Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis
Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis
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DOI：
10.1158/0008-5472.can-07-6817
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Nelson, Peter S.
中科院分区：
文献类型：
--
作者：
Pritchard, Colin;Mecham, Brig;Nelson, Peter S.
以胚胎发生和癌发生交叉为中心的研究已经发现了涉及调节发育和肿瘤过程的信号通路的惊人相似之处。在前列腺中，已知上皮和间质之间的相互作用会影响肿瘤形成，并通过泌尿生殖窦间充质发挥形态发生作用。在这项研究中，我们试图确定正常前列腺发育和前列腺癌发生之间的分子关系。我们首先描述了与小鼠前列腺器官发生的关键点相关的基因表达程序，跨越前列腺萌芽的初始子宫内诱导直至成熟。我们确定了一种高度可重复的基因表达时间程序，该程序根据前列腺诱导、分支形态发生和分泌分化的广泛发育阶段进行划分。对 Pten 肿瘤抑制基因和 Myc 癌基因的基因工程改变背景下产生的小鼠前列腺癌的基因表达谱进行比较，发现分支形态发生谱与两种癌症模型之间存在显着关联。此外，包含分支形态发生程序的基因（例如 PRDX4、SLC43A1 和 DNMT3A）的表达在人类肿瘤性前列腺上皮中显着改变。这些结果表明，正常发育过程的组成部分在前列腺肿瘤中活跃，并为利用器官发生的分子特征来了解癌症表型提供了进一步的理论依据。 [癌症研究 2009;69(5):1739-47]
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. [Cancer Res 2009;69(5):1739-47]