Abstract
Studies centered at the intersection of embryogenesis and carcinogenesis have identified striking parallels involving signaling pathways that modulate both developmental and neoplastic processes. In the prostate, reciprocal interactions between epithelium and stroma are known to influence neoplasia and also exert morphogenic effects via the urogenital sinus mesenchyme. In this study, we sought to determine molecular relationships between aspects of normal prostate development and prostate carcinogenesis. We first characterized the gene expression program associated with key points of murine prostate organogenesis spanning the initial in utero induction of prostate budding through maturity. We identified a highly reproducible temporal program of gene expression that partitioned according to the broad developmental stages of prostate induction, branching morphogenesis, and secretory differentiation. Comparisons of gene expression profiles of murine prostate cancers arising in the context of genetically engineered alterations in the Pten tumor suppressor and Myc oncogene identified significant associations between the profile of branching morphogenesis and both cancer models. Further, the expression of genes comprising the branching morphogenesis program, such as PRDX4, SLC43A1, and DNMT3A, was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal developmental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organogenesis to understand cancer phenotypes.
Highlights
Studies involving normal developmental processes have revealed important parallels with carcinogenesis that involve key signaling mechanisms controlling the three-dimensional growth and organization of tissues [1, 2]
The major events of mouse prostate development can be summarized in three steps: (a) prostate induction at E17.5, (b) branching morphogenesis at E18.5 through postnatal day 15, and (c) secretory differentiation at postnatal days 25 to 45
To characterize the transcriptional program associating with these events, we profiled gene expression in the prostate or prostate precursor tissues at seven time points corresponding to key stages of prostate organogenesis: embryonic days E15.5, E16.5, E17.5, and E18.5 and postnatal days P7, P30, and P90 (Fig. 1)
Summary
Studies involving normal developmental processes have revealed important parallels with carcinogenesis that involve key signaling mechanisms controlling the three-dimensional growth and organization of tissues [1, 2]. Organogenesis is a complex process involving proliferation, pattern specification, and cellular differentiation orchestrated by an evolving transcriptional program [3]. Many highly conserved pathways instrumental in dictating ordered organ and organismal morphogenesis, originally defined in model. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Division of Human Biology, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue, Seattle, WA 98109-1024. Phone: 206-667-3377; Fax: 206-667-2917; E-mail: pnelson@ fhcrc.org
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