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.
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.
Redox Biol. 2023 Jun;62:102685. doi: 10.1016/j.redox.2023.102685. Epub 2023 Mar 20.
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.
骨肉瘤（OS）是一种恶性骨癌，发生在骨形成增加的时期。几十年来，这些类型肿瘤的治疗策略基本没有改变，大多数晚期病例的总体生存率仍然很低。这在一定程度上是由于存在具有祖细胞特性的耐药性癌症干细胞（CSC），这些细胞是肿瘤复发和转移的原因。在寻找骨肉瘤治疗替代方法的过程中，冷大气压等离子体和等离子体处理液（PTL）作为活性氧和氮物种的来源引起了人们的关注，这些物质对各种癌细胞系具有选择性。然而，迄今为止，它们对 CSC 亚群和体内肿瘤生长的影响几乎没有研究过。通过使用生物工程 3D 肿瘤模型和体内测定，我们在这里表明，低剂量的 PTL 增加了 OS 细胞的干性前体因子水平和自我更新能力，同时增强了体内肿瘤生长潜力。这可能对该领域具有重要意义。通过提出联合治疗，我们的结果表明，当 PTL 与 STAT3 抑制剂 S3I-201 联合使用时，PTL 介导的有害干性前体信号可以被消除，从而强烈抑制体内肿瘤生长。总的来说，我们的研究揭示了 PTL 在癌症中促进干细胞的不良功能，并支持使用与 STAT3 抑制剂联合的组合策略作为避免严重副作用的骨肉瘤有效治疗方法。我们预计我们的工作将为使用相关 3D 肿瘤模型评估基于等离子体的治疗对不同癌症类型肿瘤亚群的影响的更广泛研究提供一个起点。此外，与 STAT3 抑制或其他合适的癌症类型特异性靶标结合可能与巩固该领域的发展有关。
