Transforming growth factor-beta 1 overexpression produces drug resistance in vivo: reversal by decorin

The gene for transforming growth factor-beta 1 (TGF-beta 1) was transfected into the murine EMT-6/Parent mammary carcinoma tumor line to form the EMT6/PRK5 beta 1E tumor line. In monolayer culture the EMT-6/PRK5 beta 1E tumor line secretes about 15-times as much TGF-beta 1 into the medium as the EMT-6/Parent line. There was no difference in the response of these two cell lines to 4-hydroperoxycyclophosphamide, cisplatin, melphalan or thiotepa in monolayer culture. When the EMT-6/PRK5 beta 1E cells were grown as a solid tumor in Balb/C mice, plasma levels of TGF-beta 1 were about 5-fold higher than in animals bearing the EMT-6/Parent tumor. The EMT-6/PRK5 beta 1E tumor was markedly resistant to a dosage range of cyclophosphamide, cisplatin, melphalan and thiotepa compared with the EMT-6/Parent tumor. The bone marrow CFU-GM from the animals bearing the EMT-6/PRK5 beta 1E tumor were spared from the cytotoxicity of the drugs compared with the bone marrow CFU-GM from animals bearing the EMT-6/Parent tumor. Administration of decorin, a naturally occurring inhibitor of TGF-beta 1, to animals bearing the EMT-6/PRK5 beta 1E tumor prior to treatment of the animals with the antitumor alkylating agents restored drug sensitivity to the tumor and to the bone marrow CFU-GM. Administration of decorin prior to the antitumor alkylating agents produced very little or no increase in the response of the EMT6/Parent tumor or the bone marrow CFU-GM from those animals. The EMT6/PRK5 beta 1E tumor model allows the effect of secretion of TGF-beta 1 on therapeutic resistance to be assessed directly compared with the EMT-6/Parent tumor. In vivo resistance occurred in the presence of high levels of TGF-beta 1 and was reversed by the TGF-beta 1 inhibitor decorin.