Host cyclooxygenase-2 modulates carcinoma growth

C Williams

M Tsujii

J Reese

S Dey

R DuBois

^{Department of Medicine,}^{Department of Cell Biology, and}^{The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA}^{Department of Medicine, Osaka University School of Medicine, Osaka, Japan}^{Department of Pediatrics, and}^{Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA}^{Veterans Affairs Medical Center, Nashville, Tennessee, USA}

Address correspondence to: Raymond N. DuBois, Department of Medicine/Gastroenterology; Medical Center North C-2104, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232-2279, USA. Phone: (615) 343-4747; Fax: (615) 343-6229; E-mail: ude.tlibrednav.liamcm@siobud.dnomyar.

Received 2000 Feb 15; Accepted 2000 Apr 12.

Abstract

Cyclooxygenase-2 (COX-2; Ptgs2) acts as a tumor promoter in rodent models for colorectal cancer, but its precise role in carcinogenesis remains unclear. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacological approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid tumors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2^–/–, but not COX-1^–/– or wild-type mice. Treatment of wild-type C57BL/6 mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2^–/– mice when compared with those in wild-type mice. Because COX-2 is expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2^–/– mouse fibroblasts and found a 94% reduction in their ability to produce the proangiogenic factor, VEGF. Additionally, treatment of wild-type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%.

Abstract

Acknowledgments

This work was supported in part by United States Public Health Services grants (DK 47297, P01CA77839, and P30 CA68485, to R.N. DuBois). R.N. DuBois is a recipient of a Veterans Affairs Research Merit Grant, and S.K. Dey is a recipient of an NICHD MERIT Award (HD 12304). We thank the T.J. Martell Foundation for their generous support. Thanks are due to Y. Zhu and N. Brown for genotyping of mice, and X. Zhao for in situ hybridization. We also thank Kay Washington for examining the histology of the tumors and Wade Krause for assistance with in vivo studies.

Acknowledgments

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