Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor‐On‐A‐Chip

AbstractLung cancer is the most fetal malignancy due to the high rate of metastasis and recurrence after treatment. A considerable number of patients with early-stage lung cancer relapse due to overlooked distant metastasis. Circulating tumor cells (CTCs) are tumor cells in blood circulation that originated from primary or metastatic sites, and it has been shown that CTCs are critical for metastasis and prognosis in various type of cancers. Here, we employed novel method to capture, isolate and classify CTC with FlowCell system and analyzed the CTCs from a cohort of 302 individuals. Our results illustrated that FlowCell-enriched CTCs effectively differentiated benign and malignant lung tumor and the total CTC counts increased as the tumor developed. More importantly, we showed that CTCs displayed superior sensitivity and specificity to predict lung cancer metastasis in comparison to conventional circulating biomarkers. Taken together, our data suggested CTCs can be used to assist the diagnosis of lung cancer as well as predict lung cancer metastasis. These findings provide an alternative means to screen early-stage metastasis.

Download Full-text

Nanotechnology-Assisted Isolation and Analysis of Circulating Tumor Cells on Microfluidic Devices

Micromachines ◽

10.3390/mi11080774 ◽

2020 ◽

Vol 11 (8) ◽

pp. 774 ◽

Cited By ~ 2

Author(s):

Jie Cheng ◽

Yang Liu ◽

Yang Zhao ◽

Lina Zhang ◽

Lingqian Zhang ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Liquid Biopsy ◽

Cancer Metastasis ◽

Human Peripheral Blood ◽

Microfluidic Devices ◽

Detection Sensitivity ◽

Cell Capture ◽

Primary Tumors ◽

Downstream Analysis

Circulating tumor cells (CTCs), a type of cancer cell that spreads from primary tumors into human peripheral blood and are considered as a new biomarker of cancer liquid biopsy. It provides the direction for understanding the biology of cancer metastasis and progression. Isolation and analysis of CTCs offer the possibility for early cancer detection and dynamic prognosis monitoring. The extremely low quantity and high heterogeneity of CTCs are the major challenges for the application of CTCs in liquid biopsy. There have been significant research endeavors to develop efficient and reliable approaches to CTC isolation and analysis in the past few decades. With the advancement of microfabrication and nanomaterials, a variety of approaches have now emerged for CTC isolation and analysis on microfluidic platforms combined with nanotechnology. These new approaches show advantages in terms of cell capture efficiency, purity, detection sensitivity and specificity. This review focuses on recent progress in the field of nanotechnology-assisted microfluidics for CTC isolation and detection. Firstly, CTC isolation approaches using nanomaterial-based microfluidic devices are summarized and discussed. The different strategies for CTC release from the devices are specifically outlined. In addition, existing nanotechnology-assisted methods for CTC downstream analysis are summarized. Some perspectives are discussed on the challenges of current methods for CTC studies and promising research directions.

Download Full-text

Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

International Journal of Molecular Sciences ◽

10.3390/ijms21051671 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1671 ◽

Cited By ~ 3

Author(s):

Anna Fabisiewicz ◽

Malgorzata Szostakowska-Rodzos ◽

Anna J. Zaczek ◽

Ewa A. Grzybowska

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Biology ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Current Status ◽

Molecular Profile ◽

Breast Cancer Patients

Breast cancer metastasis is the leading cause of cancer deaths in women and is difficult to combat due to the long periods in which disseminated cells retain a potential to be re-activated and start the relapse. Assessing the number and molecular profile of circulating tumor cells (CTCs) in breast cancer patients, especially in early breast cancer, should help in identifying the possibility of relapse in time for therapeutic intervention to prevent or delay recurrence. While metastatic breast cancer is considered incurable, molecular analysis of CTCs still have a potential to define particular susceptibilities of the cells representing the current tumor burden, which may differ considerably from the cells of the primary tumor, and offer more tailored therapy to the patients. In this review we inspect the routes to metastasis and how they can be linked to specific features of CTCs, how CTC analysis may be used in therapy, and what is the current status of the research and efforts to include CTC analysis in clinical practice.

Download Full-text

Detection of Circulating Tumor Cells in Early-Stage Breast Cancer Metastasis to Axillary Lymph Nodes

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-07-0419 ◽

2007 ◽

Vol 13 (14) ◽

pp. 4105-4110 ◽

Cited By ~ 71

Author(s):

Taku Nakagawa ◽

Steve R. Martinez ◽

Yasufumi Goto ◽

Kazuo Koyanagi ◽

Minoru Kitago ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Early Stage ◽

Breast Cancer Metastasis ◽

Early Stage Breast Cancer ◽

Axillary Lymph Nodes ◽

Axillary Lymph

Download Full-text

Highly Sensitive Electrochemical Biosensor for Circulating Tumor Cells Detection via Dual-Aptamer Capture and Rolling Circle Amplification Strategy

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2019.2793 ◽

2019 ◽

Vol 15 (7) ◽

pp. 1568-1577 ◽

Cited By ~ 6

Author(s):

Yang Wang ◽

Kai Chang ◽

Cheng Yang ◽

Shujing Li ◽

Lixin Wang ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Electrochemical Biosensor ◽

Rolling Circle Amplification ◽

K562 Cells ◽

Detection Sensitivity ◽

Experimental Conditions ◽

Simple Method ◽

Rolling Circle

A fast and simple strategy for early detection of circulating tumor cells (CTCs) is urgently required because of cancer metastasis. In this work, we assembled an electrochemical biosensor by two aptamers that could form hairpin and specifically recognize K562 cells. The thiolated capture aptamer was fixed on the gold electrode surface. The detection aptamer was linked with a primer at 3 end which could trigger rolling circle amplification to prolong the sequence of aptamer. The dual-aptamer model was fabricated to improve the capture specificity and efficiency for K562 cells. The rolling circle amplification improved the detection sensitivity by inhibiting electron transfer of [Fe(CN)6]3–/4– which could be measured by differential pulse voltammetry. The detection limit of 25 cells mL–1 and linear ranges of 1 × 10 2 to 1 × 105 cells mL–1 were obtained under optimal experimental conditions. Our work exhibited a label-free and simple method for detecting CTCs using cell-specific aptasensor, showing an expected possibility for further CTCs-related study and clinical applications of this novel method.

Download Full-text

Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

International Journal of Molecular Sciences ◽

10.3390/ijms22179279 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9279

Author(s):

Inés Martínez-Pena ◽

Pablo Hurtado ◽

Nuria Carmona-Ule ◽

Carmen Abuín ◽

Ana Belén Dávila-Ibáñez ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Molecular Mechanisms ◽

Zebrafish Embryo ◽

Cancer Metastasis ◽

Fluid Shear Stress ◽

In Vivo Models

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.

Download Full-text

Circulating Tumor Cells (CTCs): A Unique Model of Cancer Metastases and Non-invasive Biomarkers of Therapeutic Response

Frontiers in Genetics ◽

10.3389/fgene.2021.734595 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jialing Liu ◽

Jingru Lian ◽

Yafei Chen ◽

Xin Zhao ◽

ChangZheng Du ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Therapeutic Response ◽

Ex Vivo ◽

Short Review ◽

Metastatic Progression ◽

Culture Techniques ◽

Non Invasive ◽

Metastatic Sites

Late-stage cancer metastasis remains incurable in the clinic and is the major cause death in patients. Circulating tumor cells (CTCs) are thought to be metastatic precursors shed from the primary tumor or metastatic deposits and circulate in the blood. The molecular network regulating CTC survival, extravasation, and colonization in distant metastatic sites is poorly defined, largely due to challenges in isolating rare CTCs. Recent advances in CTC isolation and ex vivo culture techniques facilitates single-cell omics and the development of related animal models to study CTC-mediated metastatic progression. With these powerful tools, CTCs can potentially be used as non-invasive biomarkers predicting therapeutic response. These studies may open a new avenue for CTC-specific drug discoveries. In this short review, we aim to summarize recent progress in the characterization of CTCs and their clinical relevance in various cancers, setting the stage for realizing personalized therapies against metastases.

Download Full-text

EMT in breast cancer metastasis an interplay of microRNAs signaling pathways and circulating tumor cells

Frontiers in Bioscience ◽

10.2741/4844 ◽

2020 ◽

Vol 25 (5) ◽

pp. 979-1010 ◽

Cited By ~ 3

Author(s):

Lekha Dinesh Kumar

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Breast Cancer Metastasis

Download Full-text

Fibronectin Regulation of Integrin B1 and SLUG in Circulating Tumor Cells

Cells ◽

10.3390/cells8060618 ◽

2019 ◽

Vol 8 (6) ◽

pp. 618 ◽

Cited By ~ 6

Author(s):

Jeannette Huaman ◽

Michelle Naidoo ◽

Xingxing Zang ◽

Olorunseun O. Ogunwobi

Keyword(s):

Mouse Model ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Primary Tumor ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Castration Resistant Prostate Cancer ◽

Good Tool ◽

Mesenchymal Transition ◽

Syngeneic Mouse Model

Metastasis is the leading cause of cancer death worldwide. Circulating tumor cells (CTCs) are a critical step in the metastatic cascade and a good tool to study this process. We isolated CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) and a human xenograft mouse model of castration-resistant prostate cancer (CRPC). From these models, novel primary tumor and CTC cell lines were established. CTCs exhibited greater migration than primary tumor-derived cells, as well as epithelial-to-mesenchymal transition (EMT), as observed from decreased E-cadherin and increased SLUG and fibronectin expression. Additionally, when fibronectin was knocked down in CTCs, integrin B1 and SLUG were decreased, indicating regulation of these molecules by fibronectin. Investigation of cell surface molecules and secreted cytokines conferring immunomodulatory advantage to CTCs revealed decreased major histocompatibility complex class I (MHCI) expression and decreased endostatin, C-X-C motif chemokine 5 (CXCL5), and proliferin secretion by CTCs. Taken together, these findings indicate that CTCs exhibit distinct characteristics from primary tumor-derived cells. Furthermore, CTCs demonstrate enhanced migration in part through fibronectin regulation of integrin B1 and SLUG. Further study of CTC biology will likely uncover additional important mechanisms of cancer metastasis.

Download Full-text