Angiogenic signaling aberrantly induced by tumor hypoxia
Keizo Takenaga
Department of Life Science, Shimane University Faculty of Medicine, 89-1 Enya, Izumo 693-8501, Japan
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 2. Introduction
- 3. Hypoxia-responsive transcription factors involved in tumor angiogenesis
- 3.1. Hypoxia-inducible factor (HIF)
- 3.2. Nuclear factor-kappaB (NF-kappaB)
- 3.3. Other hypoxia-responsive transcription factors
- 4. Regulation of tumor angiogenesis-related molecules by hypoxia
- 4.1. Proangiogenic factors and mediators
- 4.1.1. Vascular endothelial growth factor (VEGF)
- 4.1.2. Angiopoietin-2 (Ang-2)
- 4.1.3. Platelet-derived growth factor B (PDGF-B)
- 4.1.4. Placental growth factor (PlGF)
- 4.1.5. Basic fibroblast growth factor (bFGF)
- 4.1.6. Stem cell factor (SCF)
- 4.1.7. Osteopontin (OPN)
- 4.1.8. Adrenomedullin (AM)
- 4.1.9. Endothelin (ET)
- 4.1.10. Semaphorin 4D (Sema4D)
- 4.1.11. Cyclooxygenase-2 (COX-2)
- 4.1.12. Matrix metalloproteinases (MMPs)
- 4.1.13. Plasminogen activator inhibitor-1 (PAI-1)
- 4.1.14. Nitric oxide synthases (NOS)
- 4.1.15. Endosialin
- 4.1.16. Adenosine A2A receptor
- 4.1.17. Oxygen-regulated protein-150 (Orp150)
- 4.2. Chemokines
- 4.2.1. Stromal-derived growth factor 1 (SDF-1)
- 4.2.2. Interleukin-8 (IL-8)
- 4.2.3. Chemokine (C-C motif) ligand 11 (CCL11)
- 4.2.4. Endothelial-monocyte-activating polypeptide II (EMAP II)
- 4.3. Antiangiogenic factors and mediators
- 4.3.1. VEGFxxxb
- 4.3.2. Delta-like ligand 4 (Dll4)
- 4.3.3. Vasohibins
- 4.3.4. Thrombospondin-1 (TSP-1)
- 4.3.5. Regulator of G protein signaling 5 (RGS5)
- 5. Bone marrow-derived cells mobilized and recruited to tumors
- 5.1. Myeloid lineage cells
- 5.1.1. Tumor-associated macrophages (TAMs)
- 5.1.2. Tie2-expressing monocytes (TEMs)
- 5.1.3. VEGFR1+ hemangiocytes
- 5.2. Endothelial progenitor cells (EPCs)
6. HIF inhibitors as antiangiogenesis and anticancer agents
7. Summary and Perspective
8. Acknowledgments
9. References
1. ABSTRACT
Tumor growth, invasion and metastasis are largely dependent on the development of tumor vasculature. A great number of pro- and antiangiogenic molecules, have been identified. Bone marrow-derived cells are mobilized and recruited to angiogenic sites, by a variety of growth factors and cytokines, to promote angiogenesis and the formation of new blood vessels. The hypoxic microenvironment that is inevitably generated in solid tumors is a major contributor to tumor angiogenesis. Tumor hypoxia aberrantly modulates the expression of many potent pro- and antiangiogenic molecules, primarily through the action of heterodimeric transcription factors termed hypoxia-inducible factors, HIF-1 and HIF-2. The disruption of the balance between pro- and antiangiogenic activities eventually leads to a shift in balance to a more angiogenic state. These findings have provoked considerable interest in HIFs as attractive targets for cancer therapy. Consequently, the development of small molecule HIF inhibitors is currently moving ahead at a fast pace.
