Activation of Pro-uPA Is Critical for Initial Escape from the Primary Tumor and Hematogenous Dissemination of Human Carcinoma Cells
Activation of Pro-uPA Is Critical for Initial Escape from the Primary Tumor and Hematogenous Dissemination of Human Carcinoma Cells
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DOI：
10.1593/neo.11704
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发表时间：
2011-09-01
期刊：
影响因子：
4.8
通讯作者：
Quigley, James P.
中科院分区：
文献类型：
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作者：
Bekes, Erin M.;Deryugina, Elena I.;Quigley, James P.
尿激酶型纤溶酶原激活物（uPA）和纤溶酶长期以来与癌症进展有关。然而，uPA/纤溶酶系统参与癌细胞播散的具体步骤的确切贡献尚未完全确定。在此，我们已经使用了一个高度传播的变种的人PC-3前列腺癌细胞系，PC-高/diss，作为一个原型的侵袭性癌，以研究机制，从而pro-uPA激活和uPA产生的纤溶酶功能有助于特定阶段的转移。PC-hi/diss细胞分泌并激活显著量的pro-uPA，导致在溶液中和细胞表面有效产生纤溶酶。在小鼠原位异种移植模型中，用特异性pro-uPA激活阻断抗体mAb-112治疗显著抑制了PC-hi/diss细胞的局部侵袭和远处转移。为了从机制上研究uPA/纤溶酶介导的肿瘤细胞播散方面，在许多体内试验中平行使用抗uPA原mAb-112和强效丝氨酸蛋白酶抑制剂抑肽酶，模拟早期转移性扩散中的各种限速步骤。我们的研究结果表明，通过产生纤溶酶，活化的肿瘤源性uPA促进早期阶段的PC-hi/diss传播，特别是从原发性肿瘤和肿瘤细胞内渗逃逸。此外，通过一系列的体外和体内分析，我们认为，PC-hi/diss侵入性逃逸和传播可能会增强由uPA产生的纤溶酶裂解基质纤连蛋白。总之，我们的研究结果指出，在uPA/纤溶酶级联反应的顶点抑制pro-uPA活化是控制肿瘤逃逸和随后转移扩散的有效治疗方法。
Urokinase-type plasminogen activator (uPA) and plasmin have long been implicated in cancer progression. However, the precise contributions of the uPA/plasmin system to specific steps involved in cancer cell dissemination have not been fully established. Herein, we have used a highly disseminating variant of the human PC-3 prostate carcinoma cell line, PC-hi/diss, as a prototype of aggressive carcinomas to investigate the mechanisms whereby pro-uPA activation and uPA-generated plasmin functionally contribute to specific stages of metastasis. The PC-hi/diss cells secrete and activate significant amounts of pro-uPA, leading to efficient generation of plasmin in solution and at the cell surface. In a mouse orthotopic xenograft model, treatment with the specific pro-uPA activation-blocking antibody mAb-112 significantly inhibited local invasion and distant metastasis of the PC-hi/diss cells. To mechanistically examine the uPA/plasmin-mediated aspects of tumor cell dissemination, the anti-pro-uPA mAb-112 and the potent serine protease inhibitor, aprotinin, were used in parallel in a number of in vivo assays modeling various rate-limiting steps in early metastatic spread. Our findings demonstrate that, by generating plasmin, activated tumor-derived uPA facilitates early stages of PC-hi/diss dissemination, specifically the escape from the primary tumor and tumor cell intravasation. Moreover, through a series of in vitro and in vivo analyses, we suggest that PC-hi/diss-invasive escape and dissemination may be enhanced by cleavage of stromal fibronectin by uPA-generated plasmin. Together, our findings point to inhibition of pro-uPA activation at the apex of the uPA/plasmin cascade as a therapy-valid approach to control onset of tumor escape and ensuing metastatic spread.