Regulation of the expression of the VEGF/VPS and its receptors: role in tumor angiogenesis.

Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPS) plays a crucial role for the vascularization of tumors including breast cancers. Tumors produce ample amounts of VEGF, which stimulates the proliferation and migration of endothelial cells (ECs), thereby inducing tumor vascularization by a paracrine mechanism. VEGF receptors (VEGF-Rs) are highly expressed by the ECs in tumor blood vessels. VEGF expression can be induced in various cell types by a number of stimuli including hypoxia, differentiation, growth factors and tumor promoters of the phorbol ester class, such as TPA. The VEGF inductive pathways comprise kinases, oncogenes, tumor suppressor genes, and steroid hormone transcription factors, many of which seem to converge on the activator protein (AP-1) transcription factor. Much less is known about the regulation of VEGF-R expression, which is restricted to ECs. This expression is greatly enhanced in diseased tissue such as solid tumors. So far, it appears that growth factors, cytokines, and tumor promoters are involved in the control of VEGF-R expression. Here we review current knowledge about the regulation of the expression of VEGF and its receptors.