Targeting Tie2 in the Tumor Microenvironment: From Angiogenesis to Dissemination

Abstract

The Tie2 receptor tyrosine kinase is expressed in vascular endothelial cells, tumor-associated macrophages, and tumor cells and has been a major focus of research in therapies targeting the tumor microenvironment. The most extensively studied Tie2 ligands are Angiopoietin 1 and 2 (Ang1, Ang2). Ang1 plays a critical role in vessel maturation, endothelial cell migration, and survival. Ang2, depending on the context, may function to disrupt connections between the endothelial cells and perivascular cells, promoting vascular regression. However, in the presence of VEGF-A, Ang2 instead promotes angiogenesis. Tie2-expressing macrophages play a critical role in both tumor angiogenesis and the dissemination of tumor cells from the primary tumor to secondary sites. Therefore, Ang-Tie2 signaling functions as an angiogenic switch during tumor progression and metastasis. Here we review the recent advances and complexities of targeting Tie2 signaling in the tumor microenvironment as a possible anti-angiogenic, and anti-metastatic, therapy and describe its use in combination with chemotherapy.

Novel Drugs with High Efficacy against Tumor Angiogenesis

“…Hypoxia also upregulates Tie2 expression in human tumors [101]. The receptor tyrosine kinases (RTKs) Tie1 and Tie2 were discovered by screening endothelial cells (ECs) for expressed tyrosine kinases [102,103]. Gene targeting studies show that the Ang-Tie2 system plays a critical role during vascular remodeling and maturation and stabilization of the cardiovascular system [104,105].…”

“…Following Tie2 activation, FOXO-1 is phosphorylated and inactivated, thereby, promoting EC quiescence, survival and vascular stabilization [112]. In addition, phosphorylation of Tie2 also prevents NF-κB signaling activation [102] (Figure 2). Tie2 receptors regulate downstream signaling pathways, such as PI3K/AKT, MAPK)/ERK (also known as Ras/Raf/MEK/ERK), Survivin, and eNOS, and inhibits Caspase-9 and Bad, among others.…”

“…It also can promote the development and metastasis of tumors by inducing the production of endothelial cell proteases and MMP-2 [117,118]. Under these conditions, the FOXO-1 transcription factor is activated and promotes the transcription of Ang2 mRNA, further promoting vascular destabilization [102]. In addition, the produced Ang2 protein will continue to be stored in the WBP, ready to be released into the extracellular matrix upon the detection of inflammatory signals [119].…”

Stachybotrys chartarum—A Hidden Treasure: Secondary Metabolites, Bioactivities, and Biotechnological Relevance

“…Angiogenesis is a complicated multicellular process in which specified receptors and their ligands have a considerable role. It was reported that Tie2 receptor (tyrosine kinase receptor) and its ligands have an important function in angiogenesis [ 77 , 115 ].…”

Emerging Roles of Immune Cells in Cancer Development and Progression

“…Duran et al present an elegant review of the complex effects the Ang–Tie2 signaling axis has in the context of reciprocal interactions among endothelial cells, immune cells, and tumor cells. The authors conclude that this signaling axis is a critical milestone in designing therapies to improve the survival of patients with metastatic disease [ 8 ].…”