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A promyelocytic leukemia protein-thrombospondin 2 axis and the risk of relapse in neuroblastoma

Dvorkina, M; Nieddu, V; Chakelam, S; Pezzolo, A; Cantilena, S; Leite, AP; Chayka, O; ... Salomoni, P; + view all (2016) A promyelocytic leukemia protein-thrombospondin 2 axis and the risk of relapse in neuroblastoma. Clinical Cancer Research , 22 (13) pp. 3398-3409. 10.1158/1078-0432.CCR-15-2081. Green open access

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Abstract

PURPOSE: 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 tumour 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. EXPERIMENTAL DESIGN: Neuroblastoma cell lines were used for assessment of tumour growth in vivo and in vitro. Protein expression in tissues and cells was assessed using immunofluorescence and immunohistochemistry. The association of PML expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann-Whitney tests, respectively. Gene expression was assessed using chip microarrays. RESULTS: PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or low in metastatic neuroblastoma tumours. Reduced PML expression in patients with low-risk cancers - i.e. localized and negative for the MYCN protooncogene - is strongly associated with tumour recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP-2), a key inhibitor of angiogenesis. Finally, PML-I and TSP-2 expression inversely correlates with tumour angiogenesis and recurrence in localized neuroblastomas. CONCLUSIONS: Our work reveals a novel PML-I-TSP2 axis for regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumours that might benefit from chemotherapy.

Type: Article
Title: A promyelocytic leukemia protein-thrombospondin 2 axis and the risk of relapse in neuroblastoma
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-15-2081
Publisher version: http://dx.doi.org/10.1158/1078-0432.CCR-15-2081
Language: English
Additional information: Copyright © 2016, American Association for Cancer Research.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Pop, Policy and Practice Prog
URI: http://discovery.ucl.ac.uk/id/eprint/1482388
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