title: Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells.
abstract: Neuroblastoma (NB)-associated endothelial microvessels (EMs) may be lined by tumor-derived endothelial cells (TECs), that are genetically unstable and chemoresistant. Here we have addressed the identification of TEC progenitors in NB by focusing on Octamer-binding transcription factor 4 (Oct-4) as a putative marker. Oct-4(+) cells were detected in primary NB samples (n = 23), metastatic bone marrow aspirates (n = 10), NB cell lines (n = 4), and orthotopic tumors (n = 10) formed by the HTLA-230 NB cell line in immunodeficient mice. Most Oct-4(+) cells showed a perivascular distribution, with 5% of them homing in perinecrotic areas. All Oct-4(+) cells were tumor-derived since they shared amplification of MYCN oncogene with malignant cells. Perivascular Oct-4(+) cells expressed stem cell-related, neural progenitor-related and NB-related markers, including surface Tenascin C (TNC), that was absent from perinecrotic Oct-4(+) cells and bulk tumor cells. TNC(+) but not TNC(-) HTLA-230 cells differentiated in vitro into endothelial-like cells expressing vascular-endothelial-cadherin, prostate-specific membrane antigen and CD31 upon culture in medium containing vascular endothelial growth factor (VEGF). TNC(+) but not TNC(-) HTLA-230 cells formed neurospheres when cultured in serum-free medium. Both cell fractions were tumorigenic, but only tumors formed by TNC(+) cells contained EMs lined by TECs. In conclusion, we have identified in NB tumors two putative niches containing Oct-4(+) tumor cells. Oct-4(+)/TNC(+) perivascular NB cells displayed a high degree of plasticity and served as progenitors of TECs. Therapeutic targeting of Oct4(+)/TNC(+) progenitors may counteract the contribution of NB-derived ECs to tumor relapse and chemoresistance.
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Largo G. Gaslini 5, 16147 Genova-Quarto, Italy. annalisapezzolo@ospedale-gaslini.ge.it
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pezzolo
authors.forename: Federica
authors.initials: F
authors.lastname: Parodi
authors.forename: Danilo
authors.initials: D
authors.lastname: Marimpietri
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.forename: Claudia
authors.initials: C
authors.lastname: Cocco
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.forename: Manuela
authors.initials: M
authors.lastname: Mosconi
authors.forename: Claudio
authors.initials: C
authors.lastname: Gambini
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019063:Tenascin / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D015513:Oncogene Proteins; C494173:POU5F1 protein, human; D019063:Tenascin