Ernst T, Hergenhahn M, Kenzelmann M, Cohen C D, Ikinger U, Kretzler M, Hollstein M, Gröne H J
Abteilung Zelluläre und Molekulare Pathologie, Deutsches Krebsforschungszentrum (DKFZ) Heidelberg.
Verh Dtsch Ges Pathol. 2002;86:165-75.
Basic aspects of the biology and molecular alterations in prostate carcinoma remain poorly understood. New diagnostic and prognostic markers for prostate carcinoma may add additional information to current histopathological diagnosis. In order to achieve these goals, a comprehensive gene expression analysis was performed on non-metastasizing, untreated prostate cancer tissues. RNA expression profiles of approximately 12,600 sequences from 26 human prostate tissues (17 adenocarcinomas and 9 normal adjacent to cancer tissues) were investigated using high-density oligonucleotide microarray technology (Affymetrix). We identified 63 genes which were significantly increased (at least 2.5-fold) and 153 genes which were decreased (at least 2.5-fold). Upregulated genes included several which had not yet been described, such as the genes encoding the specific granule protein (SGP28), several members of the histone family, and the alpha-methylacyl-CoA racemase, but also previously reported ones such as hepsin, LIM domain kinase 2, and carcinoma-associated antigen GA733-2. Laser capture-microdissection of epithelial and stromal compartments from cancer and histologically normal specimens followed by an amplification protocol for low amounts of RNA (< 0.1 microgram) allowed us to distinguish between gene expression profiles characteristic of epithelial cells and those typical of stroma. Most of the genes identified in bulk tumor material as upregulated were indeed overexpressed in cancerous epithelium rather than in the stromal compartment. DNA microarray data for up- and downregulated genes were confirmed by quantitative RT-PCR. We demonstrated that development of prostate cancer is associated with downregulation as well as upregulation of genes that show complex differential regulation in epithelia and stroma. Some of the alterations in gene expression identified in this study may prove useful in development of novel diagnostic and therapeutic strategies. Gene expression profiling of microdissected tumor cells in prostate biopsies may supplement histopathologic diagnosis.
前列腺癌生物学和分子改变的基本方面仍了解甚少。前列腺癌新的诊断和预后标志物可能为当前的组织病理学诊断增添更多信息。为实现这些目标，我们对未转移、未经治疗的前列腺癌组织进行了全面的基因表达分析。使用高密度寡核苷酸微阵列技术（Affymetrix）研究了来自26个人前列腺组织（17例腺癌和9例癌旁正常组织）的约12,600个序列的RNA表达谱。我们鉴定出63个显著上调（至少2.5倍）的基因和153个显著下调（至少2.5倍）的基因。上调的基因包括几个尚未被描述的基因，如编码特异性颗粒蛋白（SGP28）的基因、组蛋白家族的几个成员以及α-甲基酰基辅酶A消旋酶，也包括先前报道的基因，如肝素、LIM结构域激酶2和癌相关抗原GA733-2。通过激光捕获显微切割癌组织和组织学正常标本的上皮和基质成分，随后对少量RNA（<0.1微克）进行扩增方案，使我们能够区分上皮细胞特征性的基因表达谱和基质典型的基因表达谱。在整块肿瘤组织中鉴定为上调的大多数基因确实在癌上皮中而非基质成分中过度表达。上调和下调基因的DNA微阵列数据通过定量RT-PCR得到证实。我们证明前列腺癌的发生与上皮和基质中显示复杂差异调节的基因的下调以及上调有关。本研究中鉴定的一些基因表达改变可能在新型诊断和治疗策略的开发中证明是有用的。前列腺活检中微切割肿瘤细胞的基因表达谱分析可能补充组织病理学诊断。
