title: Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma.
abstract: 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.
authors: Department of Neurosurgery, the Brain Tumor Center, Houston, TX, USA.
authors: Tiffany A
authors: TA
authors: Doucette
authors: Ling-Yuan
authors: LY
authors: Kong
authors: Yuhui
authors: Y
authors: Yang
authors: Sherise D
authors: SD
authors: Ferguson
authors: Jinbo
authors: J
authors: Yang
authors: Jun
authors: J
authors: Wei
authors: Wei
authors: W
authors: Qiao
authors: Gregory N
authors: GN
authors: Fuller
authors: Krishna P
authors: KP
authors: Bhat
authors: Kenneth
authors: K
authors: Aldape
authors: Waldemar
authors: W
authors: Priebe
authors: Oliver
authors: O
authors: Bögler
authors: Amy B
authors: AB
authors: Heimberger
authors: Ganesh
authors: G
authors: Rao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply / Q000209:etiology / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002645:Chickens; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000098:blood supply* / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor