Abstract 2674: Stroma biology identifies heparins as differentiating agents in neuroblastoma

Abstract

Abstract The neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here we identify these factors and design a novel therapy based on their mechanism of action. We show that expression of heparan-sulfate proteoglycan co-receptors (HSPGs), including TβRIII, GPC1, GPC3, SDC3, and SDC4, is decreased in neuroblasts, localized to the stroma and correlates with improved prognosis. Treatment with soluble HSPGs promoted neuroblast differentiation via FGFR1, Erk, and Id1. HSPGs also enhanced differentiation from FGF2 released by the stroma. The anticoagulant heparin had similar differentiating effects, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-de-sulfated heparin (ODSH) as a differentiating agent that suppressed orthotopic xenograft growth while avoiding anticoagulation. These studies uncover the critical components of the differentiating stroma secretome in neuroblastoma and the central mechanism by which they act. We translate these biologic insights into novel prognostic and therapeutic biomarkers, as well as therapeutic differentiation strategies for clinical development. More generally, our work demonstrates that tumor stroma biology can inform design of targeted molecular therapeutics. Citation Format: Erik H. Knelson, Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, Gerard C. Blobe. Stroma biology identifies heparins as differentiating agents in neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2014-2674