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Circulating tumour cells and their association with bone metastases in patients with neuroendocrine tumours

British Journal of Cancervolume 120pages294300 (2019) | Download Citation



Bone metastases are associated with a worse outcome in patients with neuroendocrine tumours (NETs). Tumour overexpression of C-X-C chemokine receptor 4 (CXCR4) appears predictive of skeletal involvement. We investigated the role of circulating tumour cells (CTCs) and CXCR4 expression on CTCs as potential predictors of skeleton invasion.


Blood from patients with metastatic bronchial, midgut or pancreatic NET (pNET) was analysed by CellSearch. CXCR4 immunohistochemistry was performed on matched formalin-fixed paraffin-embedded (FFPE) samples.


Two hundred and fifty-four patients were recruited with 121 midgut and 119 pNETs, of which 51 and 36% had detectable CTCs, respectively. Bone metastases were reported in 30% of midgut and 23% of pNET patients and were significantly associated with CTC presence (p = 0.003 and p < 0.0001). In a subgroup of 40 patients, 85% patients with CTCs had CTCs positive for CXCR4 expression. The proportion of CXCR4-positive CTCs in patients with bone metastases was 56% compared to 35% in those without (p = 0.18) it. Staining for CXCR4 on matched FFPE tissue showed a trend towards a correlation with CXCR4 expression on CTCs (p = 0.08).


CTC presence is associated with bone metastases in NETs. CXCR4 may be involved in CTC osteotropism and present a therapeutic target to reduce skeletal morbidity.

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Prof. Tim Meyer is partly funded by UCLH Biomedical Research Centre and the work was supported by the UCL Experimental Cancer Medicine Centre. This research project was supported by ESMO with the aid of a grant from Roche and by University College London Cancer Research UK (UCL CRUK) Development Fund Award No. 163011. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche.

Author contributions

F.M.R. and T.M. wrote the manuscript. F.M.R., C.V., A.C., F.S., T.M. contributed to study design and conduct. T.M., L.E., H.L., A.U.A., T.L., J.A.H. contributed to the analysis of blood and tissue samples. A.C., M.S.K., D.M., M.C., C.T., D.K., C.T., and T.M. contributed to the recruitment of patients. M.C. analysed the data and provided statistical support. All authors were involved in revising the manuscript critically, approving the final version for submission and agreeing to be accountable for all aspects of the work.

Author information


  1. Department of Oncology, UCL Cancer Institute, University College London, London, UK

    • Francesca M. Rizzo
    • , Clare Vesely
    • , Alexa Childs
    • , Leah Ensell
    • , Helen Lowe
    • , Christina Thirlwell
    • , John A. Hartley
    •  & Tim Meyer
  2. Department of Pathology, UCL Cancer Institute, University College London, London, UK

    • Teresa Marafioti
    •  & Ayse U. Akarca
  3. Wales Neuroendocrine Tumour Service, Department of Gastroenterology, University Hospital of Wales, Cardiff, UK

    • Mohid S. Khan
  4. Neuroendocrine Tumour Unit, Department of Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK

    • Dalvinder Mandair
    • , Martyn Caplin
    •  & Christos Toumpanakis
  5. Department of Biomedical Sciences and Human Oncology, University of Bari “A. Moro”, Bari, Italy

    • Mauro Cives
    •  & Franco Silvestris
  6. Department of Histopathology, Royal Free London NHS Foundation Trust, London, UK

    • TuVinh Luong
  7. Neuroendocrine Tumour Unit, Department of Oncology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK

    • Daniel Krell
    • , Christina Thirlwell
    •  & Tim Meyer


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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Central Ethics Committee (IRAS ref 13/LO/0376) and performed in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Availability of data and material

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Tim Meyer.

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