title: Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia.
abstract: The aim of this study was to investigate the effect of recombinant human endostatin (rh-Endo) in combination with radiation therapy (RT) on esophageal squamous cell carcinoma (ESCC) and explore the potential mechanisms. ECA109-bearing nude mice were administered RT and/or rh-Endo treatment. Tumor volume, survival, hypoxia and vascular parameters were recorded during the treatment schedule and follow-up as measures of treatment response. ESCC cell lines (ECA109 and TE13) and human umbilical vein endothelial cells (HUVECs) were developed to investigate the outcomes and toxicities of rh-Endo and RT in vitro. Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were also evaluated. In vivo studies of ECA109-bearing xenografts showed that rh-Endo improved the radioresponse, with normalization of tumor vasculature and a reduction in hypoxia. In vitro studies showed that rh-Endo did not radiosensitize ESCC cell lines but did affect endothelial cells with a time- and dose-dependent manner. Studies of the molecular mechanism indicated that the improved radioresponse might be due to crosstalk between cancer cells and endothelial cells involving HIF and VEGF expression. Our data suggest that rh-Endo may be a potential anti-angiogenic agent in ESCC especially when combined with RT. The improved radioresponse arises from normalization of tumor vasculature and a reduction in hypoxia.
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Changzhou Cancer Hospital of Soochow University, Changzhou 213001, China.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zheming
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Changzhou Cancer Hospital of Soochow University, Changzhou 213001, China.
authors.forename: Xifa
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xinchen
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D043169:Endostatins / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D043169:Endostatins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A