Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation
Autor: | Mitra Nair, Matthew O. Old, Chelsea Bolyard, Jun-Ge Yu, Raphael E. Pollock, Gonzalo Lopez, Yoshihiro Otani, Yeshavanth Kumar Banasavadi-Siddegowda, Balveen Kaur, Ji Young Yoo, Tae Jin Lee, Maninder Khosla, Jin Muk Kang, Margaret Yeh, Toshihiko Shimizu, Flora Park |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Angiogenesis lcsh:RC254-282 Virus Article 03 medical and health sciences angiogenesis 0302 clinical medicine soft tissue sarcoma (STS) vasculostatin (Vstat120) In vivo medicine tumor microenvironment (TME) Cytotoxicity business.industry medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens rapid antiangiogenesis mediated by oncolytic virus (RAMBO) Oncolytic virus Endothelial stem cell 030104 developmental biology Oncology Viral replication 030220 oncology & carcinogenesis Cancer research Sarcoma oncolytic herpes simplex virus-1 (oHSV) business |
Zdroj: | Cancers, Vol 12, Iss 1040, p 1040 (2020) Cancers Volume 12 Issue 4 |
ISSN: | 2072-6694 |
Popis: | Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including ImlygicTM, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors. |
Databáze: | OpenAIRE |
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