title: EphB2 activation is required for ependymoma development as well as inhibits differentiation and promotes proliferation of the transformed cell.
abstract: Our intracranial implantation mouse model of ependymoma clearly demonstrates overexpression of the ephrin receptor EphB2 in Ink4a/Arf((-/-)) supratentorial embryonic neural stem cells (STeNSCs) to be essential for transformation and disease development; however the requirement for and consequence of receptor activation on transformation and neural stem cell function were not examined. We definitively illustrate the necessity for receptor activation in cellular transformation and the importance of implantation site and microenvironment in directing ependymoma development. In vitro assays of EphB2 overexpressing Ink4a/Arf((-/-)) STeNSCs showed no changes in their neural stem cell characteristics (stem cell marker expression and self-renewal) upon receptor activation, but EphB2 driven tumor cells were inhibited significantly in differentiation and exhibited increased tumorsphere formation and cellular proliferation in response to ephrin-B ligand mediated receptor activation. Additionally, we observed substantial differences in the phosphorylation state of several key proteins involved in Ras and p38 MAPK signaling when comparing EphB2 overexpressing Ink4a/Arf((-/-)) STeNSCs and tumor cells with relatively little change in total protein levels. We propose that EphB2 mediated ependymoma development is a multifactorial process requiring microenvironment directed receptor activation, resulting in changes in the phosphorylation status of key regulatory proteins, maintenance of a stem-like state and cellular proliferation.
authors: Center For Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital.
authors: Phylip
authors: P
authors: Chen
authors: Center For Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital.
authors: Nathan
authors: N
authors: Rossi
authors: Center For Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital.
authors: Samuel
authors: S
authors: Priddy
authors: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and Department of Pathology, The Ohio State University College of Medicine.
authors: Christopher R
authors: CR
authors: Pierson
authors: Center For Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital.
authors: Adam W
authors: AW
authors: Studebaker
authors: 1] Center For Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital [2] Department of Pediatrics, The Ohio State University College of Medicine.
authors: Robert A
authors: RA
authors: Johnson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004806:Ependymoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D036183:Receptor, EphB2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins