Cancers

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35 pages, 1396 KiB

Open AccessArticle

Isolation of Circulating Tumor Cells by Dielectrophoresis

by Peter R. C. Gascoyne and Sangjo Shim

Cancers 2014, 6(1), 545-579; https://doi.org/10.3390/cancers6010545 - 12 Mar 2014

Cited by 231 | Viewed by 15115

Abstract

Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell [...] Read more.

Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a) the principles of DEP; (b) the biological basis for the dielectric differences between CTCs and blood cells; (c) why such differences are expected to be present for all types of tumors; and (d) instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF) is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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10 pages, 593 KiB

Open AccessArticle

Circulating Tumor Cells Detection and Counting in Uveal Melanomas by a Filtration-Based Method

by Cinzia Mazzini, Pamela Pinzani, Francesca Salvianti, Cristian Scatena, Milena Paglierani, Francesca Ucci, Mario Pazzagli and Daniela Massi

Cancers 2014, 6(1), 323-332; https://doi.org/10.3390/cancers6010323 - 7 Feb 2014

Cited by 51 | Viewed by 8911

Abstract

Uveal melanoma is one of the most deadly diseases in ophthalmology for which markers able to predict the appearance of metastasis are needed. The study investigates the role of circulating tumor cells (CTC) as a prognostic factor in this disease. We report the [...] Read more.

Uveal melanoma is one of the most deadly diseases in ophthalmology for which markers able to predict the appearance of metastasis are needed. The study investigates the role of circulating tumor cells (CTC) as a prognostic factor in this disease. We report the detection of circulating tumor cells by Isolation by Size of Epithelial Tumor cells (ISET) in a cohort of 31 uveal melanoma patients: we identified single CTCs or clusters of cells in 17 patients, while the control population, subjects with choroidal nevi, showed no CTC in peripheral blood. The presence of CTCs did not correlate with any clinical and pathological parameter, such as tumor larger basal diameter (LBD), tumor height and TNM. By stratifying patients in groups on the basis of the number of CTC (lower or higher than 10 CTC per 10 mL blood) and the presence of CTC clusters we found a significant difference in LBD (p = 0.019), Tumor height (p = 0.048), disease-free and overall survival (p < 0.05). In conclusion, we confirm the role of CTC as a negative prognostic marker in uveal melanoma patients after a long follow-up period. Further characterization of CTC will help understanding uveal melanoma metastasization and improve patient management. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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13 pages, 501 KiB

Open AccessArticle

Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment

by Laura Muinelo-Romay, Maria Vieito, Alicia Abalo, Marta Alonso Nocelo, Francisco Barón, Urbano Anido, Elena Brozos, Francisca Vázquez, Santiago Aguín, Miguel Abal and Rafael López López

Cancers 2014, 6(1), 153-165; https://doi.org/10.3390/cancers6010153 - 21 Jan 2014

Cited by 99 | Viewed by 9459

Abstract

In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before [...] Read more.

In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells) were counted. At baseline 18 (41.9%) patients were positive for intact CTC count and 10 (23.2%) of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ³5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively). Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other “objects” such as apoptotic CTC or CK fragments to guide the clinical management of these patients. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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15 pages, 966 KiB

Open AccessArticle

Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

by Mazen A. Juratli, Mustafa Sarimollaoglu, Dmitry A. Nedosekin, Alexander V. Melerzanov, Vladimir P. Zharov and Ekaterina I. Galanzha

Cancers 2014, 6(1), 128-142; https://doi.org/10.3390/cancers6010128 - 15 Jan 2014

Cited by 38 | Viewed by 8603

Abstract

Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry [...] Read more.

Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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19 pages, 345 KiB

Open AccessArticle

Heterogeneity of Mesenchymal Markers Expression—Molecular Profiles of Cancer Cells Disseminated by Lymphatic and Hematogenous Routes in Breast Cancer

by Aleksandra Markiewicz, Magdalena Książkiewicz, Barbara Seroczyńska, Jarosław Skokowski, Jolanta Szade, Marzena Wełnicka-Jaśkiewicz and Anna J. Zaczek

Cancers 2013, 5(4), 1485-1503; https://doi.org/10.3390/cancers5041485 - 8 Nov 2013

Cited by 8 | Viewed by 8881

Abstract

Breast cancers can metastasize via hematogenous and lymphatic routes, however in some patients only one type of metastases are detected, suggesting a certain proclivity in metastatic patterns. Since epithelial-mesenchymal transition (EMT) plays an important role in cancer dissemination it would be worthwhile to [...] Read more.

Breast cancers can metastasize via hematogenous and lymphatic routes, however in some patients only one type of metastases are detected, suggesting a certain proclivity in metastatic patterns. Since epithelial-mesenchymal transition (EMT) plays an important role in cancer dissemination it would be worthwhile to find if a specific profile of EMT gene expression exists that is related to either lymphatic or hematogenous dissemination. Our study aimed at evaluating gene expression profile of EMT-related markers in primary tumors (PT) and correlated them with the pattern of metastatic spread. From 99 early breast cancer patients peripheral blood samples (N = 99), matched PT (N = 47) and lymph node metastases (LNM; N = 22) were collected. Expression of TWIST1, SNAI1, SNAI2 and VIM was analyzed in those samples. Additionally expression of CK19, MGB1 and HER2 was measured in CTCs-enriched blood fractions (CTCs-EBF). Results were correlated with each other and with clinico-pathological data of the patients. Results show that the mesenchymal phenotype of CTCs-EBF correlated with poor clinico-pathological characteristics of the patients. Additionally, PT shared more similarities with LNM than with CTCs-EBF. Nevertheless, LNM showed increased expression of EMT-related markers than PT; and EMT itself in PT did not seem to be necessary for lymphatic dissemination. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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Review

Jump to: Research, Other

24 pages, 711 KiB

Open AccessReview

Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

by Natalie Turner, Marta Pestrin, Francesca Galardi, Francesca De Luca, Luca Malorni and Angelo Di Leo

Cancers 2014, 6(2), 684-707; https://doi.org/10.3390/cancers6020684 - 25 Mar 2014

Cited by 24 | Viewed by 9719

Abstract

Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment [...] Read more.

Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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30 pages, 1031 KiB

Open AccessReview

Recent Advances in the Molecular Characterization of Circulating Tumor Cells

by Lori E. Lowes and Alison L. Allan

Cancers 2014, 6(1), 595-624; https://doi.org/10.3390/cancers6010595 - 13 Mar 2014

Cited by 48 | Viewed by 10646

Abstract

Although circulating tumor cells (CTCs) were first observed over a century ago, lack of sensitive methodology precluded detailed study of these cells until recently. However, technological advances have now facilitated the identification, enumeration, and characterization of CTCs using a variety of methods. The [...] Read more.

Although circulating tumor cells (CTCs) were first observed over a century ago, lack of sensitive methodology precluded detailed study of these cells until recently. However, technological advances have now facilitated the identification, enumeration, and characterization of CTCs using a variety of methods. The majority of evidence supporting the use of CTCs in clinical decision-making has been related to enumeration using the CellSearch^® system and correlation with prognosis. Growing evidence also suggests that CTC monitoring can provide an early indication of patient treatment response based on comparison of CTC levels before and after therapy. However, perhaps the greatest potential that CTCs hold for oncology lies at the level of molecular characterization. Clinical treatment decisions may be more effective if they are based on molecular characteristics of metastatic cells rather than on those of the primary tumor alone. Molecular characterization of CTCs (which can be repeatedly isolated in a minimally invasive fashion) provides the opportunity for a “real-time liquid biopsy” that allows assessment of genetic drift, investigation of molecular disease evolution, and identification of actionable genomic characteristics. This review focuses on recent advances in this area, including approaches involving immunophenotyping, fluorescence in situ hybridization (FISH), multiplex RT-PCR, microarray, and genomic sequencing. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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10 pages, 184 KiB

Open AccessReview

The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer

by Malgorzata Banys, Natalia Krawczyk and Tanja Fehm

Cancers 2014, 6(1), 143-152; https://doi.org/10.3390/cancers6010143 - 15 Jan 2014

Cited by 20 | Viewed by 6919

Abstract

Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs) in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly [...] Read more.

Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs) in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly worse clinical outcome than DTC-negative patients. Since DTC phenotype may differ from the primary tumor with regard to ER and HER2 status, reevaluation of predictive markers on DTCs may optimize treatment choices. In the present review, we report on the clinical relevance of DTC detection in breast cancer. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

48 pages, 3826 KiB

Open AccessReview

Circulating Tumor Cell Detection and Capture by Photoacoustic Flow Cytometry in Vivo and ex Vivo

by Ekaterina I. Galanzha and Vladimir P. Zharov

Cancers 2013, 5(4), 1691-1738; https://doi.org/10.3390/cancers5041691 - 10 Dec 2013

Cited by 117 | Viewed by 17782

Abstract

Despite progress in detecting circulating tumor cells (CTCs), existing assays still have low sensitivity (1–10 CTC/mL) due to the small volume of blood samples (5–10 mL). Consequently, they can miss up to 10³–10⁴ CTCs, resulting in the development of barely [...] Read more.

Despite progress in detecting circulating tumor cells (CTCs), existing assays still have low sensitivity (1–10 CTC/mL) due to the small volume of blood samples (5–10 mL). Consequently, they can miss up to 10³–10⁴ CTCs, resulting in the development of barely treatable metastasis. Here we analyze a new concept of in vivo CTC detection with enhanced sensitivity (up to 10²–10³ times) by the examination of the entire blood volume in vivo (5 L in adults). We focus on in vivo photoacoustic (PA) flow cytometry (PAFC) of CTCs using label-free or targeted detection, photoswitchable nanoparticles with ultrasharp PA resonances, magnetic trapping with fiber-magnetic-PA probes, optical clearance, real-time spectral identification, nonlinear signal amplification, and the integration with PAFC in vitro. We demonstrate PAFC’s capability to detect rare leukemia, squamous carcinoma, melanoma, and bulk and stem breast CTCs and its clusters in preclinical animal models in blood, lymph, bone, and cerebrospinal fluid, as well as the release of CTCs from primary tumors triggered by palpation, biopsy or surgery, increasing the risk of metastasis. CTC lifetime as a balance between intravasation and extravasation rates was in the range of 0.5–4 h depending on a CTC metastatic potential. We introduced theranostics of CTCs as an integration of nanobubble-enhanced PA diagnosis, photothermal therapy, and feedback through CTC counting. In vivo data were verified with in vitro PAFC demonstrating a higher sensitivity (1 CTC/40 mL) and throughput (up to 10 mL/min) than conventional assays. Further developments include detection of circulating cancer-associated microparticles, and super-rsesolution PAFC beyond the diffraction and spectral limits. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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15 pages, 589 KiB

Open AccessReview

Circulating Tumor Cells in Prostate Cancer

by Brian Hu, Holly Rochefort and Amir Goldkorn

Cancers 2013, 5(4), 1676-1690; https://doi.org/10.3390/cancers5041676 - 4 Dec 2013

Cited by 44 | Viewed by 11164

Abstract

Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, [...] Read more.

Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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24 pages, 1827 KiB

Open AccessReview

Towards the Biological Understanding of CTC: Capture Technologies, Definitions and Potential to Create Metastasis

by Ana M.C. Barradas and Leon W.M.M. Terstappen

Cancers 2013, 5(4), 1619-1642; https://doi.org/10.3390/cancers5041619 - 4 Dec 2013

Cited by 81 | Viewed by 11700

Abstract

Circulating Tumor Cells (CTC) are rare cells originated from tumors that travel into the blood stream, extravasate to different organs of which only a small fraction will develop into metastasis. The presence of CTC enumerated with the CellSearch system is associated with a [...] Read more.

Circulating Tumor Cells (CTC) are rare cells originated from tumors that travel into the blood stream, extravasate to different organs of which only a small fraction will develop into metastasis. The presence of CTC enumerated with the CellSearch system is associated with a relative short survival and their continued presence after the first cycles of therapy indicates a futile therapy in patients with metastatic carcinomas. Detailed characterization of CTC holds the promise to enable the choice of the optimal therapy for the individual patients during the course of the disease. The phenotype, physical and biological properties are however not well understood making it difficult to assess the merit of recent technological advancements to improve upon the capture of CTC or to evaluate their metastatic potential. Here we will discuss the recent advances in the classification of CTC captured by the CellSearch system, the implications of their features and numbers. Latest capture platforms are reviewed and placed in the light of technology improvements needed to detect CTC. Physical properties, phenotype, viability and proliferative potential and means to assess their proliferation and metastatic capacity will be summarized and placed in the context of the latest CTC capture platforms. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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21 pages, 570 KiB

Open AccessReview

Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells

by Monica Charpentier and Stuart Martin

Cancers 2013, 5(4), 1545-1565; https://doi.org/10.3390/cancers5041545 - 14 Nov 2013

Cited by 52 | Viewed by 10773

Abstract

Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with [...] Read more.

Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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9 pages, 344 KiB

Open AccessReview

Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients via RT-qPCR

by Ulrich Andergassen, Alexandra C. Kölbl, Stefan Hutter, Klaus Friese and Udo Jeschke

Cancers 2013, 5(4), 1212-1220; https://doi.org/10.3390/cancers5041212 - 25 Sep 2013

Cited by 16 | Viewed by 7737

Abstract

Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, [...] Read more.

Breast cancer is still the most frequent cause of cancer-related death in women worldwide. Often death is not caused only by the primary tumour itself, but also by metastatic lesions. Today it is largely accepted, that these remote metastases arise out of cells, which detach from the primary tumour, enter circulation, settle down at secondary sites in the body and are called Circulating Tumour Cells (CTCs). The occurrence of such minimal residual diseases in the blood of breast cancer patients is mostly linked to a worse prognosis for therapy outcome and overall survival. Due to their very low frequency, the detection of CTCs is, still a technical challenge. RT-qPCR as a highly sensitive method could be an approach for CTC-detection from peripheral blood of breast cancer patients. This assumption is based on the fact that CTCs are of epithelial origin and therefore express a different gene panel than surrounding blood cells. For the technical approach it is necessary to identify appropriate marker genes and to correlate their gene expression levels to the number of tumour cells within a sample in an in vitro approach. After that, samples from adjuvant and metastatic patients can be analysed. This approach may lead to new concepts in diagnosis and treatment. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

Other

Jump to: Research, Review

13 pages, 133 KiB

Open AccessConcept Paper

Circulating Tumor Cells: What Is in It for the Patient? A Vision towards the Future

by Anja Van de Stolpe and Jaap M. J. Den Toonder

Cancers 2014, 6(2), 1195-1207; https://doi.org/10.3390/cancers6021195 - 28 May 2014

Cited by 18 | Viewed by 7484

Abstract

Knowledge on cellular signal transduction pathways as drivers of cancer growth and metastasis has fuelled development of “targeted therapy” which “targets” aberrant oncogenic signal transduction pathways. These drugs require nearly invariably companion diagnostic tests to identify the tumor-driving pathway and the cause of [...] Read more.

Knowledge on cellular signal transduction pathways as drivers of cancer growth and metastasis has fuelled development of “targeted therapy” which “targets” aberrant oncogenic signal transduction pathways. These drugs require nearly invariably companion diagnostic tests to identify the tumor-driving pathway and the cause of the abnormal pathway activity in a tumor sample, both for therapy response prediction as well as for monitoring of therapy response and emerging secondary drug resistance. Obtaining sufficient tumor material for this analysis in the metastatic setting is a challenge, and circulating tumor cells (CTCs) may provide an attractive alternative to biopsy on the premise that they can be captured from blood and the companion diagnostic test results are correctly interpreted. We discuss novel companion diagnostic directions, including the challenges, to identify the tumor driving pathway in CTCs, which in combination with a digital pathology platform and algorithms to quantitatively interpret complex CTC diagnostic results may enable optimized therapy response prediction and monitoring. In contrast to CTC-based companion diagnostics, CTC enumeration is envisioned to be largely replaced by cell free tumor DNA measurements in blood for therapy response and recurrence monitoring. The recent emergence of novel in vitro human model systems in the form of cancer-on-a-chip may enable elucidation of some of the so far elusive characteristics of CTCs, and is expected to contribute to more efficient CTC capture and CTC-based diagnostics. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

9 pages, 310 KiB

Open AccessOpinion

The Clinical Potential of Circulating Tumor Cells; The Need to Incorporate a Modern “Immunological Cocktail” in the Assay

by Jonathan W. Uhr

Cancers 2013, 5(4), 1739-1747; https://doi.org/10.3390/cancers5041739 - 13 Dec 2013

Cited by 5 | Viewed by 5353

Abstract

The accepted clinical assay, CellSearch^®, and lab-on-a-chip tests for capturing circulating tumor cells are antibody-mediated. Attempts to improve their sensitivity have relied upon physical changes in the instruments. There have been no significant advances in improving the antibody-mediated portion of the [...] Read more.

The accepted clinical assay, CellSearch^®, and lab-on-a-chip tests for capturing circulating tumor cells are antibody-mediated. Attempts to improve their sensitivity have relied upon physical changes in the instruments. There have been no significant advances in improving the antibody-mediated portion of the capture. Modern immunologic engineering offers major possibilities for improving the sensitivity and other features of the assay. These include obtaining univalent antibody fragments such as scFvs with picomolar binding affinity and sufficient specificity; altering them to enhance their range of potential contact with target antigens; using antibodies directed against different epitopes on epithelial, mesenchymal or organ-specific cell surface markers to allow simultaneous binding and investigating non-antibody binding molecules as substitutes for antibody. These maneuvers could markedly improve the ability of current assays to improve patient care and might result in an acceptable test for detecting cancer earlier in high risk patients. Full article

(This article belongs to the Special Issue Circulating Tumor Cells in Cancers)

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