Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia.
Faculty of Health Sciences, University of Primorska, 6310 Izola, Slovenia.
Int J Mol Sci. 2023 Feb 1;24(3):2755. doi: 10.3390/ijms24032755.
Targeting the tumor vasculature through specific endothelial cell markers involved in different signaling pathways represents a promising tool for tumor radiosensitization. Two prominent targets are endoglin (CD105), a transforming growth factor β co-receptor, and the melanoma cell adhesion molecule (CD1046), present also on many tumors. In our recent in vitro study, we constructed and evaluated a plasmid for simultaneous silencing of these two targets. In the current study, our aim was to explore the therapeutic potential of gene electrotransfer-mediated delivery of this new plasmid in vivo, and to elucidate the effects of combined therapy with tumor irradiation. The antitumor effect was evaluated by determination of tumor growth delay and proportion of tumor free mice in the syngeneic murine mammary adenocarcinoma tumor model TS/A. Histological analysis of tumors (vascularization, proliferation, hypoxia, necrosis, apoptosis and infiltration of immune cells) was performed to evaluate the therapeutic mechanisms. Additionally, potential activation of the immune response was evaluated by determining the induction of DNA sensor STING and selected pro-inflammatory cytokines using qRT-PCR. The results point to a significant radiosensitization and a good therapeutic potential of this gene therapy approach in an otherwise radioresistant and immunologically cold TS/A tumor model, making it a promising novel treatment modality for a wide range of tumors.
通过针对不同信号通路中涉及的特定内皮细胞标记物来靶向肿瘤血管系统，代表了一种有前途的肿瘤放射增敏工具。两个突出的靶标是转化生长因子-β共受体内皮糖蛋白（CD105）和黑色素瘤细胞黏附分子（CD1046），许多肿瘤也存在该分子。在我们最近的体外研究中，我们构建并评估了一种同时沉默这两个靶标的质粒。在当前的研究中，我们的目的是探索体内基因电转移介导该新质粒传递的治疗潜力，并阐明与肿瘤照射相结合的联合治疗的效果。通过确定肿瘤生长延迟和同基因鼠乳腺腺癌肿瘤模型 TS/A 中无肿瘤小鼠的比例来评估抗肿瘤作用。通过对肿瘤（血管生成、增殖、缺氧、坏死、凋亡和免疫细胞浸润）进行组织学分析来评估治疗机制。此外，通过 qRT-PCR 确定 DNA 传感器 STING 和选定的促炎细胞因子的诱导来评估潜在的免疫反应激活。结果表明，在原本对放射治疗有抵抗力且免疫状态冷的 TS/A 肿瘤模型中，这种基因治疗方法具有显著的放射增敏作用和良好的治疗潜力，使其成为广泛肿瘤的有前途的新型治疗方式。
