Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors

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 c...

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Main Authors:	Hamalukic, Melanie, Huelsenbeck, Johannes, Schad, Arno, Wirtz, Stefan, Kaina, Bernd, Fritz, Gerhard
Format:	Online
Language:	English
Published:	Public Library of Science 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198428/

id	pubmed-3198428
recordtype	oai_dc
spelling	pubmed-31984282011-10-28 Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors Hamalukic, Melanie Huelsenbeck, Johannes Schad, Arno Wirtz, Stefan Kaina, Bernd Fritz, Gerhard Research Article 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 (TBI). The data obtained show that TBI dramatically enhances tumor cell extravasation and lung metastasis. This pro-metastatic radiation effect was blocked by pre-treating mice with lovastatin, glycyrrhizic acid or NSC23766. TBI of mice prior to tumor cell transplantation also stimulated metastasis, which was again blocked by lovastatin. The data point to a pro-metastatic trans-effect of RT, which likely rests on the endothelial radiation response promoting the extravasation of circulating tumor cells. Administration of the widely used lipid-lowering drug lovastatin prior to irradiation counteracts this process, likely by suppressing Rac1-regulated E-selectin expression following irradiation. The data support the concern that radiation exposure might increase the extravasation of circulating tumor cells and recommend co-administration of lipid-lowering drugs to avoid this adverse effect of ionizing radiation. Public Library of Science 2011-10-19 /pmc/articles/PMC3198428/ /pubmed/22039482 http://dx.doi.org/10.1371/journal.pone.0026413 Text en Hamalukic et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hamalukic, Melanie Huelsenbeck, Johannes Schad, Arno Wirtz, Stefan Kaina, Bernd Fritz, Gerhard
spellingShingle	Hamalukic, Melanie Huelsenbeck, Johannes Schad, Arno Wirtz, Stefan Kaina, Bernd Fritz, Gerhard Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors
author_facet	Hamalukic, Melanie Huelsenbeck, Johannes Schad, Arno Wirtz, Stefan Kaina, Bernd Fritz, Gerhard
author_sort	Hamalukic, Melanie
title	Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors
title_short	Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors
title_full	Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors
title_fullStr	Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors
title_full_unstemmed	Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors
title_sort	rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by hmg-coa reductase inhibitors
description	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 (TBI). The data obtained show that TBI dramatically enhances tumor cell extravasation and lung metastasis. This pro-metastatic radiation effect was blocked by pre-treating mice with lovastatin, glycyrrhizic acid or NSC23766. TBI of mice prior to tumor cell transplantation also stimulated metastasis, which was again blocked by lovastatin. The data point to a pro-metastatic trans-effect of RT, which likely rests on the endothelial radiation response promoting the extravasation of circulating tumor cells. Administration of the widely used lipid-lowering drug lovastatin prior to irradiation counteracts this process, likely by suppressing Rac1-regulated E-selectin expression following irradiation. The data support the concern that radiation exposure might increase the extravasation of circulating tumor cells and recommend co-administration of lipid-lowering drugs to avoid this adverse effect of ionizing radiation.
publisher	Public Library of Science
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198428/
_version_	1611482446903115776

Rac1-Regulated Endothelial Radiation Response Stimulates Extravasation and Metastasis That Can Be Blocked by HMG-CoA Reductase Inhibitors

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