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Molecular mechanisms of metastasis in breast cancer—clinical applications

Nature Reviews Clinical Oncology volume 7, pages 693–701 (2010)Cite this article

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Abstract

The metastatic cascade is a series of biological processes that enable the movement of tumor cells from the primary site to a distant location and the establishment of a new cancer growth. Circulating tumor cells (CTCs) have a crucial role in tumor dissemination. The role of CTCs in treatment failure and disease progression can be explained by their relation to biological processes, including the epithelial-to-mesenchymal transition and 'self seeding', defined as reinfiltration of the primary tumor or established metastasis by more aggressive CTCs. CTCs are a unique and heterogeneous cell population with established prognostic and predictive value in certain clinical situations. The possibility of collecting sequential blood samples for real-time monitoring of systemic-therapy efficacy presents new possibilities to evaluate targeted therapies based on the genomic profiling of CTCs and to improve the clinical management of patients by personalized therapy. Interruption of the metastatic cascade via the targeting of CTCs might be a promising therapeutic strategy.

Key Points

  • Circulating tumor cells (CTCs) have a crucial role in the metastatic cascade, tumor dissemination and progression

  • Experimental and clinical data suggest that the epithelial-to-mesenchymal transition has an important role in the generation of CTCs and the acquisition of resistance to therapy

  • CTCs represent a heterogeneous population of cells with different phenotypes and biological value

  • Detection of CTCs could represent a valuable prognostic and predictive factor, a tool for tumor biopsy in real time and for personalized anticancer treatment

  • Novel clinical design incorporating CTCs as short-term molecular and pharmacodynamic end points should be considered

  • Blockade of tumor dissemination and self seeding via the targeting of CTCs holds great therapeutic promise for the future

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Figure 1: Factors affecting CTCs count.
Figure 2: EMT may generate therapeutically resistant cancer stem cells.
Figure 3: Heterogeneity of CTCs based on expression of epithelial and mesenchymal antigens.

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Acknowledgements

We acknowledge J. M. Reuben for discussions and critical input and K. Evans for critical reading of this Review. We apologize to the many researchers whose work we were unable to cite owing to space restrictions. M. Cristofanilli is the recipient of a grant from the State of Texas Rare and Aggressive Breast Cancer Research Program. M. Mego was supported by International Union Against Cancer, American Cancer Society International Fellowship for Beginning Investigators (ACSBI Award ACS/08/006). M. Cristofanilli and S. A. Mani are the recipients of a R01 grant from National Cancer Institute entitled Human breast cancer stem cell surrogates.

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Authors and Affiliations

  1. Department of Medical Oncology, Comenius University, School of Medicine, Klenova 1, Bratislava 833 10, Slovakia

    Michal Mego

  2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    Sendurai A. Mani

  3. Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111–2497, PA, USA

    Massimo Cristofanilli

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M. Mego researched the data for the article. All authors provided a substantial contribution to discussions of the content and writing the article. S. A. Mani and M. Cristofanilli contributed to the review and/or editing of the manuscript before submission.

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Correspondence to Massimo Cristofanilli.

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Mego, M., Mani, S. & Cristofanilli, M. Molecular mechanisms of metastasis in breast cancer—clinical applications. Nat Rev Clin Oncol 7, 693–701 (2010). https://doi.org/10.1038/nrclinonc.2010.171

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