title: Reelin signalling in neuroblastoma: migratory switch in metastatic stages.
abstract: The essential functions of Reelin for the migratory behaviour of neuroblasts in the central nervous system are well documented. Its role in the dissemination of neuronal tumours of the peripheral nervous system has not been studied in detail. Here, we examined neuroblastoma (NB), a tumour derived from sympathoadrenal cells of neural crest origin. We studied the expression of Reelin, its receptors VLDLR and LRP8 and the adapter protein DAB1 in primary tumour samples and cell lines. We used real-time RT-PCR, immunohistology and western blot analysis. In NB cell lines we studied effects of all-trans retinoic acid and the in vitro effects of Reelin. In primary tumour samples of untreated patients, a significant downregulation of Reelin and DAB1 mRNA was found in the metastatic stages 3, 4 and 4s. Immunohistochemical studies revealed expression of Reelin, LRP8 and DAB1 in differentiating-type low-grade NB. In vitro, western blot analysis of selected NB cell lines showed variable expression patterns. Differentiation induction with all-trans retinoic acid induced the upregulation of Reelin and DAB1. Reelin acted as a chemoattractant for various NB cell lines but inhibited migration when applied together with the NB cells. In normal tissue, we found Reelin in lymphatic endothelial cells (LECs) but not in blood vessel endothelium (BECs). In primary NB, both BECs and LECs were positive. Our data strongly suggest that Reelin has a dual role in NB. Autocrine expression marks low-grade differentiating tumour cells, whereas paracrine Reelin presented by LECs and BECs may act as a chemoattractant and promote hematogenic and lymphogenic dissemination in progressed stages.
authors.affiliation: Department of Anatomy and Cell Biology, University Medicine Goettingen, Goettingen, Germany. juergen.becker@med.uni-goettingen.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Becker
authors.forename: Johanna
authors.initials: J
authors.lastname: Fröhlich
authors.forename: Christina
authors.initials: C
authors.lastname: Perske
authors.forename: Helena
authors.initials: H
authors.lastname: Pavlakovic
authors.forename: Jörg
authors.initials: J
authors.lastname: Wilting
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D016543:Central Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D008207:Lymphatic Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000556:secondary; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; C115785:DAB1 protein, human; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; D012697:Serine Endopeptidases