Rapa Ida, Ceppi Paolo, Bollito Enrico, Rosas Rosj, Cappia Susanna, Bacillo Elisa, Porpiglia Francesco, Berruti Alfredo, Papotti Mauro, Volante Marco
Division of Pathology, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy.
Mod Pathol. 2008 Jun;21(6):700-7. doi: 10.1038/modpathol.2008.39. Epub 2008 Feb 29.
Neuroendocrine differentiation in prostate cancer correlates with overall prognosis and disease progression after androgen-deprivation therapy, although its specific mechanisms are currently poorly understood. A role of Notch pathway has been reported in determining neuroendocrine phenotype of normal and neoplastic tissues. The aim of this study was to analyze whether this pathway might affect neuroendocrine differentiation in prostate cancer. Human achaete-scute homolog 1 (hASH1), a pivotal member of the Notch pathway, was investigated in 80 prostate cancers selected and grouped according to chromogranin A immunohistochemistry, as follows: prostate cancers without neuroendocrine differentiation, untreated (25 cases); prostate cancers with neuroendocrine differentiation, untreated (40 cases); prostate cancers with previous androgen-deprivation therapy, all having neuroendocrine differentiation (15 cases). Human ASH1 protein was analyzed by immunohistochemistry, whereas the presence of hASH1 mRNA transcripts was investigated on paraffin material by real-time PCR. By immunohistochemistry, hASH1 was colocalized with chromogranin A in neuroendocrine cells of normal prostatic gland. It was absent in all but one prostate cancers without neuroendocrine differentiation, whereas it was positive in 25% of prostate cancers with neuroendocrine differentiation/untreated, with a significant correlation with the extent of neuroendocrine features (P=0.02). Moreover, comparing untreated and treated prostate cancers with neuroendocrine differentiation, a positive association with androgen-deprivation therapy was observed (P=0.01). In prostate cancers with neuroendocrine differentiation, RNA analysis confirmed the association of higher transcript levels in androgen deprivation-treated compared with untreated patients (P=0.01). In addition, hASH1 mRNA analysis in microdissected chromogranin A-positive and chromogranin A-negative areas within the same tumor demonstrated a two- to sevenfold increase of hASH1 mRNA expression in chromogranin A-positive tumor cell populations.
前列腺癌中的神经内分泌分化与总体预后以及雄激素剥夺治疗后的疾病进展相关，尽管其具体机制目前仍知之甚少。据报道，Notch通路在决定正常组织和肿瘤组织的神经内分泌表型中发挥作用。本研究的目的是分析该通路是否可能影响前列腺癌中的神经内分泌分化。对80例前列腺癌进行了研究，根据嗜铬粒蛋白A免疫组化进行选择和分组，如下：无神经内分泌分化的未治疗前列腺癌（25例）；有神经内分泌分化的未治疗前列腺癌（40例）；先前接受过雄激素剥夺治疗且均有神经内分泌分化的前列腺癌（15例）。通过免疫组化分析人achaete-scute同源物1（hASH1）蛋白，而通过实时PCR在石蜡材料上研究hASH1 mRNA转录本的存在情况。通过免疫组化，hASH1在正常前列腺腺泡的神经内分泌细胞中与嗜铬粒蛋白A共定位。在除1例以外的所有无神经内分泌分化的前列腺癌中均未检测到hASH1，而在25%有神经内分泌分化的未治疗前列腺癌中呈阳性，与神经内分泌特征的程度显著相关（P=0.02）。此外，比较有神经内分泌分化的未治疗和已治疗前列腺癌，观察到与雄激素剥夺治疗呈正相关（P=0.01）。在有神经内分泌分化的前列腺癌中，RNA分析证实与未治疗患者相比，雄激素剥夺治疗患者的转录水平更高（P=0.01）。此外，在同一肿瘤内微切割的嗜铬粒蛋白A阳性和嗜铬粒蛋白A阴性区域进行hASH1 mRNA分析表明，嗜铬粒蛋白A阳性肿瘤细胞群体中hASH1 mRNA表达增加了2至7倍。
