Acquisition of TGF-beta 1 resistance: an important progression factor in human renal cell carcinoma.

The balance of growth regulation in tumors can be profoundly disturbed by defects in the transforming growth factor-beta 1 (TGF-beta 1) system. Thus far, investigations into the secretion of TGF-beta 1, the expression of its type I, II, and III receptors, as well as the functional intactness of the TGF-beta 1 signal transduction pathways in human renal cell carcinomas (RCC) have been lacking. The objective of the present study, therefore, was to elucidate the role of the TGF-beta 1 system in RCC. We were able to determine the status of this system in 20 primary RCC and in 30 newly established human RCC cell lines of all major histologic types. All primary RCC showed expression of TGF-beta 1 and its type I and II receptors by immunohistochemistry, irrespective of histologic type. In vitro, all RCC cell lines secreted TGF-beta 1 protein as a biologically inactive complex, which cannot interact with cell-surface receptors. Type I ALK-5-receptor mRNA and protein were detected in 29 RCC cell lines, whereas type I ALK-2-receptor mRNA was found in all cell lines. Type II-receptor mRNA and protein could be demonstrated in all cell lines analyzed, and type III-receptor mRNA was observed in five RCC cell lines. Exogenously added, biologically active TGF-beta 1 (1 ng/ml) resulted in significant (p < 0.05) inhibition of proliferation in 14 of 30 RCC cell lines. Sixteen of thirty RCC cell lines, however, proved to be TGF-beta 1-resistant. This resistance could not be explained by mutations in two "hot spot" regions of the type II-receptor gene (bp 622 to 795 and bp 1868 to 2019), as was demonstrated by DNA sequencing in the TGF-beta 1-resistant RCC cell lines. In conclusion, our observations are the first to provide evidence of an "escape" from the negative growth control of TGF-beta 1 by a significant proportion of RCC, suggesting that the acquisition of TGF-beta 1 resistance is an important progression factor for human RCC.