Inhibition of angiogenesis and breast cancer xenograft tumor growth by vegi, a novel cytokine of the tnf superfamily

Abstract

Recently, we reported a novel protein of the tumor necrosis factor (TNF) superfamily, named vascular endothelial cell growth inhibitor (VEGI), which is expressed predominantly in endothelial cells. When a secreted form of this new protein was overexpressed in mouse colon cancer cells, the growth of tumors formed by these cells in black mice was inhibited. We now report that recombinant VEGI inhibits the proliferation of endothelial cells but not that of other types of cells examined. The protein also inhibits formation of capillary‐like structures by endothelial cells in collagen gels, and the growth of capillaries into collagen gels placed on the chick chorioallantoic membrane. The anticancer potential of VEGI was examined in a breast cancer xenograft tumor model in which the cancer cells were co‐injected with Chinese hamster ovary cells overexpressing a secreted form of the protein. The co‐injection resulted in potent inhibition of xenograft tumor growth. Our findings are consistent with the view that VEGI is an endothelial cell‐specific negative regulator of angiogenesis. Int. J. Cancer 82:131–136, 1999. © 1999 Wiley‐Liss, Inc.

VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth

“…We reported previously that VEGI is a specific inhibitor of endothelial cell growth in vitro and a potent inhibitor of blood vessel growth with angiogenesis models, including the chicken chorioallantoic membrane angiogenesis model (4) and the Matrigel implant model (5). We show here that VEGI treatment of the tumor-bearing mice results in a specific elimination of endothelial cells in tumors.…”

“…We previously reported the discovery of an endothelial cellspecific gene product, vascular endothelial cell growth inhibitor (VEGI, TNFSF15), which exhibits 20% to 30% sequence homology to the tumor necrosis factor superfamily (4,5). VEGI mRNA was found in many normal adult tissues, suggesting a physiologic role for this unique gene in the maintenance of the normal vasculature (6).…”

“…The initially reported VEGI protein is composed of 174 amino acids (4,5). Hydrophobic analysis predicted VEGI-174 to be a type II transmembrane protein, similar to most tumor necrosis factor (TNF) family members (8).…”

“…Hydrophobic analysis predicted VEGI-174 to be a type II transmembrane protein, similar to most tumor necrosis factor (TNF) family members (8). Recombinant VEGI comprising only the putative extracellular domain exhibited effective inhibition of endothelial cell growth but had no effect on the proliferation of breast tumor cells or smooth muscle cells (4). Full-length VEGI-174 was found, however, to have no effect on tumor growth when overexpressed in cancer cells (5), whereas a secretable fusion protein (sVEGI) comprising a secretion signal peptide and the putative extracellular domain of VEGI-174 inhibited tumor growth when overexpressed in cancer cells (5).…”

VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis

“…Vascular endothelial cell growth inhibitor (VEGI) is a multifunctional gene that belongs to the tumor necrosis factor (TNF) superfamily (TNFSF15), and is expressed predominantly in endothelial cells [6]. Recombinant VEGI exhibits two distinctly different activities on endothelial cells: early G1 arrest of G0/G1-cells responding to growth stimuli and programmed death of proliferating cells [7], but it does not affect the growth of nonendothelial cells such as human vascular smooth muscle cells and human breast cancer cell line, MDA-MB-231 [8]. One of three identified VEGI isoforms, VEGI-251 (also known as TL1A), of which the NH 2 terminus contains a secretion signal peptide, functions as an autocrine cytokine to stabilize the vasculature [9].…”