High rates of metastasis correlate with a poor prognosis of cancer. Two major steps of the metastatic cascade are cell migration/invasion into and degradation/reorganization of the extracellular matrix. Hypoxia, the predominating situation in solid tumors, forces the tumor cells to perform anaerobic metabolism. The tumor cells cope with the resulting acid load by extruding the excess protons via the Na⁺/H⁺ exchanger NHE1. A characteristic of numerous tumor cells is the overexpression of NHE1 and/or its upregulation.

In various migrating cells such as fibroblasts, epithelial and tumor cells, NHE1 accumulates at the cell front where its activity is needed for (i) cell adhesion, (ii) directed locomotion and (iii) extracellular matrix digestion. Thus, inhibition of NHE1 reduces the invasiveness of murine melanoma cells in rat liver parenchyma by about 50%.

Human melanoma cells establish an NHE1-dependent pH-nanoenvironment at their surface with a higher proton concentration at the cell front. This pH gradient at the cell surface is stabilized by the glycocalyx and is mirrored by a reciprocal, also NHE1-generated pH gradient in the cytosol. Destroying the cell surface pH-gradient by partial removal of the glycocalyx impairs cell migration substantially, however, can be compensated for by stimulating NHE1 activity. Vice versa, knocking down b1 integrins that mediate cell adhesion and migration in a pH-dependent manner makes the cell surface pH-gradient functionally inefficient.

NHE1 activity creates a pericellular, glycocalyx-stabilized pH-nanoenvironment that promotes both the digestion of the extracellular matrix and the establishment of focal adhesion contacts at the cell front including their release at the cell rear. At the same time, the intracellular pH gradient with more alkaline pH at the leading edge controls cytokeletal remodeling and contractility. In summary, NHE1 regulates cell migration extracellularly by modulating cell-surface interactions and by remodeling the extracellular matrix, and intracellularly by fine-tuning the migratory machinery. These findings point to the therapeutic potential of NHE1 inhibition in the prevention of metastasis.