Essentials of circulating tumor cells for clinical research and practice

https://doi.org/10.1016/j.critrevonc.2013.05.002Get rights and content

Abstract

The major cause of death due to cancer is its metastatic deposit in numerous tissues and organs. The metastatic process requires the migration of malignant cells from primary sites to distant environments. Even for tumors initially spreading through lymphatic vessels, hematogenous transport is the most common metastatic pathway. The detachment of cancer cells from a primary tumor into the blood stream is called epithelial–mesenchymal transition (EMT). As these cells circulate further in the bloodstream they are known as circulating tumor cells (CTCs). The CTC population is highly resilient, enabling the cells to colonize a foreign microenvironment. Alternatively, cancer stem cells (CSCs) may arise from differentiated cancer cells through EMT and an embryonic transdifferentiation process. The presence of CTCs/CSCs in blood seems to be a determining factor of metastasis.

This paper reviews various methods of clinical cancer detection as well as the biology and molecular characterization of CTCs/CSCs. Our goal was to summarize clinical studies which used CTC/CSCs for prognosis in patients with breast, colorectal, prostate, lung, ovarian, and bladder cancer.

Introduction

Tumor formation is thought to be a multi-step process characterized by the gradual accumulation of genetic alterations caused by many environmental and internal (e.g. hormonal) factors acting on an organism. The major cause of death due to cancer is metastasis in numerous organs (e.g. brain, liver, lungs, kidneys). The first step toward successful metastasing is the detachment of malignant cells from primary tumors caused by the loss of intercellular contacts in the primary tumor, cell motility and local invasivity induction [1]. This transient process is known as epithelial–mesenchymal transition (EMT). It is characterized by the reduction of epithelial and increased mesenchymal cell traits [2], [3], [4], [5]. Further intravasation into the blood or lymphatic vessels occurs to give rise to CTCs with their subsequent transport through an organism. The metastatic process continues by extravasation of CTCs from the circulation and the establishment of a secondary tumor locus in a distant organ with increased metastasis [6], [7], [8], [9].

In this review, we will review the fate of a cancer cell released from a primary tumor and to summarize prognostic reports from CTC-examination in clinical studies.

Section snippets

EMT and its role in cancer

In addition to physiological [10] and healing functions [11] of EMT (normal embryonal development [10]), EMT is also responsible for changes generating a new cancer cell population. When these cancer cells are detached from primary tumors and float in the blood they are known as CTCs [12]. It is hypothesized that CTCs may be a cellular population with high metastatic potential similar to tumor initiating cells or cancer stem cells [13]. Typical changes in tumor cells which occur during EMT and

CTC detection

Subsequent detection, quantification and molecular characterization of CTCs have an enormous potential in numerous areas of oncology. In the early stages of the disease CTCs may be used to predict the risk of generating metastasis and to assess prognosis. In the course of therapy, CTCs may be used to evaluate therapy response or as an auxiliary method to help choose a suitable therapeutic regimen. This individualizes the therapy and minimilizes potentially adverse effects. Furthermore, by

Cancer stem cells (CSCs)

Recent findings in primary tumor tissue suggest that the metastatic potential of a tumor is based on the presence of a low number of stem cell-like cells, i.e. CSCs which may be the active source of metastatic spread. EMT has been previously linked with CSC properties [141], which have been associated with increased therapeutic resistance [142], [143], [144]. They are also known as tumor initiating cells [145] and show increased tumorigenicity, self-renewal capability and ability to give rise

Conclusion

In recent years tremendous efforts have been made to better understand the role of CTCs/CSCs in patients with tumors. Despite numerous discoveries, many questions/areas remain to be investigated in order to improve the current state of therapy in oncological patients and prepare new therapeutics which selectively target CTCs/CSCs. To be able to do that, the whole process of tumor biology and metastatic spread must be better understood. CTCs are generated within EMT, a process characterized by

Reviewers

Elisabeth Comen, MD, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, New York 10165, United States.

Antonio Giordano, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, United States.

Acknowledgements

This study was supported by the Research project P 27/2012 awarded by Charles University in Prague, 3rd Faculty of Medicine, Prague, Czech Republic.

Marian Liberko, M.D., graduated in 2010, works in the Department of Radiotherapy and Oncology at the University Hospital Kralovske Vinohrady in Prague. He is a PhD student of Biomedicine in the Department of Tumor Biology, 3rd Faculty of Medicine Charles University Prague, Czech Republic. His focus is clinical and experimental research concerning circulating tumor cells.

References (247)

  • O.O. Ogunwobi et al.

    Therapeutic and prognostic importance of epithelial–mesenchymal transition in liver cancers: insights from experimental models

    Critical Reviews in Oncology/Hematology

    (2012)
  • Imai et al.

    Hypoxia attenuates the expression of E-cadherin via upregulation of SNAIL in ovarian carcinoma cells

    American Journal of Pathology

    (2003)
  • K. Pantel et al.

    Occult micrometastasis: enrichment, identification and characterization of single disseminated tumor cells

    Seminars in Cancer Biology

    (2001)
  • Vona et al.

    Isolation by size of epithelial tumor cells: a new method for immunomorphological and molecular characterisation of circulatin tumor cells

    American Journal of Pathology

    (2000)
  • P. Paterlini-Brechot et al.

    Circulating tumor cells (CTC) detection: clinical impact and future directions

    Cancer Letters

    (2007)
  • Krebs et al.

    Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches

    Journal of Thoracic Oncology

    (2012)
  • Mostert et al.

    Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer

    Cancer Treatment Reviews

    (2009)
  • Mayer et al.

    FISH-based determination of HER2 status in circulating tumor cells isolated with the microfluidic CEE™ platform

    Cancer Genetics

    (2011)
  • Lin et al.

    Disseminated and circulating tumor cells: role in effective cancer management

    Critical Reviews in Oncology/Hematology

    (2011)
  • C. Birchmeier

    Epithelial–mesenchymal transitions in cancer progression

    Acta Anatomica (Basel)

    (1996)
  • O. De Wever et al.

    Molecular and pathological signatures of epithelial–mesenchymal transitions at the cancer invasive front

    Histochemistry and Cell Biology

    (2008)
  • Ivatsuki et al.

    Epithelial–mesenchymal transition in cancer developement and its clinical significance

    Cancer Science

    (2009)
  • Klymkowski et al.

    Epithelial–mesenchymal transition: a cancer research's conceptual friend and foe

    American Journal of Pathology

    (2009)
  • Chambers et al.

    Dissemination and growth of cancer cells in metastic sites

    Nature Reviews Cancer

    (2002)
  • I.J. Fidler

    The pathogenesis of cancer metastasis: the seed and soil hypothesis revisited

    Nature Reviews Cancer

    (2003)
  • M. Schafer et al.

    Cancer as an overhealing wound: an old hypothesis revisited

    Nature Reviews Molecular Cell Biology

    (2008)
  • J.P. Thiery

    Epithelial–mesenchymal trasnsitions in tumor progeression

    Nature Reviews Cancer

    (2002)
  • Ed. Hay

    An overview of epithelio-mesenchymal transformation

    Acta Anatomica

    (1995)
  • Jechlinger et al.

    Expression profiling of epithelial plasticity in tumor progression

    Oncogene

    (2003)
  • G. Christofori

    New signalis from the invasive front

    Nature

    (2006)
  • Perl et al.

    A casual role for E-cadherin in the transition from adenoma to carcinoma

    Nature

    (1998)
  • Hulit et al.

    N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation

    Cancer Research

    (2007)
  • Onder et al.

    Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways

    Cancer Research

    (2008)
  • J. Grossmann

    Molecular mechanisms of detachment-induced apoptosis–anoikis

    Apoptosis

    (2002)
  • S.M. Frisch et al.

    Disruption od epithelial cell–matrix interactions induces apoptosis

    Journal of Cell Biology

    (1994)
  • M. Kajita et al.

    Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress

    Mol Cell Biol.

    (2004)
  • S. Vega et al.

    Snail blocks the cell cycle and confers resistance to cell death

    Genes Dev.

    (2004)
  • A. Barrallo-Gimeno et al.

    The Snail genes as inducers of cell movement and survival: implications in developement and cancer

    Developement

    (2005)
  • Sayan et al.

    SIP1 protein protects cells from DNA damage-induced apoptosis and has indenpendent prognostic value in blader cancer

    Proceedings of the National Academy of Sciences of the United States of America

    (2009)
  • Scheel et al.

    Adaptation versus selection: the origins of metastatic behavior

    Cancer Research

    (2007)
  • Barr et al.

    Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal transitions

    Clinical and Experimental Metastasis

    (2008)
  • A. Moustakas et al.

    Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression

    Cancer Sci

    (2007)
  • van Hinsbergh et al.

    Pericellular proteases in angiogenesis and vasculogenesis

    Arteriosclerosis, Thrombosis, and Vascular Biology

    (2006)
  • C. Gilles

    Matrix metalloproteases and epithelia-to-mesenchymal transition: implications for carcinoma metastasis

    (2005)
  • Huang et al.

    Regulation of membrane-type 4,atrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis

    Neoplasia

    (2009)
  • Ota et al.

    Introduction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1

    Proceedings of the National Academy of Sciences of the United States of America

    (2009)
  • L.S. Orlichenko et al.

    Matrix metalloproteinases stimulate epithelial–mesenchymal transition durin tumor developement

    Clinical and Experimental Metastasis

    (2008)
  • Lo et al.

    Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial–mesenchymal transition in cancer cells via up-regulation of Twist gene expression

    Cancer Research

    (2007)
  • B. Boyer et al.

    Cyclic AMP distinguishes between two functions of acidic FGF in a rat bladder carcinoma cell line

    Journal of Cell Biology

    (1993)
  • Grotegut et al.

    Hepatocyte growth factore induces cell scattering through MAPK/Egr-1-mediated up-regulation of Snail

    EMBO Journal

    (2006)
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    Marian Liberko, M.D., graduated in 2010, works in the Department of Radiotherapy and Oncology at the University Hospital Kralovske Vinohrady in Prague. He is a PhD student of Biomedicine in the Department of Tumor Biology, 3rd Faculty of Medicine Charles University Prague, Czech Republic. His focus is clinical and experimental research concerning circulating tumor cells.

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    Vladimir Bobek, M.D. Ph.D., graduated in 1999, works as a thoracic surgeon in the Lower Silesian Center for Pulmonary diseases in Wroclaw, at the Surgery Clinic of the University Hospital Kralovske Vinohrady in Prague. He is a head of the Tumor Biology Deparment, 3rd Faculty of Medicine Charles University Prague, Czech Republic.

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