Departamento de Ciencias Básicas y Medicina Oral, Facultad de Odontología, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia.
Departamento de Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia.
PLoS One. 2023 May 15;18(5):e0285543. doi: 10.1371/journal.pone.0285543. eCollection 2023.
Despite advances in biomedical research, gastric cancer remains the leading cause of morbidity and mortality worldwide due to the limited efficacy of conventional therapies. In recent decades, oncolytic viruses have emerged as a biological therapeutic alternative to cancer due to their selectivity, effectiveness, and low toxicity. However, clinical trials have shown that developing a virus with selectivity for multiple tumor receptors and the ability to penetrate and diffuse through the tumor microenvironment to reactivate the immune system remains challenging. This study aimed to examine the oncolytic potential of tumor cell-adapted rotavirus Wt1-5 in gastric adenocarcinoma samples. This study focused on determining the propagation capacity of the RV Wt1-5 through the tumor and the importance of the expression of cell surface co-receptors, including integrin β3, protein disulfide isomerase (PDI), and heat shock proteins (Hsp-90, -70, -60, -40, and Hsc 70), during infection of tumor cells. These proteins were found to be differentially expressed in tumor cells compared to adjacent non-tumor cells. Preincubation of gastric tumor cells with antibodies against these proteins decreased rotavirus infections, validating their importance in the binding and entry of RV Wt1-5 into tumor cells, as previously reported. Upon RV infection, apoptosis was one of the types of death that was observed. This was evidenced by evaluating the expression of CASP-3, -9, PARP, cytochrome C, Bax, Bid, p53, and Bcl-2, as well as observing morphological changes such as chromatin margination, nuclear condensation, and fragmentation. Finally, at 60 h.p.i, histological analysis revealed that oncolysis compromised the entire thickness of the tumor. Therefore, the results suggest that RV Wt1-5 could be a novel therapeutic agent co-adjuvant agent for conventional and targeted therapies in managing GC. Ex vivo infection of the tumor tissue model showed characteristics of an immune response that could be explored in future studies.
尽管在生物医学研究方面取得了进展，但由于常规疗法的疗效有限，胃癌仍然是全球发病率和死亡率的主要原因。近几十年来，溶瘤病毒作为癌症的一种生物治疗替代方法出现，因为它们具有选择性、有效性和低毒性。然而，临床试验表明，开发一种对多种肿瘤受体具有选择性且能够穿透和扩散到肿瘤微环境中以重新激活免疫系统的病毒仍然具有挑战性。本研究旨在研究肿瘤细胞适应的轮状病毒 Wt1-5 在胃腺癌样本中的溶瘤潜力。本研究重点确定 RV Wt1-5 通过肿瘤的繁殖能力以及细胞表面共受体（包括整合素 β3、蛋白二硫键异构酶 (PDI) 和热休克蛋白 (Hsp-90、-70、-60、-40 和 Hsc 70) 的表达在感染肿瘤细胞时的重要性。与相邻的非肿瘤细胞相比，这些蛋白质在肿瘤细胞中差异表达。用针对这些蛋白质的抗体预先孵育胃肿瘤细胞会降低轮状病毒感染，这验证了它们在 RV Wt1-5 结合和进入肿瘤细胞中的重要性，如先前报道的那样。在 RV 感染后，细胞凋亡是观察到的死亡类型之一。这可以通过评估 CASP-3、-9、PARP、细胞色素 C、Bax、Bid、p53 和 Bcl-2 的表达以及观察染色质边缘化、核浓缩和碎裂等形态变化来证明。最后，在 60 h.p.i，组织学分析显示溶瘤作用破坏了整个肿瘤的厚度。因此，结果表明 RV Wt1-5 可能是一种新型治疗剂，可作为传统和靶向治疗管理 GC 的辅助剂。肿瘤组织模型的离体感染显示出免疫反应的特征，这可以在未来的研究中进行探索。
