Tumor Neovascularization and Developments in Therapeutics

Abstract

Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents.

Keywords: angiogenesis; cancer therapy; neovascularization; tumor microenvironment.

Figure 1

Hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) link the angiogenesis signaling pathways. Low oxygen tension (hypoxia) results in constitutive activation of the HIF pathway and VEGF. The tumor hypoxic environment leads to an immunosuppressive tumor microenvironment by inducing regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). Antiangiogenic therapy results in blood vessel regression by suppression of neovascularization, leading to tumor starvation and tumors falling into dormant states. CAFs, cancer-associated fibroblasts; iDCs, immature dendritic cells; mDCs, mature dendritic cells; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1.

Figure 2

Vascular endothelial growth factor (VEGF) binds to the VEGF receptor, a receptor tyrosine kinase, leading to receptor dimerization and subsequent auto phosphorylation of the receptor complex. The phosphorylated receptor then interacts with a variety of cytoplasmic signaling molecules, leading to signal transduction and eventually angiogenesis. Examples of clinical drugs (Table 2) that inhibit the pathway are shown. PI3K, phosphoinositide-3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; MEK, MAPK/ERK kinase; ERK, extracellular signal-regulated kinase.