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Published on: October 27, 2020
Prostate cancer cells lose their sensitivity to TGFβI growth inhibition with tumor progression
M S Steiner1, C T Anthony, J Metts
1From the Departments of Urology, Cell Biology, and Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Abstract:
The observation that advanced prostate cancer has reduced sensitivity to transforming growth factor βI (TGFβI) growth inhibition suggests that the acquisition of TGFβI resistance may play a role in prostate tumor progression. Using the Dunning R3327 rat prostate adenocarcinoma model, it was determined that prostate carcinoma cells became less responsive to TGFβI growth inhibition with differentiated tumors more resistant to TGFβI. A TGFβ receptor defect was not found in advanced prostate carcinoma cells because both the type I and II TGFβ receptors were present and functional. Moreover, TGFα/epidermal growth factor receptor (EGFR) and basic fibroblast growth factor (bFGF)/fibroblast growth factor receptor (FGFR) autocrine stimulatory pathways, which may potentially counter-regulate the inhibitory effects of TGFβI, were not present with prostate cancer progression. However, the likelihood that other prereceptor stimulatory pathways or TGFβ postreceptor signaling alterations are responsible for reduced sensitivity to TGFβI growth inhibition remains to be elucidated.
Insights
Advanced prostate cancer develops resistance to transforming growth factor βI (TGFβI) growth inhibition. This study found differentiated tumors are more resistant, with functional TGFβ receptors, suggesting other signaling alterations contribute to TGFβI resistance in prostate cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Prostate cancer progression is linked to altered cellular responses to growth inhibitory signals.
- Transforming growth factor βI (TGFβI) typically inhibits prostate cancer cell growth, but resistance emerges in advanced stages.
Purpose of the Study:
- To investigate the mechanisms of TGFβI resistance in advanced prostate cancer.
- To determine if TGFβ receptor function or other signaling pathways are altered in resistant prostate cancer cells.
Main Methods:
- Utilized the Dunning R3327 rat prostate adenocarcinoma model.
- Assessed TGFβI responsiveness in differentiated and advanced prostate carcinoma cells.
- Evaluated the presence and functionality of TGFβ type I and II receptors.
- Investigated potential involvement of TGFα/EGFR and bFGF/FGFR autocrine pathways.
Main Results:
- Prostate carcinoma cells exhibited reduced responsiveness to TGFβI growth inhibition as tumors became more differentiated.
- Advanced prostate cancer cells possessed functional TGFβ type I and II receptors, ruling out a receptor defect.
- Autocrine stimulatory pathways involving TGFα/EGFR and bFGF/FGFR were not implicated in TGFβI resistance.
Conclusions:
- Acquisition of TGFβI resistance is associated with prostate tumor progression.
- TGFβ receptor functionality is maintained in advanced prostate cancer, indicating resistance arises from post-receptor signaling defects.
- Further research is needed to identify other stimulatory pathways or TGFβ postreceptor alterations responsible for TGFβI resistance.
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