Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas.

The water-selective channel protein aquaporin-4 (AQP4) contributes to the migration and proliferation of gliomas, and to their resistance to therapy. Here we show, in glioma cell cultures, in subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression and can be measured via conventional dynamic-contrast-enhanced magnetic resonance imaging. Water-efflux rates correlated with stages of glioma proliferation as well as with changes in the heterogeneity of intra-tumoural and inter-tumoural AQP4 in rodent and human gliomas following treatment with temozolomide and with the AQP4 inhibitor TGN020. Regions with low water-efflux rates contained higher fractions of stem-like slow-cycling cells and therapy-resistant cells, suggesting that maps of water-efflux rates could be used to identify gliomas that are resistant to therapies.