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.
Highlights
Vasculogenesis refers to the process by which vascular endothelial cells differentiate from endothelial precursor cells to form the lumen
Long-term administration of angiogenesis inhibitors induces hypoxia in the tumor microenvironment by over-pruning blood vessels and up-regulates HIF-1α [88]. Angiogenesis promoting factors, such as P1GF, vascular endothelial growth factor (VEGF), Ang-1, and fibroblast growth factor (FGF), which are induced by HIF-1α, recruit bone marrow-derived dendritic cells (BMDCs) that mediate the growth of new blood vessels to support tumors
We have discussed the mechanism of tumor angiogenesis as well as antiangiogenic therapy from the perspective of the tumor microenvironment
Summary
Vasculogenesis refers to the process by which vascular endothelial cells differentiate from endothelial precursor cells to form the lumen. Neovascularization refers to the process, whereby new blood vessels are formed from existing ones following endothelial cell proliferation and migration [1]. This process is essential during physiological angiogenesis, such as systemic blood supply in the fetal stage, luteinization related to postpartum menstrual cycle, and wound healing [2]. Tumors located >100–200 μm from capillaries often encounter hypoxic conditions, which promote the expression of hypoxia-inducible factor-1 (HIF-1). Tortuous and dilated tumor vessels show increased vascular permeability and high interstitial pressure, further reducing blood perfusion and increasing hypoxic conditions in the tumor microenvironment [7,8,9]. This review discusses the molecular mechanisms of tumor angiogenesis and outlines options for cancer therapy with antiangiogenic agents including combined immunotherapy
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