title: Enhanced expression of Vastatin inhibits angiogenesis and prolongs survival in murine orthotopic glioblastoma model.
abstract: Antiangiogenic therapies are considered promising for the treatment of glioblastoma (GB). The non-collagenous C-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin, is an endogenous antiangiogenic polypeptide. Sustained enhanced expression of Vastatin was shown to inhibit tumour growth and metastasis in murine hepatocellular carcinoma models. In this study, we further explored the efficacy of Vastatin in the treatment of GB xenografts.
  
  
  
  Treatment of Vastatin was carried out using a nanopolymer gene vector PEI600-CyD-Folate (H1). Antiangiogenic effect of Vastatin was tested in vitro by using co-culture system and conditioned medium. An orthotopic GB murine model was established to examine the in vivo therapeutic effect of Vastatin alone treatment and its combination with temozolomide.
  
  
  
  Vastatin gene transfection mediated by H1 could target tumour cells specifically and suppress the proliferation of microvessel endothelial cells (MECs) through a paracrine inhibition manner. Enhancing Vastatin expression by intracerebral injection of H1-Vastatin significantly prolonged animal survival from 48 to 75 days in GB murine model, which was comparable to the effect of Endostatin, the most studied endogenous antiangiogenic polypeptide. The diminished presence of CD34 positive cells in the GB xenografts suggested that Vastatin induced significant antiangiogenesis. Moreover, a synergistic effect in extending survival was detected when H1-Vastatin was administered with temozolomide (TMZ) in GB chemoresistant murine models.
  
  
  
  Our results suggest, for the first time, that Vastatin is an antiangiogenic polypeptide with significant potential therapeutic benefit for GB. H1-Vastatin gene therapy may have important implications in re-sensitizing recurrent GB to standard chemotherapeutic agents.
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Kwong Wah Hospital, Hong Kong, China.
authors.forename: Yat Ming
authors.initials: YM
authors.lastname: Woo
authors.affiliation: Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Jiangsu Eng. Lab of Cancer Biotherapy, Xuzhou Medical College, Xuzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Marie Chia-Mi
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Brain Tumor Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. wpoon@surgery.cuhk.edu.hk.
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000517:prevention & control; D049109:Cell Proliferation; D024102:Collagen Type VIII / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D024102:Collagen Type VIII; C441971:vastatin
keywords: Antiangiogenesis; Chemoresistance; Gene therapy; Glioblastoma; Vastatin