oa Editorial [ Hot Topic:Proton Dynamics in Cancer (Executive Guest Editor: Agustin Hernandez )]

Decades of research on the mechanisms and processes leading to the development of cancer have provided a plethora of genes, proteins and physiological steps that may contribute to the generation and metastasis of the disease. However, despite many efforts, the success in chemotherapeutic intervention have not followed suit [1]. The causes of this are probably manifold and, among them, the difficulty to target specific proteins that are very similar to unrelated ones, (e.g. kinases), and the few cancer types or even subtypes for which they may contribute effectively in their promotion (breast cancer HER2 gene may be an example), could be discussed as potential reasons. Be that as it may, the most effective chemotherapeutic treatments to date and some of the most promising ones aim at gross differences between tumour and healthy cells: e. g. increased DNA synthesis (related to increased cell division and proliferation) and dependence on protein chaperones like Hsp90. In this sense, to target metabolic differences between neoplasms and normal tissues is an attractive approach that is currently being explored from different angles. The Warburg Effect in cancer, or glycolytic phenotype, is a feature shared by nearly all tumours, although to different degrees. Under this phenotype, tumour cells obtain their energy from glycolysis and lactic fermentation despite the presence of appropriate oxygen tensions, whereas somatic cells rely on mitochondrial respiration. Although this phenomenon was first described by Otto Warburg in the 19207apos; [2], it is in the last ten that it is receiving increasing attention, as attested by more than 30 reviews related to cancer cell metabolism published between 2010 and 2011 that deal with this phenomenon. It is beyond the scope of this issue, an in depth analysis of the glycolytic phenotype; for greater details on this, the reader may refer to some excellent works like [3, 4]. However, since this is at the base of the phenomena the present issue revisits, a short overview is imperative in order to better understand the intimate imbrication of pH homoeostasis, the proteins responsible and the glycolytic phenotype. A high rate of glucose uptake is a characteristic feature of tumour cells. This abnormal uptake is due to tumour cells metabolising glucose less efficiently than healthy cells, along with a greater demand for energy and metabolites to fuel cell proliferation. For reasons still obscure, tumour cells shut their respiratory metabolism and break glucose down to pyruvate only. In this process, the cell obtains only two ATP molecules per glucose consumed, while respiration is able to provide ca 30 under physiological conditions [5]. The advantage of using such an apparently inefficient sugar catabolism may lie on a greater availability of carbon backbones that reduce the energy expenditure necessary for their synthesis from scratch [4]. Strikingly, this same metabolic approach is chosen by micro-organisms like baker's yeast to produce high rates of growth [6]. In any event, an important issue in this type of metabolism is redox balance of pyridine nucleotide coenzymes: two NADH molecules are produced from cytosolic NAD+ per glucose molecule brought down to pyruvate. If this NADH would not be reoxidised, coenzyme pools would soon be depleted and all cellular metabolism should halt. Under respiratory conditions, these NADH molecules are re-oxidised at the mitochondria, but in tumour cells NADH is used to reduce pyruvate to lactic acid and the latter compound is, for the most part, metabolised no further. Since the dissociation constant for lactic acid is very low (pKa=3.85), one of the net results then is the release into the cytosol of two H+ per glucose molecule consumed. In addition, there may be other sources of H+ in tumours that can contribute significantly to the final count [3]. In particular, CO2 may well be a source of H+ in tumour cells, as assessed using cell lines with impaired glycolysis [7, 8]; these increased levels in CO2 have glutaminolysis at their base [8, 9]. Accumulation of protons in the cytoplasm promotes cell death, while maintenance of slightly alkaline conditions promotes proliferation [10]. Therefore, excess H+ needs to be neutralised from the cytoplasm if a tumour cell is to thrive. Keeping this in mind, it is easy to understand that proton dynamics and homoeostasis is a paramount physiological processes for a tumour cell. Moreover, it is also one of the major differential characteristics of neoplasias compared with healthy tissue. Consequently, a group of both clinical and basic cancer researchers realised the potential of targeting proton dynamics as a therapeutic strategy and gathered in Madrid in 2009. The success of this meeting led to the formation of the “International Society for Proton Dynamics in Cancer” (ISPDC) in January 2010 [1]. The present issue is inspired by the first meeting of the ISPDC held in Rome in 2010. It aims to give the reader an overview of the importance of pH and proton homoeostasis in cancer and the opportunities that proton dynamics may offer as a target for chemotherapeutic intervention.....