Original artical link: https://link.springer.com/article/10.1186/s12985-026-03162-w
Angiogenesis is the growth of new vessels from the existing vessels. In tumors, angiogenesis enables the nutrients to reach cells located in the center of the tumor, allowing the tumor to progress to a larger size and metastasize to other locations of the body through blood stream (1). Decorin is a proteoglycan that can stimulate or inhibit angiogenesis in various circumstances (2). A study has shown that in malignant tumors, where angiogenesis has taken place to benefit tumor growth, decorin expression was not detected in the tumor mass; while in benign tumors, where angiogenesis has not taken place, decorin expression was found in the tumor mass, indicating that decorin is associated with a suppressive effect on tumor angiogenesis (3). In this study by Frejborg et al., the role of decorin in angiogenesis is indicated to be angiogenesis-reducing under expression by a Herpes Simplex Virus (HSV) vector (4), demonstrating a potential for therapeutics in targeting tumor angiogenesis.
The researchers chose Chicken chorioallantoic membrane (CAM) models, commonly utilized models for angiogenesis research, and Huh7 cells as a model, limiting the oncolytic effect of the HSV vector itself owing to the intact interferon pathway of the cell line, for hepatocellular carcinoma. The Huh7 cell tumors were xenografted, or implanted, onto the CAM and were infected with the decorin-expression HSV vector to study the effect of decorin on the tumor, which was conjectured by the authors to be anti-angiogenesis and anti-tumor growth.
From the Immunoblot data by Frejborg et al., expression of decorin in their decorin-expression vector (H2252) infected tumors was validated. H2254 is the control HSV vector not expressing decorin to validate the successful infection of the vectors. The quantification of reduction in angiogenesis demonstrates a significant reduction of angiogenesis in the decorin-expressing H2252 infected tumor comparing to the H2254 infected tumor group, shown in Fig. 1 B. Their representative image of the tumor also demonstrated less new branches of vessels in the H2252 group, shown in Fig. 1 C.
Although the authors were able to observe a reduction in the new branching of the vessels in the tumors, the size reduction as an effect of the decorin-expressing HSV infection was not significant. The authors were able to rescue viable, replicative HSV from the tumors, showing the viral titer in Fig. 2B. Their immunohistological staining demonstrated that VP5, the major capsid protein of HSV located inside the envelope, was stained at the periphery of the tumor, indicating that the virus was replicating at the periphery of the tumor and that the gene therapy was functional.
The authors indicated that the oncolytic effect of the HSV vector was not detected in the experiment, which can be attributed to the intact IFN signaling pathway in the Huh7 cells and the deletion of γ134.5 virulence gene in both the H2252 and H2254 viruses they applied. The γ134.5 gene is responsible for reversing the translational shut-off by the IFN signaling pathway during viral infection and sustaining other IFN-inhibiting proteins such as ICP0, an E3-like ubiquitin ligase encoded by the HSV immediate early gene that is promotes the degradation of IRF3 and IRF7 (5). γ134.5 deletion is also widely used in oncolytic therapy research of HSV, the deletion of this virulent protein keeps the oncolytic HSV from infecting normal cells (6).
This article provides an insight into the potential of HSV vectors as a gene therapy in impairing tumor angiogenesis.
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