Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation.
High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma.HBEGFmRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis.-Gaviglio, A. L., Knelson, E. H., Blobe, G. C. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Angela L
AL
Gaviglio
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; and.
Erik H
EH
Knelson
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA; gerard.blobe@duke.edu.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Gerard C
GC
Blobe
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
C587883:HBEGF protein, human; D019812:Heparan Sulfate Proteoglycans; D066257:Heparin-binding EGF-like Growth Factor; D066246:ErbB Receptors
HBEGF; cancer; heparan sulfate; signaling; stroma