TITLE: VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment
The Schepens Eye Research Institute, Boston, Massachusetts, USA.
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Overcoming Obstacles in Antiangiogenesis Gene Therapy
Antiangiogenic gene therapy strategies against cancer are considered preferable to direct tumor-targeting strategies because tumor cells, with their high somatic mutation frequency, often develop resistance to apoptotic stimuli. Gene therapy in the vasculature, however, also has limitations, including lack of expression specificity and loss of transgene expression due to the body's immune response. Dror Harats and colleagues, from the Sheba Medical Center, have overcome these two obstacles by using a modified promoter for an endothelial cell (EC) protein to drive expression of the hybrid apoptotic induction gene Fas-c (pages 10171024). The promoter confers the necessary specificity and also includes modifications to enhance expression in hypoxic and cytokine-rich microenvironments, such as those found in tumor angiogenic vessels. The transgene produces a receptor that, upon activation by TNF-_, initiates the Fas-induced apoptotic pathway. Treatment of two tumor mouse models resulted in tumor growth rate reduction and decreased tumor size. Histology revealed that EC apoptosis was largely responsible for the antitumor effects. Liver analysis further indicated the apoptotic effects were specific to ECs, and the EC-expression restriction of apoptosis enhanced
Contact: Laurie Goodman
Journal of Clinical Investigation