Downregulation of uPAR confirms link in growth and metastasis of osteosarcoma

Abstract

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.

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

“…Interestingly, there was a preferential co-localisation of uPA, uPAR and PAI-1 mRNA to Expression of uPAR (serum) and uPA (tumour) uPAR and uPAP low uPAR low and uPA high uPAR high and uPA low uPAR and uPA high Expression of uPAR (serum) and PAI-1 (tumour) uPAR and PAI-1 low uPAR low and PAI-1 high uPAR high and PAI-1 low uPAR and PAI-1 high Expression of uPAR (serum) and uPAR (tumour) uPAR and uPARP low uPAR low and uPAR high uPAR high and uPAR low uPAR and uPAR high uPA system and prognosis in STS patients H Taubert et al the advancing front of tibial tumours (Fisher et al, 2001). Furthermore, injection of an antisense uPAR inhibitor resulted in a significant reduction in tumour volumes and in total inhibition of pulmonary metastases (Dass et al, 2005). In another mouse model, treatment with a uPAR antibody and a recombinant pigment epithelium-derived factor that may internalise uPA/uPAR complexes led to decreased ostoeosarcoma growth and metastasis .…”

Vascularised greater trochanter bone graft, combined free iliac flap and impaction bone grafting for osteonecrosis of the femoral head

“…However, a finite-elements analysis [20] of the femoral head showed that it had a harmful effect on the structural integrity of the femoral head when that surgery was used alone, and suggested it could achieve better outcomes when combined with fibular graft support [22]. A meta-analysis [23] manifested that further surgery was indicated for those who suffered Steinberg stages I, II, and III of ONFH when performing medullary core decompression (16 %, 37 %, and 71 %, respectively). Patients in Ficat II and III stage of ONFH frequently acquired satisfactory outcomes by grafting vascularized bone flaps [17,18].…”

Osteosarcoma: From Molecular Biology to Mesenchymal Stem Cells

“…An inverse relationship exists between survival time and uPA levels in osteosarcoma [44]. The downregulation of uPAR in a clinically relevant murine model of osteosarcoma resulted in limited primary tumour growth and inhibited metastatic spread [45].…”