shift of metabolism to the glycolytic pathway, etc. Around 20 years ago, it was recognized that the main player of these molecular changes is the transcription factor hypoxia-inducible factor 1 (HIF-1). The HIF-activated signaling cascade triggers various processes, leading to massive metabolic adaptations in response to hypoxia and at the level of protein expression. The high metabolic rate of tumors in the glycolytic context also leads to an increased production of acid metabolites, including lactic/pyruvic acids, carbon dioxide and protons. The resulting perturbations of both intracellular (pHi) and extracellular (pHe) acid/base regulation is thus another hallmark of most cancer cells and is the result of complex molecular mechanisms involving ion exchangers, pumps, and transporters, such as sodium–proton exchangers (NHE1), anion exchangers (AE2), sodium–bicarbonate transporters (NBCe1), monocarboxylate transporters (MCT4), V-ATP-ase, and carbonic anhydrases (CAs). Overexpression of many of these proteins as well as of the glucose transporters (GLUT1-4) constitutes another important difference between cancer and normal cells. In the last two decades, it has become obvious that interference with tumor metabolism may lead to significant antitumor effects. Many of the proteins mentioned above may thus be targeted for obtaining anticancer agents with a new mechanism of action. To date, the most advanced such therapeutic approach is based on the inhibition of tumor-associated CAs (CA IX and XII), with one compound (SLC-0111) in phase Ib/II clinical trials for the treatment of advanced, metastatic solid tumors.

This Special Issue of Metabolites has the goal to bring together research in all these fascinating fields of tumor metabolism, by presenting the latest developments in various research areas connected with it.

Prof. Dr. Claudiu T. Supuran
Guest Editor

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• Tumor metabolism
• Hypoxia
• HIF-1α
• Carbonic anhydrase
• Sodium–bicarbonate transporters
• Monocarboxylate transporters
• Anion exchangers
• Glucose transporters
• V-ATP-ase