Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma

被引:71
|
作者
Doucette, Tiffany A. [4 ]
Kong, Ling-Yuan [4 ]
Yang, Yuhui [4 ]
Ferguson, Sherise D. [4 ]
Yang, Jinbo [5 ]
Wei, Jun [4 ]
Qiao, Wei [3 ]
Fuller, Gregory N. [2 ]
Bhat, Krishna P. [2 ,4 ]
Aldape, Kenneth [2 ,4 ]
Priebe, Waldemar
Boegler, Oliver [4 ]
Heimberger, Amy B. [4 ]
Rao, Ganesh [1 ,4 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Unit 442, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA
[4] Univ Texas MD Anderson Canc Ctr, Brain Tumor Ctr, Houston, TX 77030 USA
[5] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
glioma; mesenchymal; mouse model; proneural; STAT3; HIGH-GRADE GLIOMA; PDGF; STAT3; OLIGODENDROGLIOMAS; EXPRESSION; IMMUNOSUPPRESSION; OLIGOASTROCYTOMAS; PHOSPHORYLATION; TRANSFORMATION; RADIOTHERAPY;
D O I
10.1093/neuonc/nos139
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Signal transducer and activator of transcription (STAT) 3 has been described as a "master regulator" of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target.
引用
收藏
页码:1136 / 1145
页数:10
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