ABSTRACT
During fetal prostate development, Sonic hedgehog (Shh) expression by the urogenital sinus epithelium activates Gli-1 expression in the adjacent mesenchyme and promotes outgrowth of the nascent ducts. Shh signaling is down-regulated at the conclusion of prostate ductal development. However, a survey of adult human prostate tissues reveals substantial levels of Shh signaling in normal, hyperplasic, and malignant prostate tissue. In cancer specimens, the Shh expression is localized to the tumor epithelium, whereas Gli-1 expression is localized to the tumor stroma. Tight correlation between the levels of Shh and Gli-1 expression suggests active signaling between the tissue layers. To determine whether Shh-Gli-1 signaling could be functionally important for tumor growth and progression, we performed experiments with the LNCaP xenograft tumor model and demonstrated that: 1). Shh expressed by LNCaP tumor cells activates Gli-1 expression in the tumor stroma, 2). genetically engineered Shh overexpression in LNCaP cells leads to increased tumor stromal Gli-1 expression, and 3). Shh overexpression dramatically accelerates tumor growth. These data suggest that hedgehog signaling from prostate cancer cells to the stroma can elicit the expression of paracrine signals, which promote tumor growth.
Subject(s)
Prostatic Neoplasms/pathology , Signal Transduction , Trans-Activators/physiology , Adult , Animals , Cell Line, Tumor , Hedgehog Proteins , Humans , Intracellular Signaling Peptides and Proteins , Kruppel-Like Transcription Factors , Male , Membrane Proteins , Mice , Neoplasm Transplantation , Patched Receptors , Prostatic Neoplasms/metabolism , Proteins/physiology , Receptors, Cell Surface , Trans-Activators/genetics , Transcription Factors/genetics , Transcription Factors/physiology , Transplantation, Heterologous , Zinc Finger Protein GLI1ABSTRACT
Ductal budding in the developing prostate is a testosterone-dependent event that involves signaling between the urogenital sinus epithelium (UGE) and urogenital sinus mesenchyme (UGM). We show here that ductal bud formation is associated with focused expression of Sonic hedgehog (Shh) in the epithelium of nascent prostate buds and in the growing tips of elongating prostate ducts. This pattern of localized Shh expression occurs in response to testosterone stimulation. The gene for the Shh receptor, Ptc1, is expressed in the UGM, as are the members of the Gli gene family of transcriptional regulators (Gli1, Gli2, and Gli3). Expression of Ptc1, Gli1, and Gli2 is localized primarily to mesenchyme surrounding prostate buds, whereas Gli3 is expressed diffusely throughout the UGM. A strong dependence of Gli1 (and Ptc1) expression on Shh signaling is demonstrated by induction of expression in both the intact urogenital sinus and the isolated UGM by exogenous SHH peptide. A similar dependence of Gli2 and Gli3 expression on Shh is not observed. Nonetheless, the chemical inhibitor of Shh signaling, cyclopamine, produced a graded inhibition of Gli gene expression (Gli1>Gli2>Gli3) in urogenital sinus explants that was paralleled by a severe inhibition of ductal budding.