[Frontiers in Bioscience 15, 195-212, January 1, 2010]

Regulation of tumor angiogenesis by the local environment

Kelly Hall, Sophia Ran

Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine and SimmonsCooper Cancer Institute, Springfield, IL, 62794-9678, USA


1. Abstract
2. Introduction
3. Mechanisms of tumor blood vessel formation
3.1. Step 1: tipping the angiogenic balance
3.1.1. Role of VEGF-A in induction of tumor angiogenesis
3.1.2. Regulation of VEGF-A expression and activity
3.2. Step 2: destabilization of pre-existing blood vessels
3.2.1. Role of angiopoietins in stabilization and destabilization of blood vessels
3.3. Step 3: blood vessel sprouting
3.3.1. Role of Notch and its ligand Delta-like 4 (Dll4) in vascular sprouting
3.4. Step 4: induction of endothelial cell (EC) migration, proliferation, and survival
3.5. Step 5: stabilization of new vessels
3.5.1. Role of PDGF factors in maturation and stabilization of new vessels
3.5.2. Role of Ang-1in regulation of vessel integrity 4. Abnormalities of tumor vessels and consequences of their malfunction for tumor growth and anti-cancer therapy 5. Anti-angiogenic therapies for the treatment of solid tumors
6. Concluding remarks
7. Acknowledgement
8. References


Angiogenesis is the process of formation of new blood vessels from pre-existing vessels or endothelial cell progenitors. It plays an essential role in embryogenesis, inflammation, wound healing, tumor growth and metastasis. The tumor microenvironment contains excessive amounts of pro-angiogenic factors derived from neoplastic, stromal, and infiltrating immune cells. The imbalance of pro-angiogenic and anti-angiogenic factors promotes abnormal angiogenesis, creating numerous blood vessels with structural abnormalities and functional defects. These defective vessels often create an inflammatory environment within the tumor that promotes coagulation, thrombosis, and impairs blood supply, causing further complications to the cancer patient. The structural and functional abnormalities of the tumor vessels promote hematogenous metastasis, which is strongly associated with shorter patient survival. Furthermore, tumor blood vessels are poorly perfused, which impedes drug delivery to the tumor, thus reducing the efficacy of anti-cancer agents. Tumor angiogenesis is widely studied as an important target for suppressing tumor growth and metastasis. This review will briefly summarize the current findings related to regulation of angiogenesis by the tumor microenvironment, while highlighting potential targets for inhibiting this process.