Circulating Tumor Cells: Not All Detected Cells Are Bad and Not All Bad Cells Are Detected

The University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2011; 29(12):1508-11. DOI: 10.1200/JCO.2010.34.0026
Source: PubMed
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Available from: Max S Wicha, May 09, 2014
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    • "These CTCs tend to be very rare (Sheng et al., 2012); it is often assumed their concentration may be as low as $ 1–100 cells/mL in whole blood (Coumans et al., 2013; Hou et al., 2013). Nevertheless, their concentration in blood has (Pantel et al., 2008) diagnostic and prognostic clinical relevance (Dotan et al., 2009; Lianidou et al., 2012; Scher et al., 2009; Wicha and Hayes, 2011). Current methods for the detection and staging of cancer are mostly pathological and provide clinicians with a snapshot of the primary tumour and the spread of cancer from one organ to another, but not necessarily the total tumour burden. "
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    ABSTRACT: An electrochemical Lab-on-a-Disc (eLoaD) platform for the automated quantification of ovarian cancer cells (SKOV3) from whole blood is reported. This centrifugal microfluidic system combines complex sample handling, i.e., blood separation and cancer cell extraction from plasma, with specific capture and sensitive detection using label-free electrochemical impedance. Flow control is facilitated using rotationally actuated valving strategies including siphoning, capillary and centrifugo-pneumatic dissolvable-film (DF) valves. For the detection systems, the thiol-containing amino acid, l-Cysteine, was self-assembled onto smooth gold electrodes and functionalized with anti-EpCAM. By adjusting the concentration of buffer electrolyte, the thickness of the electrical double layer was extended so the interfacial electric field interacts with the bound cells. Significant impedance changes were recorded at 117.2Hz and 46.5Hz upon cell capture. Applying AC amplitude of 50mV at 117.2Hz and open circuit potential, a minimum of 214capturedcells/mm(2) and 87% capture efficiency could be recorded. The eLoaD platform can perform five different assays in parallel with linear dynamic range between 16,400 and (2.6±0.0003)×10(6)cancercells/mL of blood, i.e. covering nearly three orders of magnitude. Using the electrode area of 15.3mm(2) and an SKOV3 cell radius of 5µm, the lower detection limit is equivalent to a fractional surface coverage of approximately 2%, thus making eLoaD a highly sensitive and efficient prognostic tool that can be developed for clinical settings where ease of handling and minimal sample preparation are paramount. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biosensors & Bioelectronics 12/2014; 68C:382-389. DOI:10.1016/j.bios.2014.12.049 · 6.41 Impact Factor
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    • "We addressed the issue of heterogeneity by a rigorous methodological approach that used the random-effects model for more conservative estimates. Prognostic factors of gastric cancer are complicated, our data for meta-analysis was from the included studies and primary data was hard to get, we were unable to exclude every possible confounding factors; approaches based on RT-PCR have high sensitivity for the detection of CTCs, but they cannot quantify the number of CTCs and lack biologic specificity [38]. Secondly, languages selection brings another bias, we have restricted our analysis to published studies written in English, other language such as Japanese, German were excluded based on language criteria. "
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    ABSTRACT: Objective The prognostic significance of circulating tumor cells (CTCs) is controversial in gastric cancer (GC). We performed a meta-analysis of available studies to assess its prognostic value detected by RT-PCR for patients diagnosed with GC. Methods EMBase, PubMed, Ovid, Web of Science, Cochrane library and Google Scholar database search was conducted on all studies reporting the outcomes of interest. The studies were set up according to the inclusion/exclusion criteria. Meta-analysis was performed by using a random-effects model; hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were set as effect measures. The information about trial design, results from the data was independently extracted. Heterogeneity of the studies was tested for each pooled analysis. Results Nineteen studies published matched the selection criteria and were included in this meta-analysis. CTCs positivity was significantly associated with poor relapse free survival (RFS) (HR 2.42, 95% CI: [1.94–3.02]; P<0.001) and poor overall survival (OS) (HR 2.42, 95% CI: [1.94–3.02]; P<0.001). CTCs positivity were also significantly associated with regional lymph nodes (RLNs) metastasis (RR 1.42, 95% CI: [1.20–1.68]; p<0.0001), depth of infiltration (RR 1.51, 95% CI: [1.27–1.79]; p<0.0001), vascular invasion (RR = 1.43, 95% CI: [1.18–1.74], p = 0.0002) and TNM stage(I,II versus III) (RR 0.63, 95% CI [0.48–0.84]; p = 0.001). Conclusion Preoperative CTCs positivity indicates poor prognosis in patients with gastric cancer, and associated with poor clinicopathological prognostic factors.
    PLoS ONE 06/2014; 9(6):e99259. DOI:10.1371/journal.pone.0099259 · 3.23 Impact Factor
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    • "Detection of CTCs appears to be a marker of metastasis development, cancer recurrence, and therapy efficacy (Alix-Panabiè res et al., 2012; Hayes and Smerage, 2010; Attard and de Bono, 2011; Balic et al., 2013). Although substantial efforts have been made to develop new methods for studying CTCs in vitro and recently in vivo (Alix-Panabiè res et al., 2012; Hayes and Smerage, 2010; Attard and de Bono, 2011; Balic et al., 2013; Georgakoudi et al., 2004; He et al., 2007; Galanzha et al., 2009; Hwu et al., 2011; Yu et al., 2011), many aspects of CTC dissemination, recirculation, migration, and final destination (e.g., dormancy and self-seeding) remain poorly known (Alix- Panabiè res et al., 2012; Attard and de Bono, 2011; Wicha and Hayes, 2011). For example, it is not clear how long spontaneous CTCs (i.e., naturally shed from a primary tumor or metastasis) linger in circulation (referred to as CTC lifespan); how their lifespan depends on their biochemical, molecular, and genetic properties; or how their lifespan correlates with metastasis progression . "
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    ABSTRACT: Photoswitchable fluorescent proteins (PSFPs) that change their color in response to light have led to breakthroughs in studying static cells. However, using PSFPs to study cells in dynamic conditions is challenging. Here we introduce a method for in vivo ultrafast photoswitching of PSFPs that provides labeling and tracking of single circulating cells. Using in vivo multicolor flow cytometry, this method demonstrated the capability for studying recirculation, migration, and distribution of circulating tumor cells (CTCs) during metastasis progression. In tumor-bearing mice, it enabled monitoring of real-time dynamics of CTCs released from primary tumor, identifying dormant cells, and imaging of CTCs colonizing a primary tumor (self-seeding) or existing metastasis (reseeding). Integration of genetically encoded PSFPs, fast photoswitching, flow cytometry, and imaging makes in vivo single cell analysis in the circulation feasible to provide insights into the behavior of CTCs and potentially immune-related and bacterial cells in circulation.
    Chemistry & biology 05/2014; 21(6). DOI:10.1016/j.chembiol.2014.03.012 · 6.65 Impact Factor
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