Department of Pediatrics, University of Chicago, KCBD Rm. 5100, Chicago, IL 60637, USA.
Mol Cancer. 2010 Jun 4;9:138. doi: 10.1186/1476-4598-9-138.
New, more effective strategies are needed to treat highly aggressive neuroblastoma. Our laboratory has previously shown that full-length Secreted Protein Acidic and Rich in Cysteine (SPARC) and a SPARC peptide corresponding to the follistatin domain of the protein (FS-E) potently block angiogenesis and inhibit the growth of neuroblastoma tumors in preclinical models. Peptide FS-E is structurally complex and difficult to produce, limiting its potential as a therapeutic in the clinic.
In this study, we synthesized two smaller and structurally more simple SPARC peptides, FSEN and FSEC, that respectively correspond to the N-and C-terminal loops of peptide FS-E. We show that both peptides FSEN and FSEC have anti-angiogenic activity in vitro and in vivo, although FSEC is more potent. Peptide FSEC also significantly inhibited the growth of neuroblastoma xenografts. Histologic examination demonstrated characteristic features of tumor angiogenesis with structurally abnormal, tortuous blood vessels in control neuroblastoma xenografts. In contrast, the blood vessels observed in tumors, treated with SPARC peptides, were thin walled and structurally more normal. Using a novel method to quantitatively assess blood vessel abnormality we demonstrated that both SPARC peptides induced changes in blood vessel architecture that are consistent with blood vessel normalization.
Our results demonstrate that SPARC peptide FSEC has potent anti-angiogenic and anti-tumorigenic effects in neuroblastoma. Its simple structure and ease of production indicate that it may have clinical utility in the treatment of high-risk neuroblastoma and other types of pediatric and adult cancers, which depend on angiogenesis.
需要新的、更有效的策略来治疗高度侵袭性神经母细胞瘤。我们的实验室之前已经表明，全长 Secreted Protein Acidic and Rich in Cysteine (SPARC) 和对应于该蛋白的 follistatin 结构域的 SPARC 肽 (FS-E) 能够强有力地阻断血管生成并抑制神经母细胞瘤肿瘤在临床前模型中的生长。肽 FS-E 结构复杂且难以生产，限制了其在临床上作为治疗药物的潜力。
在这项研究中，我们合成了两个更小且结构更简单的 SPARC 肽，FSEN 和 FSEC，它们分别对应于肽 FS-E 的 N-和 C-末端环。我们表明，两种肽 FSEN 和 FSEC 都具有体外和体内的抗血管生成活性，尽管 FSEC 更有效。肽 FSEC 还显著抑制了神经母细胞瘤异种移植物的生长。组织学检查显示，在对照神经母细胞瘤异种移植物中，肿瘤血管生成具有结构异常、扭曲的血管的特征。相比之下，在用 SPARC 肽处理的肿瘤中观察到的血管壁薄且结构更正常。使用一种新的定量评估血管异常的方法，我们证明了两种 SPARC 肽诱导的血管结构变化与血管正常化一致。
我们的结果表明，SPARC 肽 FSEC 对神经母细胞瘤具有强大的抗血管生成和抗肿瘤作用。其简单的结构和易于生产表明，它可能在治疗高风险神经母细胞瘤和其他依赖血管生成的儿科和成人癌症方面具有临床应用价值。
