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Suppression of Prostate Tumor Cell Growth by Stromal Cell Prostaglandin D Synthase–Derived Products

Departments of ¹ Genitourinary Medical Oncology, ² Experimental Therapeutics, and ³ Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: David G. Menter, Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Box 1360, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-0626; Fax: 713-794-4403; E-mail: dmenter{at}mdanderson.org.

Stromal-epithelial interactions and the bioactive molecules produced by these interactions maintain tissue homeostasis and influence carcinogenesis. Bioactive prostaglandins produced by prostaglandin synthases and secreted by the prostate into seminal plasma are thought to support reproduction, but their endogenous effects on cancer formation remain unresolved. No studies to date have examined prostaglandin enzyme production or prostaglandin metabolism in normal prostate stromal cells. Our results show that lipocalin-type prostaglandin D synthase (L-PGDS) and prostaglandin D₂ (PGD₂) metabolites produced by normal prostate stromal cells inhibited tumor cell growth through a peroxisome proliferator–activated receptor (PPAR)–dependent mechanism. Enzymatic products of stromal cell L-PGDS included high levels of PGD₂ and 15-deoxy-^12,14-PGD₂ but low levels of 15-deoxy-^12,14-prostaglandin J₂. These PGD₂ metabolites activated the PPAR ligand-binding domain and the peroxisome proliferator response element reporter systems. Thus, growth suppression of PPAR-expressing tumor cells by PGD₂ metabolites in the prostate microenvironment is likely to be an endogenous mechanism involved in tumor suppression that potentially contributes to the indolence and long latency period of this disease.