Brain angiogenesis in developmental and pathological processes: mechanism and therapeutic intervention in brain tumors

Abstract

Formation of new blood vessels is required for the growth and metastasis of all solid tumors. New blood vessels are established in tumors mainly through angiogenesis. Brain tumors in particular are highly angiogenic. Therefore, interventions designed to prevent angiogenesis may be effective at controlling brain tumors. Indeed, many recent findings from preclinical and clinical studies of antiangiogenic therapy for brain tumors have shown that it is a promising approach to managing this deadly disease, especially when combined with other cytotoxic treatments. In this minireview, we summarize the basic characteristics of brain tumor angiogenesis and the role of known angiogenic factors in regulating this angiogenesis, which may be targets of antiangiogenic therapy. We also discuss the current status of antiangiogenic therapy for brain tumors, the suggested mechanisms of this therapy and the limitations of this strategy.

Fig. 1

Angiogenic interaction between brain tumor and endothelial cells and antiangiogenic therapy. VEGF expression is induced in tumor cells by hypoxia [19], radiation, receptor tyrosine kinase signaling, and Akt pathways [114]. VEGF and other proangiogenic factors are secreted by brain cancer cells in a paracrine and endocrine manner [83]. These factors support endothelial cell survival. Also, VEGF induces the permeability of the BBB [78]. Notch signaling mediated by γ-secretase suppresses angiogenesis but is required for proper vascular development [38-40, 44]. The signaling required for angiogenesis in brain tumors can be targeted using an antibody against VEGF[20, 68], a decoy receptor to VEGF [115], small-molecule TKIs of VEGFR[82], inhibitors of other kinases in the signaling cascade, and inhibitors of γ-secretase [85]. Ab, antibody; HGF/SF, hepatocyte growth factor/scatter factor; IR, ionizing radiation; RTK, receptor tyrosine kinase; PTEN, phosphatase and tensin homologue; PI3K, phosphatidylinositol-3 kinase; HRE, hypoxia-responsive element; ROS, reactive oxygen species; γ-Sec, γ–secretase.