Armando Federico, Fayyad Adnan, Arms Stefanie, Barthel Yvonne, Schaudien Dirk, Rohn Karl, Gambini Matteo, Lombardo Mara Sophie, Beineke Andreas, Baumgärtner Wolfgang, Puff Christina
Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany.
Department of Veterinary Medicine, An-Najah National University, 9720061 Nablus, Palestine.
Int J Mol Sci. 2021 Mar 30;22(7):3578. doi: 10.3390/ijms22073578.
Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.
组织细胞肉瘤是指侵袭性很强、预后很差且对传统治疗方法反应不佳的肿瘤。近几十年来，溶瘤病毒作为一种癌症治疗方法受到了广泛关注，通过其复制和/或调节肿瘤微环境，溶瘤病毒是治疗组织细胞肉瘤的一个有前景的选择。减毒活犬瘟热病毒（CDV）疫苗株 Onderstepoort 是溶瘤病毒治疗的一个有吸引力的候选者。在本研究中，使用 CDV 进行溶瘤病毒治疗，以研究这种病毒感染通过直接溶瘤作用或通过病毒介导的肿瘤微环境调节对肿瘤细胞生长的影响，特别关注犬组织细胞肉瘤小鼠异种移植模型中的血管生成、选定的基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制因子-1（TIMP-1）的表达以及肿瘤相关巨噬细胞。用 CDV 治疗移植了犬组织细胞肉瘤的小鼠，可导致肿瘤进展明显迟缓，伴有肿瘤细胞坏死、瘤内巨噬细胞数量增加、血管生成减少以及 MMPs 和 TIMP-1 表达的调节。目前的数据表明，CDV 以多因素方式抑制肿瘤生长，包括直接细胞裂解、减少血管生成以及调节 MMPs 及其抑制剂 TIMP-1，这为其在溶瘤治疗中的作用概念提供了进一步支持。
