Related Experiment Videos
Antiangiogenic therapy against experimental glioblastoma using genetically engineered cells producing
Sophie De Boüard1, Jean-Sébastien Guillamo, Christo Christov
1INSERM U 421, Neuroplasticity and Therapeutics, Faculté de Médecine, 8 rue du Général Sarrail, 94010 Créteil, France.
Abstract:
Inhibition of angiogenesis has been considered among the most promising approaches to treat highly vascularized solid tumors such as glioblastoma. In this study, we designed and validated a new in vitro assay system based on the implantation of tumor cells into organotypic brain slice cultures. We evaluated the effects of local production of three endogenous inhibitors of angiogenesis, angiostatin, endostatin, and interferon (IFN)-alpha(1), using stably transfected rat (9L) and human (GL15) glioblastoma cells on tumor vascularization and growth. Despite similar effectiveness of the three proteins in a classic in vitro endothelial cell migration assay, IFN-alpha(1) demonstrated the most potent antiangiogenic effect in organotypic brain slice cultures. In vivo, after intracerebral implantation of such genetically modified glioblastoma cells, IFN-alpha(1) caused a dramatic decrease in tumor volume revealed by magnetic resonance imaging and by postmortem histology. The mechanisms of this antitumor effect were most likely caused by the major antiangiogenic action of the cytokine, because IFN-alpha(1) expression provoked a pronounced decrease in blood vessel density, which was accompanied by extensive necrosis in the body mass of the tumors. The median survival time of rats implanted intracerebrally with IFN-alpha-expressing 9L cells tripled, and was still significantly increased when these constituted only 1% of transplanted tumor cells. A similar effect was seen when 50% of the transplanted cells were replaced by IFN-alpha-expressing bone marrow stromal cells. These data point to the local delivery of IFN-alpha(1) using cell vectors as a potent tool for the inhibition of tumor-induced angiogenesis.
Insights
Interferon (IFN)-alpha(1) significantly inhibits glioblastoma growth by blocking tumor angiogenesis. Local delivery of IFN-alpha(1) using cell vectors offers a potent strategy for treating highly vascularized brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Angiogenesis inhibition is a key strategy for treating vascularized solid tumors like glioblastoma.
- Endogenous angiogenesis inhibitors include angiostatin, endostatin, and interferon (IFN)-alpha(1).
Purpose of the Study:
- To evaluate the antiangiogenic and antitumor effects of local IFN-alpha(1) production in glioblastoma models.
- To establish and validate a novel in vitro organotypic brain slice culture system for assessing antiangiogenic therapies.
Main Methods:
- Development of an in vitro assay using organotypic brain slice cultures with transfected glioblastoma cells.
- Comparison of angiostatin, endostatin, and IFN-alpha(1) in endothelial cell migration and brain slice assays.
- In vivo studies involving intracerebral implantation of genetically modified glioblastoma cells in rats.
Main Results:
- IFN-alpha(1) showed the most potent antiangiogenic effect in organotypic brain slice cultures compared to angiostatin and endostatin.
- In vivo, IFN-alpha(1) expression led to a significant decrease in glioblastoma tumor volume and blood vessel density.
- Median survival time in rats tripled with IFN-alpha(1)-expressing glioblastoma cells, even at low percentages.
Conclusions:
- Local delivery of IFN-alpha(1) via cell vectors is a potent strategy for inhibiting tumor-induced angiogenesis in glioblastoma.
- IFN-alpha(1) demonstrates significant antitumor efficacy through its antiangiogenic properties.
- The organotypic brain slice culture system is a valuable tool for evaluating antiangiogenic therapies in a relevant tumor microenvironment.