rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by hmg-coa reductase inhibitorsrac1-regulated内皮辐射响应刺激外渗和转移,可以被β-还原酶抑制剂.pdfVIP

Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors 1 1 2 3 1 Melanie Hamalukic , Johannes Huelsenbeck , Arno Schad , Stefan Wirtz , Bernd Kaina , Gerhard Fritz1,4* 1 Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany, 2 Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany, 3 Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, ¨ ¨ Mainz, Germany, 4 Institute of Toxicology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany Abstract Radiotherapy (RT) plays a key role in cancer treatment. Although the benefit of ionizing radiation (IR) is well established, some findings raise the possibility that irradiation of the primary tumor not only triggers a killing response but also increases the metastatic potential of surviving tumor cells. Here we addressed the question of whether irradiation of normal cells outside of the primary tumor augments metastasis by stimulating the extravasation of circulating tumor cells. We show that IR exposure of human endothelial cells (EC), tumor cells (TC) or both increases TC-EC adhesion in vitro. IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin. Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion. To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (T