Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo.
Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo.
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发表时间：
1994-05
期刊：
影响因子：
11.2
通讯作者：
Abderrahim Achbarou;S. Kaiser;Gilles Tremblay;L. Ste-Marie;P. Brodt;David Goltzman;S. Rabbani
中科院分区：
文献类型：
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作者：
Abderrahim Achbarou;S. Kaiser;Gilles Tremblay;L. Ste-Marie;P. Brodt;David Goltzman;S. Rabbani
我们之前曾报道过尿激酶(UPA)是由人前列腺癌PC-3细胞株产生的，可以作为成骨细胞表型细胞的生长因子。为了研究uPA在骨骼和骨外转移中的作用，我们建立了一个uPA在大鼠前列腺癌细胞系中过度表达的同源模型。我们分离了大鼠(R)uPA的全长cDNA，并将其作为1.4kb的XbaI-BspHI正、反义片段亚克隆到Moloney小鼠白血病逆转录病毒载体PYN中。将对照(PYN)和实验(PYN-RUPA，PYN-RUPA-AS)质粒分别导入大鼠前列腺癌细胞系Dunning R 3227，Mat LyLu。选择比对照组高5倍或低3倍的实验克隆，将对照细胞和实验细胞接种到近交系雄性哥本哈根大鼠的左心室内。每隔一定时间处死动物以检查转移灶的演变。对照组动物在接种后20-21天出现腰椎转移瘤，导致脊髓受压和后肢瘫痪。接种高表达uPA的细胞的动物出现后肢瘫痪的时间明显提前(到接种后14-15天)。此外，还可以看到更广泛的骨骼(肋骨、肩胛骨和股骨)转移。实验动物的血清显示碱性磷酸酶水平逐渐升高，组织学检查显示腰椎转移瘤的成骨细胞活性明显高于对照组动物。与此相反，接种uPA低表达细胞的动物发生后肢瘫痪的时间明显更晚(接种后25-29天)，并显示出较少的肿瘤转移。这些研究支持uPA的催化结构域在增强骨骼和非骨骼前列腺癌侵袭性方面的作用，并与uPA的生长因子结构域在介导成骨细胞骨骼反应中的作用一致。
We previously reported that urokinase (uPA) is produced by the human prostate cancer cell line, PC-3, and could function as a growth factor for cells of the osteoblast phenotype. To examine the role of uPA in metastasis to the skeleton and to extraskeletal sites, we have developed a homologous model of uPA overexpression in a rat prostate cancer cell line. Full length cDNA encoding rat (r) uPA was isolated and subcloned as a 1.4-kilobase XbaI-BspHI fragment in the sense and antisense orientation into the Moloney murine leukemia retroviral vector pYN. The control (pYN) and experimental (pYN-ruPA, pYN-ruPA-AS) plasmids were transfected into Dunning R 3227, Mat LyLu rat prostate carcinoma cells. Experimental clones expressing at least 5-fold higher (pYN-ruPA) or 3-fold lower (pYN-ruPA-AS) than controls were selected, and control and experimental cells were inoculated into the left ventricles of inbred male Copenhagen rats. Animals were sacrificed at timed intervals to examine the evolution of metastatic lesions. Control animals developed metastases to the lumbar vertebrae resulting in spinal cord compression and hind limb paralysis at 20-21 days postinoculation. Animals inoculated with cells overexpressing uPA developed hind limb paralysis significantly earlier (by day 14-15 postinoculation). Additionally, more widespread skeletal (ribs, scapula, and femora) metastases were seen. Serum from experimental animals showed a progressive elevation in alkaline phosphatase levels, and histological examination of lumbar metastases revealed markedly increased osteoblastic activity over that observed in control animals. In contrast to this, animals inoculated with cells underexpressing uPA developed hind limb paralysis significantly later (days 25-29 postinoculation) and displayed decreased tumor metastasis. These studies support a role for the catalytic domain of uPA in enhancing both skeletal and nonskeletal prostate cancer invasiveness and are consistent with a role for the growth factor domain of uPA in mediating an osteoblastic skeletal response.