Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

Abstract

The development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation. Blood vessel neoformation is also important in the pathogenesis of many disorders, particularly rapid growth and metastasis of solid tumours. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-alpha and transforming factors-alpha and -beta. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosarcoma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells in vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

“…Experimental tumours transfected with VEGF can show a higher vascular density and volumetric growth rate than wild-type control tumours (Zhang et al, 1995;Potgens et al, 1996), whereas tumours initiated from cells transfected with antisense-VEGF c-DNA can show reduced vascular density and growth in vivo (Saleh et al, 1996). The neovascularization and growth of experimental tumours can be inhibited by treatment with monoclonal antibodies against VEGF (Kim et al, 1993;Asano et al, 1995;Melnyk et al, 1996). Finally, VEGF increases microvascular permeability to macromolecules, thereby leading to fibrinogen extravasation and fibrin deposition, which are important processes in tumour angiogenesis (Senger et al, 1993).…”

Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression

“…Human tumor biopsies exhibit enhanced expression of VEGF mRNAs by malignant cells and VEGF receptor mRNAs in adjacent endothelial cells (Plate et al, 1992;Weindel et al, 1994). Interference with the VEGF/VEGF receptor system either by application of anti-VEGF monoclonal antibodies to nude mice which carry VEGF-producing tumor cells, or by retrovirus-driven expression of a dominant-negative mutant of the VEGF receptor¯k-1 in tumor endothelia of such animals resulted in an almost complete inhibition of vascularization and tumor growth (Kim et al, 1993;Millauer et al, 1994).…”

A peptide corresponding to the neuropilin-1-binding site on VEGF165 induces apoptosis of neuropilin-1-expressing breast tumour cells

“…Numerous angiogenic factors have been identified to date, the most potent of these being vascular endothelial growth factor (VEGF), otherwise known as vascular permeability factor (VPF). Anti-VEGF strategies have been shown to potently inhibit tumour growth and metastasis (Kim et al, 1993;Millauer et al, 1996;Yuan et al, 1996;Xu et al, 2000).…”