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Transforming growth factor beta 1 in liver carcinogenesis: messenger RNA expression and growth effects
L Braun1, P Gruppuso, R Mikumo
1Department of Pathology, Brown University, Providence, Rhode Island 02912.
Abstract:
Transforming growth factor beta 1 (TGF-beta 1) is a potent inhibitor of hepatocyte proliferation. Since loss of sensitivity to growth inhibition is thought to contribute to the development of neoplasia, we analyzed the expression of TGF-beta 1 mRNA during hepatocarcinogenesis in vivo and in cultured liver epithelial cells (oval cells) obtained from carcinogen-treated animals. We found that TGF-beta 1 mRNA increases in the liver during carcinogenesis and that, at the early stages of the process, oval cells but not hepatocytes contain the growth factor mRNA. Moreover, immortalized, nontumorigenic oval cells (LE/6 cell line) continued to produce TGF-beta 1 mRNA in culture. TGF-beta 1 message markedly decreased upon cell transformation, but message levels, although generally low, were variable in various tumor cell clones. A consistent feature of the tumorigenic cell lines was a loss of sensitivity to TGF-beta 1 growth inhibition. Tumor cells could bind TGF-beta 1 with similar capacity as normal cells and had the same type of receptors (Mr 280,000, 85,000, and 65,000) capable of binding iodinated TGF-beta 1, suggesting that the loss of sensitivity to TGF-beta 1 in transformed liver epithelial cells involves postreceptor mechanisms. Further studies showed that c-myc is not a target for TGF-beta 1 in liver epithelial cells and that TGF-beta 1 no longer induces fibronectin mRNA in transformed cells. The data presented are consistent with the hypothesis that TGF-beta 1 secreted during liver carcinogenesis may inhibit the proliferation of normal cells while providing a selective advantage for the growth of cells that are "partially transformed" and are unresponsive to the factor.
Insights
Transforming growth factor beta 1 (TGF-beta 1) inhibits liver cell growth. During liver cancer development, TGF-beta 1 mRNA increases, but tumor cells lose sensitivity to its growth-inhibiting effects, suggesting post-receptor resistance.
Area of Science:
- Hepatocarcinogenesis research
- Cellular signaling pathways
- Cancer biology
Background:
- Transforming growth factor beta 1 (TGF-beta 1) is a key inhibitor of hepatocyte proliferation.
- Loss of sensitivity to growth inhibitors is a hallmark of neoplastic development.
- Understanding TGF-beta 1's role in liver cancer is crucial for therapeutic strategies.
Purpose of the Study:
- To investigate the expression and role of TGF-beta 1 during hepatocarcinogenesis.
- To determine the sensitivity of liver epithelial cells and hepatocytes to TGF-beta 1 during cancer progression.
- To elucidate the mechanisms underlying resistance to TGF-beta 1 in transformed liver cells.
Main Methods:
- Analysis of TGF-beta 1 mRNA expression in vivo and in cultured liver epithelial cells (oval cells) from carcinogen-treated animals.
- Assessment of TGF-beta 1 binding capacity and receptor types in normal and tumor cells.
- Investigation of TGF-beta 1's effect on c-myc and fibronectin mRNA levels in transformed cells.
Main Results:
- TGF-beta 1 mRNA levels increase during liver carcinogenesis, with oval cells expressing it early on.
- Immortalized oval cells produce TGF-beta 1 mRNA, which decreases upon transformation.
- Tumorigenic cells exhibit loss of sensitivity to TGF-beta 1 growth inhibition, with intact TGF-beta 1 receptors, indicating post-receptor resistance mechanisms.
- TGF-beta 1 does not affect c-myc expression and fails to induce fibronectin mRNA in transformed cells.
Conclusions:
- TGF-beta 1 secreted during liver carcinogenesis may inhibit normal cell proliferation while favoring the growth of partially transformed, unresponsive cells.
- The findings suggest that resistance to TGF-beta 1, mediated by post-receptor events, plays a significant role in hepatocarcinogenesis.
- Targeting TGF-beta 1 signaling or overcoming resistance mechanisms could be potential therapeutic avenues for liver cancer.