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Altered responsiveness of rat liver epithelial cells to transforming growth factor beta 1 following their
A C Huggett1, L L Hampton, C P Ford
1Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Abstract:
The effects of transforming growth factor beta (type 1) (TGF-beta 1) on DNA synthesis, cell proliferation, and protein synthesis were examined in a series of v-raf-transformed rat liver epithelial (RLE) cells, which exhibit a range of transformed phenotypes. All of the transformed cells were relatively resistant to the growth-inhibitory effects of TGF-beta 1, compared to normal RLE cells and control cells infected with a helper virus. The more tumorigenic cell lines had very few surface receptors for TGF-beta 1 and showed no increase in the secretion of a number of specific proteins, including fibronectin, following TGF-beta 1 treatment. In contrast, the more normal-looking, less tumorigenic v-raf-transformed cells bound similar amounts of TGF-beta 1 as normal RLE and control cells and showed a similar pattern of TGF-beta 1-stimulated protein secretion. These findings suggest that the effects of TGF-beta 1 on cell proliferation and on the expression of certain secreted proteins are mediated through different mechanisms. Following transformation of RLE cells with v-raf, the signalling pathways controlling TGF-beta 1 growth inhibition are perturbed, while those involved in regulating the synthesis of certain proteins may remain intact. Thus, the escape from the various distinct biological effects of TGF-beta 1 may be an important stage in the progression of neoplastic transformation of RLE cells in vitro.
Insights
Transforming growth factor beta 1 (TGF-beta 1) resistance increases with cancer progression in rat liver cells. Tumorigenic cells lose TGF-beta 1 receptors, impacting growth inhibition and protein synthesis differently.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Biology
Background:
- Transforming growth factor beta 1 (TGF-beta 1) is a key regulator of cell growth and differentiation.
- v-raf oncogene transformation of rat liver epithelial (RLE) cells leads to a spectrum of neoplastic phenotypes.
- Understanding TGF-beta 1 signaling in cancer progression is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the impact of TGF-beta 1 on DNA synthesis, cell proliferation, and protein synthesis in v-raf-transformed RLE cells.
- To correlate TGF-beta 1 responsiveness with the degree of cellular transformation and tumorigenicity.
- To elucidate the mechanisms underlying resistance to TGF-beta 1's biological effects during neoplastic progression.
Main Methods:
- Culturing of normal RLE cells, control helper virus-infected cells, and v-raf-transformed RLE cells with varying phenotypes.
- Treatment with TGF-beta 1 to assess effects on DNA synthesis, cell proliferation, and protein secretion (e.g., fibronectin).
- Quantification of cell-surface TGF-beta 1 receptors and analysis of secreted protein profiles.
Main Results:
- All v-raf-transformed RLE cells exhibited resistance to TGF-beta 1's growth-inhibitory effects compared to normal RLE cells.
- Highly tumorigenic cell lines displayed significantly fewer TGF-beta 1 surface receptors and impaired TGF-beta 1-induced protein secretion.
- Less tumorigenic, more normal-appearing transformed cells retained TGF-beta 1 receptor binding and protein secretion responses.
Conclusions:
- TGF-beta 1's effects on cell proliferation and specific protein expression are mediated by distinct signaling pathways.
- v-raf transformation perturbs TGF-beta 1 growth inhibition signaling, while pathways regulating certain protein synthesis may remain intact.
- Acquisition of resistance to TGF-beta 1's diverse biological actions is a critical event in the in vitro neoplastic transformation of RLE cells.
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