title: 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: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors: Lihong
authors: L
authors: Xu
authors: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors: Janine
authors: J
authors: Stevens
authors: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health, Frederick, MD 21702, USA. Basic Research Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Mary Beth
authors: MB
authors: Hilton
authors: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors: Steven
authors: S
authors: Seaman
authors: Laboratory of Proteomics and Analytical Technologies, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Thomas P
authors: TP
authors: Conrads
authors: Laboratory of Proteomics and Analytical Technologies, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Timothy D
authors: TD
authors: Veenstra
authors: Basic Research Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Daniel
authors: D
authors: Logsdon
authors: Transgenic Core Facility, MCGP, NCI, Frederick, MD 21702, USA.
authors: Holly
authors: H
authors: Morris
authors: Transgenic Core Facility, MCGP, NCI, Frederick, MD 21702, USA.
authors: Deborah A
authors: DA
authors: Swing
authors: Small Animal Imaging Program/LASP, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Nimit L
authors: NL
authors: Patel
authors: Small Animal Imaging Program/LASP, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Joseph
authors: J
authors: Kalen
authors: Pathology/Histotechnology Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Diana C
authors: DC
authors: Haines
authors: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors: Enrique
authors: E
authors: Zudaire
authors: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health, Frederick, MD 21702, USA. stcroix@ncifcrf.gov.
authors: Brad
authors: B
authors: St Croix
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000077784:Axitinib; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D002999:Clone Cells; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D020360:Neoadjuvant Therapy; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D007191:Indazoles; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone