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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Dasari, A. et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the united states. JAMA Oncol. 3, 1335–1342 (2017).
Riihimaki, M., Hemminki, A., Sundquist, K., Sundquist, J. & Hemminki, K. The epidemiology of metastases in neuroendocrine tumors. Int. J. Cancer 139, 2679–2686 (2016).
Strosberg, J., Gardner, N. & Kvols, L. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology 89, 471–476 (2009).
Cives, M. et al. Reviewing the osteotropism in neuroendocrine tumors: the role of epithelial-mesenchymal transition. Neuroendocrinology 103, 321–334 (2016).
Mazo, I. B., Massberg, S. & von Andrian, U. H. Hematopoietic stem and progenitor cell trafficking. Trends Immunol. 32, 493–503 (2011).
Taichman, R. S. et al. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 62, 1832–1837 (2002).
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Circelli, L. et al. CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. Oncotarget 7, 18865–18875 (2016).
Kaemmerer, D. et al. Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms. Oncotarget 6, 3346–3358 (2015).
Kaemmerer, D. et al. Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget 6, 27566–27579 (2015).
Arvidsson, Y. et al. Hypoxia stimulates CXCR4 signalling in ileal carcinoids. Endocr. Relat. Cancer 17, 303–316 (2010).
Cives, M. et al. Osteotropism of neuroendocrine tumors: role of the CXCL12/ CXCR4 pathway in promoting EMT in vitro. Oncotarget 8, 22534–22549 (2017).
Khan, M. S. et al. Circulating tumor cells and EpCAM expression in neuroendocrine tumors. Clin. Cancer Res. 17, 337–345 (2011).
Khan, M. S. et al. Circulating tumor cells as prognostic markers in neuroendocrine tumors. J. Clin. Oncol. 31, 365–372 (2013).
Khan, M. S. et al. Early changes in circulating tumor cells are associated with response and survival following treatment of metastatic neuroendocrine neoplasms. Clin. Cancer Res. 22, 79–85 (2016).
Childs, A. et al. Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours. Br. J. Cancer 115, 1540–1547 (2016).
Helo, P. et al. Circulating prostate tumor cells detected by reverse transcription-PCR in men with localized or castration-refractory prostate cancer: concordance with CellSearch assay and association with bone metastases and with survival. Clin. Chem. 55, 765–773 (2009).
De Giorgi, U. et al. Circulating tumor cells and bone metastases as detected by FDG-PET/CT in patients with metastatic breast cancer. Ann. Oncol. 21, 33–39 (2010).
Cheng, M., Liu, L., Yang, H. S. & Liu, G. F. Circulating tumor cells are associated with bone metastasis of lung cancer. Asian Pac. J. Cancer Prev. 15, 6369–6374 (2014).
Salgia, R. et al. Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study. Invest. New Drugs 35, 334–344 (2017).
Marafioti, T. et al. Novel markers of normal and neoplastic human plasmacytoid dendritic cells. Blood 111, 3778–3792 (2008).
Patel, L. R., Camacho, D. F., Shiozawa, Y., Pienta, K. J. & Taichman, R. S. Mechanisms of cancer cell metastasis to the bone: a multistep process. Future Oncol. 7, 1285–1297 (2011).
Don-Salu-Hewage, A. S. et al. Cysteine (C)-x-C receptor 4 undergoes transportin 1-dependent nuclear localization and remains functional at the nucleus of metastatic prostate cancer cells. PLoS. ONE. 8, e57194 (2013).
Wang, S. C. et al. Nuclear expression of CXCR4 is associated with advanced colorectal cancer. Int. J. Colorectal Dis. 25, 1185–1191 (2010).
Masuda, T. et al. Nuclear expression of chemokine receptor CXCR4 indicates poorer prognosis in gastric cancer. Anticancer Res. 34, 6397–6403 (2014).
Busillo, J. M. & Benovic, J. L. Regulation of CXCR4 signaling. Biochim. Biophys. Acta 1768, 952–963 (2007).
Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 22, 725–736 (2012).
Tsuji, T. et al. Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res. 68, 10377–10386 (2008).
Baccelli, I. et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat. Biotechnol. 31, 539–544 (2013).
Werner, R. A. et al. Imaging of chemokine receptor 4 expression in neuroendocrine tumors - a triple tracer comparative approach. Theranostics 7, 1489–1498 (2017).
Kashyap, M. K. et al. Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway. Oncotarget 7, 2809–2822 (2016).
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.
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.