title: Human mesenchymal stem cells enhance the systemic effects of radiotherapy.
abstract: The outcome of radiotherapy treatment might be further improved by a better understanding of individual variations in tumor radiosensitivity and normal tissue reactions, including the bystander effect. For many tumors, however, a definitive cure cannot be achieved, despite the availablity of more and more effective cancer treatments. Therefore, any improvement in the efficacy of radiotherapy will undoubtedly benefit a significant number of patients. Many experimental studies measure a bystander component of tumor cell death after radiotherapy, which highlights the importance of confirming these observations in a preclinical situation. Mesenchymal stem cells (MSCs) have been investigated for use in the treatment of cancers as they are able to both preferentially home onto tumors and become incorporated into their stroma. This process increases after radiation therapy. In our study we show that in vitro MSCs, when activated with a low dose of radiation, are a source of anti-tumor cytokines that decrease the proliferative activity of tumor cells, producing a potent cytotoxic synergistic effect on tumor cells. In vivo administration of unirradiated mesenchymal cells together with radiation leads to an increased efficacy of radiotherapy, thus leading to an enhancement of short and long range bystander effects on primary-irradiated tumors and distant-non-irradiated tumors. Our experiments indicate an increased cell loss rate and the decrease in the tumor cell proliferation activity as the major mechanisms underlying the delayed tumor growth and are a strong indicator of the synergistic effect between RT and MSC when they are applied together for tumor treatment in this model.
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas, Granada, Spain.
authors.forename: Virgínea
authors.initials: V
authors.lastname: de Araújo Farias
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: O'Valle
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Borja Alonso
authors.initials: BA
authors.lastname: Lerma
authors.affiliation: Biochemistry Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz de Almodóvar
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Unidad de Radiología Experimental, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Jesús J
authors.initials: JJ
authors.lastname: López-Peñalver
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Unidad de Experimentación Animal, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Unidad de Microscopia, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Santos
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Beatriz Irene
authors.initials: BI
authors.lastname: Fernández
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Guerra-Librero
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Ruiz-Ruiz
authors.affiliation: Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Damián
authors.initials: D
authors.lastname: Guirado
authors.affiliation: Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas, Granada, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Oliver
authors.affiliation: Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: José Mariano
authors.initials: JM
authors.lastname: Ruiz de Almodóvar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D024201:Bystander Effect; D049109:Cell Proliferation / Q000528:radiation effects; D002588:Cesium Radioisotopes; D005720:Gamma Rays; D006801:Humans; D007124:Immunoenzyme Techniques; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002588:Cesium Radioisotopes; D012333:RNA, Messenger
keywords: bystander effect; cancer; mesenchymal cells; radiosensitizers; radiotherapy