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, A.P., Chayka, O., Regad, T. ORCID: 0000-0003-4028-6368, Pistorio, A., Sementa, A.R., Virasami, A., Barton, J., Montano, X., Lechertier, T., Brindle, N., Morgenstern, D., Le Bras, M., Burns, A., Saunders, N., Hodivala-Dilke, K., Bagella, L., de The, H., Anderson, J., Sebire, N., Pistoia, V., Sala, A. and Salomoni, P., 2016. A promyelocytic leukemia protein-thrombospondin 2 axis and the risk of relapse in neuroblastoma. Clinical Cancer Research, 22 (13), pp. 3398-3409. ISSN 1078-0432

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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. Dvorkina et al. A promyelocytic leukaemia protein-thrombospondin 2 axis and the risk of relapse in neuroblastoma 3 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.

Item Type: Journal article
Publication Title: Clinical Cancer Research
Creators: Dvorkina, M., Nieddu, V., Chakelam, S., Pezzolo, A., Cantilena, S., Leite, A.P., Chayka, O., Regad, T., Pistorio, A., Sementa, A.R., Virasami, A., Barton, J., Montano, X., Lechertier, T., Brindle, N., Morgenstern, D., Le Bras, M., Burns, A., Saunders, N., Hodivala-Dilke, K., Bagella, L., de The, H., Anderson, J., Sebire, N., Pistoia, V., Sala, A. and Salomoni, P.
Publisher: American Association for Cancer Research
Date: 2016
Volume: 22
Number: 13
ISSN: 1078-0432
Identifiers:
NumberType
10.1158/1078-0432.CCR-15-2081DOI
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 21 Apr 2016 13:11
Last Modified: 13 Oct 2017 09:20
URI: http://irep.ntu.ac.uk/id/eprint/27660

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