Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide
Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide
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DOI：
10.1158/0008-5472.can-06-3145
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发表时间：
2007-01-15
期刊：
影响因子：
11.2
通讯作者：
Martuza, Robert L.
中科院分区：
文献类型：
--
作者：
Aghi, Manish;Rabkin, Samuel D.;Martuza, Robert L.
野生型（WT）单纯疱疹病毒（HSV）通过增加感染的组织血管分布（可能反映感染的细胞中血管生成因子表达的改变）引起一些病理学，例如眼角膜炎。溶瘤HSV具有能够在肿瘤细胞中选择性复制的特异性突变。我们研究了这种增强感染组织血管分布的能力是否保留在溶瘤HSV中，这可能是溶瘤HSV的不良作用，当用溶瘤HSV治疗肿瘤时可能需要解决。S.C.在存在或不存在由血小板反应蛋白-1（TSP-1）的三个1型重复序列（3TSR）组成的重组蛋白的情况下，用溶瘤HSVG207或G47 δ处理无胸腺小鼠中源自U87人神经胶质瘤细胞的肿瘤。实时逆转录-PCR和Western blot检测感染的培养细胞的血管生成因子表达。采用免疫荧光法检测微血管密度。G207处理的U87 s.c.与盐水和G47Delta处理的肿瘤相比，肿瘤具有升高的微血管密度，并且G207处理导致延迟的肿瘤生长恢复。G207感染的U87和U373细胞表现出降低的蛋白质，而不是mRNA，表达的血管生成抑制剂TSPI和血小板反应蛋白-2（TSP-2）。3TSR使G207处理的肿瘤微血管密度恢复到G47 Delta处理的肿瘤的低水平，并防止延迟的生长恢复。因此，溶瘤HSV G207保留了WT HSV增加感染组织血管分布的能力。在感染的肿瘤中，这种增加的血管分布是由TSP-1和TSP-2水平降低介导的，并导致延迟的肿瘤生长恢复。消除病毒突变，如在G47A或给予血小板反应蛋白衍生肽中观察到的突变，抵消了溶瘤HSV的血管生成作用，在设计溶瘤HSV治疗时应予以考虑。
Wild-type (WT) herpes simplex virus (HSV) causes some pathology, such as ocular keratitis, by increasing infected tissue vascularity, possibly reflecting altered angiogenic factor expression in infected cells. Oncolytic HSVs possess specific mutations enabling selective replication in tumor cells. We investigated whether this ability to enhance infected tissue vascularity is retained in oncolytic HSV, which could be an undesirable effect of oncolytic HSVs that may need to be addressed when treating tumors with oncolytic HSVs. s.c. tumors derived from U87 human glioma cells in athymic mice were treated with oncolytic HSVs G207 or G47 Delta in the presence or absence of a recombinant protein composed of the three type-1 repeats (3TSR) of thrombospondin-1 (TSP-1). Real-time reverse transcription-PCR and Western blot of infected cultured cells measured angiogenic factor expression. Microvessel density was assessed using immunofluorescence. G207-treated U87 s.c. tumors had elevated microvessel densities compared with saline- and G47 Delta-treated tumors, and G207 treatment caused delayed tumor growth resumption. G207-infected U87 and U373 cells exhibited reduced protein, not mRNA, expression of angiogenesis inhibitors TSPI and thrombospondin-2 (TSP-2). 3TSR restored the G207-treated tumor microvessel density to the low level of G47 Delta-treated tumors and prevented delayed growth resumption. Oncolytic HSV G207 thus retains the ability of WT HSV to increase infected tissue vascularity. In infected tumors, this increased vascularity is mediated by reduced TSP-1 and TSP-2 levels and causes delayed tumor growth resumption. Incorporating viral mutations, such as those seen in G47A or administering thrombospondin-derived peptides, counteracts the angiogenic effect of oncolytic HSV and should be considered when designing oncolytic HSV therapies.