The Human Cytomegalovirus―Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 7; pp. 2861 - 2869
• Main Authors: MAUSSANG, David, LANGEMEIJER, Ellen, VAN DONGEN, Guus A. M. S, LEURS, Rob, SMIT, Martine J, FITZSIMONS, Carlos P, STIGTER-VAN WALSUM, Marijke, DIJKMAN, Remco, BORG, Martin K, SLINGER, Erik, SCHREIBER, Andreas, MICHEL, Detlef, TENSEN, Cornelis P
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2009
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Celecoxib; Cell Line; Cell Transformation, Viral - genetics; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cytomegalovirus - genetics; Cytomegalovirus - metabolism; Enzyme Induction; Humans; Medical sciences; Mice; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; NIH 3T3 Cells; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Pyrazoles - pharmacology; Receptors, Chemokine - biosynthesis; Receptors, Chemokine - genetics; Sulfonamides - pharmacology; Transcription, Genetic; Transfection; Tumors; Up-Regulation; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; Viral Proteins - biosynthesis; Viral Proteins - genetics; Virus; Angiogenesis; Enzyme; Herpesviridae; Cyclooxygenase 2; Chemokine receptor; Tumorigenicity; Oxidoreductases; Neovascularization; Betaherpesvirinae; Carcinogenesis; Human cytomegalovirus
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-2487

The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes the constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-kappaB, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2. Finally, the involvement of COX-2 in US28-mediated tumor formation was evaluated using the COX-2 selective inhibitor Celecoxib. Targeting COX-2 in vivo with Celecoxib led to a marked delay in the onset of tumor formation in nude mice injected with US28-transfected NIH-3T3 cells and a reduction of subsequent growth by repressing the US28-induced angiogenic activity. Hence, the development of HCMV-related proliferative diseases may partially be ascribed to the ability of US28 to activate COX-2.