title: A Promyelocytic Leukemia Protein-Thrombospondin-2 Axis and the Risk of Relapse in Neuroblastoma.
abstract: Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations.
  
  
  
  Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann-Whitney tests, respectively. Gene expression was assessed using chip microarrays.
  
  
  
  PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas.
  
  
  
  Our work reveals a novel PML-I-TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398-409. ©2016 AACR.
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Dvorkina
authors.affiliation: Department of Life Sciences, Institute of Environment and Health, Brunel University London, Uxbridge, United Kingdom. Department of Biomedical Sciences, National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nieddu
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom.
authors.forename: Shalini
authors.initials: S
authors.lastname: Chakelam
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pezzolo
authors.affiliation: Department of Life Sciences, Institute of Environment and Health, Brunel University London, Uxbridge, United Kingdom. Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cantilena
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Leite
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom. UCL Institute of Child Health, London, United Kingdom.
authors.forename: Olesya
authors.initials: O
authors.lastname: Chayka
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom. Nottingham Trent University, Nottingham, United Kingdom.
authors.forename: Tarik
authors.initials: T
authors.lastname: Regad
authors.affiliation: Nottingham Trent University, Nottingham, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.affiliation: Laboratorio di Anatomia Patologica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Angela Rita
authors.initials: AR
authors.lastname: Sementa
authors.affiliation: UCL Institute of Child Health, London, United Kingdom. Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Alex
authors.initials: A
authors.lastname: Virasami
authors.affiliation: UCL Institute of Child Health, London, United Kingdom. Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Jack
authors.initials: J
authors.lastname: Barton
authors.affiliation: UCL Institute of Child Health, London, United Kingdom. Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Ximena
authors.initials: X
authors.lastname: Montano
authors.affiliation: Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Lechertier
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brindle
authors.affiliation: UCL Institute of Child Health, London, United Kingdom. Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgenstern
authors.affiliation: Barts Cancer Institute, Queen Mary University, London, United Kingdom.
authors.forename: Morgane
authors.initials: M
authors.lastname: Lebras
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy. Birth Defects Research Centre. Dept. Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Burns
authors.affiliation: Department of Life Sciences, Institute of Environment and Health, Brunel University London, Uxbridge, United Kingdom.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Saunders
authors.affiliation: Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodivala-Dilke
authors.affiliation: Department of Biomedical Sciences, National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy. Institut Universitaire d'Hematologie, Sant-Louis Hospital, Paris Diderot University, Paris, France.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bagella
authors.affiliation: Barts Cancer Institute, Queen Mary University, London, United Kingdom.
authors.forename: Hugues
authors.initials: H
authors.lastname: De The
authors.affiliation: UCL Institute of Child Health, London, United Kingdom. Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.affiliation: UCL Institute of Child Health, London, United Kingdom. Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Neil
authors.initials: N
authors.lastname: Sebire
authors.affiliation: Nottingham Trent University, Nottingham, United Kingdom.
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.affiliation: Department of Life Sciences, Institute of Environment and Health, Brunel University London, Uxbridge, United Kingdom. p.salomoni@ucl.ac.uk Arturo.Sala@brunel.ac.uk.
authors.forename: Arturo
authors.initials: A
authors.lastname: Sala
authors.affiliation: Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom. p.salomoni@ucl.ac.uk Arturo.Sala@brunel.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Salomoni
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D009432:Neural Crest / Q000196:embryology; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D000090063:Proto-Oncogene Mas; D012307:Risk Factors; D013234:Stem Cells / Q000166:cytology; D013564:Sympathetic Nervous System / Q000196:embryology; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099262:Thrombospondin 2
chemical_list: D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D019699:Thrombospondins; D025521:Tumor Suppressor Proteins; D000099262:Thrombospondin 2; C000715470:MAS1 protein, human; C070576:PML protein, human