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Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis
Alan H Shih1, Chengkai Dai, Xiaoyi Hu
1Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Abstract:
Platelet-derived growth factor (PDGF) is expressed in many different tumors, but its precise roles in tumorigenesis remain to be fully defined. Here, we report on a mouse model that demonstrates dose-dependent effects of PDGF-B on glial tumorigenesis. By removing inhibitory regulatory elements in the PDGFB mRNA, we are able to substantially elevate its expression in tumor cells using a retroviral delivery system. This elevation in PDGF-B production results in tumors with shortened latency, increased cellularity, regions of necrosis, and general high-grade character. In addition, elevated PDGF-B in these tumors also mediates vascular smooth muscle cell recruitment that supports tumor angiogenesis. PDGF receptor (PDGFR) signaling appears to be required for the maintenance of these high-grade characteristics, because treatment of high-grade tumors with a small molecule inhibitor of PDGFR results in reversion to a lower grade tumor histology. Our data show that PDGFR signaling quantitatively regulates tumor grade and is required to sustain high-grade oligodendrogliomas.
Insights
Platelet-derived growth factor-B (PDGF-B) drives glial tumor growth and grade in a dose-dependent manner. Inhibiting PDGF receptor (PDGFR) signaling can revert high-grade tumors to a lower grade, highlighting PDGFR
Area of Science:
- Oncology
- Molecular Biology
- Neuro-oncology
Background:
- Platelet-derived growth factor (PDGF) is implicated in various cancers, but its specific role in glial tumorigenesis is not fully understood.
- Understanding the mechanisms driving tumor progression is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the dose-dependent effects of Platelet-derived growth factor-B (PDGF-B) on glial tumorigenesis using a mouse model.
- To determine the role of PDGF receptor (PDGFR) signaling in maintaining high-grade tumor characteristics.
Main Methods:
- Developed a retroviral delivery system to elevate PDGF-B expression in tumor cells by removing inhibitory regulatory elements in PDGFB mRNA.
- Utilized a mouse model to observe tumor development and characteristics following PDGF-B overexpression.
- Administered a small molecule inhibitor of PDGFR to assess its impact on established high-grade tumors.
Main Results:
- Elevated PDGF-B expression led to tumors with shorter latency, increased cellularity, necrosis, and high-grade features.
- Increased PDGF-B promoted tumor angiogenesis by recruiting vascular smooth muscle cells.
- Inhibition of PDGFR signaling in high-grade tumors resulted in a reversion to lower-grade histology.
Conclusions:
- PDGF-B plays a critical, dose-dependent role in the development and progression of glial tumors.
- PDGFR signaling is essential for sustaining the high-grade characteristics of oligodendrogliomas.
- Targeting PDGFR signaling represents a potential therapeutic strategy for high-grade gliomas.
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