Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy

Abstract

Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, vascular endothelial growth factor (VEGF) was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFRs). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for ~20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently “normalize” tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest, and has led to the FDA-approval of 7 different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

“…Vascular endothelial growth factor (VEGF), also known as a vascular permeability factor, is another important protein for regulating vascular endothelium. It not only induces angiogenesis but also mediates the disruption of the vascular barrier, resulting in vascular leakage 27 . VEGF receptor-2 (VEGFR-2) phosphorylates tyrosine at the Y658 and Y731 sites of VE-cadherin by inducing SRC family kinases, leading to destabilization of adherens junctions and increased endothelial cell permeability 28 , 29 .…”

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

“…VEGF‐C and D normally regulate lymphangiogenesis, whereas VEGF‐A, B, and PlGF primarily induce angiogenesis. Different biological reactions are triggered when VEGF‐A, B, Placental Growth Factor (PlGF), and D are bound to VEGFR‐2, VEGFR‐1, and VEGFR‐3, respectively 75 . Tumor angiogenesis and proliferation increase when VEGFs activate the intrinsic MEK/ERK/RAS/Raf, PKC/PLC, and AKT/PI3K signaling pathways.…”

“…Different biological reactions are triggered when VEGF-A, B, Placental Growth Factor (PlGF), and D are bound to VEGFR-2, VEGFR-1, and VEGFR-3, respectively. 75 Tumor angiogenesis and proliferation increase when VEGFs activate the intrinsic MEK/ERK/RAS/Raf, PKC/PLC, and AKT/ PI3K signaling pathways. Among these, the VEGF-A receptors VEGFR-1 and VEGFR-2 are considered attractive targets for cancer treatment in therapeutic settings.…”

Research Progress of Anti-Angiogenic Drugs in First-Line Treatment of Small Cell Lung Cancer

“…These drugs were originally designed to "starve the tumor". However, in clinical studies, it has been found that they temporarily "normalize" tumor blood vessels [8], and increase lymphocyte infiltration and T-cell activation [9]. In addition, vascular normalization can reduce the expansion of Myeloid-Derived Suppressor Cells (MDSCs) and the proliferation and differentiation of regulatory T cells (Treg) [10], eventually leading to the transformation of an immunosuppressive state into an immune-promoting state.…”