title: Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma.
abstract: 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.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Doucette
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Dima
authors.initials: D
authors.lastname: Suki
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fults
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002645:Chickens; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009837:Oligodendroglioma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D020574:Proto-Oncogene Proteins c-sis