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      IRX1 influences peritoneal spreading and metastasis via inhibiting BDKRB2-dependent neovascularization on gastric cancer


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          The overexpression of IRX1 gene correlates with the growth arrest in gastric cancer. Furthermore, overexpression of IRX1 gene suppresses peritoneal spreading and long distance metastasis. To explore the precise mechanisms, we investigated whether restoring IRX1 expression affects the angiogenesis or vasculogenic mimicry (VM). Human umbilical vein endothelial cells (HUVECs) and chick embryo and SGC-7901 gastric cancer cells were used for angiogenesis and VM analysis. Small interfering RNA was used for analyzing the function of BDKRB2, a downstream target gene of IRX1. As results, the remarkable suppression on peritoneal spreading and pulmonary metastasis of SGC-7901 cells by IRX1 transfectant correlates to reduced angiogenesis as well as VM formation. Using the supernatant from SGC-7901/ IRX1 cells, we found a strong inhibiting effect on angiogenesis both in vitro and in chick embryo. SGC-7901/ IRX1 cells revealed strong inhibiting effect on VM formation too. By gene-specific RNA interference for BDKRB2, or its effector PAK1, we got an effective inhibition on tube formation, cell proliferation, cell migration and invasion in vitro. In conclusion, enforcing IRX1 expression effectively suppresses peritoneal spreading and pulmonary metastasis via anti-angiogenesis and anti-VM mechanisms, in addition to previously found cell growth and invasion. BDKRB2 and its downstream effector might be potential targets for anti-cancer strategy.

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              A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis.

                Author and article information

                Nature Publishing Group
                03 November 2011
                23 May 2011
                : 30
                : 44
                : 4498-4508
                [1 ]simpleDepartment of Surgery, Shanghai Ruijin Hospital and Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Diagnosis and Treatment for Gastric Cancer, Shanghai Jiao Tong University, School of Medicine , Shanghai, China
                Author notes
                [* ]simpleDpartment of Surgery, Ruijin Hospital and Shanghai Institute of Digestive Surgery, ShanghaiJiao Tong University, School of Medicine , Ruijin er Road, No. 197, Shanghai 200025, PR China. E-mail: yingyan3y@ 123456yahoo.com.cn or surgeryzhu@ 123456yahoo.com.cn

                These authors contributed equally to this work.

                Copyright © 2011 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                Original Article

                Oncology & Radiotherapy
                vasculogenic mimicry,angiogenesis,bdkrb2,irx1,gastric carcinoma
                Oncology & Radiotherapy
                vasculogenic mimicry, angiogenesis, bdkrb2, irx1, gastric carcinoma


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