title: Malignant gliomas induce and exploit astrocytic mesenchymal-like transition by activating canonical Wnt/β-catenin signaling.
abstract: The complex microenvironment of malignant gliomas plays a dynamic and usually cancer-promoting role in glioma progression. Astrocytes, the major stromal cells in the brain, can be activated by glioma microenvironment, resulting in a layer of reactive astrocytes surrounding the gliomas. Reactive astrocytes are universally characterized with the upregulation of glial fibrillary protein and glycoprotein podoplanin. In this work, we investigated the role of reactive astrocytes on malignant glioma microenvironment and the potential mechanism by which glioma cells activated the tumor-associated astrocytes (TAAs). The reactive astrocytes were observed around gliomas in the intracranial syngeneic implantation of rat C6 and mouse GL261 glioma cells in vivo, as well as primary astrocytes cultured with glioma cells condition medium in vitro. Besides, reactive astrocytes exhibited distinct epithelial-to-mesenchymal (-like) transition and enhanced migration and invasion activity, with the decrease of E-cadherin and concomitant increase of vimentin and matrix metalloproteinases. Furthermore, canonical Wnt/β-catenin signaling was activated in TAAs. The Wnt/β-catenin pathway inhibitor XAV939 and β-catenin plasmid were used to verify the regulation of Wnt/β-catenin signaling on TAAs and their invasion ability. Taken together, our findings established that glioma cells remarkably activated astrocytes via upregulating Wnt/β-catenin signaling, with obviously mesenchymal-like transition and increased migration and invasion ability, indicating that glioma cells may stimulate adjacent astrocytes to degrade extracellular matrix and thereby promoting tumor invasiveness.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China.
authors.forename: Xiuting
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China.
authors.forename: Kequan
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, Jiangsu, 214002, Wuxi, China. wxwqnj@hotmail.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Jiangsu, 210009, Nanjing, China. ronghu@cpu.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology*
keywords: GFAP; Malignant glioma; PDPN; Tumor microenvironment; Tumor-associated astrocytes (TAAs); Wnt/β-catenin signaling