Abstract
BackgroundNew, 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.ResultsIn 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.ConclusionOur 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.
Highlights
New, more effective strategies are needed to treat highly aggressive neuroblastoma
Peptide design Our previous studies demonstrated that peptide follistatin domain of the protein (FS-E), representing the N-terminal epidermal growth factor (EGF)-like module of the Secreted Protein Acidic and Rich in Cysteine (SPARC) follistatin domain, potently inhibits angiogenesis [26]
Matrigel plugs containing basic fibroblast growth factor (bFGF) and either SPARC peptides FSEN or FSEC were less hemorrhagic than the positive control Matrigel plugs containing bFGF with or without scrambled SPARC peptides (Figure 3A)
Summary
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. A strong correlation between high-risk tumors and angiogenesis has been reported by us and other investigators [3,4], suggesting that blood vessels may be clinically relevant therapeutic targets. In support of this hypothesis, preclinical studies have demonstrated that neuroblastoma tumor growth can be significantly impaired following treatment with anti-angiogenic agents [5,6]. SPARC belongs to a group of non-structural components of the extracellular matrix (ECM) that modulate interactions between cells and their environment [11,12] It is highly expressed in a variety of cell types associated with remodeling tissues [13]. SPARC has been shown to down-regulate VEGF in glioma cells [15]
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