Vadasz Zahava, Rubinstein Jacob, Bejar Jacob, Sheffer Hilla, Halachmi Sarel
The Department of Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel.
The Department of Mathematic, Technion, Israeli Institute of Technology, Haifa, Israel.
Urol Oncol. 2018 Apr;36(4):161.e1-161.e6. doi: 10.1016/j.urolonc.2017.12.007. Epub 2017 Dec 27.
A highly sensitive and specific urine marker for the detection of recurrent urothelial cancer and for screening healthy population or people at risk for urothelial cancer has not been found yet. As urine cytology is not sensitive enough, patients with non-muscle-invasive bladder cancer need lifelong follow-up involving multiple invasive cystoscopies. Our aims of study were to examine the expression of semaphorin 3A in urothelial cancer patients and to evaluate semaphorin 3A as a potential marker for urothelial cancer.
Urine samples were taken from patients with known bladder tumor, hospitalized for transurethral resection of lesions, from patients with history of urothelial cancer admitted for endoscopic follow up, from patients with other nonmalignant urological conditions such as prostatic hyperplasia, stress incontinence, urethral stricture, ureteral and kidney stones, and from healthy volunteers with no history of urothelial malignancy and no urological symptoms. Semaphorin 3A (sema3A) protein level was measured using enzyme-linked immunosorbent assay in every sample and levels were correlated with endoscopic and pathological findings. In addition, we performed immunohistochemically staining with semaphorin 3A of 15 tissue samples (various tumors and normal bladder tissues).
A total of 183 urine samples were tested. Out of them, 116 patients (mean age 70.7; 94 males and 22 females) had positive cystoscopy, and 67 (mean age 64.7; 51 males and 16 females) had negative cystoscopy. Higher sema3A values were significantly correlated (P = 0.006) with presence of urothelial cancer, as determined by positive cystoscopy or urethroscopy and pathological biopsy. Sema3A levels also showed positive correlation with the number of tumors. Sema3A levels combined with urine cytology showed much higher sensitivity compared with cytology alone (66% vs. 33%), with smaller reduction of specificity (77% vs. 90%). Immunohistochemical staining showed intense staining in high stage and grade tumors, and almost no staining in normal tissue.
Semaphorin 3A is overexpressed in urothelial cancer patients, as evidenced both in its presence in urine and in bladder tissue. Semaphorin 3A in urine is a promising potential urothelial cancer biomarker either independently or in conjunction with cytology. Further tests are needed to elucidate the sex difference in the expression of Sema3A in the urine of bladder cancer patients.
尚未找到一种用于检测复发性尿路上皮癌以及筛查健康人群或尿路上皮癌高危人群的高灵敏度和特异性的尿液标志物。由于尿液细胞学检查不够灵敏，非肌层浸润性膀胱癌患者需要终身随访，包括多次侵入性膀胱镜检查。我们的研究目的是检测尿路上皮癌患者中信号素3A的表达，并评估信号素3A作为尿路上皮癌潜在标志物的价值。
收集已知患有膀胱肿瘤并因经尿道病变切除术住院患者的尿液样本、有尿路上皮癌病史并因内镜随访入院患者的尿液样本、患有其他非恶性泌尿系统疾病（如前列腺增生、压力性尿失禁、尿道狭窄、输尿管和肾结石）患者的尿液样本，以及无尿路上皮恶性肿瘤病史且无泌尿系统症状的健康志愿者的尿液样本。使用酶联免疫吸附测定法测量每个样本中信号素3A（sema3A）蛋白水平，并将这些水平与内镜和病理检查结果相关联。此外，我们对15个组织样本（各种肿瘤和正常膀胱组织）进行了信号素3A免疫组织化学染色。
共检测了183份尿液样本。其中，116例患者（平均年龄70.7岁；94例男性，22例女性）膀胱镜检查呈阳性，67例（平均年龄64.7岁；51例男性，16例女性）膀胱镜检查呈阴性。经膀胱镜或尿道镜检查及病理活检确定，较高的sema3A值与尿路上皮癌的存在显著相关（P = 0.006）。Sema3A水平也与肿瘤数量呈正相关。Sema3A水平与尿液细胞学检查相结合显示出比单独细胞学检查更高的灵敏度（66%对33%），特异性降低较小（77%对90%）。免疫组织化学染色显示高分期和高分级肿瘤中染色强烈，正常组织中几乎无染色。
信号素3A在尿路上皮癌患者中过度表达，这在尿液和膀胱组织中均有体现。尿液中的信号素3A无论是单独还是与细胞学检查相结合，都是一种有前景的潜在尿路上皮癌生物标志物。需要进一步测试以阐明膀胱癌患者尿液中Sema3A表达的性别差异。
