The Role of SPARC in Neuroblastoma Angiogenesis

SPARC 在神经母细胞瘤血管生成中的作用

• 批准号: 7231633
• 负责人: SUSAN L. COHN
• 金额: $ 31.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231633
• 关键词: Affect; Angiogenesis Inhibitors; Animals; Apoptosis; Behavior; Benign; Biological Assay; Blood Vessels; Caspase; Cell Differentiation process; Cell Line; Cell physiology; Cells; Child; Chromatography; Clinical; Complex; Cysteine; Cysteine Protease; Cytochromes; Development; Endothelial Cells; Equilibrium; Gene Expression; Goals; Grant; Growth; Histologic; In Vitro; Lead; Length; Malignant Childhood Neoplasm; Measures; Modeling; Neoplasm Metastasis; Neuroblastoma; Normal Cell; Outcome; Pattern; Peptides; Phenotype; Play; Pre-Clinical Model; Production; Proteins; Pump; Recombinant Proteins; Recombinants; Regulation; Reporting; Research Project Grants; Risk; Role; Schwann Cells; Schwannian Stroma; Site-Directed Mutagenesis; Stromal Cells; Tertiary Protein Structure; Testing; Tissue Inhibitor of Metalloproteinases; Tumor-Derived; Xenograft procedure; angiogenesis; antiangiogenesis therapy; cell stroma; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; outcome forecast; paracrine; pigment epithelium-derived factor; pre-clinical; preclinical study; programs; research study; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): The pediatric cancer neuroblastoma (NB) is biologically and clinically heterogeneous. NB tumors contain both neuroblastic/ganglionic cells and Schwannian stroma. The presence of abundant Schwannian stroma favorably impacts prognosis and is inversely correlated with tumor vascularity. Schwann cells as well as differentiated NB tumor cells produce a spectrum of angiogenesis inhibitors including tissue inhibitor of metalloproteinase-2 (TIMP-2) and pigment epithelium-derived factor (PEDF). Chromatography studies have recently led to the identification of another Schwann cell-derived secreted inhibitor of angiogenesis, Secreted Protein Acidic and Rich in Cysteine (SPARC). In vitro and in vivo studies show that SPARC potently inhibits angiogenesis, and that SPARC induces endothelial cell apoptosis. We hypothesize that the low level of vascularity and more benign clinical behavior of NB tumors with abundant Schwannian stroma results from the Schwann cell production of a spectrum of angiogenesis inhibitors, and that SPARC is a key contributor to the anti-angiogenic activity of factors secreted by the Schwann cells. In the current proposal, the role SPARC plays in the regulation of NB angiogenesis will be investigated. The first specific aim is to examine the effects of SPARC on NB tumor vascularity and growth in vivo. We plan to expand and extend our preliminary preclinical studies that suggest that SPARC inhibits NB angiogenesis. SPARC will be administered to animals with subcutaneous NB xenografts as well as an orthotopic NB nude mouse model using ALZET osmotic pumps. Additional experiments will be performed testing the effects of exogenously expressed SPARC on tumor growth. The second specific aim is to produce and characterize recombinant SPARC, and SPARC domains and peptides that confer angiogenesis inhibitory activity. Recombinant proteins and peptides found to have anti-angiogenesis activity will be further evaluated in the preclinical models. The third specific aim of this grant is to delineate the mechanisms by which SPARC induces apoptosis and analyze its effects on endothelial cell function. The studies outlined in this grant will lead to a further understanding of the complex regulation of angiogenesis in NB, and provide insight into the role that SPARC plays in determining NB phenotype. The long-term goal of this research grant is to generate potent anti-angiogenic SPARC-derived molecules that will prove to be effective in the treatment of children with highly vascular, clinically aggressive NB.

描述（由申请人提供）：小儿癌神经母细胞瘤（NB）在生物学和临床上是异质的。 NB肿瘤既包含神经细胞/神经节细胞和雪旺氏基质。大量的雪旺尼基质的存在对预后有利，并且与肿瘤血管成反比。 Schwann细胞以及分化的NB肿瘤细胞会产生一系列血管生成抑制剂，包括金属蛋白酶-2（TIMP-2）的组织抑制剂（TIMP-2）和颜料上皮细胞衍生因子（PEDF）。色谱研究最近导致鉴定出Schwann细胞衍生的分泌的血管生成抑制剂，分泌的蛋白质酸性并富含半胱氨酸（SPARC）。体外和体内研究表明，SPARC有效抑制血管生成，而SPARC诱导内皮细胞凋亡。我们假设，具有丰富的Schwannian基质的NB肿瘤的低血管性和更良性的临床行为是由于schwann细胞产生的血管生成抑制剂的谱系，而SPARC是Schwann细胞分泌的抗血管生成活性的关键因素。在当前的建议中，将研究SPARC在调节NB血管生成中的作用。第一个具体目的是检查SPARC对体内NB肿瘤血管性和生长的影响。我们计划扩展和扩展我们的初步临床前研究，这表明SPARC抑制NB血管生成。 SPARC将用于使用Alzet渗透泵的原位NB裸小鼠模型，以皮下NB异种移植物以及原位NB裸鼠模型施用SPARC。将进行其他实验，以测试外源表达的SPARC对肿瘤生长的影响。第二个特定目的是产生和表征重组SPARC，以及赋予血管生成抑制活性的SPARC结构域和肽。在临床前模型中将进一步评估发现具有抗血管生成活性的重组蛋白和肽。该赠款的第三个具体目的是描述SPARC诱导凋亡并分析其对内皮细胞功能的影响的机制。该赠款中概述的研究将进一步了解NB中血管生成的复杂调控，并洞悉SPARC在确定NB表型中所起的作用。这项研究补助金的长期目标是产生有效的抗血管生成SPARC衍生的分子，这些分子将被证明可以有效治疗高度血管，临床上侵略性NB的儿童。

项目成果

Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors.

• DOI: 10.1038/modpathol.2009.52
• 发表时间: 2009-07
• 期刊: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors.

• DOI: 10.1186/1476-4598-9-138
• 发表时间: 2010-06-04
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Chlenski A;Guerrero LJ;Peddinti R;Spitz JA;Leonhardt PT;Yang Q;Tian Y;Salwen HR;Cohn SL
• 通讯作者: Cohn SL