PREVENTION OF METASTASIS BY INHIBITION OF THE UROKINASE RECEPTOR
PREVENTION OF METASTASIS BY INHIBITION OF THE UROKINASE RECEPTOR
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DOI：
10.1073/pnas.90.11.5021
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发表时间：
1993-06-01
影响因子：
11.1
通讯作者：
LEVINSON, AD
中科院分区：
文献类型：
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作者：
CROWLEY, CW;COHEN, RL;LEVINSON, AD
纤溶酶原激活剂尿激酶（u-PA）介导多种人类肿瘤细胞的蛋白水解。 u-PA从细胞结合位点的竞争性置换导致体外蛋白水解减少，表明细胞表面是u-PA介导的蛋白降解的优选位点。我们研究了u-PA受体阻断剂对人前列腺癌PC 3细胞转移能力的影响，使用表达氯霉素乙酰转移酶（CAT）的转染子。将这些细胞皮下接种到裸鼠体内8周后，在局部淋巴结、股骨、肺和脑中检测到CAT活性，从而模拟了对前列腺癌自然发生的转移所观察到的器官嗜性。在第二次转染中，表达CAT的PC 3细胞接受编码突变型u-PA（Ser 356-> Ala）的cDNA，该突变型u-PA缺乏酶活性但保留完全的受体结合亲和力。三种突变的u-PA表达者，每种在局部淋巴结中有300个，在脑组织中有40-100个，在肺组织中有10-20个。当动物间歇性腹膜内注射u-PA/IgG融合蛋白能够取代u-PA活性从肿瘤细胞表面时，转移能力也受到类似的抑制。我们的研究结果表明，细胞表面u-PA活性是必不可少的转移过程。此外，这些实验中采用的测定系统通常可用于测试其他治疗方式以限制原发性肿瘤的扩散。
The plasminogen activator urokinase (u-PA) mediates proteolysis by a variety of human tumor cells. Competitive displacement of u-PA from cellular binding sites results in decreased proteolysis in vitro, suggesting that the cell surface is the preferred site for u-PA-mediated protein degradation. We studied the effect of u-PA receptor blockade on the metastatic capacity of human PC3 prostate carcinoma cells, using transfectants which expressed chloramphenicol acetyl-transferase (CAT). Eight weeks after subcutaneous inoculation of these cells into nude mice, CAT activity was detected in regional lymph nodes, femurs, lungs, and brain, thereby mimicking the organ tropism observed for naturally occurring metastases of prostate cancer. In a second transfection, CAT-expressing PC3 cells received cDNA encoding a mutant u-PA (Ser356 --> Ala) which lacks enzymatic activity but which retains full receptor binding affinity. Three mutant u-PA expressors, each with 300 in regional lymph nodes, 40-100 in brain tissue, and 10-20 in lung tissue. Metastatic capacity was inhibited similarly when animals were given intermittent intraperitoneal injections of a u-PA/IgG fusion protein capable of displacing u-PA activity from the tumor cell surface. Our results indicate that cell surface u-PA activity is essential to the metastatic process. In addition, the assay system employed in these experiments may be generally useful in testing other therapeutic modalities to limit the spread of primary tumors.