Dass Crispin R, Nadesapillai Anne P W, Robin Daniel, Howard Monique L, Fisher Jane L, Zhou Hong, Choong Peter F M
Department of Orthopaedics, The University of Melbourne, St. Vincent's Hospital Melbourne, P.O. Box 2900, 3065 Fitzroy, VIC, Australia.
Clin Exp Metastasis. 2005;22(8):643-52. doi: 10.1007/s10585-006-9004-3. Epub 2006 Apr 29.
The uPA/uPAR system is involved in tumour progression and metastasis of a variety of cancers. Previously, we have shown that increased expression of urokinase plasminogen activator (uPA) correlated with malignancy grade in certain sarcomas. A study looking at in vivo inhibition of this system has not been done to date for osteosarcoma. More recently, this laboratory developed a clinically relevant mouse model where intratibial injection of UMR106-01 cells resulted in the development of osteosarcoma and lung metastases. Expression of uPA and its receptor (uPAR) were localised to the invading front of the tumours. Pulmonary metastasis is a predominant feature of the disease and is the major cause of death in patients. In the present study, the effects of down-regulating uPAR were observed in vitro and in vivo. UMR106-01 cells were transfected with either antisense-uPAR or vector control plasmids. Two antisense clones, exhibiting uPAR downregulation, demonstrated decreased adhesion, migration and invasion in cell-based assays in vitro (P<0.05). Cellular proliferation was not affected by uPAR downregulation. In vivo, a marked reduction of 80% in tibial tumour volumes (P<0.05), and total inhibition of pulmonary metastases were observed in mice injected with the more potent of the antisense clones. This study proves seminally the usefulness of uPAR antisense in curbing the growth and spread of osteosarcoma.
尿激酶型纤溶酶原激活剂（uPA）/uPA受体（uPAR）系统参与多种癌症的肿瘤进展和转移。此前，我们已经表明，尿激酶型纤溶酶原激活剂（uPA）表达增加与某些肉瘤的恶性程度相关。迄今为止，尚未针对骨肉瘤进行该系统体内抑制作用的研究。最近，本实验室建立了一种与临床相关的小鼠模型，经胫骨内注射UMR106 - 01细胞可导致骨肉瘤及肺转移的发生。uPA及其受体（uPAR）的表达定位于肿瘤的侵袭前沿。肺转移是该疾病的主要特征，也是患者死亡的主要原因。在本研究中，观察了下调uPAR在体外和体内的作用。用反义uPAR或载体对照质粒转染UMR106 - 01细胞。两个表现出uPAR下调的反义克隆，在体外细胞实验中显示出黏附、迁移和侵袭能力下降（P<0.05）。细胞增殖不受uPAR下调的影响。在体内，注射更强效反义克隆的小鼠胫骨肿瘤体积显著减少80%（P<0.05），且肺转移完全受到抑制。本研究开创性地证明了uPAR反义技术在抑制骨肉瘤生长和扩散方面的有效性。
