Transforming growth factor beta type I receptor acts as a potent tumor suppressor in rat bladder carcinoma

Transforming growth factor beta1 (TGFbeta1) is a potent growth inhibitor for most cells, including neoplastic cells. However, there are several types of malignant cells that are resistant to its growth-inhibitory effect. LMC19, a highly malignant rat urothelial cell line, lacks TGFbeta1 receptor (TbetaRI) and is insensitive to the growth-suppresive effect of TGFbeta1. We transfected an expression vector containing human TbetaRI into this cell line. In control cells transfected with the neo gene alone, no inhibitory effect on growth was observed in vitro by the addition of anti-TGFbeta1 antibody or recombinant TGFbeta1 into serum-free medium. In contrast, the growth of all transfectants tested was inhibited significantly under serum-free conditions because of their endogenous TGFbeta synthesis. The growth was reduced further by the addition of recombinant TGFbeta1. This response pattern is consistent with TGFbeta1 mediating its effects by an autocrine and paracrine mechanism. The tumorigenicity of the cells was tested in a heterotopically transplanted urinary bladder system, which was generated as an orthotopic test site in athymic nude mice. All nine mice tested receiving control cells formed deeply invasive, undifferentiated-cell carcinomas and multiple metastatic foci in the lungs. In contrast, none of the mice receiving transfectants of TbetaRI formed bladder tumors or metastases. Taken together, these observations indicate that TbetaRI exhibits a potent tumor suppressor effect in bladder carcinoma.