Abstract
Despite significant improvements, the current management of primary osteosarcoma is still limited by the development of metastatic disease, which occurs in approximately 30% of patients despite aggressive multiagent chemotherapy and tumor-ablative surgery. Therefore, there is a need for the development of novel agents to improve the outcome of these patients. Pigment epithelium-derived factor (PEDF) has been shown to be one of the most potent inhibitors of angiogenesis, and more recently has demonstrated a functional role in tumor growth, invasion and metastasis. In this study we report, for the first time, the multitargeted role of PEDF in the inhibition of growth, angiogenesis and metastasis of two orthotopic models of osteosarcoma (rat UMR 106-01 and human SaOS-2). Through stable plasmid-mediated gene transfer of full-length human PEDF, we show that PEDF overexpression significantly reduced tumor cell proliferation (P<0.05) and Matrigel invasion (UMRPEDF, P<0.001; SaOSPEDF, P<0.05) and increased adhesion to collagen type-1 (P<0.01), in vitro. In vivo, PEDF overexpression dramatically suppressed orthotopic osteosarcoma growth (P<0.05) and the development of spontaneous pulmonary metastases (UMRPEDF, P<0.05; SaOSPEDF, P<0.001). Furthermore, PEDF-overexpressing tumors exhibited reduced intratumoral angiogenesis, evidenced by a significant decrease in microvessel density (P<0.05). Therefore, together these results suggest that PEDF may be a new and promising approach for the treatment of osteosarcoma.
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Acknowledgements
We thank Dr Joseline Ojaimi for construction of the human PEDF plasmid used throughout this study. Dr Eugene TH Ek is supported by scholarships awarded by the University of Melbourne, the Royal Australasian College of Surgeons and the National Health and Medical Research Council of Australia (NHMRC). This study was generously supported by grants from the Australian Orthopaedic Association, the Victorian Orthopaedic Research Trust Grant and the Cancer Council of Victoria.
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Ek, E., Dass, C., Contreras, K. et al. Pigment epithelium-derived factor overexpression inhibits orthotopic osteosarcoma growth, angiogenesis and metastasis. Cancer Gene Ther 14, 616–626 (2007). https://doi.org/10.1038/sj.cgt.7701044
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DOI: https://doi.org/10.1038/sj.cgt.7701044
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