Farach Andrew, Ding Yi, Lee MinJae, Creighton Chad, Delk Nikki A, Ittmann Michael, Miles Brian, Rowley David, Farach-Carson Mary C, Ayala Gustavo E
Division of Radiation Oncology, Department of Radiology, Baylor College of Medicine, Houston, Texas.
Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
Prostate. 2016 Oct;76(14):1312-25. doi: 10.1002/pros.23221. Epub 2016 Jul 12.
Neuroendocrine (NE) differentiation in prostate cancer (PCa) is an aggressive phenotype associated with therapy resistance. The complete phenotype of these cells is poorly understood. Clinical classification is based predominantly on the expression of standard NE markers.
We analyzed the phenotype of NE carcinoma of the prostate utilizing in vitro methods, in silico, and immunohistochemical analyses of human disease.
LNCaP cells, subjected to a variety of stressors (0.1% [v/v] fetal bovine serum, cyclic AMP) induced a reproducible phenotype consistent with neuronal trans-differentiation. Cells developed long cytoplasmic processes resembling neurons. As expected, serum deprived cells had decreased expression in androgen receptor and prostate specific antigen. A significant increase in neuronal markers also was observed. Gene array analysis demonstrated that LNCaP cells subjected to low serum or cAMP showed statistically significant manifestation of a human brain gene expression signature. In an in silico experiment using human data, we identified that only hormone resistant metastatic prostate cancer showed enrichment of the "brain profile." Gene ontology analysis demonstrated categories involved in neuronal differentiation. Three neuronal markers were validated in a large human tissue cohort.
This study proposes that the later stages of PCa evolution involves neuronal trans-differentiation, which would enable PCa cells to acquire independence from the neural axis, critical in primary tumors. Prostate 76:1312-1325, 2016. © 2016 Wiley Periodicals, Inc.
前列腺癌（PCa）中的神经内分泌（NE）分化是一种与治疗抵抗相关的侵袭性表型。这些细胞的完整表型尚不清楚。临床分类主要基于标准NE标志物的表达。
我们利用体外方法、计算机分析和人类疾病的免疫组织化学分析，对前列腺NE癌的表型进行了分析。
LNCaP细胞在受到多种应激源（0.1%[v/v]胎牛血清、环磷酸腺苷）作用后，诱导出一种与神经元转分化一致的可重复表型。细胞长出了类似于神经元的长细胞质突起。正如预期的那样，血清剥夺的细胞中雄激素受体和前列腺特异性抗原的表达降低。同时还观察到神经元标志物有显著增加。基因阵列分析表明，低血清或环磷酸腺苷处理的LNCaP细胞显示出人脑基因表达特征的统计学显著表现。在一项使用人类数据的计算机实验中，我们发现只有激素抵抗性转移性前列腺癌表现出“脑图谱”的富集。基因本体分析显示了与神经元分化相关的类别。在一个大型人类组织队列中验证了三种神经元标志物。
本研究提出，PCa演变的后期阶段涉及神经元转分化，这将使PCa细胞能够从神经轴获得独立性，这在原发性肿瘤中至关重要。《前列腺》76:1312 - 1325，2016年。©2016威利期刊公司。
