Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy

Abstract

Vascular normalization is a new concept of targeting angiogenesis to restore vessel structure and function and to increase blood perfusion and delivery of drugs. It has been confirmed that vascular normalization can decrease relapse and benefit other cancer therapy, including chemotherapy, radiotherapy, and immune cell therapy. The key point of this therapy is to inhibit pro-angiogenic factors and make it be balanced with anti-angiogenic factors, resulting in a mature and normal vessel characteristic. Vascular endothelial growth factor (VEGF) is a key player in the process of tumor angiogenesis, and inhibiting VEGF is a primary approach to tumor vessel normalization. Herein, we review newly uncovered mechanisms governing angiogenesis and vascular normalization of cancer and place emphasis on targeting VEGF pathway to normalize the vasculature. Also, important methods to depress VEGF pathway and make tumor vascular are discussed.

Keywords: anti-angiogenesis; cancer therapy; treatment resistance; vascular endothelial growth factor; vascular normalization.

Figure 1

Effects of HIF-1α, STAT3, NO, and miRNA in VEGF expression. Notes: STAT3 and HIF-1α promote VEGF expression. miRNA has positive or negative effect on VEGF expression. NO released by eNOS in endothelial cells form organized NO gradient around vessels. NO released by iNOS and nNOS in tumor cells disturb the NO gradient. Abbreviations: HIF-1α, hypoxia-inducible factor 1α; NO, nitric oxide; VEGF, vascular endothelial growth factor; STAT3, Signal transducer and activation of transcription 3; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase.