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TGF-beta 1 and skin carcinogenesis: antiproliferative effect in vitro and TGF-beta 1 mRNA expression during epidermal
P Krieg1, R Schnapke, G Fürstenberger
1Institute for Virus Research, German Cancer Research Center, Heidelberg.
Abstract:
The role of transforming growth factor-beta 1 (TGF-beta 1) in multisage carcinogenesis in mouse skin was assessed by studying its growth inhibitory effects on nontumorigenic and tumorigenic keratinocytes and by examining its mRNA expression in vitro and during epidermal hyperproliferation and multistage carcinogenesis. While growth of primary basal keratinocytes was inhibited by TGF-beta 1 in doses as low as 0.1 ng/mL, the immortal keratinocyte line MCA/3D ("putatively initiated" cells) responded to TGF-beta 1 with slightly reduced sensitivity, and the papilloma-producing keratinocyte line 308 was considerably less sensitive. In contrast, the squamous carcinoma cell line Carc B was completely nonresponsive, and two other tumorigenic cell lines (PDV and PDVC57) were sensitive to growth inhibition by TGF-beta 1. Steady-state levels of TGF-beta 1 mRNA were high in all the malignant cell lines and in line 308 papilloma cells, but low in primary basal cells and in the nontumorigenic keratinocyte lines V2, Reb1, and MCA/3D. Our in vivo studies showed that tumor promoters, but not mitogenic or weak hyperplasiogenic agents, were able to induce transient expression of TGF-beta 1 mRNA in mouse epidermis. A constitutive overexpression of TGF-beta 1 mRNA was observed in malignant carcinomas but not in the benign premalignant lesions, indicating that overexpression may be associated with malignant progression.
Insights
Transforming growth factor-beta 1 (TGF-beta 1) shows varied effects on skin cell growth during carcinogenesis. Overexpression of TGF-beta 1 mRNA correlates with malignant progression in mouse skin cancer.
Area of Science:
- Dermatology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-beta 1 (TGF-beta 1) is a key regulator of cell growth and differentiation.
- Its precise role in multistage skin carcinogenesis remains incompletely understood.
- Investigating TGF-beta 1's effects on keratinocytes is crucial for understanding skin cancer development.
Purpose of the Study:
- To assess the role of TGF-beta 1 in mouse skin carcinogenesis.
- To evaluate TGF-beta 1's growth inhibitory effects on keratinocytes at different stages of tumorigenesis.
- To examine TGF-beta 1 mRNA expression during epidermal hyperproliferation and carcinogenesis.
Main Methods:
- Assessing growth inhibitory effects of TGF-beta 1 on primary basal keratinocytes, immortalized, and tumorigenic keratinocyte lines.
- Measuring TGF-beta 1 mRNA expression in vitro using cell lines.
- Analyzing TGF-beta 1 mRNA expression in vivo during epidermal hyperproliferation and multistage carcinogenesis in mouse skin.
Main Results:
- TGF-beta 1 inhibited primary basal keratinocyte growth, with reduced sensitivity in immortalized and less in tumorigenic keratinocyte lines.
- Malignant cell lines and papilloma cells showed high TGF-beta 1 mRNA levels, unlike normal or nontumorigenic cells.
- Tumor promoters induced transient TGF-beta 1 mRNA expression in mouse epidermis; constitutive overexpression was seen in carcinomas, not premalignant lesions.
Conclusions:
- TGF-beta 1 exhibits differential growth inhibitory effects on keratinocytes depending on their tumorigenic potential.
- TGF-beta 1 mRNA expression patterns correlate with keratinocyte malignancy and progression.
- Overexpression of TGF-beta 1 mRNA is associated with the malignant progression of mouse skin cancer.