Godara Geeta, Pecher Stefana, Jukic Drazen M, D'Antonio Jason M, Akhavan Ardavan, Nelson Joel B, Pflug Beth R
Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15232, USA.
Urology. 2007 Jul;70(1):209-15. doi: 10.1016/j.urology.2007.03.017.
Emerging evidence supports a role for endothelin-1 (ET-1), endothelin A and B receptors (ET(A) and ET(B), respectively), and neutral endopeptidase (NEP) in the progression of prostate carcinoma. In clinical trials for advanced prostate cancer, ET axis blockade significantly delayed the time to disease progression in a subset of patients. We examined ET axis expression in prostate cancer, prostatic intraepithelial neoplasia, and normal adjacent tissue and then analyzed the relationship of the protein levels with disease progression.
The expression levels of ET(A), ET(B), and NEP were determined in 120 prostate cancer specimens obtained at surgery or biopsy by immunohistochemistry. In situ hybridization on a subset of the specimens was used to confirm the immunohistochemistry findings.
In regions of adenocarcinoma, immunohistochemistry analysis demonstrated high ET(A) expression in 72% of the specimens. ET(A) expression was significantly elevated with increased pathologic stage and grade. ET(B) and NEP levels were significantly decreased in adenocarcinoma compared with normal adjacent tissue and prostatic intraepithelial neoplasia; however, reduced expression did not correlate with tumor grade or stage. Patients with prostate-specific antigen recurrence had significantly greater ET(A) levels in their primary tumors than did patients who were disease free 5 years after prostatectomy. Patients with high ET(A) expression in the adenocarcinoma regions with low ET(B) and NEP had a significantly decreased interval to prostate-specific antigen progression compared with patients with low ET(A) or high ET(B)/NEP expression.
These data suggest two patterns of ET(A) expression in primary prostate cancer, with increased expression correlating with more advanced disease. The use of these expression patterns to identify patients more likely to respond to ET axis blockade might enhance treatment outcomes.
新出现的证据支持内皮素-1（ET-1）、内皮素A和B受体（分别为ET(A)和ET(B)）以及中性内肽酶（NEP）在前列腺癌进展过程中发挥作用。在晚期前列腺癌的临床试验中，ET轴阻断在部分患者中显著延迟了疾病进展时间。我们检测了前列腺癌、前列腺上皮内瘤变及相邻正常组织中ET轴的表达情况，然后分析了蛋白水平与疾病进展之间的关系。
通过免疫组织化学法测定了120例手术或活检获取的前列腺癌标本中ET(A)、ET(B)和NEP的表达水平。对部分标本进行原位杂交以证实免疫组织化学结果。
在腺癌区域，免疫组织化学分析显示72%的标本中ET(A)表达较高。ET(A)表达随病理分期和分级增加而显著升高。与相邻正常组织和前列腺上皮内瘤变相比，腺癌中ET(B)和NEP水平显著降低；然而，表达降低与肿瘤分级或分期无关。前列腺特异性抗原复发的患者其原发肿瘤中的ET(A)水平显著高于前列腺切除术后5年无疾病的患者。与ET(A)低表达或ET(B)/NEP高表达的患者相比，腺癌区域ET(A)高表达、ET(B)和NEP低表达的患者前列腺特异性抗原进展间隔显著缩短。
这些数据提示原发性前列腺癌中ET(A)存在两种表达模式，表达增加与更晚期疾病相关。利用这些表达模式识别更可能对ET轴阻断有反应的患者可能会提高治疗效果。
