COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models.

Abstract

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.

• Authors: Lihong Xu, Janine Stevens, Mary Beth Hilton, Steven Seaman, Thomas P Conrads, Timothy D Veenstra, Daniel Logsdon, Holly Morris, Deborah A Swing, Nimit L Patel, Joseph Kalen, Diana C Haines, Enrique Zudaire, Brad St Croix
• Journal: Science translational medicine (Sci Transl Med) Vol. 6 Issue 242 Pg. 242ra84 (Jun 25 2014) ISSN: 1946-6242 [Electronic] United States
• PMID: 24964992 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2014, American Association for the Advancement of Science.

Chemical References

• Angiogenesis Inhibitors
• Cyclooxygenase 2 Inhibitors
• Imidazoles
• Indazoles
• Vascular Endothelial Growth Factor A
• Axitinib
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Dinoprostone

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Axitinib
• Carcinogenesis (pathology)
• Cell Line, Tumor
• Clone Cells
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology, therapeutic use)
• Dinoprostone (metabolism)
• Female
• Humans
• Imidazoles (pharmacology)
• Indazoles (pharmacology)
• Liver Neoplasms (blood supply, drug therapy, prevention & control, secondary)
• Mammary Neoplasms, Experimental (blood supply, drug therapy, prevention & control, secondary)
• Mice
• Neoadjuvant Therapy
• Signal Transduction (drug effects)
• Survival Analysis
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays