Abstract
BackgroundOncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors.MethodsFor this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC-3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation.ResultsGLV-1h255-treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV-1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV.ConclusionsTaken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome.
Highlights
Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy
MMP-9 is expressed in GLV-1h255 infected PC-3-cells and shows enzymatic activity in vitro In this study, the recombinant VACVs (rVACVs) GLV-1h255 was constructed to express human MMP-9 under control of the synthetic early promoter as shown in (Figure 1A)
MMP-9 is expressed in GLV-1h255 infected areas of PC-3 tumors Expression of MMP-9 was analyzed in PC-3 tumor sections at 7 days p.i
Summary
Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. A promising therapeutic approach for the treatment of PCa are oncolytic viruses such as vaccinia virus (VACV) GLV-1h68 [6]. This virus was successfully used in other malignancies such as pancreatic tumors, squamous cell carcinoma, breast cancer or in combination with a prodrug activated by the GLV-1h68carried marker gene β-galactosidase [7,8,9,10]. VACV replicates exclusively in the cytoplasm [11] and has a large genome well suited for inserts of up to 25 kb [12]. The inserted genes can be used to enhance therapeutic efficacy as in the case of a GLAF-1 (a single chain antibody against vascular endothelial growth factor (VEGF)) encoding VACV [13], or to allow the use of imaging techniques such as positron emission tomography (PET) [14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
