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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2016) | Viewed by 95303

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Prof. Dr. Dario Marchetti

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1. Division of Molecular Medicine, Department of Internal Medicine, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
2. Department of Pathology, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
3. Full Member, UNM Comprehensive Cancer Center, Albuquerque, NM 87131, USA
Interests: the biology and therapeutic utility of circulating tumor cells (CTCs); liquid biopsies; mechanisms of brain metastasis and dormancy in breast and melanoma cancers; molecular crosstalks between dormant bone-marrow (BM) cells and CTCs; roles of BM and BM cellular heterogeneity interplaying with metastasis and dormancy
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Dear Colleagues,

The major cause of patient mortality in cancer is metastasis, however, understanding of the metastatic cascade and mechanisms underlying this complex set of events remain poorly understood. Cancer cells invade the surrounding tissue of primary or metastatic tumors, intravasate into lymphatic and blood vessels, disseminate to distant tissues, extravasate by adapting to the new microenvironment, and colonize these tissues. Because dissemination mostly occurs through the blood, circulating tumor cells (CTCs) are of paramount importance and one of the most promising areas of oncology research. CTCs might serve as “liquid biopsy” as a better way to diagnose cancer patients compared to painful biopsies of the primary tumor, and can represent a clinically useful tool to better reflect cancer progression and monitoring in the patient.

The isolation, characterization, and interrogation of CTCs are hampered by their rarity and heterogeneity, either inherited from respective primary or metastatic tumors or as a result of CTC evolution in blood by genetic/epigenetic progression that may or may not lead to a fully metastatic-competent CTC. Significant technical challenges in the field also persist in regard to identifying and interrogating CTC heterogeneity, assessing CTC biomarkers of clinical utility, and comprehensively capturing these cells (usually, a ratio of one CTC per 10⁶ leukocytes and 10⁹ erythrocytes in one milliliter of blood). Finally, many studies have reported the clinical impact of enumerating CTCs, considering that CTC testing is being employed in over 300 clinical trials worldwide. However, much of the CTC biology needs to be discovered and many scientific/technical challenges must be overcome before their clinical promise as biomarkers and targets for improved therapies can be fulfilled.

The objective of this Special Issue is to publish the latest findings in CTC research and clinical implementation. Contributions outlining CTC discoveries in biological and clinical settings, CTC theoretical and pre-clinical models, CTC technologies and methods for their detection, and clinical findings applying CTC concepts, are welcome.

Prof. Dr. Dario Marchetti
Guests Editors

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Keywords

circulating tumor cells
liquid biopsy
cancer metastasis
minimal residual disease
early-detection of cancer
cancer diagnostics
CTC technologies and platforms
CTC biology
CTC clinical intervention

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Published Papers (10 papers)

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Research

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880 KiB

Open AccessArticle

Epidermal Growth Factor Receptor Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated with Docetaxel Chemotherapy

by Takatsugu Okegawa, Naoshi Itaya, Hidehiko Hara, Mitsuhiro Tambo and Kikuo Nutahara

Int. J. Mol. Sci. 2016, 17(12), 2008; https://doi.org/10.3390/ijms17122008 - 30 Nov 2016

Cited by 18 | Viewed by 4585

Abstract

Objective: We examined whether epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced treatment failure with androgen-deprivation therapy and had received docetaxel chemotherapy were eligible. CTCs and EGFR expression in CTCs were enumerated with the CellSearch System in whole blood. This system is a semi-automated system that detects and enriches epithelial cells from whole blood using an EpCAM antibody-based immunomagnetic capture. In addition, the EGFR-positive CTCs were assessed using CellSearch^® Tumor Phenotyping Reagent EGFR. Results: The median CTC count at baseline before starting trial treatment was eight CTCs per 7.5 mL of blood (range 0–184). There were 37 patients (61.7%) who had ≥5 CTCs, with median overall survival of 11.5 months compared with 20.0 months for 23 patients (38.3%) with <5 CTCs (p < 0.001). A total of 15 patients (40.5%, 15/37) with five or more CTCs were subjected to automated immunofluorescence staining and cell sorting for EGFR protein. Patients with EGFR-positive CTCs had a shorter overall survival (OS) (5.5 months) than patients with EGFR-negative CTCs (20.0 months). CTCs, EGFR-positive CTCs, and alkaline phosphatase (ALP) were independent predictors of overall survival time (p = 0.002, p < 0.001, and p = 0.017, respectively). Conclusion: CTCs may be an independent predictor of OS in CRPC treated with docetaxel chemotherapy. The EGFR expression detected in CTCs was important for assessing the response to chemotherapy and predicting disease outcome. Full article

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

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2582 KiB

Open AccessArticle

Detection and Characterization of Circulating Tumor Associated Cells in Metastatic Breast Cancer

by Zhaomei Mu, Naoual Benali-Furet, Georges Uzan, Anaëlle Znaty, Zhong Ye, Carmela Paolillo, Chun Wang, Laura Austin, Giovanna Rossi, Paolo Fortina, Hushan Yang and Massimo Cristofanilli

Int. J. Mol. Sci. 2016, 17(10), 1665; https://doi.org/10.3390/ijms17101665 - 30 Sep 2016

Cited by 62 | Viewed by 8957

Abstract

The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial–mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively. Full article

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

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1606 KiB

Open AccessArticle

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

by Yafeng Ma, Alison Luk, Francis P. Young, David Lynch, Wei Chua, Bavanthi Balakrishnar, Paul De Souza and Therese M. Becker

Int. J. Mol. Sci. 2016, 17(8), 1264; https://doi.org/10.3390/ijms17081264 - 4 Aug 2016

Cited by 54 | Viewed by 11459

Abstract

Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies. Full article

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

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Open AccessArticle

KRAS G12V Mutation Detection by Droplet Digital PCR in Circulating Cell-Free DNA of Colorectal Cancer Patients

by Susana Olmedillas López, Dolores C. García-Olmo, Mariano García-Arranz, Héctor Guadalajara, Carlos Pastor and Damián García-Olmo

Int. J. Mol. Sci. 2016, 17(4), 484; https://doi.org/10.3390/ijms17040484 - 1 Apr 2016

Cited by 45 | Viewed by 8816

Abstract

KRAS mutations are responsible for resistance to anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer patients. These mutations sometimes appear once treatment has started. Detection of KRAS mutations in circulating cell-free DNA in plasma (“liquid biopsy”) by droplet digital PCR (ddPCR) has emerged as a very sensitive and promising alternative to serial biopsies for disease monitoring. In this study, KRAS G12V mutation was analyzed by ddPCR in plasma DNA from 10 colorectal cancer patients and compared to six healthy donors. The percentage of KRAS G12V mutation relative to wild-type sequences in tumor-derived DNA was also determined. KRAS G12V mutation circulating in plasma was detected in 9 of 10 colorectal cancer patients whose tumors were also mutated. Colorectal cancer patients had 35.62 copies of mutated KRAS/mL plasma, whereas in healthy controls only residual copies were found (0.62 copies/mL, p = 0.0066). Interestingly, patients with metastatic disease showed a significantly higher number of mutant copies than M0 patients (126.25 versus 9.37 copies/mL, p = 0.0286). Wild-type KRAS was also significantly elevated in colorectal cancer patients compared to healthy controls (7718.8 versus 481.25 copies/mL, p = 0.0002). In conclusion, KRAS G12V mutation is detectable in plasma of colorectal cancer patients by ddPCR and could be used as a non-invasive biomarker. Full article

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

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Review

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1180 KiB

Open AccessReview

Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis

by Marta Tellez-Gabriel, Benjamin Ory, Francois Lamoureux, Marie-Francoise Heymann and Dominique Heymann

Int. J. Mol. Sci. 2016, 17(12), 2142; https://doi.org/10.3390/ijms17122142 - 20 Dec 2016

Cited by 126 | Viewed by 16186

Abstract

Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level. Full article

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

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1035 KiB

Open AccessReview

Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

by Michela Bulfoni, Matteo Turetta, Fabio Del Ben, Carla Di Loreto, Antonio Paolo Beltrami and Daniela Cesselli

Int. J. Mol. Sci. 2016, 17(10), 1775; https://doi.org/10.3390/ijms17101775 - 24 Oct 2016

Cited by 54 | Viewed by 9579

Abstract

Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM⁺/CK⁺) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well. Full article

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

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549 KiB

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Clinical Application of Circulating Tumour Cells in Prostate Cancer: From Bench to Bedside and Back

by Luis León-Mateos, María Vieito, Urbano Anido, Rafael López López and Laura Muinelo Romay

Int. J. Mol. Sci. 2016, 17(9), 1580; https://doi.org/10.3390/ijms17091580 - 20 Sep 2016

Cited by 11 | Viewed by 7454

Abstract

Prostate cancer is the most common cancer in men worldwide. To improve future drug development and patient management, surrogate biomarkers associated with relevant outcomes are required. Circulating tumour cells (CTCs) are tumour cells that can enter the circulatory system, and are principally responsible for the development of metastasis at distant sites. In recent years, interest in detecting CTCs as a surrogate biomarker has ghiiukjrown. Clinical studies have revealed that high levels of CTCs in the blood correlate with disease progression in patients with prostate cancer; however, their predictive value for monitoring therapeutic response is less clear. Despite the important progress in CTC clinical development, there are critical requirements for the implementation of their analysis as a routine oncology tool. The goal of the present review is to provide an update on the advances in the clinical validation of CTCs as a surrogate biomarker and to discuss the principal obstacles and main challenges to their inclusion in clinical practice. Full article

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

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Open AccessReview

The Significance of Epithelial-to-Mesenchymal Transition for Circulating Tumor Cells

by Alexandra C. Kölbl, Udo Jeschke and Ulrich Andergassen

Int. J. Mol. Sci. 2016, 17(8), 1308; https://doi.org/10.3390/ijms17081308 - 11 Aug 2016

Cited by 43 | Viewed by 7732

Abstract

Epithelial to mesenchymal transition (EMT) is a process involved in embryonic development, but it also plays a role in remote metastasis formation in tumor diseases. During this process cells lose their epithelial features and adopt characteristics of mesenchymal cells. Thereby single tumor cells, which dissolve from the primary tumor, are enabled to invade the blood vessels and travel throughout the body as so called “circulating tumor cells” (CTCs). After leaving the blood stream the reverse process of EMT, the mesenchymal to epithelial transition (MET) helps the cells to seed in different tissues, thereby generating the bud of metastasis formation. As metastasis is the main reason for tumor-associated death, CTCs and the EMT process are in the focus of research in recent years. This review summarizes what was already found out about the molecular mechanisms driving EMT, the consequences of EMT for tumor cell detection, and suitable markers for the detection of CTCs which underwent EMT. The research work done in this field could open new roads towards combating cancer. Full article

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

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211 KiB

Open AccessReview

Circulating Tumor Cells in the Adenocarcinoma of the Esophagus

by Giulia Gallerani and Francesco Fabbri

Int. J. Mol. Sci. 2016, 17(8), 1266; https://doi.org/10.3390/ijms17081266 - 4 Aug 2016

Cited by 14 | Viewed by 4704

Abstract

Circulating tumor cells (CTCs) are elements of indisputable significance as they seem to be responsible for the onset of metastasis. Despite this, research into CTCs and their clinical application have been hindered by their rarity and heterogeneity at the molecular and cellular level, and also by a lack of technical standardization. Esophageal adenocarcinoma (EAC) is a highly aggressive cancer that is often diagnosed at an advanced stage. Its incidence has increased so much in recent years that new diagnostic, prognostic and predictive biomarkers are urgently needed. Preliminary findings suggest that CTCs could represent an effective, non-invasive, real-time assessable biomarker in all stages of EAC. This review provides an overview of EAC and CTC characteristics and reports the main research results obtained on CTCs in this setting. The need to carry out further basic and translational research in this area to confirm the clinical usefulness of CTCs and to provide oncologists with a tool to improve therapeutic strategies for EAC patients was herein highlighted. Full article

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

Other

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573 KiB

Open AccessConference Report

Circulating Tumor Cells (CTC) and Cell-Free DNA (cfDNA) Workshop 2016: Scientific Opportunities and Logistics for Cancer Clinical Trial Incorporation

by Lori E. Lowes, Scott V. Bratman, Ryan Dittamore, Susan Done, Shana O. Kelley, Sabine Mai, Ryan D. Morin, Alexander W. Wyatt and Alison L. Allan

Int. J. Mol. Sci. 2016, 17(9), 1505; https://doi.org/10.3390/ijms17091505 - 8 Sep 2016

Cited by 52 | Viewed by 14511

Abstract

Despite the identification of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) as potential blood-based biomarkers capable of providing prognostic and predictive information in cancer, they have not been incorporated into routine clinical practice. This resistance is due in part to technological limitations hampering CTC and cfDNA analysis, as well as a limited understanding of precisely how to interpret emergent biomarkers across various disease stages and tumor types. In recognition of these challenges, a group of researchers and clinicians focused on blood-based biomarker development met at the Canadian Cancer Trials Group (CCTG) Spring Meeting in Toronto, Canada on 29 April 2016 for a workshop discussing novel CTC/cfDNA technologies, interpretation of data obtained from CTCs versus cfDNA, challenges regarding disease evolution and heterogeneity, and logistical considerations for incorporation of CTCs/cfDNA into clinical trials, and ultimately into routine clinical use. The objectives of this workshop included discussion of the current barriers to clinical implementation and recent progress made in the field, as well as fueling meaningful collaborations and partnerships between researchers and clinicians. We anticipate that the considerations highlighted at this workshop will lead to advances in both basic and translational research and will ultimately impact patient management strategies and patient outcomes. Full article

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

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