Abstract
Pigment epithelium-derived factor (PEDF) is the most potent endogenous inhibitor of angiogenesis and decreased PEDF expression has been shown, in many tumours, to be associated with increased intratumoural microvascularity, enhanced tumour growth and metastases and poor patient prognosis. We evaluated the role of PEDF in osteosarcoma growth inhibition and examined it’s potential as a possible anti-cancer therapeutic agent.
We investigated the effects of overexpressed and recombinant PEDF (rPEDF) in several cell-based assays and in two orthotopic models of osteosarcoma (UMR 106-01 and SaOS-2).
In vitro, overexpression of PEDF significantly decreased cell proliferation, migration, invasion and increased adhesion to collagen-1. rPEDF resulted in a dose-dependent inhibition of cell proliferation, increased collagen adhesion, decreased invasion, and down-regulation of VEGF. The pro-differentiation ability of rPEDF was confirmed by upregulation of several osteoblastic markers after treatment of a pre-osteoblastic cell line (UMR 201). Furthermore, both cell lines displayed increased mineralised nodule formation after administration. In vivo, PEDF inhibited osteosarcoma growth and metastasis when overexpressed and in the recombinant form. In addition, anti-tumour activity was observed upon testing with shorter peptides of PEDF. Pharmacoevaluation of rPEDF demonstrated stability within media over several days, and no significant side effects in terms of wound healing.
From these results, PEDF demonstrates multi-modal anti-tumour activity via anti-proliferation, anti-angiogenesis, pro-differentiation and anti-metastasis. PEDF may be a promising therapeutic agent for the treatment of patients with osteosarcoma.
Correspondence should be addressed to: Cynthia Vezina, Communications Manager, COA, 4150-360 Ste. Catherine St. West, Westmount, QC H3Z 2Y5, Canada
