Retinoids: novel immunomodulators and tumour-suppressive agents?
The effects and interactions were investigated of the two growth regulatory molecules alltrans retinoic acid (RA), and epidermal growth factor (EGF) on the in vitro expression by bladder cancer cell lines of the transformed phenotype (anchorage-independent growth in soft agar). When tested individually, the two molecules had opposite effects: RA (10(-11) to 10(-5) M) caused a dose-related reduction in anchorage-independent growth, whereas EGF (0.1 to 50 ng/ml) caused a dose-dependent increase. These effects were observed with both cell lines tested: RT112, a human papillary, non-metastatic bladder cancer cell line and RU-CL2, a rat metastatic bladder carcinoma cell line. When the effect of EGF (2.5 ng/ml) was tested against the growth inhibition produced by a range of doses of RA, EGF stimulated growth and reduced the degree of inhibition produced by RA at all dose levels. Conversely, a single dose of 10(-8) M RA tested against a range of EGF concentrations reduced the dose-related EGF-induced increase in anchorage-independent growth. The two cell lines responded similarly to those combinations of RA and EGF in vitro, regardless of their different biological potentials in vivo. These experiments provide no evidence that RA potentiates EGF-induced growth, as has been observed by others using mesenchymal cells. RA could, therefore, theoretically be used to inhibit or delay bladder tumour recurrences. Trials would show whether oral doses of RA, or of synthetic retinoids metabolized to RA, would reach therapeutic levels and be chemopreventive in bladder cancer patients.