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Identification of SFRP1 as a Candidate Mediator of Stromal-to-Epithelial Signaling in Prostate Cancer

¹ Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota; ² Biogen Idec, Inc., Cambridge, Massachusetts; ³ Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland; ⁴ Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and ⁵ Departments of Urology and Anatomy, University of California-San Francisco, San Francisco, California

Requests for reprints: Paul C. Marker, University of Minnesota Cancer Center, MMC 806, 420 Delaware Street Southeast, Minneapolis, MN 55455. Phone: 612-625-4191; Fax: 612-626-4915; E-mail: marke032{at}umn.edu.

Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normal-derived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/ß-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells.

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