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E1A gene therapy inhibits angiogenesis in a Ewing's sarcoma animal model
Zhichao Zhou1, Rong-Rong Zhou, Hui Guan
1Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
We assessed vascular endothelial growth factor (VEGF) expression in four different human Ewing's sarcoma cell lines (TC71, SK-ES, RD, and A4573) and in tumors in nude mice induced following s.c. injection of TC71 cells. Three of the four cell lines (TC71, SK-ES, and A4573) expressed significantly higher levels of VEGF than did normal human osteoblasts. Transfection of the adenovirus type 5 early region 1A (E1A) gene into TC71 cells down-regulated VEGF expression in vitro. In the mice bearing TC71 cell tumors, intratumoral injections of an adenoviral vector containing the E1A gene (Ad-E1A) decreased VEGF expression, inhibited tumor growth, and increased the survival rates in comparison with the mice given injections of PBS or an adenoviral vector containing beta-galactosidase (Ad-beta-gal). E1A gene therapy also significantly reduced blood vessel density and induced cell apoptosis in the tumors. These results demonstrate that E1A gene therapy inhibits angiogenesis, most likely by suppression of VEGF expression. Thus, E1A gene therapy may be a new therapeutic approach for Ewing's sarcoma.
Insights
Ewing sarcoma cells overexpress vascular endothelial growth factor (VEGF). Adenovirus type 5 early region 1A (E1A) gene therapy suppressed VEGF, inhibited tumor growth, and improved survival in mice, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Ewing sarcoma is a rare bone cancer with limited treatment options.
- Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and growth.
- Understanding VEGF regulation in Ewing sarcoma is vital for developing targeted therapies.
Purpose of the Study:
- To investigate VEGF expression in human Ewing sarcoma cell lines.
- To evaluate the therapeutic potential of adenovirus type 5 early region 1A (E1A) gene therapy in Ewing sarcoma.
- To determine the effect of E1A gene therapy on tumor angiogenesis and growth.
Main Methods:
- Assessed VEGF expression in four human Ewing sarcoma cell lines and normal osteoblasts.
- Utilized adenovirus-mediated E1A gene transfer in vitro and in vivo.
- Administered intratumoral injections of Ad-E1A in a mouse model of Ewing sarcoma.
- Measured tumor growth, survival rates, blood vessel density, and apoptosis.
Main Results:
- Three of four Ewing sarcoma cell lines showed significantly higher VEGF expression than osteoblasts.
- In vitro E1A gene transfection down-regulated VEGF expression in TC71 cells.
- In vivo Ad-E1A treatment reduced VEGF expression, inhibited tumor growth, and increased survival in mice.
- E1A gene therapy decreased tumor vascularity and induced apoptosis.
Conclusions:
- Ewing sarcoma cells exhibit elevated VEGF expression.
- E1A gene therapy effectively suppresses VEGF expression and angiogenesis in Ewing sarcoma.
- E1A gene therapy demonstrates therapeutic potential for treating Ewing sarcoma by inhibiting tumor growth and improving survival.