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Published online 27 March 2006 doi:10.1084/jem.20052124
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 941-951
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ARTICLE

 CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer

Dingzhi Wang1, Haibin Wang2, Joanne Brown1, Takiko Daikoku2, Wei Ning1, Qiong Shi1, Ann Richmond3, Robert Strieter6, Sudhansu K. Dey2,3,4,5, and Raymond N. DuBois1,3,4,5

1 Department of Medicine, 2 Department of Pediatrics, 3 Department of Cancer Biology, 4 Department of Cell and Developmental Biology and Pharmacology, and 5 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 6 Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095

CORRESPONDENCE Raymond N. DuBois: raymond.dubois{at}vanderbilt.edu

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene {alpha}), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.

Abbreviations used: BLMVEC, bovine lung microvascular endothelial cell; COX-2, cyclooxygenase-2; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; GRO, growth-regulated oncogene; MAPK, mitogen-activated protein kinase; MIP, macrophage inflammatory protein; PGE2, prostaglandin E2; VEGF, vascular endothelial growth factor.


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