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  • Review Article
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Detection, clinical relevance and specific biological properties of disseminating tumour cells

Nature Reviews Cancer volume 8, pages 329–340 (2008)Cite this article

Key Points

  • Tumour cell dissemination is an early event in tumorigenesis and is relevant for metastatic progression (in particular for breast cancer). These data have led to the introduction of disseminating tumour cells (DTCs) in international tumour classification systems.

  • Bone marrow (BM) is a common homing organ for tumour cells that are derived from various types of epithelial tumours including breast, prostate and colon cancer. Tumour cells may either establish overt metastases in the BM, as is seen for patients with breast or prostate cancer, or re-circulate to other organs, such as liver or lung, where they find better growth conditions, as is evident in patients with colon cancer.

  • Significant technical advancements in immunological procedures and quantitative real-time PCR-based assays now allow DTCs to be identified and enumerated at frequencies of 1 per 106–107 nucleated blood or BM cells.

  • Sophisticated molecular techniques such as whole-genome analysis or gene expression profiling have been applied to obtain initial information on the molecular characteristics of DTCs. The current data indicate that most DTCs are dormant (non-proliferative) in situ. However, these cells are viable and can proliferate in cell culture in response to appropriate growth factors, such as the stem cell growth factors epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2).

  • DTCs can express cancer stem cell profiles (such as CD44+/CD24− in breast cancer patients) and exhibit stem cell properties such as resistance to chemotherapy and long-term persistence in the BM.

  • Identification of therapeutic targets on DTCs and circulating tumour cells (CTCs) and real-time monitoring of CTCs in cancer patients undergoing systemic therapy are the most important future clinical applications. In this context, the ERBB2 proto-oncogene has served as a proof-of-principle target for the monitoring and treatment of DTCs in human breast cancer.

Abstract

Most cancer deaths are caused by haematogenous metastatic spread and subsequent growth of tumour cells at distant organs. Disseminating tumour cells present in the peripheral blood and bone marrow can now be detected and characterized at the single-cell level. These cells are highly relevant to the study of the biology of early metastatic spread and provide a diagnostic source in patients with overt metastases. Here we review the evidence that disseminating tumour cells have a variety of uses for understanding tumour biology and improving cancer treatment.

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Figure 1: Methods for circulating tumour cell (CTC) enrichment, detection and characterization.
Figure 2: A metastatic model derived from disseminated tumour cell (DTC) and circulating tumour cell studies in human patients.
Figure 3: Search for molecular determinants of early tumour cell dissemination.

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Acknowledgements

We thank I. Alpers for support in the manuscript preparation and D. Kemming for the technical assistance in art work. This work was supported by the European Commission (DISMAL project, contract no. LSHC-CT-2005-018911 and OVCAD project, contract no. LSHC-CT-2005-018698), Deutsche Forschungsgemeinschaft, Bonn, Germany and the Netherlands Organization for Scientific Research.

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Authors and Affiliations

  1. Institute of Tumour Biology, Center of Experimental Medicine, University Medical Center Hamburg Eppendorf, Martinistrasse 52, Hamburg, Germany

    Klaus Pantel & Burkhard Brandt

  2. Department of Otolaryngology/Head-Neck Surgery, Section of Tumour Biology, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, the Netherlands

    Ruud H. Brakenhoff

Authors
  1. Klaus Pantel
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  2. Ruud H. Brakenhoff
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  3. Burkhard Brandt
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Correspondence to Klaus Pantel.

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DATABASES

National Cancer Institute

breast cancer

colon cancer

head and neck cancer

lung cancer

pancreatic cancer

prostate cancer

National Cancer Institute Drug Dictionary

trastuzumab

FURTHER INFORMATION

K. Pantel's homepage

ALTTO

DISMAL

GEPARQuattro trial

Metastasis Research Society

OVCAD

Southwest Oncology Group clinical trail

SUCCESS trial

VU University Medical Center

Glossary

Ferrofluid

A suspension of 10 nm colloidal iron particles stabilized by polymers.

Pharmacodynamics

The effects on the biochemistry of the body resulting from treatment with a drug or combination of drugs.

ELISPOT

An antibody-capture-based method for enumerating specific T cells (CD4+ and CD8+) that secrete a particular cytokine (often interferon-γ).

Iliac crest

The outer rim of the pelvic bone, accessed for needle aspiration of bone marrow.

Anoikis

Apoptosis induced in isolated cells leaving an epithelial tissue.

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Pantel, K., Brakenhoff, R. & Brandt, B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8, 329–340 (2008). https://doi.org/10.1038/nrc2375

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