Transcriptional profiling of circulating tumor cells: Quantification and cancer progression (Review)

In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies.

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Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells

Cancers ◽

10.3390/cancers12010039 ◽

2019 ◽

Vol 12 (1) ◽

pp. 39 ◽

Cited By ~ 2

Author(s):

Andreas Josefsson ◽

Karin Larsson ◽

Eva Freyhult ◽

Jan-Erik Damber ◽

Karin Welén

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

Expression Patterns ◽

Therapy Resistance ◽

Castration Resistant Prostate Cancer ◽

Cancer Specific Survival ◽

Castration Resistant

Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

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Cell-surface major vault protein promotes cancer progression through harboring mesenchymal and intermediate circulating tumor cells in hepatocellular carcinomas

Scientific Reports ◽

10.1038/s41598-017-13501-1 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 14

Author(s):

Hyun Min Lee ◽

Jae Won Joh ◽

Se-Ri Seo ◽

Won-Tae Kim ◽

Min Kyu Kim ◽

...

Keyword(s):

Cell Surface ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

Major Vault Protein ◽

Hepatocellular Carcinomas

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Classifying circulating tumor cells to monitor cancer progression

Expert Review of Molecular Diagnostics ◽

10.1080/14737159.2017.1275572 ◽

2016 ◽

Vol 17 (2) ◽

pp. 153-165 ◽

Cited By ~ 5

Author(s):

Panagiota Economopoulou ◽

Vassilis Georgoulias ◽

Athanasios Kotsakis

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression

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The Long-Term Prognostic Significance of Circulating Tumor Cells in Ovarian Cancer—A Study of the OVCAD Consortium

Cancers ◽

10.3390/cancers13112613 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2613

Author(s):

Eva Obermayr ◽

Angelika Reiner ◽

Burkhard Brandt ◽

Elena Ioana Braicu ◽

Alexander Reinthaller ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

Residual Disease ◽

Prognostic Significance ◽

Immunofluorescent Staining ◽

Prognostic Impact ◽

Risk Of Recurrence

Introduction: We previously reported the prognostic impact of circulating tumor cells (CTCs) in a multicenter study on minimal residual disease in primary ovarian cancer. With additional follow-up data, we evaluated the combined CTC approach (CTCscombo), in particular for the patients who had survived more than five years. Material and Methods: Blood samples taken at baseline and six months after adjuvant treatment (follow-up) were assessed by quantitative PCR (qPCR) measuring PPIC transcripts and immunofluorescent staining (IF). A positive result with either IF or qPCR was classified as CTCcombo-positive. Further, PPIC was assessed in the primary tumor tissue. Results: The concordance of IF and qPCR was 65% at baseline and 83% after treatment. Results showed that 50.5% of the baseline and 29.5% of the follow-up samples were CTCcombo-positive. CTCscombo after treatment were associated with increased mortality after adjusting for FIGO stage (HR 2.574, 95% CI: 1.227–5.398, p = 0.012), a higher risk of recurrence after adjusting for peritoneal carcinosis (HR 4.068, 95% CI: 1.948–8.498, p < 0.001), and increased mortality after five survived years. Discussion: The two-sided analytical approach revealed CTC subpopulations associated with ovarian cancer progression and may illuminate a potential treatment-related shift in molecular phenotypes. That approach can identify patients who have elevated risk of recurrence and death due to ovarian cancer and who may require risk-adapted treatment strategies.

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Epithelial-to-mesenchymal transition of tumor cells: cancer progression and metastasis

The International Journal of Developmental Biology ◽

10.1387/ijdb.210180gk ◽

2021 ◽

Author(s):

Vasileios Vardas ◽

Eleni Politaki ◽

Evangelia Pantazaka ◽

Vassilis Georgoulias ◽

Galatea Kallergi

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Metastatic Breast ◽

Cellsearch System ◽

Mesenchymal Transition ◽

Specificity And Sensitivity

Detection and characterization of circulating tumor cells (CTCs) with an epithelial-to-mesenchymal transition (EMT) phenotype is very important as it can contribute to the identification of high-risk for relapse and death patients. However, most of the methods are underestimating CTC numbers, due to their dependence on epithelial markers. In the current study, we evaluated the EMT phenotype in CTCs isolated from breast cancer (BC) patients, using the CellSearch system. Spiking experiments for the evaluation of the specificity and sensitivity of our method were performed using HeLa cells. Sixty-five breast cancer (BC) patients (47 early and 18 metastatic) were enrolled in the study. Vimentin is a mesenchymal marker which indicates tumoral cells acquiring invasive and malignant properties. We studied the vimentin (VIM) expression using the extra channel of the CellSearch system and an anti-vimentin antibody conjugated with FITC. In our present results, we reported the percentage of circulating tumor cells that expressed vimentin in early and in metastatic breast cancer patients. Interestingly, the incidence of cells with a CK-VIM+CD45- phenotype was detected in both settings. These cells were detected in 31.4% of CK-negative (11/35) and 82.3% of CK-positive (10/12) early BC patients. The corresponding numbers for metastatic disease were 15.4% (2/13) and 100% (5/5), respectively. Our results suggest that in CTC-negative patients, potentially undetectable tumor cells could be identified using the FDA-approved CellSearch system, based on the (CK-VIM+CD45-)-phenotype, offering additional information regarding the metastatic dissemination in cancer patients. Further experiments evaluating more biomarkers are necessary to elucidate the mechanisms that regulate tumorigenesis and metastasis.

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Relevance of Circulating Tumor Cells as Predictive Markers for Cancer Incidence and Relapse

Pharmaceuticals ◽

10.3390/ph15010075 ◽

2022 ◽

Vol 15 (1) ◽

pp. 75

Author(s):

Chaithanya Chelakkot ◽

Hobin Yang ◽

Young Kee Shin

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

Cancer Incidence ◽

Single Cells ◽

Circulatory System ◽

Predictive Marker ◽

Response To Therapy ◽

Cancer Prognosis ◽

Novel Technologies

Shedding of cancer cells from the primary site or undetectable bone marrow region into the circulatory system, resulting in clinically overt metastasis or dissemination, is the hallmark of unfavorable invasive cancers. The shed cells remain in circulation until they extravasate to form a secondary metastatic lesion or undergo anoikis. The circulating tumor cells (CTCs) found as single cells or clusters carry a plethora of information, are acknowledged as potential biomarkers for predicting cancer prognosis and cancer progression, and are supposed to play key roles in determining tailored therapies for advanced diseases. With the advent of novel technologies that allow the precise isolation of CTCs, more and more clinical trials are focusing on the prognostic and predictive potential of CTCs. In this review, we summarize the role of CTCs as a predictive marker for cancer incidence, relapse, and response to therapy.

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On the Design of a DLD-DEP Device for Separation of Circulating Tumor Cells in Blood

Volume 13: Micro- and Nano-Systems Engineering and Packaging ◽

10.1115/imece2020-23505 ◽

2020 ◽

Author(s):

Mehdi Rahmati ◽

Xiaolin Chen

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Progression ◽

High Throughput ◽

Blood Cells ◽

Lateral Displacement ◽

Uniform Electric Field ◽

Label Free ◽

Particle Tracing ◽

Key Factor

Abstract Circulating Tumor Cells (CTCs), which migrate from original sites in a body to distant organs through blood, are a key factor in cancer detection. Emerging Label-free techniques owing to their inherent advantage to preserve characteristics of sorted cells and low consumption of samples can be promising to the prediction of cancer progression and metastasis research. Deterministic Lateral Displacement (DLD) is one of the label-free separation techniques employing a specific arrangement of micro-posts for continuous separation of suspended cells in a buffer based on the size of cells. Separation based solely on size is challenging since the size distributions of CTCs might overlap with those of normal blood cells. To address this problem, DLD can be combined with dielectrophoresis (DEP) technique which is the phenomenon of particle movement in a non-uniform electric field owing to the polarization effect. Although, DLD devices employ the laminar flow in low Reynolds number (Re) fluid flow due to predictability of such flow regimes, they should be improved to work in higher Re flow regime so as to attain high throughput devices. In this paper, a particle tracing simulation is developed to study the effects of different post shapes, shift fraction of micropost arrays, and dielectrophoresis forces on separation of CTCs from peripheral blood cells. Our numerical model and results provide a groundwork for design and fabrication of high-throughput DLD-DEP devices for improvement of CTC separation.

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