title: Bone marrow of neuroblastoma patients shows downregulation of CXCL12 expression and presence of IFN signature.
abstract: BACKGROUND
  At diagnosis, children with neuroblastoma (NB) present with either localized or metastatic disease. Since the mechanisms responsible for BM invasion are not well known, we investigated the transcriptome of resident BM cells from NB patients as compared to healthy children.
  
  
  METHODS
  Ninety-two and 88 children with localized and metastatic NB, respectively, and 15 healthy children were included in the study. BM resident cells recovered from BM aspirates by immunomagnetic bead manipulation were subjected to genome-wide microarray analysis. After validation in an independent set of samples, the genes significantly modulated in resident BM cells from NB patients were tested for their diagnostic/prognostic values.
  
  
  RESULTS
  BM resident cells, irrespective of neoplastic cell invasion, significantly overexpressed genes involved in innate immune responses, and interferon (IFN) and IFN-DRS signatures were enriched. Genes coding for metallothioneins and zinc finger proteins, and involved in histone and nucleosome/chromatin organization were also overexpressed. Resident BM cells from NB patients significantly downregulated genes involved in cell adhesion, and in erythrocyte, myeloid, and platelet differentiation pathways. Among downregulated genes, CXCL12 expression reached near complete silencing in patients with metastatic disease. The downregulation of CXCL12 expression was independent of contact between NB cell and resident BM cell.
  
  
  CONCLUSIONS
  We demonstrated that NB tumor growth at the primary site can alter the BM microenvironment, and the presence of BM-infiltrating NB cells makes the alterations more pronounced. Therefore, the restoration of a BM physiological state by means of IFN-α monoclonal antibody, Sifalimumab, and selective noradrenaline receptor blockers should be further studied to ameliorate patients' clinical management.
authors: Translational Oncopathology, National Cancer Research Institute, Genoa, Italy.
authors: Paola
authors: P
authors: Scaruffi
authors: Fabio
authors: F
authors: Morandi
authors: Fabio
authors: F
authors: Gallo
authors: Sara
authors: S
authors: Stigliani
authors: Stefano
authors: S
authors: Parodi
authors: Stefano
authors: S
authors: Moretti
authors: Stefano
authors: S
authors: Bonassi
authors: Paolo
authors: P
authors: Fardin
authors: Alberto
authors: A
authors: Garaventa
authors: Giulio
authors: G
authors: Zanazzo
authors: Vito
authors: V
authors: Pistoia
authors: Gian Paolo
authors: GP
authors: Tonini
authors: Maria Valeria
authors: MV
authors: Corrias
mesh_terms: D000293:Adolescent; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007372:Interferons / Q000096:biosynthesis*; D007558:Italy; D008297:Male; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012042:Registries; D012189:Retrospective Studies; D059016:Tumor Microenvironment
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D009363:Neoplasm Proteins; D007372:Interferons