Plasticity of disseminating cancer cells
Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S. Science. 2013 Feb 1;339(6119):580-4. doi:10.1126/science.1228522 . PMID: #23372014# [Free]
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Plasticity of disseminating cancer cells
metastasis-initiating cells (MICs)
Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, et al., editors. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31:539–544. [http://www.ncbi.nlm.nih.gov/pubmed/23609047]
CTC clusters; CTCCs
Circulating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Although rare in the circulation compared with single CTCs, CTC clusters have 23- to 50-fold increased metastatic potential.
Using mouse models with tagged mammary tumors, it has been demonstrated that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events. (#25171411#) (...)
KRAS mutations are known to block the effect of therapeutic EGFR inhibition by antibodies or small inhibitors in colorectal cancer patients (Wan et al, 2013).
The analysis of individual CTCs has shown a remarkable intra-patient KRAS mutation heterogeneity (i.e., KRASWT and KRASMT CTCs are present in the same patient) (Gasch et al, 2013).
Indeed, the presence of KRAS-mutated CTCs in patients with KRAS wild-type primary colon carcinomas might be one explanation for failure of (...)
Molecular characterization of CTCs might be essential to identify therapeutic targets and contribute to more ‘tailored’ and personalized anti-metastatic therapies.
In current clinical practice, the decision on targeted therapies is solely based on the analysis of the primary tumor although the therapy is directed against metastatic cells (Wan et al, 2013). However, metastatic relapse may occur many years after primary tumor diagnosis and surgical resection (Uhr & Pantel, 2011). Thus, (...)
Another strategy for the identification of CTCs is to enumerate and analyze proteins specifically secreted by viable tumor cells (EPISPOT, EPithelial Immuno SPOT). CTCs are enriched by negative depletion and subsequently cultured on a membrane coated with antibodies that capture the secreted proteins. Afterward, the proteins are readily identifiable by immunofluorescence microscopy using fluorochrome-labeled secondary antibodies targeting the protein of interest.
Using this (...)
Identification of CTCs by multiplex PCR targeting the numerous tumor-associated mRNA transcripts overcomes filter set limitations.
CTC enrichment combined with a RT–PCR technology could already be used for the identification of tumor-related markers (EpCAM,MUC1, and ERBB2), EMT-associated transcripts (PI3Kα (phosphatidylinositol 3-kinase alpha), Akt-2, or Twist1), or stem cell markers such as ALDH1 (aldehyde dehydrogenase 1) (Kasimir-Bauer et al, 2012).
Sequential peripheral blood drawings in particular for real-time monitoring of minimal residual disease in cancer patients undergoing systemic therapies are clearly more acceptable than repeated bone marrow aspirations.
Indeed, many research groups are currently assessing the clinical value of CTC analyses, which so far has been proven to provide significant prognostic information in metastatic breast cancer (Zhang et al, 2012; Bidard et al, 2014), and other solid tumors such as of the (...)
Morphologic investigation together with fluorescence immunocytochemistry (ICC) is a common procedure for the identification and enumeration of CTCs after enrichment.
The CellSearch ® system classifies a CTC as positive event if the cell is ≥ 4 μm, DAPI+ (4,6-diamino-2-phenylindole), pan-keratin+, and CD45−.
The additional 4th fluorescence channel is accessible for a user-defined detection of, for example, therapy-relevant markers such as the androgen receptor (AR), (...)
CTCs are infrequent and appear at an estimated level of one against the background of millions (106–107) of surrounding normal peripheral mononuclear blood cells (PBMCs) (Alix-Panabieres et al, 2012). The occurrence rate might even be lower in cancer patients without obvious metastases (Rink et al, 2012; Rack et al, 2014).
Hence, selective enrichment of tumor cells and/or systematic removal of PBMCs and red blood cells (RBCs) is required to detect CTCs in the blood of a cancer patient.