Oncotarget

Research Papers:

Human mesenchymal stem cells enhance the systemic effects of radiotherapy

Virgínea de Araújo Farias, Francisco O’Valle, Borja Alonso Lerma, Carmen Ruiz de Almodóvar, Jesús J. López-Peñalver, Ana Nieto, Ana Santos, Beatriz Irene Fernández, Ana Guerra-Librero, María Carmen Ruiz-Ruiz, Damián Guirado, Thomas Schmidt, Francisco Javier Oliver and José Mariano Ruiz de Almodóvar _

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Oncotarget. 2015; 6:31164-31180. https://doi.org/10.18632/oncotarget.5216

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Abstract

Virgínea de Araújo Farias1,2, Francisco O’Valle1, Borja Alonso Lerma1, Carmen Ruiz de Almodóvar3, Jesús J. López-Peñalver1,4, Ana Nieto1,5, Ana Santos1,6, Beatriz Irene Fernández1, Ana Guerra-Librero1, María Carmen Ruiz-Ruiz1,7, Damián Guirado8, Thomas Schmidt9, Francisco Javier Oliver2 and José Mariano Ruiz de Almodóvar1,8

1 Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain

2 Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, Granada, Spain

3 Biochemistry Center, University of Heidelberg, Heidelberg, Germany

4 Unidad de Radiología Experimental, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain

5 Unidad de Experimentación Animal, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain

6 Unidad de Microscopia, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain

7 Departamento de Bioquímica y Biología Molecular III e Inmunología, IBIMER, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain

8 Hospital Universitario San Cecilio, Granada, Spain

9 Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany

Correspondence to:

José Mariano Ruiz de Almodóvar, email:

Keywords: radiotherapy, bystander effect, mesenchymal cells, cancer, radiosensitizers

Received: July 07, 2015 Accepted: August 12, 2015 Published: August 17, 2015

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.


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