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Circulating tumor cells as Trojan Horse for understanding, preventing, and treating cancer: a critical appraisal

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Abstract

Circulating tumor cells (CTCs) are regarded as harbingers of metastases. Their ability to predict response to therapy, relapse, and resistance to treatment has proposed their value as putative diagnostic and prognostic indicators. CTCs represent one of the zeniths of cancer evolution in terms of cell survival; however, the triggers of CTC generation, the identification of potentially metastatic CTCs, and the mechanisms contributing to their heterogeneity and aggressiveness represent issues not yet fully deciphered. Thus, prior to enabling liquid biopsy applications to reach clinical prime time, understanding how the above mechanistic information can be applied to improve treatment decisions is a key challenge. Here, we provide our perspective on how CTCs can provide mechanistic insights into tumor pathogenesis, as well as on CTC clinical value. In doing so, we aim to (a) describe how CTCs disseminate from the primary tumor, and their link to epithelial–mesenchymal transition (EMT); (b) trace the route of CTCs through the circulation, focusing on tumor self-seeding and the possibility of tertiary metastasis; (c) describe possible mechanisms underlying the enhanced metastatic potential of CTCs; (d) discuss how CTC could provide further information on the tissue of origin, especially in cancer of unknown primary origin. We also provide a comprehensive review of meta-analyses assessing the prognostic significance of CTCs, to highlight the emerging role of CTCs in clinical oncology. We also explore how cell-free circulating tumor DNA (ctDNA) analysis, using a combination of genomic and phylogenetic analysis, can offer insights into CTC biology, including our understanding of CTC heterogeneity and tumor evolution. Last, we discuss emerging technologies, such as high-throughput quantitative imaging, radiogenomics, machine learning approaches, and the emerging breath biopsy. These technologies could compliment CTC and ctDNA analyses, and they collectively represent major future steps in cancer detection, monitoring, and management.

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Acknowledgements

This study was not supported by any funding or grant scheme. AFAM is highly indebted to Anna S. Gkika for her continuous support during this study. AFAM would like to dedicate this study to the memory of late Prof. George Vlastos, M.D., Ph.D., who served as Head of the Senology Unit, University Hospitals of Geneva, Switzerland. Prof. Vlastos provided the initial inspiration to AFAM to work on this topic.

Author information

Authors and Affiliations

  1. Public Health Laboratories, Hellenic Pasteur Institute, Athens, Greece

    Alexios-Fotios A. Mentis

  2. Department of Microbiology, University Hospital of Thessaly, Larissa, Greece

    Alexios-Fotios A. Mentis

  3. Division of Oncology, Department of Medicine, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Petros D. Grivas

  4. Department of Neurology, University Hospital of Thessaly, Larissa, Greece

    Efthimios Dardiotis

  5. Department of Urology, Columbia University Medical Center, Vagelos College of Physicians and Surgeons, New York, NY, USA

    Nicholas A. Romas

  6. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street-Bldg. 16, 11527, Athens, Greece

    Athanasios G. Papavassiliou

Authors
  1. Alexios-Fotios A. Mentis
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  2. Petros D. Grivas
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  3. Efthimios Dardiotis
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  4. Nicholas A. Romas
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  5. Athanasios G. Papavassiliou
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Contributions

AFAM, PG, ED, NAR, and AGP conceived the study. AFAM, PG, and ED performed literature search. NAR provided critical clinical input to this study. AGP supervised this study. AFAM, PG, and ED prepared first draft. NAR and AGP revised the manuscript for important intellectual content. AFAM, PG, ED, NAR, and AGP approved the final version of the manuscript.

Corresponding author

Correspondence to Athanasios G. Papavassiliou.

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Conflict of interest

AFAM, ED, NAR, and AGP report no financial or other conflicts of interest. PDG has provided unrelated consulting/advisory role for the following entities in the last 2 years: Merck, Bristol-Myers Squibb, AstraZeneca, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver, Pfizer, QED Therapeutics, Heron Therapeutics, Janssen, Bayer, Genzyme, Mirati Therapeutics, Exelixis, Roche, GlaxoSmithKline. Also, he has received Research Funding at his Institution from the following entities: Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Bristol-Myers Squibb, and Debiopharm Group.

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Mentis, AF.A., Grivas, P.D., Dardiotis, E. et al. Circulating tumor cells as Trojan Horse for understanding, preventing, and treating cancer: a critical appraisal. Cell. Mol. Life Sci. 77, 3671–3690 (2020). https://doi.org/10.1007/s00018-020-03529-4

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  • DOI: https://doi.org/10.1007/s00018-020-03529-4

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