Distinct Roles of Direct Transduction Versus Exposure to the Tumor Secretome on Murine Endothelial Cells After Melanoma Gene Therapy with Interferon-beta and p19Arf

Author(s)

Vieira, Igor de Luna ^[1] ; Tamura, Rodrigo Esaki ^{[2, 1]} ; Hunger, Aline ^{[1, 3]} ; Strauss, Bryan E. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Viral Vector Lab, Ctr Invest Translac Oncol LIM24, Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Biol Sci, Diadema, SP - Brazil

^[3] Cristalia, Biotecnol Unidade 1, Itapira, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF INTERFERON AND CYTOKINE RESEARCH; v. 39, n. 4, p. 246-258, APR 1 2019.
• Web of Science Citations: 0

Abstract

Tumor vasculature plays a central role in tumor progression, making it an attractive therapeutic target. In this study, we explore the antiangiogenic potential of our melanoma gene therapy approach combining interferon beta (IFN beta) and p19Arf gene transfer. Since these proteins are modulators of tumor vasculature, we explore the impact of IFN beta and p19Arf gene transfer on murine endothelial cells (tEnd). Adenovirus-mediated gene transfer of p19Arf to tEnd cells inhibited proliferation, tube formation, migration, and led to increased expression of genes related to the p53 cell death pathway, yet IFN beta gene transfer had no significant impact on tEnd viability. Alternatively, tEnd cells were exposed to the factors generated by transduced B16 (mouse melanoma) cells using either coculture or conditioned medium. In either case, transduction of B16 cells with the IFN beta vector, whether alone or in combination with p19Arf, resulted in endothelial cell death. Strikingly, treatment of tEnd cells with recombinant IFN beta did not induce death, demonstrating that additional factors produced by B16 cells contributed to the demise of tEnd cells. In this work, we have shown that our melanoma gene therapy strategy produces desirable negative effects on endothelial cells, possibly correlating with antiangiogenic activity. (AU)

• FAPESP's process: 13/25167-5 - P19Arf and interferon-beta gene transfer: delineating the importance of their combination in mouse models of cancer gene therapy
• Grantee: Bryan Eric Strauss
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/10656-5 - Evaluation of the molecular mechanisms of p53/ARF and IFN-beta pathways involved in the the response of melanoma cells to treatment with the p19Arf and IFN-beta transgenes.
• Grantee: Aline Hunger Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/21256-8 - Combination of chemotherapy and adenoviral vectors expressing p53 for the therapy of prostate cancer
• Grantee: Rodrigo Esaki Tamura
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/26580-9 - Cancer gene therapy: strategic positioning for translational studies
• Grantee: Bryan Eric Strauss
• Support Opportunities: Research Projects - Thematic Grants