PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma.
Pigment epithelium-derived factor (PEDF) is one of the most potent inhibitors of angiogenesis, and has recently been demonstrated to have an important multifunctional role in tumor growth, invasion, and metastasis. However, relatively little is known of mechanisms through which PEDF exerts its antitumor activity. Therefore, with the aim of identifying potential functional epitopes specifically against osteosarcoma, we evaluated the bioactivity of four 25-mer synthetic PEDF-derived peptides (termed StVOrth-1, -2 -3, and -4) against a human osteosarcoma cell line, SaOS-2. We found that StVOrth-2 (residues 78-102) predominantly inhibited tumor cell proliferation, while StVOrth-3 (residues 90-114) markedly increased cellular adhesion to collagen type-1, with StVOrth-4 (residues 387-411) demonstrating most significant inhibition of Matrigel invasion. Furthermore, we show that StVOrth-1 (residues 40-64), -2 and -3 induce osteoblastic differentiation, evidenced by increased mineralized nodule formation. Interestingly, although no peptide inhibited angiogenesis in the tube formation assay, StVOrth-3 and -4 markedly suppressed VEGF expression. We further tested the activity of StVOrth-2 and StVOrth-3 in vivo, in an orthotopic model of osteosarcoma and found that both peptides significantly inhibited primary tumor growth and the development of pulmonary metastases. Together these results provide greater insight into the potential mechanisms through which PEDF exerts its antitumor function. Furthermore, this raises the possibility of developing short PEDF fragments as lead compounds for the treatment of osteosarcoma.
Ek
Eugene T H
ET
Department of Orthopaedics, University of Melbourne, St. Vincent's Hospital, Melbourne, P.O. Box 2900, Fitzroy, 3065, Melbourne, VIC, Australia.
Dass
Crispin R
CR
Contreras
Karla G
KG
Choong
Peter F M
PF
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000627:therapeutic use; D005136:Eye Proteins / Q000737:chemistry / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000601:surgery; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009414:Nerve Growth Factors / Q000737:chemistry / Q000627:therapeutic use*; D010012:Osteogenesis / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D010455:Peptides / Q000138:chemical synthesis / Q000627:therapeutic use; D015843:Serpins / Q000737:chemistry / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D000970:Antineoplastic Agents; D000939:Epitopes; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010455:Peptides; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor