Endostatin inhibits the tumorigenesis of hemangioendothelioma via downregulation of CXCL1

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.