Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia.
Clinic for Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Int J Mol Sci. 2022 May 19;23(10):5691. doi: 10.3390/ijms23105691.
Tumor cells with stem cell properties are considered to play major roles in promoting the development and malignant behavior of aggressive cancers. Therapeutic strategies that efficiently eradicate such tumor stem cells are of highest clinical need. Herein, we performed the validation of the polycationic phosphorus dendrimer-based approach for small interfering RNAs delivery in in vitro stem-like cells as models. As a therapeutic target, we chose Lyn, a member of the Src family kinases as an example of a prominent enzyme class widely discussed as a potent anti-cancer intervention point. Our selection is guided by our discovery that Lyn mRNA expression level in glioma, a class of brain tumors, possesses significant negative clinical predictive value, promoting its potential as a therapeutic target for future molecular-targeted treatments. We then showed that anti-Lyn siRNA, delivered into Lyn-expressing glioma cell model reduces the cell viability, a fact that was not observed in a cell model that lacks Lyn-expression. Furthermore, we have found that the dendrimer itself influences various parameters of the cells such as the expression of surface markers PD-L1, TIM-3 and CD47, targets for immune recognition and other biological processes suggested to be regulating glioblastoma cell invasion. Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.
具有干细胞特性的肿瘤细胞被认为在促进侵袭性癌症的发展和恶性行为中起主要作用。高效清除此类肿瘤干细胞的治疗策略是临床的最大需求。在此，我们对基于聚阳离子磷树突的小分子干扰 RNA 传递方法在体外类干细胞细胞模型中的验证进行了研究。作为治疗靶点，我们选择 Lyn 作为范例，它是 Src 家族激酶的一个成员，是一个广泛讨论的作为潜在抗癌干预点的突出酶类。我们的选择是基于我们的发现，即脑肿瘤（一类脑肿瘤）中的 Lyn mRNA 表达水平具有显著的负临床预测价值，这使其成为未来分子靶向治疗的潜在治疗靶点。然后，我们表明，递送至 Lyn 表达的神经胶质瘤细胞模型中的抗 Lyn siRNA 降低了细胞活力，而在缺乏 Lyn 表达的细胞模型中则未观察到这种现象。此外，我们发现树突本身会影响细胞的各种参数，如 PD-L1、TIM-3 和 CD47 等表面标志物的表达，这些标志物是免疫识别的靶点，以及其他被认为调节神经胶质瘤细胞侵袭的生物学过程。我们的研究结果证明了基于树突的平台在治疗应用中的潜力，这可能有助于根除具有增强化疗耐药性的癌细胞群体。此外，这些结果进一步推动了我们的功能性干细胞技术作为早期药物开发的合适组成部分。
