Circulating tumor cells: the ‘leukemic phase’ of solid cancers

https://doi.org/10.1016/j.molmed.2006.01.006Get rights and content

It is well known that malignant cells circulate in the bloodstream of patients with solid tumors. However, the biological significance of circulating tumor cells (CTCs) and the clinical relevance of their detection are still debated. Besides technical issues regarding CTC-detection methods, discontinuous shedding of CTCs from established cancer deposits, genomic instability and metastatic inefficiency might underlie the conflicting results currently available. Nevertheless, technological advances and recent clinical findings are prompting researchers to dissect CTC biology further. Here, we review these recent findings, and discuss the prospects for the identification and molecular characterization of the CTC subset that is responsible for metastasis development. This would provide a formidable tool for prognosis evaluation, anticancer-drug development and, ultimately, cancer-therapy personalization.

Section snippets

Biology of circulating tumor cells

Although therapeutic advances were made during the past few decades, many patients still die from metastatic cancer despite having no clinically detectable disease after treatment. In these patients, cancer recurrence originates from microscopic tumor residues known as minimal residual disease (MRD) (see Glossary). MRD can affect different body compartments, including the bone marrow, lymph nodes and peripheral blood 1, 2, 3. The search for MRD in the peripheral blood is performed routinely for

CTC detection

Several approaches to detect CTCs have been described (Figure 2) and can be classified into PCR-based and cytometric methods. Because of the lack of comparative investigations, no ideal technique is available and many issues must be addressed when searching for CTCs.

Clinical results

Several studies have investigated the prognostic value of CTC detection in patients who have almost every type of solid malignancy (for examples, see Table 1). Because the false-positive rate among control subjects (i.e. healthy subjects or patients with non-malignant diseases) is extremely low, the specificity of both PCR-based and cytometric methods is ∼100% 23, 24. Nevertheless, because there are some conflicting results, no definitive conclusion on CTC biological significance in solid

Future perspectives

Technical and biological hurdles might prevent oncologists from proving the prognostic value of CTC detection. Several steps can be taken to address these issues and improve the quality of future studies that are designed to investigate the prognostic value of CTCs in patients with solid tumors (Table 2).

Concluding remarks

The current evidence is that malignant cells circulate in the peripheral blood of patients with solid tumors 5, 6, 7, 23. Although the results of several studies support a correlation between CTCs and patient clinical outcome, the findings of other studies question the biological significance, and thus the clinical usefulness, of CTC detection. Because the presence of CTCs is necessary (although not sufficient) for the development of metastatic-tumor spread, researchers are prompted to

Acknowledgements

We apologize to those authors whose work could not be cited owing to length restrictions.

Glossary

β-type error:
the statistical error (also known as type-II error) made in testing an hypothesis when it is concluded that an intervention (or prediction) is not effective (or true) but it really is.
Cell-enrichment methods:
any biotechnology aimed at sorting target cells (e.g. CTCs) from a pool of ‘unwanted’ cells (e.g. peripheral mononucleated cells) to increase the number of cells of interest per unit of volume (enrichment) and thus enable collection of enough biological material for molecular

References (82)

  • S. Langer

    Sequential application of interphase-FISH and CGH to single cells

    Lab. Invest.

    (2005)
  • S.H. Diks et al.

    Single cell proteomics for personalised medicine

    Trends Mol. Med.

    (2004)
  • J.A. Schardt

    Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer

    Cancer Cell

    (2005)
  • T. Jotsuka

    Persistent evidence of circulating tumor cells detected by means of RT-PCR for CEA mRNA predicts early relapse: a prospective study in node-negative breast cancer

    Surgery

    (2004)
  • S. Mocellin

    Targeted therapy for colorectal cancer: mapping the way

    Trends Mol. Med.

    (2005)
  • T.G. Lugo

    Detection and measurement of occult disease for the prognosis of solid tumors

    J. Clin. Oncol.

    (2003)
  • J. Lacroix et al.

    Technical aspects of minimal residual disease detection in carcinoma patients

    Semin. Surg. Oncol.

    (2001)
  • K. Pantel et al.

    Dissecting the metastatic cascade

    Nat. Rev. Cancer

    (2004)
  • I.J. Fidler

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

    Nat. Rev. Cancer

    (2003)
  • A. Ulmer

    Immunomagnetic enrichment, genomic characterization, and prognostic impact of circulating melanoma cells

    Clin. Cancer Res.

    (2004)
  • T. Fehm

    Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant

    Clin. Cancer Res.

    (2002)
  • Y.S. Chang

    Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • S. Meng

    Circulating tumor cells in patients with breast cancer dormancy

    Clin. Cancer Res.

    (2004)
  • K.W. Hunter

    Host genetics and tumour metastasis

    Br. J. Cancer

    (2004)
  • R. Jung

    Detection of micrometastasis by cytokeratin 20 RT-PCR is limited due to stable background transcription in granulocytes

    Br. J. Cancer

    (1999)
  • B. Weigelt

    Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients

    Br. J. Cancer

    (2003)
  • B.M. Smith

    Response of circulating tumor cells to systemic therapy in patients with metastatic breast cancer: comparison of quantitative polymerase chain reaction and immunocytochemical techniques

    J. Clin. Oncol.

    (2000)
  • H. Lauschke

    Detection of APC and k-ras mutations in the serum of patients with colorectal cancer

    Cancer Detect. Prev.

    (2001)
  • S. Ashida

    Detection of circulating cancer cells with von hippel–lindau gene mutation in peripheral blood of patients with renal cell carcinoma

    Clin. Cancer Res.

    (2000)
  • G. Schleiermacher

    Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor

    J. Clin. Oncol.

    (2003)
  • J.M. Silva

    Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells

    Gut

    (2002)
  • T.E. Witzig

    Detection of circulating cytokeratin-positive cells in the blood of breast cancer patients using immunomagnetic enrichment and digital microscopy

    Clin. Cancer Res.

    (2002)
  • W.J. Allard

    Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases

    Clin. Cancer Res.

    (2004)
  • H. Tsao

    A meta-analysis of reverse transcriptase-polymerase chain reaction for tyrosinase mRNA as a marker for circulating tumor cells in cutaneous melanoma

    Arch. Dermatol.

    (2001)
  • P. Kufer

    Heterogeneous expression of MAGE-A genes in occult disseminated tumor cells: a novel multimarker reverse transcription-polymerase chain reaction for diagnosis of micrometastatic disease

    Cancer Res.

    (2002)
  • P. Quaglino

    Clinical significance of sequential tyrosinase expression in the peripheral blood of disease-free melanoma patients: a review of literature data

    Melanoma Res.

    (2004)
  • S. Mocellin

    Molecular detection of circulating tumor cells is an independent prognostic factor in patients with high-risk cutaneous melanoma

    Int. J. Cancer

    (2004)
  • G.G. Brownbridge

    Evaluation of the use of tyrosinase-specific and melanA/MART-1-specific reverse transcriptase-coupled-polymerase chain reaction to detect melanoma cells in peripheral blood samples from 299 patients with malignant melanoma

    Br. J. Dermatol.

    (2001)
  • C. Voit

    Molecular staging in stage II and III melanoma patients and its effect on long-term survival

    J. Clin. Oncol.

    (2005)
  • S. Osella-Abate

    Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients

    Br. J. Cancer

    (2003)
  • R.A. Wascher

    Molecular tumor markers in the blood: early prediction of disease outcome in melanoma patients treated with a melanoma vaccine

    J. Clin. Oncol.

    (2003)
  • Cited by (0)

    View full text