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Inhibition of glioma cell growth by a truncated platelet-derived growth factor-beta receptor
L M Strawn1, E Mann, S S Elliger
1SUGEN, Inc., Redwood City, California 94063.
Abstract:
Abnormal expression of platelet-derived growth factor (PDGF) receptors has been observed in malignant glioma and other tumors such as osteosarcomas and malignant melanomas. However, their role in the development and maintenance of the tumors is not understood. Signaling through the PDGF receptors is activated by ligand-induced dimerization. Thus, introduction of mutant receptors that are kinase deficient but still dimerization competent is one strategy to study the importance of PDGF receptors in glioma cell growth. A truncated PDGF-beta receptor was introduced into C6 rat glioma cells and the PDGF-mediated signaling and subsequent cell growth studied. In clones expressing the mutant receptor, PDGF-BB-induced tyrosine phosphorylation of the endogenous receptor was significantly reduced. In addition, these cells grew to lower density in culture and formed smaller colonies in soft agar than the C6 parental cells. Furthermore, the ability of cells expressing the truncated receptor to grow as xenografts in nude mice was significantly impaired. These results support the important role for the PDGF-beta receptor in C6 glioma cell growth. They also demonstrate the usefulness of dominant-negative mutants of the PDGF receptor for the evaluation of the role of the receptor in tumorigenesis.
Insights
Platelet-derived growth factor (PDGF) receptors play a key role in glioma cell growth. Introducing a mutant PDGF-beta receptor significantly impaired tumor growth, supporting its role in tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Abnormal expression of platelet-derived growth factor (PDGF) receptors is linked to malignant glioma and other cancers.
- The precise role of PDGF receptors in tumor development and maintenance remains unclear.
- PDGF receptor signaling is initiated by ligand-induced dimerization.
Purpose of the Study:
- To investigate the importance of PDGF receptors in glioma cell growth using a dominant-negative mutant approach.
- To elucidate the role of the PDGF-beta receptor in the proliferation and tumorigenesis of C6 rat glioma cells.
Main Methods:
- Introduction of a kinase-deficient, dimerization-competent truncated PDGF-beta receptor into C6 rat glioma cells.
- Assessment of PDGF-BB-induced tyrosine phosphorylation of endogenous PDGF receptors.
- Evaluation of cell proliferation, colony formation in soft agar, and xenograft tumor growth in nude mice.
Main Results:
- Expression of the truncated PDGF-beta receptor significantly reduced PDGF-BB-induced tyrosine phosphorylation.
- Cells expressing the mutant receptor exhibited reduced proliferation in culture and smaller colony formation in soft agar.
- Tumorigenic potential was significantly impaired, with reduced xenograft growth in nude mice.
Conclusions:
- The PDGF-beta receptor plays a crucial role in C6 glioma cell growth and tumorigenesis.
- Dominant-negative mutants of the PDGF receptor are effective tools for studying its role in cancer development.
- These findings highlight the PDGF-beta receptor as a potential therapeutic target in glioma.