Soff G A, Sanderowitz J, Gately S, Verrusio E, Weiss I, Brem S, Kwaan H C
Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Clin Invest. 1995 Dec;96(6):2593-600. doi: 10.1172/JCI118323.
Expression of urokinase-type plasminogen activator (uPA) by malignant cells correlates with an aggressive phenotype, including increased invasiveness, tumor-associated angiogenesis, and metastases. Plasminogen activator inhibitor type 1 (PAI-1) is undetectable in cells of some aggressive malignancies, but present in the stroma of tumor-associated microvasculature. This analysis of an athymic mouse model of prostate carcinoma further defines the role of the uPA/PAI-1/plasmin system in primary growth and metastasis. A marked increase in PAI-1 expression was induced in clones of the aggressive human prostate carcinoma line, PC-3, by stable transfection. Primary PC-3 tumors, in mice, were significantly smaller when derived from PAI-1 expressing versus control cells. PAI-1 expression reduced the density of tumor-associated microvasculature by 22-38%. Microscopic metastases were quantitated using stable expression of the chromogenic label (beta-galactosidase) in control and PAI-1 expressing cells. PAI-1 expression resulted in a significant inhibition of lung metastases, and liver metastases. Expression of PAI-1 by malignant prostate cells resulted in a less aggressive phenotype, presumably by inhibition of uPA activity, suggesting pharmacologic or molecular inhibition of uPA activity as a potential therapeutic target.
恶性细胞中尿激酶型纤溶酶原激活剂（uPA）的表达与侵袭性表型相关，包括侵袭性增加、肿瘤相关血管生成和转移。在一些侵袭性恶性肿瘤细胞中检测不到纤溶酶原激活剂抑制剂1型（PAI-1），但在肿瘤相关微血管的基质中存在。对前列腺癌无胸腺小鼠模型的这项分析进一步明确了uPA/PAI-1/纤溶酶系统在原发性生长和转移中的作用。通过稳定转染，在侵袭性人前列腺癌细胞系PC-3的克隆中诱导PAI-1表达显著增加。在小鼠中，源自表达PAI-1的细胞的原发性PC-3肿瘤明显小于源自对照细胞的肿瘤。PAI-1表达使肿瘤相关微血管密度降低22%-38%。使用对照细胞和表达PAI-1的细胞中显色标记（β-半乳糖苷酶）的稳定表达对显微镜下转移灶进行定量。PAI-1表达导致肺转移和肝转移显著受到抑制。恶性前列腺细胞表达PAI-1导致侵袭性表型减弱，推测是通过抑制uPA活性，这表明对uPA活性进行药理或分子抑制是一个潜在的治疗靶点。
