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Acquisition of TGF-beta 1 resistance: an important progression factor in human renal cell carcinoma
1Institute of Pathology, University of Düsseldorf, Germany.
Abstract:
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.
Insights
Defects in the transforming growth factor-beta 1 (TGF-beta 1) system disrupt tumor growth regulation. Many renal cell carcinomas (RCC) develop resistance to TGF-beta 1, indicating a key factor in tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumor growth is regulated by complex signaling pathways.
- The transforming growth factor-beta 1 (TGF-beta 1) system plays a crucial role in cellular growth control.
- Dysregulation of the TGF-beta 1 system is implicated in various cancers, including renal cell carcinoma (RCC).
Purpose of the Study:
- To investigate the role and status of the TGF-beta 1 system in human renal cell carcinomas (RCC).
- To determine TGF-beta 1 secretion, receptor expression, and signaling pathway integrity in RCC.
- To elucidate mechanisms of TGF-beta 1 resistance in RCC.
Main Methods:
- Immunohistochemistry was used to assess TGF-beta 1 and receptor expression in 20 primary RCC.
- 30 human RCC cell lines were analyzed for TGF-beta 1 secretion and receptor expression (Types I, II, III).
- In vitro proliferation assays with active TGF-beta 1 were performed on RCC cell lines; DNA sequencing analyzed the TGF-beta 1 Type II receptor gene.
Main Results:
- All primary RCC expressed TGF-beta 1 and its Type I and II receptors.
- All analyzed RCC cell lines secreted biologically inactive TGF-beta 1.
- While most RCC cell lines expressed TGF-beta receptors, 16 out of 30 were resistant to TGF-beta 1's growth-inhibitory effects, with no identified mutations in key regions of the Type II receptor gene.
Conclusions:
- Human RCC exhibits an "escape" from TGF-beta 1's negative growth control.
- Acquisition of TGF-beta 1 resistance is a significant factor in the progression of human RCC.
- Further research into TGF-beta 1 resistance mechanisms is warranted for therapeutic strategies.