Genes upregulated in prostate cancer reactive stroma promote prostate cancer progression in vivo.
Genes upregulated in prostate cancer reactive stroma promote prostate cancer progression in vivo.
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DOI：
10.1158/1078-0432.ccr-13-1184
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Ittmann M
中科院分区：
文献类型：
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作者：
Dakhova O;Rowley D;Ittmann M
明显的反应性间质形成与临床上局限性前列腺癌的不良预后相关。我们之前已经确定了在反应性基质中上调的具有不同功能的基因。本研究验证了基质细胞中这些基因的表达在体内促进前列腺癌生长的假设。采用RT-PCR和Q-RT-PCR检测前列腺基质细胞株中反应性基质基因的表达。使用shrna的稳定表达敲除基因，并使用差异反应性基质（DRS）系统评估对肿瘤发生的影响，其中前列腺基质细胞系与LNCaP前列腺癌细胞混合，并作为皮下异种移植物评估生长。10个反应性基质基因中有9个在一个或多个前列腺基质细胞系中表达。在DRS模型中，c-Kit、Wnt10B、Bmi1、Gli2或COMP基因敲低均导致肿瘤发生减少。在所分析的所有肿瘤中，LNCaP细胞的血管生成减少，增殖和凋亡受到不同程度的影响。在其他组织类型中，Wnt10B与干细胞/祖细胞表型相关。使用RT-PCR阵列，我们检测到Wnt10B敲低的细胞中涉及干细胞/祖细胞生物学的多个基因（如OCT4和LIF）以及细胞因子（如VEGFA， BDNF和CSF2）的下调。这些发现表明，在前列腺癌反应性基质中上调的基因在前列腺基质细胞中表达时，会促进进展。此外，这些数据表明DRS模型概括了前列腺癌中癌细胞/反应性基质相互作用的关键方面。
Marked reactive stroma formation is associated with poor outcome in clinically localized prostate cancer. We have previously identified genes with diverse functions that are upregulated in reactive stroma. This study tests the hypothesis that expression of these genes in stromal cells enhances prostate cancer growth in vivo. The expression of reactive stroma genes in prostate stromal cell lines was evaluated by RT-PCR and Q-RT-PCR. Genes were knocked down using stable expression of shRNAs and the impact on tumorigenesis assessed using the differential reactive stroma (DRS) system, in which prostate stromal cell lines are mixed with LNCaP prostate cancer cells and growth as subcutaneous xenografts assessed. Nine of 10 reactive stroma genes tested were expressed in one or more prostate stromal cell lines. Gene knockdown of c-Kit, Wnt10B, Bmi1, Gli2 or COMP all resulted in decreased tumorigenesis in the DRS model. In all tumors analyzed, angiogenesis was decreased and there were variable effects on proliferation and apoptosis in the LNCaP cells. Wnt10B has been associated with stem/progenitor cell phenotype in other tissue types. Using a RT-PCR array, we detected downregulation of multiple genes involved in stem/progenitor cell biology such as OCT4 and LIF as well as cytokines such as VEGFA, BDNF and CSF2 in cells with Wnt10B knockdown. These findings show that genes upregulated in prostate cancer reactive stroma promote progression when expressed in prostate stromal cells. Moreover, these data indicate that the DRS model recapitulates key aspects of cancer cell/reactive stroma interactions in prostate cancer.