Targeting Tie2 in the Tumor Microenvironment: From Angiogenesis to Dissemination

SIMPLE SUMMARY: The 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. 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.