Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis

Abstract

The shaping of new blood vessels is a significant event in cancer growth and metastasis. Therefore, the molecular system of cancer angiogenesis has garnered considerable interest in cancer research. The vascular endothelial growth factor (VEGF) and VEGF receptor pathway are recognized as the key regulators of the angiogenic process. Activation of the VEGF/VEGF-receptor pathway initiates signaling cascades that promote endothelial cell growth, migration, and differentiation. Recently, VEGF was shown to play a role in the recruitment of bone marrow-derived endothelial progenitor cells to neovascularization sites. The role of VEGF in promoting tumor angiogenesis and the occurrence of human cancers has led to the rational design and development of agents that selectively target this pathway. Moreover, these anti-VEGF/VEGF receptor agents show therapeutic potential by inhibition of angiogenesis and tumor growth in preclinical models. In this review, we summarize the role of the VEGF pathway during tumor angiogenesis.

Keywords: Angiogenesis inhibitors; Cell hypoxia; Tumor microenvironment; Vascular endothelial growth factor receptors.

Fig. 1. VEGF/VEGFR induces tumor angiogenesis with endothelial cells. When hypoxic stress occurs in tumor cells, transcription of hypoxia-inducible factor (HIF)-1α is activated, which promotes VEGF expression. The secreted VEGF binds to the VEGFR on the surface of endothelial cells, and increases MMP expression in tumor cells. As a result, tumor angiogenesis is increased leading to endothelial cell growth, proliferation, and migration. VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; MMP, matrix metalloproteinase; ECM, extracellular matrix.

Fig. 2. Role of the VEGFRs. VEGFR-1 and -2 are expressed on the cell surface of most blood endothelial cells. By contrast, VEGFR-3 is mostly expressed on lymphatic endothelial cells. VEGFR-1 binds to VEGF-B and PGF, and functions as a positive-angiogenesis regulator. VEGFR-2 binds to VEGF-A, and mostly has a proangiogenesis effect such as by increasing microvascular permeability, endothelial cell proliferation and migration, and invasion.VEGFR-3 binds to VEGF-C and -D, and has a similar function to VEGFR-2, but is expressed in different endothelial cells. VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; PGF, placental growth factor.