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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049814-02
Application #
6915629
Study Section
Special Emphasis Panel (ZRG1-DT (01))
Program Officer
Finkelstein, Robert
Project Start
2004-07-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$284,391
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Zeine, Rana; Salwen, Helen R; Peddinti, Radhika et al. (2009) Presence of cancer-associated fibroblasts inversely correlates with Schwannian stroma in neuroblastoma tumors. Mod Pathol 22:950-8
Schneiderman, Jennifer; London, Wendy B; Brodeur, Garrett M et al. (2008) Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group. J Clin Oncol 26:913-8
Yang, Qiwei; Tian, Yufeng; Liu, Shuqing et al. (2007) Thrombospondin-1 peptide ABT-510 combined with valproic acid is an effective antiangiogenesis strategy in neuroblastoma. Cancer Res 67:1716-24
Yang, Qiwei; Kiernan, Colleen M; Tian, Yufeng et al. (2007) Methylation of CASP8, DCR2, and HIN-1 in neuroblastoma is associated with poor outcome. Clin Cancer Res 13:3191-7
Peddinti, Radhika; Zeine, Rana; Luca, Dragos et al. (2007) Prominent microvascular proliferation in clinically aggressive neuroblastoma. Clin Cancer Res 13:3499-506
Chlenski, A; Guerrero, L J; Yang, Q et al. (2007) SPARC enhances tumor stroma formation and prevents fibroblast activation. Oncogene 26:4513-22
Maris, John M; Hogarty, Michael D; Bagatell, Rochelle et al. (2007) Neuroblastoma. Lancet 369:2106-20
Chlenski, Alexandre; Liu, Shuqing; Guerrero, Lisa J et al. (2006) SPARC expression is associated with impaired tumor growth, inhibited angiogenesis and changes in the extracellular matrix. Int J Cancer 118:310-6
Liu, Shuqing; Tian, Yufeng; Chlenski, Alexandre et al. (2005) 'Cross-talk' between Schwannian stroma and neuroblasts promotes neuroblastoma tumor differentiation and inhibits angiogenesis. Cancer Lett 228:125-31
Liu, Shuqing; Tian, Yufeng; Chlenski, Alexandre et al. (2005) Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma xenografts. Am J Pathol 166:891-900

Showing the most recent 10 out of 11 publications