Lokeshwar V B, Obek C, Pham H T, Wei D, Young M J, Duncan R C, Soloway M S, Block N L
Department of Urology, University of Miami School of Medicine, Florida, USA.
J Urol. 2000 Jan;163(1):348-56. doi: 10.1016/s0022-5347(05)68050-0.
Specific patterns of progression and frequent recurrence of bladder tumors determine the choice of treatment, frequency of surveillance, quality of life, and ultimately, patient prognosis. The prognosis would be improved if an accurate noninvasive test was available for diagnosis. Identification of markers that function in bladder cancer progression would be helpful in designing such diagnostic tests. The glycosaminoglycan, hyaluronic acid (HA), promotes tumor metastasis. Hyaluronidase (HAase), an endoglycosidase, degrades HA into small fragments that promote angiogenesis. We have previously shown that both HA and HAase are associated with bladder cancer and may function in bladder tumor angiogenesis. In this study we examined whether urinary HA and HAase levels serve as bladder cancer markers.
Among the 513 urine specimens analyzed, 261 were from transitional cell carcinoma (TCC) patients, 9 from patients with non-TCC tumors, and 243 from controls (normals, patients with other genitourinary (GU) conditions or a history of bladder cancer (HxBCa)). The urinary HA and HAase levels were measured by two ELISA-like assays that utilize a biotinylated HA binding protein for detection. These levels were normalized to total urinary protein and were expressed as ng./mg. (HA test) and mU/mg. (HAase test), respectively.
The urinary HA levels were elevated (2.5 to 6.5 fold) in bladder cancer patients (1173.7+/-173.4; n = 261) as compared with normals (246.1+/-38.5; n = 41); GU patients (306.6+/-32.2; n = 133), and patients with a HxBCa (351.1+/-49.1; n = 69) (p <0.001). The urinary HAase levels were elevated (3 to 7 fold) in G2/G3 bladder cancer patients (26.2+/-3.2) as compared with normals (4.5+/-0.9) and patients with either GU conditions (5.8+/-1.3), HxBCa (8.2+/-2.6) or G1 tumors (9.7+/-2.5) (p <0.001). The HA test showed 83.1% sensitivity, 90.1% specificity and 86.5% accuracy in detecting bladder cancer, regardless of the tumor grade. The HAase test showed 81.5% sensitivity, 83.8% specificity and 82.9% accuracy to detect G2/G3 patients. Combining the inferences of the HA and HAase tests (HA-HAase test) resulted in detection of bladder cancer, regardless of tumor grade and stage, with higher sensitivity (91.2%) and accuracy (88.3%), and comparable specificity (84.4%).
Our results show that the HA-HAase urine test is a noninvasive, highly sensitive and specific method for detecting bladder cancer and evaluating its grade.
膀胱肿瘤特定的进展模式和频繁复发决定了治疗方案的选择、监测频率、生活质量以及最终的患者预后。如果能有准确的非侵入性检测方法用于诊断，预后将会得到改善。鉴定在膀胱癌进展过程中起作用的标志物将有助于设计此类诊断检测。糖胺聚糖透明质酸（HA）可促进肿瘤转移。透明质酸酶（HAase）是一种内切糖苷酶，可将HA降解为促进血管生成的小片段。我们之前已经表明，HA和HAase均与膀胱癌相关，并且可能在膀胱肿瘤血管生成中发挥作用。在本研究中，我们检测了尿HA和HAase水平是否可作为膀胱癌标志物。
在分析的513份尿液标本中，261份来自移行细胞癌（TCC）患者，9份来自非TCC肿瘤患者，243份来自对照组（正常人群、患有其他泌尿生殖系统（GU）疾病的患者或有膀胱癌病史（HxBCa）的患者）。采用两种类似酶联免疫吸附测定（ELISA）的方法测量尿HA和HAase水平，这两种方法利用生物素化的HA结合蛋白进行检测。这些水平以尿总蛋白为参照进行标准化，并分别表示为ng./mg.（HA检测）和mU/mg.（HAase检测）。
与正常人群（246.1±38.5；n = 41）、GU疾病患者（306.6±32.2；n = 133）以及有膀胱癌病史的患者（351.1±49.1；n = 69）相比，膀胱癌患者（1173.7±173.4；n = 261）的尿HA水平升高（2.5至6.5倍）（p<0.001）。与正常人群（4.5±0.9）、患有GU疾病的患者（5.8±1.3）、有膀胱癌病史的患者（8.2±2.6）或G1期肿瘤患者（9.7±2.5）相比，G2/G3期膀胱癌患者（26.2±3.2）的尿HAase水平升高（3至7倍）（p<0.001）。HA检测在检测膀胱癌时，无论肿瘤分级如何，均显示出83.1%的敏感性、90.1%的特异性和86.5%的准确性。HAase检测在检测G2/G3期患者时，显示出81.5%的敏感性、83.8%的特异性和(82.9%)的准确性。结合HA和HAase检测的推断结果（HA-HAase检测），无论肿瘤分级和分期如何，均能检测出膀胱癌，且具有更高的敏感性（91.2%）和准确性（88.3%），特异性相当（84.4%）。
我们的结果表明，HA-HAase尿液检测是一种用于检测膀胱癌及其分级的非侵入性、高敏感性和特异性的方法。
