Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research

Grover, Phulwinder K.; Cummins, Adrian G.; Price, Tim; Roberts‐Thomson, Ian C.; Hardingham, Jennifer E.

doi:10.1093/annonc/mdu018

Cited by 193 publications

(181 citation statements)

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“…For instance, EpCAM expression was found to be in the order of 10-fold less on CTCs compared with primary and metastatic tissues, suggesting that EpCAM expression is dependent on the local microenvironment and is downregulated in disseminated cells (31). This is quite probably the reason why CTCs were undetected by the CellSearch system in a significant proportion of patients with colorectal (32) and other cancers (reviewed in [33]). Downregulation of EpCAM has also been reported in DTCs in bone marrow in breast cancer patients following adjuvant therapy (34) and was found to be the reason for failure to detect any CTCs in a murine breast cancer xenograft model (35).…”

Section: Enrichment and Detection Of Ctcsmentioning

confidence: 99%

“…The EMT phenotype of CTC has been linked to resistance to both chemotherapy and radiation therapy (reviewed in [40]). Methodologies that rely on positive capture of CTC, which have to assume specific criteria such as high expression of EpCAM, are intrinsically flawed, so that the real CTC load is underestimated and stem cell populations of likely high relevance to disease progression are missed (33). On balance, due to the relatively low sensitivity and specificity of the EpCAM-based approach EpCAMtargeted capture strategies cannot still be considered the best approach for CTC isolation (41)(42)(43).…”

Section: Enrichment and Detection Of Ctcsmentioning

confidence: 99%

“…There is increasing evidence that CTCs comprise a heterogeneous pool of cells that includes epithelial tumor cells, tumor cells undergoing EMT, and tumor stem cells, and they may circulate as single cells or clusters of cells (33,38,42). We believe that it is the stem cells within the circulating tumor cell pool that are responsible for metastatic disease progression: these cells are termed circulating tumor stem cells (CTSC) (33) (Figure 1).…”

Section: The Emerging Circulating Tumor Stem Cell Hypothesismentioning

confidence: 99%

“…We believe that it is the stem cells within the circulating tumor cell pool that are responsible for metastatic disease progression: these cells are termed circulating tumor stem cells (CTSC) (33) (Figure 1). This view is bolstered by the presence of stem cell phenotypes CD26+ and CD133+ in CTCs of metastatic CRC patients (44,45) and the finding that increased expression of the exclusive stem cell marker leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in colorectal tumors indicates a poor prognosis (46,47).…”

Section: The Emerging Circulating Tumor Stem Cell Hypothesismentioning

confidence: 99%

“…Considering the now well-established phenotypical heterogeneity of CTCs, in particular the variation in antigen expression in cancer cells at various stages of EMT (reviewed in [33]), unbiased CTC isolation technologies are now being developed that avoid the use of antibodybased enrichment. Some of these methods exploit physical differences in size, density, deformability or electrical properties between CTCs and blood cells (reviewed in [59]), (9,60).…”

Section: New Techniques For Ctc Enrichment and Identificationmentioning

confidence: 99%

See 4 more Smart Citations

Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer—20 Years of Progress

Hardingham

Grover

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et al. 2015

Mol Med

124

104

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Circulating tumor cells (CTC) may be defined as tumor-or metastasis-derived cells that are present in the bloodstream. The CTC pool in colorectal cancer (CRC) patients may include not only epithelial tumor cells, but also tumor cells undergoing epithelial-mesenchymal transition (EMT) and tumor stem cells. A significant number of patients diagnosed with early stage CRC subsequently relapse with recurrent or metastatic disease despite undergoing "curative" resection of their primary tumor. This suggests that an occult metastatic disease process was already underway, with viable tumor cells being shed from the primary tumor site, at least some of which have proliferative and metastatic potential and the ability to survive in the bloodstream. Such tumor cells are considered to be responsible for disease relapse in these patients. Their detection in peripheral blood at the time of diagnosis or after resection of the primary tumor may identify those early-stage patients who are at risk of developing recurrent or metastatic disease and who would benefit from adjuvant therapy. CTC may also be a useful adjunct to radiological assessment of tumor response to therapy. Over the last 20 years many approaches have been developed for the isolation and characterization of CTC. However, none of these methods can be considered the gold standard for detection of the entire pool of CTC. Recently our group has developed novel unbiased inertial microfluidics to enrich for CTC, followed by identification of CTC by imaging flow cytometry. Here, we provide a review of progress on CTC detection and clinical significance over the last 20 years.

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Section: Enrichment and Detection Of Ctcsmentioning

confidence: 99%