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  • Review Article
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Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?

Nature Reviews Clinical Oncology volume 14, pages 32–44 (2017)Cite this article

Subjects

Key Points

  • Distant metastasis remains a frequent cause of death, even after locoregional disease control is achieved using surgery, radiotherapy, and/or systemic therapy

  • Antitumour therapies can, under some circumstances, mobilize tumour cells into the peripheral circulation that might influence the risk of distant metastasis

  • Irradiation can enable tumour cells to acquire properties that facilitate their dissemination and the subsequent generation of metastases

  • Several mechanisms might explain a metastasis-promoting effect derived from surgical procedures, such as tissue disruption and leakage of blood containing tumour cells

  • A potential link between systemic therapies and metastasis has not been established, but the results of isolated studies indicate that this question needs to be addressed

  • The risk of distant failure from antitumour therapy can potentially be reduced if treatment-related factors capable of promoting metastasis are identified, and targeted therapeutically

Abstract

Despite progressive improvements in the management of patients with locoregionally confined, advanced-stage solid tumours, distant metastasis remains a very common — and usually fatal — mode of failure after attempted curative treatment. Surgery and radiotherapy are the primary curative modalities for these patients, often combined with each other and/or with chemotherapy. Distant metastasis occurring after treatment can arise from previously undetected micrometastases or, alternatively, from persistent locoregional disease. Another possibility is that treatment itself might sometimes cause or promote metastasis. Surgical interventions in patients with cancer, including biopsies, are commonly associated with increased concentrations of circulating tumour cells (CTCs). High CTC numbers are associated with an unfavourable prognosis in many cancers. Radiotherapy and systemic antitumour therapies might also mobilize CTCs. We review the preclinical and clinical data concerning cancer treatments, CTC mobilization and other factors that might promote metastasis. Contemporary treatment regimens represent the best available curative options for patients who might otherwise die from locally confined, advanced-stage cancers; however, if such treatments can promote metastasis, this process must be understood and addressed therapeutically to improve patient survival.

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Figure 1: Progressive effects of fractionated radiotherapy on tumour cells in vivo.
Figure 2: Routes of cancer cell mobilisation during treatment of an intact tumour.
Figure 3: Tumour extension into the venous system.

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Acknowledgements

We are grateful to David Ball for fruitful discussions and his continuous support of our scientific initiatives, and to Bernhard Riedel for his critical reading of the manuscript. We thank Tim Akhurst for his assistance with Figure 3. O.A.M. and M.P.M. receive support from the Australian National Health and Medical Research Council (NHMRC) grant 1104139, and the Peter MacCallum Cancer Foundation grant 1218. R.L.A. receives fellowship support from the National Breast Cancer Foundation of Australia.

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Authors and Affiliations

  1. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Victoria, Australia

    Olga A. Martin, Kailash Narayan & Michael P. MacManus

  2. Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Victoria, Australia

    Olga A. Martin

  3. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000, Victoria, Australia

    Robin L. Anderson

  4. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan street, Melbourne, 3000, Victoria, Australia

    Olga A. Martin, Robin L. Anderson, Kailash Narayan & Michael P. MacManus

  5. Department of Obstetrics and Gynaecology, University of Melbourne, Grattan street, Melbourne, 3000, Victoria, Australia

    Kailash Narayan

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O.A.M., R.L.A. and M.P.M. researched data for the article, and K.N. contributed to discussion of the article's content. All authors wrote, reviewed and edited the manuscript before submission.

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Correspondence to Michael P. MacManus.

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Martin, O., Anderson, R., Narayan, K. et al. Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?. Nat Rev Clin Oncol 14, 32–44 (2017). https://doi.org/10.1038/nrclinonc.2016.128

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