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Prokineticin signaling is required for the maintenance of a de novo population of c-KIT+ cells to sustain neuroblastoma progression

Oncogene volume 34, pages 1019–1034 (2015)Cite this article

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Abstract

High cellular heterogeneity within neuroblastomas (NBs) may account for the non-uniform response to treatment. c-KIT+ cells are frequently detected in NB, but how they influence NB behavior still remains elusive. Here, we used NB tumor-initiating cells to reconstitute NB development and demonstrated that c-KIT+ cells are de novo generated and dynamically maintained within the tumors to sustain tumor progression. c-KIT+ NB cells express higher levels of neural crest and stem cell markers (SLUG, SOX2 and NANOG) and are endowed with high clonogenic capacity, differentiation plasticity and are refractory to drugs. With serial transplantation assays, we found that c-KIT expression is not required for tumor formation, but c-KIT+ cells are more aggressive and can induce tumors ninefold more efficiently than c-KIT−/low cells. Intriguingly, c-KIT+ cells exhibited a long-term in vivo self-renewal capacity to sustain the formation of secondary and tertiary tumors in mice. In addition, we showed that Prokineticin signaling and mitogen-activated protein kinase pathways are crucial for the maintenance of c-KIT+ cells in tumor to promote NB progression. Our results highlight the importance of this de novo population of NB cells in sustainable growth of NB and reveal specific signaling pathways that may provide targets leading to more effective NB therapies.

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Acknowledgements

Seed funding grant for basic research from the University of Hong Kong, General Research Grant HKU773909 from the Hong Kong Research Grants Council, research grant from Hong Kong Children’s Cancer Foundation and SK Yee Medical Research Fund to ES-WN. Small project grant from the University of Hong Kong to S-TL. We thank Robin Lovell-Badge (MRC National Institute for Medical Research, London, UK) and Chi-Chung Hui (University of Toronto, Canada) for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Surgery, University of Hong Kong, Hong Kong SAR, China,

    S-T Lau, K K-Y Wong, P K-H Tam & E S-W Ngan

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto Medical Discovery Towers, Toronto, Ontario, Canada

    L M Hansford & D R Kaplan

  3. Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong SAR, China,

    W-K Chan & G C-F Chan

  4. Department of Pathology, University of Hong Kong, Hong Kong SAR, China,

    T S-K Wan

  5. Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong SAR, China

    P K-H Tam & E S-W Ngan

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  1. S-T Lau
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Lau, ST., Hansford, L., Chan, WK. et al. Prokineticin signaling is required for the maintenance of a de novo population of c-KIT+ cells to sustain neuroblastoma progression. Oncogene 34, 1019–1034 (2015). https://doi.org/10.1038/onc.2014.24

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