Protons make tumor cells move like clockwork

Abstract

Cancer accounts for 13% of the yearly total mortality worldwide. Most cancer deaths are the sequel of metastatic diseases rather than of primary tumor growth. Thus, the major challenge in tumor therapy is the tumor cells' ability to metastasize. The extent to which a tumor metastasizes correlates with the tumor cells' migratory activity. Tumor cell migration requires a coordinated formation and release of cell adhesion contacts, a controlled cytoskeletal dynamics, the digestion and reorganization of the extracellular matrix, and local ion and water transport across the plasma membrane. All of these operations depend on intracellular pH (pH(i)) and extracellular pH (pH(e)). Numerous H(+), HCO (3) (-) , and monocarboxylate transporters as well as different carbonic anhydrase isozymes have considerable impact on pH(i) and pH(e) which spotlights them as possible, potential targets for anticancer therapeutics. Especially in solid tumors whose vascularization is often not sufficient, tumor cells cope with hypoxia and the resulting glycolysis by overexpressing the Na(+)/H(+) exchanger NHE1, monocarboxylate transporters MCT1 and/or MCT4, and the carbonic anhydrase CA IX. NHE1, MCT, and CA IX activity lead to an acidification of the extracellular space in order to maintain the cytosolic pH homeostasis stable. The present article gives a review on how this characteristic, acidic tumor micro- and nanoenvironment controls tumor cell migration.

NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

“…Na v 1.5 promotes NHE1-dependent invasiveness L Brisson et al cells to adapt to their high metabolic H þ production (Gatenby et al, 2007). Indeed it has been shown to have a predominant role in extracellular acidification of tumor cells (Bourguignon et al, 2004) and also to be involved in their invasive process (Cardone et al, 2005;Stock and Schwab, 2009;Busco et al, 2010). In this study, we showed for the first time the evidence that Na V 1.5 channels, abnormally expressed in breast cancer cells, functionally interact with NHE1 in caveolae to enhance its H þ -efflux activity and consequently promote acidic-dependent invasion of the extracellular matrix.…”

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…This in turn may facilitate the activity of pro-migratory and pro-invasive enzymes and transporters, including matrix metalloproteinases. 46,47 On the other hand, the MCT1-CD147 complex is known to behave as a scaffold for other proteins involved in cell migration and invasion. 48 The composition of these supercomplexes is cell type-dependent and could logically be influenced by the cell environment and MCT1 expression and activity (conformation change).…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…This re sults from the ab nor mal meta bolic ac tiv ity of can cer cells, in clud ing in creased gly colytic flux and lac tic acid re lease [150]; car bon diox ide pro duc tion by the TCA cy cle and the pen tose phos phate path way (PPP) [151][152][153][154]; over ex pres sion or up reg u lated ac tiv ity of car bonic an hy drases [155,156] and pro ton trans porters [156]; and de creased pro ton clear ance in the tu mor en vi ron ment [157]. Pro ton ex tru sion and ex tra cel lu lar acid i fi ca tion make ad her ent junc tions lose [158], stim u late mi gra tion and cy toskele ton re or ga ni za tion [159][160][161][162][163], and pro mote the ex pres sion [164,165], re lease [166,167] and ac tiv ity [167,168] of pro teases that de grade the ex tra cel lu lar ma trix. Hence, acidic prim ing was shown to be suf fi cient to in crease lung col o niza tion fol low ing sar coma and melanoma tu mor cell in jec tion in the tail vein of mice [163,167,169,170].…”