Malignant pleural mesotheliomas is in most cases associated with elevated amounts of hyaluronan. To investigate the importance of hyaluronan for the malignant properties of mesotheliomas, we have expressed murine hyaluronan synthase 2 (HAS2) in the non-hyaluronan producing mesothelioma cell line, Mero-25. We found that upon hyaluronan overproduction the mesothelioma cells changed their epitheloid character to a fibroblastic phenotype and were surrounded by pericellular matrices, the size of which correlated to the amount of synthesized hyaluronan. HAS2-transfected cells with the ability to synthesize about 520 ng hyaluronan/5 x 10(4)cells/24 h exhibited about a 2-fold increase in the expression of the cell surface hyaluronan receptor CD44 and their locomotion increased compared to that of mock-transfected Mero-25 cells. Furthermore, the malignant properties of mesothelioma cell clones as determined by the ability to grow in a soft agar assay correlated to their hyaluronan production. These results provide evidence for an important role of hyaluronan in the aggressive spread of mesotheliomas in adjacent non-cancerous stromal tissues.