Biologic Challenges in the Detection of Circulating Tumor Cells

Joosse, Simon A.; Pantel, Klaus

doi:10.1158/0008-5472.can-12-3422

Cited by 177 publications

(154 citation statements)

References 25 publications

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“…Increasing evidence suggests that EpCAM-negative CTCs might have undergone an epithelial-to-mesenchymal transition, a process linked to the stemness of cancer cells and increased chemoresistance (36). Other emerging CTC isolation techniques, including nonEpCAM or size-based enrichment approaches (5), have the advantage of assessing the relevant genomic changes in a broader range of CTC subsets.…”

Section: Discussionmentioning

confidence: 99%

Complex Tumor Genomes Inferred from Single Circulating Tumor Cells by Array-CGH and Next-Generation Sequencing

et al. 2013

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Circulating tumor cells (CTC) released into blood from primary cancers and metastases reflect the current status of tumor genotypes, which are prone to changes. Here, we conducted the first comprehensive genomic profiling of CTCs using array-comparative genomic hybridization (CGH) and next-generation sequencing. We used the U.S. Food and Drug Administration-cleared CellSearch system, which detected CTCs in 21 of 37 patients (range, 1-202/7.5 mL sample) with stage IV colorectal carcinoma. In total, we were able to isolate 37 intact CTCs from six patients and identified in those multiple colorectal cancer-associated copy number changes, many of which were also present in the respective primary tumor. We then used massive parallel sequencing of a panel of 68 colorectal cancer-associated genes to compare the mutation spectrum in the primary tumors, metastases, and the corresponding CTCs from two of these patients. Mutations in known driver genes [e.g., adenomatous polyposis coli (APC), KRAS, or PIK3CA] found in the primary tumor and metastasis were also detected in corresponding CTCs. However, we also observed mutations exclusively in CTCs. To address whether these mutations were derived from a small subclone in the primary tumor or represented new variants of metastatic cells, we conducted additional deep sequencing of the primary tumor and metastasis and applied a customized statistical algorithm for analysis. We found that most mutations initially found only in CTCs were also present at subclonal level in the primary tumors and metastases from the same patient. This study paves the way to use CTCs as a liquid biopsy in patients with cancer, providing more effective options to monitor tumor genomes that are prone to change during progression, treatment, and relapse. Cancer Res; 73(10); 2965-75. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Complex Tumor Genomes Inferred from Single Circulating Tumor Cells by Array-CGH and Next-Generation Sequencing

et al. 2013

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“…Many groups have reported that CTC detection using real-time PCR (RT-PCR) or immunologic techniques was associated with CRC progression and poor prognosis (3,(20)(21)(22). Rahbari and colleagues conducted a meta-analysis of 36 studies that included 3,094 patients with CRC to determine the clinical significance of CTC/disseminated tumor cells in the circulation.…”

Section: Introductionmentioning

confidence: 99%

“…Recent reports have indicated the presence of post-EMT CTCs in patients with various types of epithelial tumors (20,21). Therefore, it is important to discover new CTC markers that are not suppressed by the induction of EMT in CTC.…”

Section: Introductionmentioning

confidence: 99%

Plastin3 Is a Novel Marker for Circulating Tumor Cells Undergoing the Epithelial–Mesenchymal Transition and Is Associated with Colorectal Cancer Prognosis

et al. 2013

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Circulating tumor cells (CTC) in blood have attracted attention both as potential seeds for metastasis and as biomarkers. However, most CTC detection systems might miss epithelial-mesenchymal transition (EMT)-induced metastatic cells because detection is based on epithelial markers. First, to discover novel markers capable of detecting CTCs in which EMT has not been repressed, microarray analysis of 132 colorectal cancers (CRC) from Japanese patients was conducted, and 2,969 genes were detected that were overexpressed relative to normal colon mucosa. From the detected genes, we selected those that were overexpressed CRC with distant metastasis. Then, we analyzed the CRC metastasis-specific genes (n ¼ 22) to determine whether they were expressed in normal circulation. As a result, PLS3 was discovered as a CTC marker that was expressed in metastatic CRC cells but not in normal circulation. Using fluorescent immunocytochemistry, we validated that PLS3 was expressed in EMTinduced CTC in peripheral blood from patients with CRC with distant metastasis. PLS3-expressing cells were detected in the peripheral blood of approximately one-third of an independent set of 711 Japanese patients with CRC. Multivariate analysis showed that PLS3-positive CTC was independently associated with prognosis in the training set (n ¼ 381) and the validation set [n ¼ 330; HR ¼ 2.17; 95% confidence interval (CI) ¼ 1.38-3.40 and HR ¼ 3.92; 95% CI ¼ 2.27-6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR ¼ 4.07; 95% CI ¼ 1.50-11.57) and Dukes C (HR ¼ 2.57; 95% CI ¼ 1.42-4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value. Cancer Res; 73(7); 2059-69. Ó2012 AACR.

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“…Their role in the formation of metastases derived from OSCC is currently unclear [102,103] . According to current hypotheses, most DTCs remain in a dormant state and probably never initiate a relapse or metastasis [56,104] , whereas others return to a proliferating state by still unknown molecular alterations or changes in environmental conditions [105,106] . Interestingly, also a re-circulation from the dormant site back to the primary location of the cancer has been reported in an mouse breast cancer model [107] , but because of the high rate of locoregional failure, the concept does not seem apparent for OSCC in the reviewers opinion due to the concept of FC [67] .…”

Section: A Discussion Of the Results From Studies On Head And Neck Camentioning

confidence: 99%

Squamous cell carcinoma of the oral cavity and circulating tumour cells

Wikner

Gröbe

Pantel

2014

WJCO

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Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma (OSCC) during the past decades, current staging methods need to be revised. This disease is associated with poor survival rates despite considerable advances in diagnosis and treatment. The early detection of metastases is an important indicator of survival, prognosis and relapse. Therefore, a better understanding of the mechanisms underlying metastasis is crucial. Exploring alternative measures apart from common procedures is needed to identify new prognostic markers. Similar to previous findings predominantly for other solid tumours, recently published studies demonstrate that circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) might serve as prognostic markers and could supplement routine staging in OSCC. Thus, the detection of CTCs/DTCs is a promising tool to determine the individual need for therapeutic intervention. Encouraging results and new approaches point to the future use of targeted therapies for OSCC, an exceedingly heterogeneous subgroup of head and neck cancer. This review focuses on summarising technologies currently used to detect CTCs/DTCs. The translational relevance for OSCC is highlighted. The inherent challenges in detecting CTCs/DTCs will be emphasised. Core tip: Oral squamous cell carcinoma (OSCC), among head and neck cancer, is related to poor survival rates despite considerable advances in diagnosis and treatment. Therefore, detecting tumour cell dissemination early and understanding the underlying mechanisms are crucial for predicting prognosis, relapse and survival. According to previous findings, circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) might serve as prognostic markers to supplement routine staging and support determining individual therapeutic interventions. This review focuses on summarising the current knowledge about the detection of CTCs/DTCs with special emphasis on patients suffering from OSCC. The translational relevance of CTCs/DTCs and challenges for clinical application are highlighted.Wikner J, Gröbe A, Pantel K, Riethdorf S. Squamous cell carcinoma of the oral cavity and circulating tumour cells.

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Biologic Challenges in the Detection of Circulating Tumor Cells

Cited by 177 publications

References 25 publications

Complex Tumor Genomes Inferred from Single Circulating Tumor Cells by Array-CGH and Next-Generation Sequencing

Complex Tumor Genomes Inferred from Single Circulating Tumor Cells by Array-CGH and Next-Generation Sequencing

Plastin3 Is a Novel Marker for Circulating Tumor Cells Undergoing the Epithelial–Mesenchymal Transition and Is Associated with Colorectal Cancer Prognosis

Squamous cell carcinoma of the oral cavity and circulating tumour cells

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