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Proliferation of human malignant astrocytomas is dependent on Ras activation
1Programme in Molecular Biology and Cancer, Samuel Lunenfield Research Institute, Toronto, Ontario, Canada.
Oncogene
|January 7, 1998
Summary
Activated receptor tyrosine kinases in malignant astrocytomas elevate Ras.GTP, driving cell proliferation. Inhibiting the Ras pathway significantly reduced astrocytoma cell growth, suggesting potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Malignant astrocytomas exhibit overexpression and activation of receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptors (PDGFRs) and epidermal growth factor receptor (EGFR).
- While oncogenic Ras mutations are uncommon in these tumors, elevated Ras activation secondary to RTK signaling is hypothesized.
Purpose of the Study:
- To investigate whether activated Ras.GTP levels are elevated in human malignant astrocytomas.
- To elucidate the mechanism of Ras activation in these cells and assess the therapeutic potential of targeting the Ras pathway.
Main Methods:
- Analysis of Ras.GTP levels in astrocytoma cell lines and patient specimens.
- Stimulation of PDGFR and EGFR to observe downstream signaling events, including Shc phosphorylation and Grb2 association.
- Inhibition of Ras activation using a dominant-negative Ha-Ras mutant and farnesyl transferase inhibitors.
Main Results:
- High levels of Ras.GTP were detected in malignant astrocytoma cell lines and specimens.
- RTK stimulation led to Shc adaptor protein tyrosine phosphorylation and association with Grb2, indicating Ras pathway activation.
- Blocking Ras activation significantly decreased in vitro proliferation of astrocytoma cells.
Conclusions:
- Proliferative signals in human malignant astrocytomas originate from receptor tyrosine kinases and utilize the Ras mitogenic pathway.
- Pharmacological inhibition of the Ras pathway holds therapeutic promise for treating malignant astrocytomas.