Anticancer Therapeutic Potential of VEGI, an Antiangiogenic Cytokine
Abstract
Vascular endothelial cell growth inhibitor (VEGI), a member of the TNF family, is an endothelial cell-specific inhibitor of angiogenesis. Overexpression by cancer cells of a secretable VEGI fusion protein resulted in abrogation of xenograft tumor progression, but overexpression of full-length VEGI was completely without effect. This finding indicates that secretion is essential for VEGI action. Here we report the identification of two new VEGI isoforms consisting of 251 and 192 amino acid residues. Both isoforms show endothelial cell-specific expression and share a C-terminal 151-residues segment with the previously described VEGI, which comprises 174 residues. The isoforms are generated from a 17 kb human gene by alternative splicing. Their expression is regulated by TNF-alpha and interferon-gamma. VEGI-25l, the most abundant isoform, contains a putative secretion signal. VEGI protein is detected in conditioned media of endothelial cells and VEGI-25l- transfected mammalian cells. Overexpression of VEGI-25l in endothelial cells causes dose- dependent cell death. VEGI-25l-transfected cancer cells form xenograft tumors of reduced growth rate and microvessel density compared with tumors of empty vector transfectants. These findings support the view that VEGI may function as an autocrine inhibitor of angiogenesis and a naturally existing modulator of vascular homeostasis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2002
- Accession Number
- ADA410262
Entities
People
- Luyuan Li
Organizations
- Georgetown University