Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization

Autor: Luigi Di Luigi, Roberto Maggio, Ilaria Pietrantoni, Francesco Marampon, Paolo Tini, Giovanni Luca Gravina, Ilenia Giordani, Francesco Petragnano, Giampiero Macioce, Nicola Bernabò, Alessandro Fanzani, Alessandra Ordinelli, Francesca Megiorni, Alessandra Rossetti, Claudio Festuccia, Luisa Milazzo, Antonella Polimeni, Amalia Schiavetti, Cinzia Marchese, Carmela Ciccarelli, Cristina Antinozzi, Vincenzo Tombolini, Silvia Codenotti, Annunziata Mauro, Sara Cheleschi, Francesca Vulcano, Simona Delle Monache, Simona Camero, Barboni Barbara
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of Biomedical Science, Vol 27, Iss 1, Pp 1-18 (2020)
Journal of Biomedical Science
ISSN: 1423-0127
Popis: 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 non-homologous 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. Conclusions These results suggest that RMS could sustain intrinsic and acquire radioresistance by different mechanisms and indicate potential targets for future combined radiosensitizing strategies.
Databáze: OpenAIRE
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