title: Endostatin inhibits the tumorigenesis of hemangioendothelioma via downregulation of CXCL1.
abstract: Hemangioendotheliomas could be repressed by various anti-angiogenic agents in animal models. It was unclear whether the agents target hemangioendothelioma cells directly. This study elucidated the mechanism by which endostatin inhibited hemangioendothelioma progression. Expression of the endostatin receptors nucleolin and integrin α5β1 in hemangioendothelioma was assessed by immunohistochemistry. The effects of endostatin on the hemangioendothelioma-derived cells (EOMA) were evaluated by proliferation and apoptosis assays and by angiogenesis array screening. This revealed the contribution of the Chemokine (C-X-C motif) ligand 1 (CXCL1) to hemangioendothelioma progression, which was explored in vitro and in vivo. The clinical relevance of CXCL1 expression in hemangioendothelioma was also evaluated using tissue array. EOMA cells expressed nucleolin and integrin α5β1 and bound to endostatin. Endostatin did not alter proliferation or hypoxia-induced apoptosis in EOMA cells but it did impair the pro-angiogenic capacity of the cells. Endothelial cell migration was induced by CXCL1 produced by EOMA cells and endostatin downregulated CXCL1 production by inactivating its transcriptional factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In vivo, the knockdown of CXCL1 significantly impaired EOMA cell growth in nude mice; endostatin had no effect when CXCL1 was overexpressed. A strong correlation was observed between CXCL1 levels and hemangioendothelioma occurrence in patients. CXCL1, which was responsible for hemangioendothelioma progression by stimulating angiogenesis, was impaired by endostatin via inactivation of NF-κB in an animal model. In vascular lesions in patients, CXCL1 expression was a negative prognostic factor. CXCL1-inhibting agents such as endostatin may constitute a useful approach to treat the malignant or intermediate vascular lesions.
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.|School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Song
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Qi
authors.affiliation: Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, China.
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Xu
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, China.
authors.forename: Hong-Duo
authors.initials: HD
authors.lastname: Chen
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D043169:Endostatins / Q000494:pharmacology*; D005260:Female; D006390:Hemangioendothelioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D000097796:Nucleolin
chemical_list: D020533:Angiogenesis Inhibitors; D054360:Chemokine CXCL1; D043169:Endostatins; D039081:Integrin alpha5beta1; D016328:NF-kappa B; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C475829:CXCL1 protein, human
keywords: CXCL1; NF-κB; angiogenesis; endostatin; hemangioendothelioma