Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate.
Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate.
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DOI：
10.1038/onc.2011.312
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Thomson, A. A.
中科院分区：
文献类型：
--
作者：
Orr, B.;Riddick, A. C. P.;Stewart, G. D.;Anderson, R. A.;Franco, O. E.;Hayward, S. W.;Thomson, A. A.
关键词：
基质微环境在前列腺发育和癌症中起着关键作用，癌症相关成纤维细胞（CAFs）通过多种机制刺激肿瘤发生，包括促肿瘤因子的表达。间充质（胚胎间质）控制前列腺器官发生，在某些情况下可以重新分化前列腺肿瘤。我们将下一代标签分析应用于胎儿人前列腺、正常人前列腺成纤维细胞（NPFs）和CAFs，以鉴定前列腺基质中表达的分子。比较患者配对的一对NPFs与CAFs的基因表达谱，发现671个转录本在CAFs中富集，356个转录本的水平相对于NPFs降低。基因本体论分析显示，富含caf1的转录本与前列腺形态发生有关，而缺乏caf1的转录本与细胞周期有关。我们通过将我们的数据集与已发表的前列腺癌成纤维细胞微阵列谱进行比较，以及关注编码分泌和外周膜蛋白的转录本，以及我们小组先前研究中鉴定的间充质转录本，选择mrna进行随访。我们利用qrt - pcr技术证实了CAFs和NPFs之间的转录物表达差异，并利用免疫组化技术确定了胎儿前列腺、成人前列腺和前列腺癌中caf和NPFs的蛋白定位。我们发现ASPN、CAV1、CFH、CTSK、DCN、FBLN1、FHL1、FN、NKTR、OGN、PARVA、S100A6、SPARC、STC1和ZEB1蛋白在人胎儿前列腺和前列腺癌中具有特异性和不同的表达模式。共定位研究表明，一些间质表达分子也在肿瘤上皮亚群中表达，表明它们可能是EMT的新标志物。此外，两个分子（ASPN和STC1）标记与肿瘤上皮相关的基质重叠和不同的亚区，可能代表新的CAF标志物。
The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers.
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