Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Division of Biostatistics and Bioinformatics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Mol Cancer Res. 2017 Oct;15(10):1410-1420. doi: 10.1158/1541-7786.MCR-17-0016. Epub 2017 Jul 5.
The tumor microenvironment (TME) is a relevant target for novel biological therapies. MV-m-uPA and MV-h-uPA are fully retargeted, species-specific, oncolytic measles viruses (MV) directed against murine or human urokinase receptor (PLAUR/uPAR), expressed in tumor and stromal cells. The effects of stromal-selective targeting by uPAR-retargeted MVs were investigated. infection, virus-induced GFP expression, and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer-associated fibroblasts in a species-specific manner. In a murine fibroblast/human breast cancer 3D coculture model, selective fibroblast targeting by MV-m-uPA inhibited breast cancer cell growth. Systemic administration of murine-specific MV-m-uPA in mice bearing human MDA-MB-231 xenografts was associated with a significant delay in tumor progression and improved survival compared with controls. Experiments comparing tumor (MV-h-uPA) versus stromal (MV-m-uPA) versus combined virus targeting showed that tumor and stromal targeting was associated with improved tumor control over the other groups. Correlative studies confirmed viral targeting of tumor stroma by MV-m-uPA, increased apoptosis, and virus-induced differential regulation of murine stromal genes associated with inflammatory, angiogenesis, and survival pathways, as well as indirect regulation of human cancer pathways, indicating viral-induced modulation of tumor-stroma interactions. These data demonstrate the feasibility of stromal-selective targeting by an oncolytic MV, virus-induced modulation of tumor-stroma pathways, and subsequent tumor growth delay. These findings further validate the critical role of stromal uPAR in cancer progression and the potential of oncolytic viruses as antistromal agents. The current report demonstrates for the first time the biological, , and antitumor and molecular effects of stromal selective targeting by an oncolytic virus. .
肿瘤微环境（TME）是新型生物治疗的相关靶点。MV-m-uPA 和 MV-h-uPA 是完全重定向的、种特异性的、针对鼠类或人类尿激酶受体（PLAUR/uPAR）的溶瘤麻疹病毒（MV），在肿瘤和基质细胞中表达。研究了 uPAR 重定向 MV 的基质选择性靶向的影响。MV-h-uPA 和 MV-m-uPA 以种特异性方式感染、病毒诱导 GFP 表达和细胞毒性，在人类和鼠类癌细胞和癌相关成纤维细胞中。在鼠类成纤维细胞/人乳腺癌 3D 共培养模型中，MV-m-uPA 的选择性成纤维细胞靶向抑制了乳腺癌细胞的生长。在携带人 MDA-MB-231 异种移植物的小鼠中，全身性给予鼠特异性 MV-m-uPA 与对照组相比，与肿瘤进展显著延迟和生存率提高相关。比较肿瘤（MV-h-uPA）与基质（MV-m-uPA）与联合病毒靶向的实验表明，肿瘤和基质靶向与其他组相比，改善了肿瘤控制。相关性研究证实，MV-m-uPA 对肿瘤基质的病毒靶向、增加的细胞凋亡和病毒诱导的与炎症、血管生成和存活途径相关的鼠类基质基因的差异调节以及对人类癌症途径的间接调节，表明病毒诱导的肿瘤-基质相互作用的调节。这些数据证明了溶瘤 MV 的基质选择性靶向、病毒诱导的肿瘤-基质途径的调节以及随后的肿瘤生长延迟的可行性。这些发现进一步验证了基质 uPAR 在癌症进展中的关键作用和溶瘤病毒作为抗基质剂的潜力。本报告首次证明了溶瘤病毒基质选择性靶向的生物学、、抗肿瘤和分子作用。
