Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterizatio
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(2020) 27:90
RESEARCH
Open Access
Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization Francesco Petragnano1†, Ilaria Pietrantoni1†, Simona Camero2†, Silvia Codenotti3, Luisa Milazzo4, Francesca Vulcano4, Giampiero Macioce4, Ilenia Giordani5, Paolo Tini6,7, Sara Cheleschi8, Giovanni Luca Gravina1, Claudio Festuccia1, Alessandra Rossetti1, Simona Delle Monache1, Alessandra Ordinelli9, Carmela Ciccarelli1, Annunziata Mauro9, Barboni Barbara9, Cristina Antinozzi10, Amalia Schiavetti2, Roberto Maggio1, Luigi Di Luigi10, Antonella Polimeni11, Cinzia Marchese12, Vincenzo Tombolini13, Alessandro Fanzani3, Nicola Bernabò9, Francesca Megiorni12† and Francesco Marampon13*†
Abstract Background: The probability of local tumor control after radiotherapy (RT) remains still miserably poor in pediatric rhabdomyosarcoma (RMS). Thus, understanding the molecular mechanisms responsible of tumor relapse is essential to identify personalized RT-based strategies. Contrary to what has been done so far, a correct characterization of cellular radioresistance should be performed comparing radioresistant and radiosensitive cells with the same isogenic background. Methods: Clinically relevant radioresistant (RR) embryonal (RD) and alveolar (RH30) RMS cell lines have been developed by irradiating them with clinical-like hypo-fractionated schedule. RMS-RR cells were compared to parental isogenic counterpart (RMS-PR) and studied following the radiobiological concept of the “6Rs”, which stand for repair, redistribution, repopulation, reoxygenation, intrinsic radioresistance and radio-immuno-biology. Results: RMS-RR cell lines, characterized by a more aggressive and in vitro pro-metastatic phenotype, showed a higher ability to i) detoxify from reactive oxygen species; ii) repair DNA damage by differently activating nonhomologous end joining and homologous recombination pathways; iii) counteract RT-induced G2/M cell cycle arrest by re-starting growth and repopulating after irradiation; iv) express cancer stem-like profile. Bioinformatic analyses, performed to assess the role of 41 cytokines after RT exposure and their network interactions, suggested TGF-β, MIF, CCL2, CXCL5, CXCL8 and CXCL12 as master regulators of cancer immune escape in RMS tumors. (Continued on next page)
* Correspondence: [email protected] † Francesco Petragnano, Ilaria Pietrantoni, Simona Camero, Francesca Megiorni and Francesco Marampon contributed equally to this work. 13 Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if c
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