Cold plasma and inhibition of STAT3 selectively target tumorigenicity in osteosarcoma
Juan Tornín,
Miguel Mateu-Sanz,
Verónica Rey,
Dzohara Murillo,
Carmen Huergo,
Borja Gallego,
Aida Rodríguez,
René Rodríguez,
Cristina Canal
Affiliations
Juan Tornín
Biomaterials, Biomechanics and Tissue Engineering Group, Materials Science and Engineering Department, and Research Center for Biomedical Engineering, BarcelonaTech (UPC), Escola d'Enginyeria Barcelona Est (EEBE), C/Eduard Maristany 14, 08019, Barcelona, Spain; Barcelona Research Center in Multiscale Science and Engineering, UPC, 08019, Barcelona, Spain; Institut de Recerca Sant Joan de Déu, 08034, Barcelona, Spain; Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Miguel Mateu-Sanz
Biomaterials, Biomechanics and Tissue Engineering Group, Materials Science and Engineering Department, and Research Center for Biomedical Engineering, BarcelonaTech (UPC), Escola d'Enginyeria Barcelona Est (EEBE), C/Eduard Maristany 14, 08019, Barcelona, Spain; Barcelona Research Center in Multiscale Science and Engineering, UPC, 08019, Barcelona, Spain; Institut de Recerca Sant Joan de Déu, 08034, Barcelona, Spain
Verónica Rey
Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en Oncología (CIBERONC), 28029, Madrid, Spain
Dzohara Murillo
Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Carmen Huergo
Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en Oncología (CIBERONC), 28029, Madrid, Spain
Borja Gallego
Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Aida Rodríguez
Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
René Rodríguez
Sarcomas and Experimental Therapeutics Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en Oncología (CIBERONC), 28029, Madrid, Spain; Corresponding author. Sarcomas and Experimental Therapeutics Unit, Instituto de Investigación Sanitaria del Principado de Asturias, Av. de Roma s/n, 33011, Oviedo, Spain.
Cristina Canal
Biomaterials, Biomechanics and Tissue Engineering Group, Materials Science and Engineering Department, and Research Center for Biomedical Engineering, BarcelonaTech (UPC), Escola d'Enginyeria Barcelona Est (EEBE), C/Eduard Maristany 14, 08019, Barcelona, Spain; Barcelona Research Center in Multiscale Science and Engineering, UPC, 08019, Barcelona, Spain; Institut de Recerca Sant Joan de Déu, 08034, Barcelona, Spain; Corresponding author. Biomaterials, Biomechanics and Tissue Engineering Group, Materials Science and Engineering Department, and Research Center for Biomedical Engineering, Universitat Politècnica de Catalunya (UPC) – BarcelonaTech, Escola d'Enginyeria Barcelona Est (EEBE), C/Eduard Maristany 14, 08019, Barcelona, Spain.
Osteosarcoma (OS) is a malignant type of bone cancer that arises in periods of increased bone formation. Curative strategies for these types of tumors have remained essentially unchanged for decades and the overall survival for most advanced cases is still dismally low. This is in part due to the existence of drug resistant Cancer Stem Cells (CSC) with progenitor properties that are responsible for tumor relapse and metastasis. In the quest for therapeutic alternatives for OS, Cold Atmospheric Plasmas and Plasma-Treated Liquids (PTL) have come to the limelight as a source of Reactive Oxygen and Nitrogen Species displaying selectivity towards a variety of cancer cell lines. However, their effects on CSC subpopulations and in vivo tumor growth have been barely studied to date. By employing bioengineered 3D tumor models and in vivo assays, here we show that low doses of PTL increase the levels of pro-stemness factors and the self-renewal ability of OS cells, coupled to an enhanced in vivo tumor growth potential. This could have critical implications to the field. By proposing a combined treatment, our results demonstrate that the deleterious pro-stemness signals mediated by PTL can be abrogated when this is combined with the STAT3 inhibitor S3I-201, resulting in a strong suppression of in vivo tumor growth. Overall, our study unveils an undesirable stem cell-promoting function of PTL in cancer and supports the use of combinatorial strategies with STAT3 inhibitors as an efficient treatment for OS avoiding critical side effects. We anticipate our work to be a starting point for wider studies using relevant 3D tumor models to evaluate the effects of plasma-based therapies on tumor subpopulations of different cancer types. Furthermore, combination with STAT3 inhibition or other suitable cancer type-specific targets can be relevant to consolidate the development of the field.
