CD44 Interaction with Na+-H+ Exchanger (NHE1) Creates Acidic Microenvironments Leading to Hyaluronidase-2 and Cathepsin B Activation and Breast Tumor Cell Invasion

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

“…The importance of an acidic tumor microenvironment for cancer cell invasiveness and malignant progression is well established (Kraus and Wolf, 1996;MartinezZaguilan et al, 1996;Moellering et al, 2008). The activation of acidic gelatinolytic cathepsins, mainly cathepsin B, is known to be critical in these effects (Rozhin et al, 1994;Bourguignon et al, 2004;Giusti et al, 2008). Among all pH regulators, the ubiquitous Na þ /H þ exchanger NHE1 has drawn substantial attention in the field of cancer research, allowing cancer (d) Representative sodium currents recorded from a holding potential of À100 to À5 mV in physiological saline solution (PSS), or in presence of EIPA (10 mM), TTX (30 mM) or when cells were transfected with siNa V 1.5.…”

“…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.…”

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…HYAL2 has low (Lepperdinger et al, 1998;Vigdorovich et al, 2005), or even undetectable (Rai et al, 2001) hyaluronidase activity reported to be optimal pH 4.0 (Lepperdinger et al, 1998). It is thought that highmolecular-weight HA is tethered to the cell surface by CD44 and HYAL2, particularly in special microdomains (Bourguignon et al, 2004) through which the fragments can become internalized and digestion completed by HYAL1. Even though the level of hyaluronidase activity exhibited by HYAL2 is controversial it is indicated to be physiologically important, not least by the failure to produce viable Hyal2 À/À mice (Lepperdinger et al, 2001).…”

Hyaluronan-dependent pericellular matrix☆

“…These chains are then further degraded by HYAL 1 and other glycosidases in the lysosome [29,91]. Recently, a novel mechanism for creating acidic microenvironments for hyaluronan degradation at the cell surface has been described [93]. In this model, hyaluronan degradation is based on the formation of acidic microenvironments under the control of the Na+/H+ exchanger, NHE1, following hyaluronan binding to CD44.…”