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[Cancer Research 63, 1748-1751, April 15, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Stromal Production of Prostacyclin Confers an Antiapoptotic Effect to Colonic Epithelial Cells1

N. Shane Cutler, Ramona Graves-Deal, Bonnie J. LaFleur, Zhenqiang Gao2, Bruce M. Boman, Robert H. Whitehead, Erin Terry, Jason D. Morrow and Robert J. Coffey3

Departments of Medicine [N. S. C., R. G-D., R. H. W., R. J. C.], Cell and Developmental Biology [R. J. C.], Biostatistics [B. L.], and Pharmacology [E. T., J. D. M.], Vanderbilt University Medical Center and Department of Veterans Affairs Medical Center [R. J. C.], Nashville, Tennessee 37232-2279, and Genetic and Preventive Medicine Division, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [Z. G., B. M. B.]

The mechanism whereby cyclooxygenase-2 and its prostaglandin (PG) products are involved in colonic carcinogenesis is not fully understood. Prostacyclin (PGI2) is a major PG with antiapoptotic activity and is produced in the gastrointestinal tract. We reported previously that a human colorectal cancer (CRC) cell line, HCA-7, produces significant levels of PGE2, PGD2, thromboxane, and PGF2{alpha}, but not PGI2. We now report that human colonic fibroblast cell lines produce significant amounts of PGI2 and that fibroblast lines derived from normal-appearing colonic mucosa of hereditary nonpolyposis CRC individuals produce 50-fold more PGI2 than normal fibroblast lines derived from individuals with nonhereditary CRC. Coculture of HCA-7 cells with hereditary nonpolyposis CRC fibroblasts, but not normal fibroblasts, markedly reduced butyrate-induced apoptosis of HCA-7 cells. This antiapoptotic effect was inhibited by the cyclooxygenase-2 inhibitor rofecoxib and was restored by the stable PGI2 analogue carbaprostacyclin. PGI2 binds either G protein-coupled cell surface PGI2 receptor or the nuclear peroxisome proliferator-activated receptor (PPAR) {delta}. PPAR {delta} likely mediates this antiapoptotic effect because HCA-7 cells express this receptor, and another PPAR {delta} agonist, docosahexaenoic acid, mimics the effect. We propose a novel mechanism by which stromal production of PGI2 promotes survival of colonocytes through PPAR {delta} activation. This mechanism may have relevance to maintenance of cells in the normal crypt and to clonal expansion of mutant colonocytes during tumorigenesis.




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Copyright © 2003 by the American Association for Cancer Research.