br Conclusions Finally continued systematic clinical

Conclusions Finally, continued systematic clinical investigation that integrates active agents such as the camptothecins into Ewing sarcoma therapy will likely lead to improved outcomes or salvage regimens. These methods will undoubtedly evolve and integrate preclinical investigations that identify predictors of sensitivity such as SLFN11 (Barretina et al., 2012). These investigations will be important to the realization of the success of all these agents and hopefully improve survival for patients with Ewing sarcoma.
Introduction Cancer 4945 survive and proliferate in competition with somatic cells and according to the physical and biological properties of their microenvironment [1]. During cancer progression, as the tumor mass increases in size, neoplastic cells outgrow their blood supply and lack of adequate access to oxygen and nutrients. It is well documented that tumors induce a program of adaptive responses to thrive under hypoxic conditions by switching their metabolism to upregulated glycolysis and by releasing pro-angiogenic factors [2]. However, according to Otto Warburg\'s findings [3], tumor cells may continue to metabolize carbon by the glycolytic pathway even under adequate oxygen conditions. Therefore, regardless of hypoxia [4], aerobic glycolysis is a constant feature in cancer development, as suggested by the high levels of glucose consumption detected by positron emission tomography in most malignancies [5]. The high, constant level of glycolytic activity of tumor cells leads to an increased production of lactic acid that decreases the pH of the extracellular microenvironment. Previous authors have demonstrated that the extracellular pH (pHe) of different tumors is in the range of 5.7–7.3 [6], [7], [8], whereas the pHe level of normal tissues is significantly more alkaline (7.2–7.5). The existence of an acidic intracellular pH (pHi) is also indicated in vivo by magnetic resonance spectroscopy [9]. To maintain pH homeostasis and escape apoptosis induced by an increase in proton concentration in the cytosol, cancer cells increase the activity and/or expression of several pH regulators, resulting in the alkalinization of pHi and acidification of pHe [10]. Indeed, an increased expression and activity of the transmembrane vacuolar (H+)-ATPase (V-ATPase) is a constant feature of several tumor types, and its inhibition has been suggested as a promising therapeutic target [11], [12], [13], [14]. V-ATPase is an ATP-driven proton pump that acidifies the intracellular compartment and transports protons across the plasma membranes, both in physiological processes and in human diseases [15]. V-ATPase is a large multisubunit complex composed of a peripheral domain (V1), responsible for hydrolysis of ATP, and an integral domain (V0) that carries out proton transport [15]. In sarcoma cells, the survival mechanism under acidic conditions and the activity of V-ATPase are still entirely unexplored.