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

International Journal of Radiation Oncology, Biology, Physics
Mark De RidderGuy A Storme

Abstract

This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. 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)-kappaB in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 microg/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-kappaB 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. ...Continue Reading

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Oct 8, 2003·International Journal of Radiation Oncology, Biology, Physics·Mark de RidderGuy A Storme

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Citations

Jun 29, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Xiaoli LiHong Zhou
Nov 24, 2007·Nature Reviews. Cancer·Dirk VerellenGuy Storme
Jul 8, 2010·International Journal of Radiation Oncology, Biology, Physics·Hendrik EveraertMark De Ridder
Jun 3, 2008·International Journal of Radiation Oncology, Biology, Physics·Mark De RidderGuy A Storme
May 14, 2008·Nitric Oxide : Biology and Chemistry·Mark De RidderGuy Storme
Dec 1, 2006·Veterinary and Comparative Oncology·D H Thamm
Apr 12, 2016·Frontiers in Pharmacology·Natacha LeroiPhilippe Martinive
Apr 29, 2009·Journal of Radiation Research·Sandro ConradKathryn Nixdorff
Jan 31, 2014·Journal of Neuro-oncology·Emmanuel ChautardPierre Verrelle
Feb 22, 2014·Cancer Research·Heather J DaltonAnil K Sood

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