A significant subset of
gliomas arises after activation of the proproliferative
platelet-derived growth factor (PDGF) pathway. The progression of low-grade
gliomas to more malignant
tumors may be due to oncogenic cellular programs combining with those suppressing apoptosis. Antiapoptotic genes are overexpressed in a variety of
cancers, and the antiapoptotic gene, BCL2, is associated with treatment resistance and
tumor recurrence in
gliomas. However, the impact of antiapoptotic gene expression to
tumor formation and progression is unclear. We overexpressed Bcl-2 in a
PDGFB-dependent mouse model of
oligodendroglioma, a common
glioma subtype, to assess its effect in vivo. We hypothesized that the antiapoptotic effect would
complement the proproliferative effect of
PDGFB to promote
tumor formation and progression to
anaplastic oligodendroglioma (AO). Here, we show that coexpression of
PDGFB and Bcl-2 results in a higher overall
tumor formation rate compared to
PDGFB alone. Coexpression of
PDGFB and Bcl-2 promotes progression to AO with prominent foci of
necrosis, a feature of high-grade
gliomas. Median
tumor latency was shorter in mice injected with
PDGFB and Bcl-2 compared to those injected with
PDGFB alone. Although independent expression of Bcl-2 was insufficient to induce
tumors, suppression of apoptosis (detected by cleaved
caspase-3 expression) was more pronounced in AOs induced by
PDGFB and Bcl-2 compared to those induced by
PDGFB alone.
Tumor cell proliferation (detected by phosphohistone H3 activity) was also more robust in high-grade
tumors induced by
PDGFB and Bcl-2. Our results indicate that suppressed apoptosis enhances
oligodendroglioma formation and engenders a more malignant phenotype.