title: Neuroblastoma in dialog with its stroma: NTRK1 is a regulator of cellular cross-talk with Schwann cells.
abstract: In neuroblastoma, the most common solid tumor of childhood, excellent prognosis is associated with extensive Schwann cell (SC) content and high-level expression of the neurotrophin receptor, NTRK1/TrkA, which is known to mediate neuroblastoma cell differentiation. We hypothesized that both stromal composition and neuroblastic differentiation are based on bidirectional neuroblastoma-SC interaction. Reanalysis of microarray data from human SY5Y neuroblastoma cells stably transfected with either NTRK1 or NTRK2 revealed upregulation of the mRNA for the SC growth factor, NRG1, in NTRK1-positive cells. Media conditioned by NTRK1-expressing neuroblastoma cells induced SC proliferation and migration, while antibody-based NRG1 neutralization significantly decreased these effects. Vice versa, NRG1-stimulated SC secreted the NTRK1-specific ligand, NGF. SC-conditioned medium activated the NTRK1 receptor in a neuroblastoma cell culture model conditionally expressing NTRK1 and induced differentiation markers in NTRK1-expressing cells. NTRK1 induction in neuroblastoma xenografts mixed with primary SC also significantly reduced tumor growth in vivo. We propose a model for NTRK1-mediated and NRG1-dependent attraction of adjacent SC, which in turn induce neuroblastic differentiation by secretion of the NTRK1-specific ligand, NGF. These findings have implications for understanding the mature and less malignant neuroblastoma phenotype associated with NTRK1 expression, and could assist the development of new therapeutic strategies for neuroblastoma differentiation.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Pajtler
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Mahlow
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Odersky
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Lindner
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stephan
authors.affiliation: Department of Peditrics I/ Neonatology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), Germany. Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D064593:Heterografts; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human