Circulating Tumor Cells: Moving Biological Insights into Detection.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen L
PROVIDER: S-EPMC5558556 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Molecular characterization of tumor cells is a key step in the diagnosis and optimal treatment of lung cancer. However, analysis of tumor samples, often corresponding to small biopsies, can be difficult and does not accurately reflect tumor heterogeneity. Recent studies have shown that isolation of circulating tumor cells (CTCs) is feasible in non-small cell lung cancer patients, even at early disease stages. The amount of CTCs corresponds to the metastatic potential of the tumor and to patient prognosis. Moreover, molecular analyses, even at the single-cell level, can be performed on CTCs. This review describes the technologies currently available for detecting and capturing CTCs, the potential for downstream molecular diagnostics, and the clinical applications of CTCs isolated from lung cancer patients as screening, prognostic, and predictive tools. Main limitations of CTCs are also discussed.
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Project description:Circulating tumor cells (CTCs) are cancer cells that circulate in the blood stream after being naturally shed from original or metastatic tumors, and can lead to a new fatal metastasis. CTCs have become a hotspot research field during the last decade. Detection of CTCs, as a liquid biopsy of tumors, can be used for early diagnosis of cancers, earlier evaluation of cancer recurrence and chemotherapeutic efficacy, and choice of individual sensitive anti-cancer drugs. Therefore, CTC detection is a crucial tool to fight against cancer. Herein, we classify the currently reported CTC detection technologies, introduce some representative samples for each technology, conclude the advantages and limitations, and give a future perspective including the challenges and opportunities of CTC detection.
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Project description:During the process of metastasis, which is the leading cause of cancer-related death, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. The migrating tumor cells in circulation, e.g., those found in peripheral blood (PB) or bone marrow (BM), are called circulating tumor cells (CTCs). CTCs in the BM are generally called disseminated tumor cells (DTCs). Many studies have reported the detection and characterization of CTCs to facilitate early diagnosis of relapse or metastasis and improve early detection and appropriate treatment decisions. Initially, epithelial markers, such as EpCAM and cytokeratins (CKs), identified using immunocytochemistry or reverse transcription polymerase chain reaction (RT-PCR) were used to identify CTCs in PB or BM. Recently, however, other markers such as human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and immuno-checkpoint genes also have been examined to facilitate detection of CTCs with metastatic potential. Moreover, the epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) have also received increasing attention as important CTC markers owing to their roles in the biological progression of metastasis. In addition to these markers, researchers have attempted to develop detection or capture techniques for CTCs. Notably, however, the establishment of metastasis requires cancer-host interactions. Markers from host cells, such as macrophages, mesenchymal stem cells, and bone marrow-derived cells, which constitute the premetastatic niche, may become novel biomarkers for predicting relapse or metastasis or monitoring the effects of treatment. Biological studies of CTCs are still emerging. However, recent technical innovations, such as next-generation sequencing, are being used more commonly and could help to clarify the mechanism of metastasis. Additionally, biological findings are gradually being accumulated, adding to our body of knowledge on CTCs. In this review, we will summarize recent approaches to detect or capture CTCs. Moreover, we will introduce recent studies of the clinical and biological importance of CTCs and host cells.
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Project description:BACKGROUND: Although national surveillance programs are in place to monitor norovirus epidemiology, the emergence of new strains and the genetic diversity among genotypes can be challenging for clinical laboratories. This study evaluated the analytical and clinical performance characteristics of one real-time RT-PCR and two end-point RT-PCRs commonly used in microbiology laboratories. METHODS: Lower limit of detection (LoD) was determined using 10-fold dilutions of noroviruses belonging to different genotypes. The clinical performance of the real-time and end-point RT-PCRs was assessed in parallel using nucleic acids extracted from 186 stool specimens. RESULTS: The real-time RT-PCR was highly sensitive and specific for the detection of norovirus genotypes that are currently circulating in Canada. In contrast, the two end-point RT-PCRs displayed poor analytical sensitivity or complete failure to detect certain norovirus genotypes, which was correlated to sequence mismatches in the primer-binding sites. In an attempt to improve norovirus detection with the end-point RT-PCRs, both assays were processed concurrently and detection from either assay was considered a positive result. Concurrent testing resulted in only a modest increase in clinical sensitivity (75.0%) compared to each assay alone (62.5% and 71.9%). However, the false positivity rate increased from 1.98% and 3.36% for the assays alone to 5.47% with concurrent testing. CONCLUSIONS: This study emphasizes the benefits of a real-time method and provides support for routine surveillance to monitor norovirus epidemiology and ongoing proficiency testing to ensure detection of circulating norovirus genotypes.
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Project description:Metastasis, the cause for 90% of cancer mortality, is a complex and poorly understood process involving the invasion of circulating tumor cells (CTCs) into blood vessels. These cells have potential prognostic value as biomarkers for early metastatic risk. But their rarity and the lack of specificity and sensitivity in measuring them render their interrogation by current techniques very challenging. How and when these cells are circulating in the blood, on their way to potentially give rise to metastasis, is a question that remains largely unanswered. In order to provide an insight into this "black box" using non-invasive imaging, we developed a novel miniature intravital microscopy (mIVM) strategy capable of real-time long-term monitoring of CTCs in awake small animals. We established an experimental 4T1-GL mouse model of metastatic breast cancer, in which tumor cells express both fluorescent and bioluminescent reporter genes to enable both single cell and whole body tumor imaging. Using mIVM, we monitored blood vessels of different diameters in awake mice in an experimental model of metastasis. Using an in-house software algorithm we developed, we demonstrated in vivo CTC enumeration and computation of CTC trajectory and speed. These data represent the first reported use we know of for a miniature mountable intravital microscopy setup for in vivo imaging of CTCs in awake animals.
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Project description:Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.
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Project description:EpCAM expressing circulating tumor cells, detected by CellSearch, are predictive of short survival in several cancers and may serve as a liquid biopsy to guide therapy. Here we investigate the presence of EpCAM(+) CTC detected by CellSearch and EpCAM(-) CTC discarded by CellSearch, after EpCAM based enrichment. EpCAM(-) CTC were identified by filtration and fluorescent labelling. This approach was validated using different cell lines spiked into blood and evaluated on blood samples of 27 metastatic lung cancer patients. The majority of spiked EpCAM(+) cells could be detected with CellSearch, whereas most spiked cells with EpCAM(low) or EpCAM(-) expression were detected using filtration. Five or more CTC were detected in 15% of the patient samples, this increased to 41% when adding the CTC detected in the discarded blood. The number of patients with CTC and the number of CTC detected were doubled by the presence of EpCAM(-) CTC. In this pilot study, the presence of EpCAM(+) CTC was associated with poor outcome, whereas the EpCAM(-) CTC were not. This observation will need to be confirmed in larger studies and molecular characterization needs to be conducted to elucidate differences between EpCAM(-) and EpCAM(+) CTC.
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Project description:Circulating tumor cells (CTCs) in tumor draining vein blood (DB) are potential sources for liquid biopsy. However, the identification of CTCs in DB of breast cancer has not been attempted. In this study, we investigated the feasibility of CTC detection in DB of breast cancer patients using a newly developed filtration-based microfluidic CTC detection device. Samples of peripheral vein blood (PB) and DB drawn from the lateral thoracic vein of the resected breast tissue were collected during the perioperative period. We investigated 41 breast cancer patients who underwent breast surgery with axillary lymph node dissection. DB was successfully collected in 36 patients (87.8%), with a mean amount of 0.85?ml. CTCs were detected in 58.3% of PB samples and 80.6% of DB samples. DB had significant higher number of CTCs compared with PB (p?<?0.001). CTCs were detected in 75.0% of DB samples and 50.0% of PB samples from patients achieving pathological complete response after neoadjuvant chemotherapy. These results suggest that abundant CTCs are released into the DB of breast cancer patients, indicating that CTCs in DB would be alternative sources for liquid biopsy and potential indicators for monitoring of treatment response and prognosis in breast cancer patients.
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Project description:Circulating Tumor Cells (CTC) and Circulating Tumor Microemboli (CTM) are Circulating Rare Cells (CRC) which herald tumor invasion and are expected to provide an opportunity to improve the management of cancer patients. An unsolved technical issue in the CTC field is how to obtain highly sensitive and unbiased collection of these fragile and heterogeneous cells, in both live and fixed form, for their molecular study when they are extremely rare, particularly at the beginning of the invasion process. We report on a new protocol to enrich from blood live CTC using ISET® (Isolation by SizE of Tumor/Trophoblastic Cells), an open system originally developed for marker-independent isolation of fixed tumor cells. We have assessed the impact of our new enrichment method on live tumor cells antigen expression, cytoskeleton structure, cell viability and ability to expand in culture. We have also explored the ISET® in vitro performance to collect intact fixed and live cancer cells by using spiking analyses with extremely low number of fluorescent cultured cells. We describe results consistently showing the feasibility of isolating fixed and live tumor cells with a Lower Limit of Detection (LLOD) of one cancer cell per 10 mL of blood and a sensitivity at LLOD ranging from 83 to 100%. This very high sensitivity threshold can be maintained when plasma is collected before tumor cells isolation. Finally, we have performed a comparative next generation sequencing (NGS) analysis of tumor cells before and after isolation from blood and culture. We established the feasibility of NGS analysis of single live and fixed tumor cells enriched from blood by our system. This study provides new protocols for detection and characterization of CTC collected from blood at the very early steps of tumor invasion.
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Project description:Circulating tumor cells (CTCs) are important targets for treatment and critical surrogate markers when evaluating cancer prognosis and therapeutic response. A sensitive methodology for detecting CTCs in gastric cancer (GC) patients is needed. In this study we demonstrate a device for enrichment and cultivation of CTCs. In total, 22 patients with GC, all candidates for surgery, were enrolled in the study. Peripheral blood samples were collected before surgery, and patients were re-evaluated within operation and divided into two groups: resectable and non-resectable GC. A new size-based separation test for enrichment and cultivation of CTCs was used (MetaCell(®)). In addition to cytomorphological analysis, gene expression of tumor associated genes (Cytokeratin-18, Cytokeratin-19, Cytokeratin-20, Cytokeratin-7, EPCAM, MUC1, HER2, EGFR) and of leukocyte markers (e.g. CD45, CD68) was tested in enriched CTC fractions. CTCs were detected in 59 % of the patients studied (n = 13/22). CTCs were detected in seven patients of the resection group (7/10, 70 %) and six of the non-resectable group (6/12, 50 %). Enrichment of the viable CTCs allowed subsequent successful cultivation in vitro. The cytomorphological characterization of the CTCs was a prerequisite of random gene expression testing in CTC-positive samples. In CTC-positive samples gene expression of cytokeratin 18 and 19 was elevated in comparison to the whole blood gene expression analysis. CTCs were found to be present in both resectable and non-resectable gastric cancer patients. The size-based separation platform for CTCs may be used for in vitro cultivation, as well as in subsequent molecular analysis if desired. The sensitivity of CTC-detection could be enhanced by the combination of cytomorphological and molecular analysis.
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