PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma
PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma
复制标题
DOI：
10.1002/jor.20434
复制
发表时间：
2007-12-01
影响因子：
2.8
通讯作者：
Choong, Peter F. M.
中科院分区：
文献类型：
--
作者：
Ek, Eugene T. H.;Dass, Crispin R.;Choong, Peter F. M.
色素上皮衍生因子（PEDF）是最有效的血管生成抑制剂之一，最近被证明在肿瘤生长、侵袭和转移中具有重要的多功能作用。然而，对PEDF发挥其抗肿瘤活性的机制知之甚少。因此，为了鉴定针对骨肉瘤的潜在功能表位，我们评估了四种25-mer合成pedf衍生肽（称为StVOrth-1， -2 -3和-4）对人骨肉瘤细胞系SaOS-2的生物活性。我们发现StVOrth-2（残基78-102）主要抑制肿瘤细胞增殖，而StVOrth-3（残基90-114）显著增加细胞对1型胶原的粘附，其中StVOrth-4（残基387-411）对Matrigel侵袭的抑制作用最显著。此外，我们发现stvorth - 1（残留物40-64）、-2和-3诱导成骨细胞分化，这可以通过矿化结节形成的增加来证明。有趣的是，尽管在试管形成实验中没有肽抑制血管生成，但StVOrth-3和-4明显抑制VEGF的表达。我们进一步在骨肉瘤原位模型中测试了StVOrth-2和StVOrth-3在体内的活性，发现这两种肽均能显著抑制原发肿瘤的生长和肺转移的发展。总之，这些结果为PEDF发挥其抗肿瘤功能的潜在机制提供了更深入的了解。此外，这增加了开发短PEDF片段作为骨肉瘤治疗先导化合物的可能性。(C) 2007骨科研究学会。
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-I (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 anorthotopic 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. (C) 2007 Orthopaedic Research Society.