Targeting Tie2 in the Tumor Microenvironment: From Angiogenesis to Dissemination.

Camille L Duran,John S Condeelis,George S Karagiannis,David Entenberg,Lucia Borriello,Maja H Oktay

doi:10.3390/cancers13225730

Camille L Duran, John S Condeelis + Show 4 more

Open Access

https://doi.org/10.3390/cancers13225730

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Abstract

Simple SummaryThe dissemination of cancer cells from their original location to distant organs where they grow, a process called metastasis, causes more than 90% of cancer deaths. The identification of the molecular mechanisms of metastasis and the development of anti-metastatic therapies are essential to increase patient survival. In recent years, targeting the tumor microenvironment has become a promising avenue to prevent both tumor growth and metastasis. As the tumor microenvironment contains not only cancer cells but also blood vessels, immune cells, and other non-cancerous cells, it is naïve to think that therapy only affects a single cell type in this complex environment. Here we review the importance, and ways to inhibit the function, of one therapeutic target: the receptor Tie2. Tie2 is a receptor present on the cell surface of several cell types within the tumor microenvironment and regulates tumor angiogenesis, growth, and metastasis to distant organs.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.

Highlights

The critical role of Tie2high /VEGFhigh macrophages in TMEM doorway function was further demonstrated by the conditional ablation of macrophages in PyMT transgenic mice and by VEGF deletion in the monocyte/macrophage lineage in FVB mice; in both cases, there was a dramatic inhibition of TMEM function and, of tumor cell intravasation and metastasis formation [71,77]
Anti-angiogenic treatments such as bevacizumab and other VEGF-A pathway inhibitors have shown an initial efficacy in decreasing tumor angiogenesis and disease burden, patients rapidly develop a resistance to these agents [83,84]
We summarized the current knowledge of Tie2 signaling in several of the major cells that make up the tumor milieu and described the promising approach of targeting this signaling pathway to thwart the metastatic cascade

Summary

Introduction

The receptor tyrosine kinases (RTKs) Tie (TIE) and Tie (TEK) were discovered in the early 1990s through a screen for tyrosine kinases expressed by endothelial cells (ECs) [1,2,3,4]. Tie2-null embryos exhibit more severe phenotypes with death occurring between E9.5 and E12.5 [3,16,17] These Tie2-deficient embryos proceed through the early stages of cardiovascular development but not beyond the capillary plexus, which is poorly organized with decreased numbers of vessel branches and a severe lack of supporting smooth muscle cells and pericytes. Formation of the microvasculature during late organogenesis and postnatal hematopoiesis require both receptors [21] Taken together, these studies indicate that the Ang-Tie system is dispensable for initial vascular development, it plays an essential role in the recruitment of the supporting mural cells, vessel remodeling and maturation in the embryo, and in angiogenesis in the adult. Lethality by postnatal day P14; chylous ascites develop a few days after birth; severe vascular defects including collapsed endocardial lining from the myocardium and disruption of vascular integrity; impaired response to inflammatory challenges

Role of Ang-Tie2 in Tumor Angiogenesis

Tie2 Macrophages Regulate Tumor Angiogenesis

Tie2 Macrophages Regulate Vascular Permeably and Intravasation

Targeting Tie2 to Prevent Tumor Progression and Metastasis Formation

Role of Tie2 Expression in Cancer Cells

Conclusions