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Published on: October 27, 2020
Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas
Mahlon D Johnson1, Aubie K Shaw, Mary J O'Connell
1Department of Pathology, Division of Neuropathology, University of Rochester Medical Center, 601 Elmwood Ave. Box 626, Rochester, NY 14642, USA. mahlon_johnson@urmc.rochester.edu
Abstract:
TGF-β receptors (TGF-βRs) inhibit growth of many cell types. Loss of TGF-βRs or its signaling components have been found in several human malignancies. The expression and the role of TGF-βRs in regulating anaplastic meningioma growth has not been studied. Real time PCR found TGF-β RIII expression significantly lower in five grade III compared to eight grade I and eight grade II tumors (P = 0.0481). By western blot analysis, TGF-βRI was detected in the four fetal and adult leptomeninges, all 18 grade I, 14 grade II and six grade III meningiomas. TGF-βRII was detected in none of the leptomeninges, 55% of grade I, 71% of grade II and weak to negative in five of six the grade III meningiomas analyzed. TGF-βRIII immunoreactivity was not detected in the fetal meninges but was detected in 94% of grade I, 70% of grade II and 67% grade III tumors. Phospho-SMAD 3 and Smad 7 were detected in nearly all tumors. TGF-β1 had no effect on PDGF-BB stimulation of DNA synthesis in six of seven WHO grade II and the grade III cells. It produced an increase in phosphorylation of SMAD 3 and p38MAPK in two of four and p44/42MAPK in three of four grade II cells showing no change in DNA synthesis after treatment. Thus, only attenuated TGF-βRIII expression and TGFB growth inhibition may occur in select higher grade meningiomas. Nonetheless, restoring TGF-β inhibition of meningioma cell proliferation may be an important objective in the design of new chemotherapies for these tumors.
Insights
Transforming growth factor-beta receptors (TGF-βRs) are crucial for cell growth regulation. This study reveals attenuated TGF-βRIII expression and reduced growth inhibition in higher-grade meningiomas, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor-beta receptors (TGF-βRs) play a role in inhibiting cell growth.
- Loss of TGF-βRs is implicated in various human cancers.
- The role of TGF-βRs in anaplastic meningioma growth is largely unstudied.
Purpose of the Study:
- To investigate the expression and function of TGF-β receptors in meningiomas of different grades.
- To determine the impact of TGF-β signaling on meningioma cell proliferation.
Main Methods:
- Real-time PCR and Western blot analysis were used to assess TGF-β receptor expression (TGF-βRI, TGF-βRII, TGF-βRIII) in meningioma tissues.
- Immunohistochemistry was employed to detect receptor expression.
- Cell proliferation assays and SMAD phosphorylation analysis were performed on meningioma cells treated with TGF-β1.
Main Results:
- TGF-βRIII expression was significantly lower in grade III meningiomas compared to grades I and II.
- TGF-βRI was detected in all tumor grades, while TGF-βRII expression decreased in higher-grade tumors.
- TGF-βRIII immunoreactivity was present in most meningiomas, but decreased in grade III.
- TGF-β1 treatment did not inhibit DNA synthesis in most tested cells but affected SMAD and MAPK phosphorylation.
Conclusions:
- Attenuated TGF-βRIII expression correlates with higher-grade meningiomas.
- TGF-β growth inhibition may be compromised in some advanced meningiomas.
- Restoring TGF-β-mediated growth inhibition could be a therapeutic strategy for meningiomas.
