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Title: Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse

Abstract

Purpose: This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. Methods and materials: RAW 264.7 macrophages were activated by lipid A, and the conditioned medium (CM) was analyzed for the secretion of cytokines and the production of nitric oxide (NO) through inducible nitric oxide synthase (iNOS). EMT-6 tumor cells were exposed to CM and analyzed for hypoxic cell radiosensitivity. The role of nuclear factor (NF)-{kappa}B in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Results: Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 {mu}g/mL, stimulated RAW 264.7 macrophages to release NO, tumor necrosis factor (TNF)-{alpha}, and other cytokines. This in turn activated iNOS-mediated NO production in EMT-6 tumor cells and drastically enhanced their radiosensitivity. Radiosensitization was abrogated by the iNOS inhibitor aminoguanidine but not by a neutralizing anti-TNF-{alpha} antibody. The mechanism of iNOS induction was linked to NF-{kappa}B but not to JAK/STAT signaling. Interferon-{gamma} further increased the NO production by macrophages to a level that caused radiosensitization of EMT-6 cells through the bystanding effect of diffused NO. Conclusions: We demonstrate for the first time that activated macrophages may radiosensitize tumor cells through the induction of NO synthesis,more » which occurs in both tumor and immune cells.« less

Authors:
 [1];  [1];  [2];  [1];  [1];  [1];  [1]
  1. Academic Hospital, Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium)
  2. Laboratory of Experimental Medicine, Universite Libre de Bruxelles (ULB), Brussels (Belgium)
Publication Date:
OSTI Identifier:
20630933
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 60; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2004.05.065; PII: S0360-3016(04)00957-5; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; BIOLOGICAL RADIATION EFFECTS; INDIUM OXIDES; INTERFERON; LIPIDS; LUCIFERASE; MACROPHAGES; NEOPLASMS; NITRIC OXIDE; RADIOSENSITIVITY; TUMOR CELLS

Citation Formats

Ridder, Mark de, Verovski, Valeri N, Darville, Martine I, Berge, Dirk L. van den, Monsaert, Christinne, Eizirik, Decio L, and Storme, Guy A. Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse. United States: N. p., 2004. Web. doi:10.1016/j.ijrobp.2004.05.065.
Ridder, Mark de, Verovski, Valeri N, Darville, Martine I, Berge, Dirk L. van den, Monsaert, Christinne, Eizirik, Decio L, & Storme, Guy A. Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse. United States. https://doi.org/10.1016/j.ijrobp.2004.05.065
Ridder, Mark de, Verovski, Valeri N, Darville, Martine I, Berge, Dirk L. van den, Monsaert, Christinne, Eizirik, Decio L, and Storme, Guy A. 2004. "Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse". United States. https://doi.org/10.1016/j.ijrobp.2004.05.065.
@article{osti_20630933,
title = {Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse},
author = {Ridder, Mark de and Verovski, Valeri N and Darville, Martine I and Berge, Dirk L. van den and Monsaert, Christinne and Eizirik, Decio L and Storme, Guy A},
abstractNote = {Purpose: This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. Methods and materials: RAW 264.7 macrophages were activated by lipid A, and the conditioned medium (CM) was analyzed for the secretion of cytokines and the production of nitric oxide (NO) through inducible nitric oxide synthase (iNOS). EMT-6 tumor cells were exposed to CM and analyzed for hypoxic cell radiosensitivity. The role of nuclear factor (NF)-{kappa}B in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Results: Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 {mu}g/mL, stimulated RAW 264.7 macrophages to release NO, tumor necrosis factor (TNF)-{alpha}, and other cytokines. This in turn activated iNOS-mediated NO production in EMT-6 tumor cells and drastically enhanced their radiosensitivity. Radiosensitization was abrogated by the iNOS inhibitor aminoguanidine but not by a neutralizing anti-TNF-{alpha} antibody. The mechanism of iNOS induction was linked to NF-{kappa}B but not to JAK/STAT signaling. Interferon-{gamma} further increased the NO production by macrophages to a level that caused radiosensitization of EMT-6 cells through the bystanding effect of diffused NO. Conclusions: We demonstrate for the first time that activated macrophages may radiosensitize tumor cells through the induction of NO synthesis, which occurs in both tumor and immune cells.},
doi = {10.1016/j.ijrobp.2004.05.065},
url = {https://www.osti.gov/biblio/20630933}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 2,
volume = 60,
place = {United States},
year = {Fri Oct 01 00:00:00 EDT 2004},
month = {Fri Oct 01 00:00:00 EDT 2004}
}