We investigated the production of hyaluronan and the presence of hyaluronan receptors in a panel of human lung carcinoma cell lines, consisting of small cell carcinomas (SCLC) and non-small cell carcinomas (non-SCLC). These transformed cell lines produced only minute amounts of hyaluronan, whereas normal lung fibroblasts synthesized high amounts. CD44 molecules (an integral membrane glycoprotein suggested previously to function as a hyaluronan receptor) were differentially expressed on non-SCLC cell lines but essentially not on the SCLC cell lines. In contrast, RHAMM molecules (receptor for hyaluronan-mediated motility) were preferentially expressed on SCLC cells. Although all the lung tumor cell lines expressed various amounts of CD44 and RHAMM, only the SCLC line U-1752 could bind [3H]hyaluronan. The binding sites were saturated with about 19,700 hyaluronan molecules (Mr 1.4 x 10(6)) bound per cell with a Kd of 0.16 x 10(-9) M. CD44 molecules were responsible for the binding activity since Hermes-1 antibodies that block the binding of hyaluronan to CD44 blocked the binding of [3H]hyaluronan to U-1752 cells. 4-Phorbol 12-myristate 13-acetate (PMA) treatment of U-1752 cells both increased the hyaluronan-binding activity in U-1752 cells as well as induced abrogation of cell-cell and cell-matrix interactions. Addition of hyaluronan inhibited the PMA-induced disassembly of the cells. The fact that CD44 molecules are able to bind [3H]hyaluronan only on the SCLC line U-1752 but not on other lung carcinoma cell lines may be of value as a marker for squamous cell carcinoma differentiation. Furthermore, the inhibitory effect of hyaluronan on the PMA-promoted cell disassembly suggest that hyaluronan surrounding squamous cell carcinoma cells may affect their migration and invasiveness.