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Stromal-epithelial signaling is known to play an important role in prostate development and prostate cancer, but studies of the molecular interactions involved in these processes have been stymied by the lack of suitable prostate stromal cell lines. We have isolated a genetically stable, non-carcinogenic, contact-inhibited, immortalized prostate mesenchymal cell line from the mouse E16 urogenital sinus. The UGSM-2 cell line expresses vimentin and smooth muscle actin, but not the mature smooth muscle markers heavy chain myosin and desmin, indicating a myofibroblast phenotype. UGSM-2 cells express androgen receptor mRNA and androgen stimulation increases their proliferation. UGSM-2 cells mimic the response of E16 urogenital sinus mesenchyme by activating transcription of Shh target genes Gli1, Ptc1, and IGFBP-6 when stimulated with Shh peptide. We are using this cell line to model the stromal response to Sonic hedgehog (Shh) in prostate tumor growth. Shh is a paracrine factor involved in development of many organs including the prostate. Recently, we and others have found that Shh signaling drives prostate tumor growth. Shh signaling appears to stimulate growth of prostate xenograft tumors by inducing stromal genes which stimulate tumor cell proliferation. To investigate the mechanisms involved, we are utilizing co-cultures and xenografts of UGSM-2 cells combined with the human tumor cell line LNCaP. When UGSM-2 cells are co-injected with LNCaP to form subcutaneous tumors, UGSM-2 cells take up residence in the xenograft tumor stroma. Xenografts generated with LNCaP tumor cells overexpressing Shh (LN-Shh) exhibit a faster growth rate than tumors generated with parent LNCaP and UGSM-2. Shh-induced paracrine mediated stimulation of tumor cell proliferation can be modeled in co-culture, where LN-Shh proliferate faster than the parent LNCaP only when co-cultured with UGSM-2. We will use these models to identify the stromal target genes activated by Shh and to elucidate their effect on tumor growth.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]