Clinical relevance and biology of circulating tumor cells
Breast Cancer Research
Clinical relevance and biology of circulating tumor cells
Natalia Bednarz-Knoll 0
Catherine Alix-Panabières
Klaus Pantel 0
0 Department of Tumour Biology, University Medical Centre Hamburg-Eppendorf , Martinistr. 52, 20246 Hamburg , Germany
Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer.
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Introduction
Detection of circulating tumor cells (CTCs) in peripheral
blood and disseminated tumor cells (DTCs) in bone
marrow of tumor patients has become an active area of
translational cancer research, with numerous groups
developing new diagnostic assays and more than 200
clinical trials incorporating CTC counts as a biomarker
in patients with various types of solid tumors. Among
these activities, breast cancer has played the most
prominent role as a ‘driver’ of research on CTCs/DTCs.
The clinical relevance of DTCs is already well-established
[1,2] and has been confirmed by different large-scale
studies, including a pooled analysis on almost 5,000
patients [3]. Aspirations of bone marrow, a common
homing organ for many types of solid tumors [1,4], are
part of the routine screening of leukemia patients and are
much less difficult to perform than biopsies of other
organs (for example, lungs or liver). Nevertheless, it is
Tumor cell dissemination: a complex process
During tumorigenesis subsets of tumor cells localized
within the primary tumor might acquire features of
invasiveness and motility and enter blood or lymph
vessels (Figure 1). Mechanisms involved in this process
are still under investigation; however, they are already
reported to be linked to variable interactions between
tumor cells and the surrounding stroma, including, for
example, response to hypoxia and
metalloproteinasedependent invasion into surrounding tissue,
(neo-)vascularization of a tumor [7], as well as gain of a phenotype
revealing signatures of epithelial-mesenchymal transition
(EMT) observed in at least a subpopulation of tumor
cells with certain ‘stemness’ properties [8-10].
Once cells spread and survive, they might establish a
separate secondary tumor site in a new environment of a
epithelialphenotype
semi-mesenchymal
phenotype
epithelialphenotype
host organ (for example, bone marrow, liver, lung or
brain). CTCs/DTCs, however, can also undergo apoptosis
or persist in an inactive, so-called dormant state for years
[11]. CTCs that extravasate need to survive as DTCs in
their new microenvironment, which might be supported
by finding and/or establishing a proper niche. These
DTCs might transform into more aggressive variants and
grow out to overt metastasis [7] and/or they may
recirculate to other secondary organs or even back to their
primary tumor site [12,13].
Dissemination might appear in a late phase of
tumorigenesis when a primary tumor achieves a critical
mass of cells and gains a highly aggressive phenotype
(linear model) or it might be initiated much earlier, even
when a malignant tumor is still of small size (parallel
model) [14]. In the linear model subsequent events
gradually lead to tumor progression, whereas in the
concurrent parallel model CTCs/DTCs settle down in
distant organs, creating a clone that evolves in parallel to
a primary site. In both models occurrence of metastasis is
usually fatal for a patient.
Circulating tumor cell detection
CTC detection remains a big technical challenge despite
the continued development of many new exciting
technologies [1]. The key problem is to define a technology
that will detect the real metastasis-initiating CTC that
will give rise to distant metastases. It is conceivable that
this will be a combination of complementary technologies
or even several technologies optimized for specific tumor
types, including breast cancer. Some of the current key
technologies for the enrichment and detection of CTCs
are listed in Table 1. As CTCs occur at very low
concentrations of one tumor cell in a background of millions of
blood cells, enrichment is usually required prior to CTC
detection. CTC enrichment involves a large panel of
technologies based on the different properties of CTCs
that distinguish them from the surrounding normal
hematopoietic cells: physical properties (size, density,
electric charges, deformability) and/or biological
properties (surface protein expression, viability and invasion
capacity). It is important to note that (...truncated)