|
1
|
Chung YD, Tsai YC, Wang CH, Lee GB. Aptamer selection via versatile microfluidic platforms and their diverse applications. LAB ON A CHIP 2025; 25:1047-1080. [PMID: 39774569 DOI: 10.1039/d4lc00859f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Aptamers are synthetic oligonucleotides that bind with high affinity and specificity to various targets, making them invaluable for diagnostics, therapeutics, and biosensing. Microfluidic platforms can improve the efficiency and scalability of aptamer selection, especially through advancements in systematic evolution of ligands by exponential enrichment (SELEX) methods. Microfluidic SELEX methods are less time-consuming and labor-intensive and include critical steps like library preparation, binding, partitioning, and amplification. This review examines the contributions of microfluidic technology to SELEX-based aptamer identification, with alternative methods like conditional SELEX, in vivo-like SELEX and Non-SELEX for selecting aptamers and also discusses critical SELEX steps over the past decade. This work also examined the integrated microfluidic systems for SELEX, highlighting innovations such as conditional SELEX and in vivo-like SELEX. These advancements provide potential solutions to existing challenges in aptamer selection using conventional SELEX, especially concerning biological samples. A trend toward non-SELEX methods was also reviewed and discussed, wherein nucleic acid amplification was eliminated to improve aptamer selection. Microfluidic platforms have demonstrated versatility not only in aptamer selection but also in various detection applications; they allow for precise control of liquid flow and have been essential in the advancement of therapeutic aptamers, facilitating accurate screening, enhancing drug delivery systems, and enabling targeted therapeutic interventions. Although advances in microfluidic technology are expected to enhance aptamer-based diagnostics, therapeutics, and biosensing, challenges still persist, especially in up-scaling microfluidic systems for various clinical applications. The advantages and limitations of integrating microfluidic platforms with aptamer development are further addressed, emphasizing areas for future research. We also present a perspective on the future of microfluidic systems and aptamer technologies, highlighting their increasing significance in healthcare and diagnostics.
Collapse
Affiliation(s)
- Yi-Da Chung
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
| | - Yi-Cheng Tsai
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
| | - Chi-Hung Wang
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
| | - Gwo-Bin Lee
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
- Institute of NanoEngineering and MicroSystems, National Tsing Hua University, Hsinchu, Taiwan
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| |
Collapse
|
|
2
|
Kefayat A, Sartipzadeh O, Molaabasi F, Amiri M, Gholami R, Mirzadeh M, Shokati F, Khandaei M, Ghahremani F, Poursamar SA, Sarrami-Forooshani R. Microfluidic System Consisting of a Magnetic 3D-Printed Microchannel Filter for Isolation and Enrichment of Circulating Tumor Cells Targeted by Anti-HER2/MOF@Ferrite Core-Shell Nanostructures: A Theranostic CTC Dialysis System. Anal Chem 2024; 96:4377-4384. [PMID: 38442207 DOI: 10.1021/acs.analchem.3c03567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
Low number of circulating tumor cells (CTCs) in the blood samples and time-consuming properties of the current CTC isolation methods for processing a small volume of blood are the biggest obstacles to CTC usage in practice. Therefore, we aimed to design a CTC dialysis system with the ability to process cancer patients' whole blood within a reasonable time. Two strategies were employed for developing this dialysis setup, including (i) synthesizing novel in situ core-shell Cu ferrites consisting of the Cu-CuFe2O4 core and the MIL-88A shell, which are targeted by the anti-HER2 antibody for the efficient targeting and trapping of CTCs; and (ii) fabricating a microfluidic system containing a three-dimensional (3D)-printed microchannel filter composed of a polycaprolactone/Fe3O4 nanoparticle composite with pore diameter less than 200 μm on which a high-voltage magnetic field is focused to enrich and isolate the magnetic nanoparticle-targeted CTCs from a large volume of blood. The system was assessed in different aspects including capturing the efficacy of the magnetic nanoparticles, CTC enrichment and isolation from large volumes of human blood, side effects on blood cells, and the viability of CTCs after isolation for further analysis. Under the optimized conditions, the CTC dialysis system exhibited more than 80% efficacy in the isolation of CTCs from blood samples. The isolated CTCs were viable and were able to proliferate. Moreover, the CTC dialysis system was safe and did not cause side effects on normal blood cells. Taken together, the designed CTC dialysis system can process a high volume of blood for efficient dual diagnostic and therapeutic purposes.
Collapse
Affiliation(s)
- Amirhosein Kefayat
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 15179-64311, Iran
- Department of Oncology, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
| | - Omid Sartipzadeh
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 15179-64311, Iran
| | - Fatemeh Molaabasi
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 15179-64311, Iran
| | - Maryam Amiri
- Faculty of Chemistry, Shahid Beheshti University, G.C., Evin, Tehran 19839-63113, Iran
| | - Reza Gholami
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 15179-64311, Iran
| | - Motahareh Mirzadeh
- Research & Development Department, H.B. Adli Ltd., Isfahan 81746-73461, Iran
| | - Farhad Shokati
- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 15179-64311, Iran
| | - Mansoureh Khandaei
- Biomaterials, Nanotechnology and Tissue Engineering Department, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
| | - Fatemeh Ghahremani
- School of Paramedicine, Arak University of Medical Sciences, Arak 38196-93345, Iran
| | - Seyed Ali Poursamar
- Biomaterials, Nanotechnology and Tissue Engineering Department, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
| | - Ramin Sarrami-Forooshani
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 15179-64311, Iran
| |
Collapse
|
|
3
|
Nguyen TH, Nguyen HA, Tran Thi YV, Hoang Tran D, Cao H, Chu Duc T, Bui TT, Do Quang L. Concepts, electrode configuration, characterization, and data analytics of electric and electrochemical microfluidic platforms: a review. Analyst 2023; 148:1912-1929. [PMID: 36928639 DOI: 10.1039/d2an02027k] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Microfluidic cytometry (MC) and electrical impedance spectroscopy (EIS) are two important techniques in biomedical engineering. Microfluidic cytometry has been utilized in various fields such as stem cell differentiation and cancer metastasis studies, and provides a simple, label-free, real-time method for characterizing and monitoring cellular fates. The impedance microdevice, including impedance flow cytometry (IFC) and electrical impedance spectroscopy (EIS), is integrated into MC systems. IFC measures the impedance of individual cells as they flow through a microfluidic device, while EIS measures impedance changes during binding events on electrode regions. There have been significant efforts to improve and optimize these devices for both basic research and clinical applications, based on the concepts, electrode configurations, and cell fates. This review outlines the theoretical concepts, electrode engineering, and data analytics of these devices, and highlights future directions for development.
Collapse
Affiliation(s)
- Thu Hang Nguyen
- University of Engineering and Technology, Vietnam National University, Hanoi, Vietnam.
| | | | - Y-Van Tran Thi
- University of Science, Vietnam National University, Hanoi, Vietnam.
| | | | - Hung Cao
- University of California, Irvine, USA
| | - Trinh Chu Duc
- University of Engineering and Technology, Vietnam National University, Hanoi, Vietnam.
| | - Tung Thanh Bui
- University of Engineering and Technology, Vietnam National University, Hanoi, Vietnam.
| | - Loc Do Quang
- University of Science, Vietnam National University, Hanoi, Vietnam.
| |
Collapse
|
|
4
|
Xiao J, Sharma U, Arab A, Miglani S, Bhalla S, Suguru S, Suter R, Mukherji R, Lippman ME, Pohlmann PR, Zeck JC, Marshall JL, Weinberg BA, He AR, Noel MS, Schlegel R, Goodarzi H, Agarwal S. Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis. Cancers (Basel) 2023; 15:1831. [PMID: 36980717 PMCID: PMC10046547 DOI: 10.3390/cancers15061831] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/08/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFβ signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.
Collapse
Affiliation(s)
- Jerry Xiao
- School of Medicine, Georgetown University, Washington, DC 20057, USA
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| | - Utsav Sharma
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Abolfazl Arab
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Sohit Miglani
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Sonakshi Bhalla
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Shravanthy Suguru
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| | - Robert Suter
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Reetu Mukherji
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Marc E. Lippman
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Paula R. Pohlmann
- Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Jay C. Zeck
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - John L. Marshall
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Benjamin A. Weinberg
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Aiwu Ruth He
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Marcus S. Noel
- Department of Medicine, The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Richard Schlegel
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| | - Hani Goodarzi
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA
| | - Seema Agarwal
- Department of Pathology, Center for Cell Reprogramming, Georgetown University, Washington, DC 20057, USA
| |
Collapse
|
|
5
|
Caputo V, Ciardiello F, Corte CMD, Martini G, Troiani T, Napolitano S. Diagnostic value of liquid biopsy in the era of precision medicine: 10 years of clinical evidence in cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:102-138. [PMID: 36937316 PMCID: PMC10017193 DOI: 10.37349/etat.2023.00125] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 11/13/2022] [Indexed: 03/06/2023] Open
Abstract
Liquid biopsy is a diagnostic repeatable test, which in last years has emerged as a powerful tool for profiling cancer genomes in real-time with minimal invasiveness and tailoring oncological decision-making. It analyzes different blood-circulating biomarkers and circulating tumor DNA (ctDNA) is the preferred one. Nevertheless, tissue biopsy remains the gold standard for molecular evaluation of solid tumors whereas liquid biopsy is a complementary tool in many different clinical settings, such as treatment selection, monitoring treatment response, cancer clonal evolution, prognostic evaluation, as well as the detection of early disease and minimal residual disease (MRD). A wide number of technologies have been developed with the aim of increasing their sensitivity and specificity with acceptable costs. Moreover, several preclinical and clinical studies have been conducted to better understand liquid biopsy clinical utility. Anyway, several issues are still a limitation of its use such as false positive and negative results, results interpretation, and standardization of the panel tests. Although there has been rapid development of the research in these fields and recent advances in the clinical setting, many clinical trials and studies are still needed to make liquid biopsy an instrument of clinical routine. This review provides an overview of the current and future clinical applications and opening questions of liquid biopsy in different oncological settings, with particular attention to ctDNA liquid biopsy.
Collapse
Affiliation(s)
- Vincenza Caputo
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Fortunato Ciardiello
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Carminia Maria Della Corte
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Giulia Martini
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Teresa Troiani
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Stefania Napolitano
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| |
Collapse
|
|
6
|
Calero-Castro FJ, Pereira S, Laga I, Villanueva P, Suárez-Artacho G, Cepeda-Franco C, de la Cruz-Ojeda P, Navarro-Villarán E, Dios-Barbeito S, Serrano MJ, Fresno C, Padillo-Ruiz J. Quantification and Characterization of CTCs and Clusters in Pancreatic Cancer by Means of the Hough Transform Algorithm. Int J Mol Sci 2023; 24:ijms24054278. [PMID: 36901704 PMCID: PMC10002258 DOI: 10.3390/ijms24054278] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/24/2023] Open
Abstract
Circulating Tumor Cells (CTCs) are considered a prognostic marker in pancreatic cancer. In this study we present a new approach for counting CTCs and CTC clusters in patients with pancreatic cancer using the IsofluxTM System with the Hough transform algorithm (Hough-IsofluxTM). The Hough-IsofluxTM approach is based on the counting of an array of pixels with a nucleus and cytokeratin expression excluding the CD45 signal. Total CTCs including free and CTC clusters were evaluated in healthy donor samples mixed with pancreatic cancer cells (PCCs) and in samples from patients with pancreatic ductal adenocarcinoma (PDAC). The IsofluxTM System with manual counting was used in a blinded manner by three technicians who used Manual-IsofluxTM as a reference. The accuracy of the Hough-IsofluxTM approach for detecting PCC based on counted events was 91.00% [84.50, 93.50] with a PCC recovery rate of 80.75 ± 16.41%. A high correlation between the Hough-IsofluxTM and Manual-IsofluxTM was observed for both free CTCs and for clusters in experimental PCC (R2 = 0.993 and R2 = 0.902 respectively). However, the correlation rate was better for free CTCs than for clusters in PDAC patient samples (R2 = 0.974 and R2 = 0.790 respectively). In conclusion, the Hough-IsofluxTM approach showed high accuracy for the detection of circulating pancreatic cancer cells. A better correlation rate was observed between Hough-IsofluxTM approach and with the Manual-IsofluxTM for isolated CTCs than for clusters in PDAC patient samples.
Collapse
Affiliation(s)
- Francisco José Calero-Castro
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Sheila Pereira
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Imán Laga
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Paula Villanueva
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Gonzalo Suárez-Artacho
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Carmen Cepeda-Franco
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Patricia de la Cruz-Ojeda
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Elena Navarro-Villarán
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | - Sandra Dios-Barbeito
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
| | | | - Cristóbal Fresno
- Health and Sciences Research Center, Health and Sciences Faculty, Anahuac University, Huixquilucan 52760, Mexico
- Correspondence: (C.F.); (J.P.-R.)
| | - Javier Padillo-Ruiz
- Department of General Surgery, Hospital University Virgen del Rocío/CSIC/University of Seville/IBiS, 41013 Seville, Spain
- Oncology Surgery, Cell Therapy, and Organ Transplantation Group, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain
- Correspondence: (C.F.); (J.P.-R.)
| |
Collapse
|
|
7
|
Geus PF, Hehnen F, Krakowski S, Lücke K, Hoon DSB, Frost N, Kertzscher U, Wendt G. Verification of a Novel Minimally Invasive Device for the Isolation of Rare Circulating Tumor Cells (CTC) in Cancer Patients’ Blood. Cancers (Basel) 2022; 14:cancers14194753. [PMID: 36230675 PMCID: PMC9562020 DOI: 10.3390/cancers14194753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Detection of circulating tumor cells (CTCs) in blood can be used to diagnose cancer or monitor treatment response for various cancers. However, these cells are rare in the bloodstream in the early stages of cancers, and it, therefore, remains a technical challenge to isolate them. To overcome the limitations of a blood draw, we introduce a minimally invasive device, called the BMProbe™, for the isolation of CTCs directly from the bloodstream. Thereby a large volume of blood is screened. This study first shows how the geometry of the in vivo BMProbe™ causes improved cell deposition conditions. We then performed a verification of the in vivo device using blood samples from lung cancer patients. The results indicate the functionality of the BMProbe™ to isolate CTCs in blood samples. The future step is to use the BMProbe™ in various types of cancer patients to detect CTCs. Abstract Circulating tumor cells (CTCs) exist in low quantities in the bloodstream in the early stages of cancers. It, therefore, remains a technical challenge to isolate them in large enough quantities for a precise diagnosis and downstream analysis. We introduce the BMProbe™, a minimally invasive device that isolates CTCs during a 30-minute incubation in the median cubital vein. The optimized geometry of the device creates flow conditions for improved cell deposition. The CTCs are isolated using antibodies that are bound to the surface of the BMProbe™. In this study, flow experiments using cell culture cells were conducted. They indicate a 31 times greater cell binding efficiency of the BMProbe™ compared to a flat geometry. Further, the functionality of isolating CTCs from patient blood was verified in a small ex vivo study that compared the cell count from seven non-small-cell lung carcinoma (NSCLC) patients compared to nine healthy controls with 10 mL blood samples. The median cell count was 1 in NSCLC patients and 0 in healthy controls. In conclusion, the BMProbe™ is a promising method to isolate CTCs in large quantities directly from the venous bloodstream without removing blood from a patient. The future step is to verify the functionality in vivo.
Collapse
Affiliation(s)
- Paul Friedrich Geus
- Biofluid Mechanics Laboratory, Institute of Computer-assisted Cardiovascular Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Correspondence:
| | - Felix Hehnen
- Biofluid Mechanics Laboratory, Institute of Computer-assisted Cardiovascular Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Sophia Krakowski
- Biofluid Mechanics Laboratory, Institute of Computer-assisted Cardiovascular Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Klaus Lücke
- Invicol GmbH, Müllerstraße 178, 13353 Berlin, Germany
- HaimaChek Inc., 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA
| | - Dave S. B. Hoon
- HaimaChek Inc., 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA
- Department of Translational Molecular Medicine, Saint John’s Cancer Institute (SJCI), Providence Saint John’s Health Center (SJHC), Santa Monica, CA 90404, USA
| | - Nikolaj Frost
- Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Ulrich Kertzscher
- Biofluid Mechanics Laboratory, Institute of Computer-assisted Cardiovascular Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Gabi Wendt
- Invicol GmbH, Müllerstraße 178, 13353 Berlin, Germany
| |
Collapse
|
|
8
|
Vasantharajan SS, Barnett E, Gray ES, McCall JL, Rodger EJ, Eccles MR, Munro F, Pattison S, Chatterjee A. Assessment of a Size-Based Method for Enriching Circulating Tumour Cells in Colorectal Cancer. Cancers (Basel) 2022; 14:3446. [PMID: 35884509 PMCID: PMC9319975 DOI: 10.3390/cancers14143446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/01/2022] [Accepted: 07/12/2022] [Indexed: 12/07/2022] Open
Abstract
Circulating tumour cells (CTC) from solid tumours are a prerequisite for metastasis. Isolating CTCs and understanding their biology is essential for developing new clinical tests and precision oncology. Currently, CellSearch is the only FDA (U.S. Food and Drug Administration)-approved method for CTC enrichment but possesses several drawbacks owing to a reliance on the epithelial cell adhesion molecule (EpCAM) and a resource-intensive nature. Addressing these shortcomings, we optimised an existing size-based method, MetaCell, to enrich CTCs from blood of colorectal cancer (CRC) patients. We evaluated the ability of MetaCell to enrich CTCs by spiking blood with CRC cell lines and assessing the cell recovery rates and WBC depletion via immunostaining and gene expression. We then applied MetaCell to samples from 17 CRC patients and seven controls. Recovery rates were >85% in cell lines, with >95% depletion in WBCs. MetaCell yielded CTCs and CTC clusters in 52.9% and 23.5% of the patients, respectively, without false positives in control patients. CTCs and cluster detection did not correlate with histopathological parameters. Overall, we demonstrated that the MetaCell platform enriched CRC cells with high recovery rates and high purity. Our pilot study also demonstrated the ability of MetaCell to detect CTCs in CRC patients.
Collapse
Affiliation(s)
- Sai Shyam Vasantharajan
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.S.V.); (E.B.); (E.J.R.); (M.R.E.)
| | - Edward Barnett
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.S.V.); (E.B.); (E.J.R.); (M.R.E.)
| | - Elin S. Gray
- Centre for Precision Health and School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia;
| | - John L. McCall
- Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (J.L.M.); (F.M.)
| | - Euan J. Rodger
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.S.V.); (E.B.); (E.J.R.); (M.R.E.)
| | - Michael R. Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.S.V.); (E.B.); (E.J.R.); (M.R.E.)
| | - Fran Munro
- Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (J.L.M.); (F.M.)
| | - Sharon Pattison
- Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; (S.S.V.); (E.B.); (E.J.R.); (M.R.E.)
- School of Health Sciences and Technology, UPES University, Dehradun 248007, India
| |
Collapse
|
|
9
|
Regmi S, Poudel C, Adhikari R, Luo KQ. Applications of Microfluidics and Organ-on-a-Chip in Cancer Research. BIOSENSORS 2022; 12:bios12070459. [PMID: 35884262 PMCID: PMC9313151 DOI: 10.3390/bios12070459] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 06/11/2022] [Accepted: 06/17/2022] [Indexed: 12/27/2022]
Abstract
Taking the life of nearly 10 million people annually, cancer has become one of the major causes of mortality worldwide and a hot topic for researchers to find innovative approaches to demystify the disease and drug development. Having its root lying in microelectronics, microfluidics seems to hold great potential to explore our limited knowledge in the field of oncology. It offers numerous advantages such as a low sample volume, minimal cost, parallelization, and portability and has been advanced in the field of molecular biology and chemical synthesis. The platform has been proved to be valuable in cancer research, especially for diagnostics and prognosis purposes and has been successfully employed in recent years. Organ-on-a-chip, a biomimetic microfluidic platform, simulating the complexity of a human organ, has emerged as a breakthrough in cancer research as it provides a dynamic platform to simulate tumor growth and progression in a chip. This paper aims at giving an overview of microfluidics and organ-on-a-chip technology incorporating their historical development, physics of fluid flow and application in oncology. The current applications of microfluidics and organ-on-a-chip in the field of cancer research have been copiously discussed integrating the major application areas such as the isolation of CTCs, studying the cancer cell phenotype as well as metastasis, replicating TME in organ-on-a-chip and drug development. This technology’s significance and limitations are also addressed, giving readers a comprehensive picture of the ability of the microfluidic platform to advance the field of oncology.
Collapse
Affiliation(s)
- Sagar Regmi
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Department of Physics, Kathmandu University, Dhulikhel 45200, Nepal;
- Research Centre for Applied Science and Technology (RECAST), Tribhuvan University, Kathmandu 44600, Nepal;
- Nepal Academy of Science and Technology (NAST), Khumaltar, Lalitpur 44700, Nepal
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Chetan Poudel
- Department of Physics, Kathmandu University, Dhulikhel 45200, Nepal;
| | - Rameshwar Adhikari
- Research Centre for Applied Science and Technology (RECAST), Tribhuvan University, Kathmandu 44600, Nepal;
| | - Kathy Qian Luo
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau, China
- Correspondence:
| |
Collapse
|
|
10
|
Lin AA, Nimgaonkar V, Issadore D, Carpenter EL. Extracellular Vesicle-Based Multianalyte Liquid Biopsy as a Diagnostic for Cancer. Annu Rev Biomed Data Sci 2022; 5:269-292. [PMID: 35562850 DOI: 10.1146/annurev-biodatasci-122120-113218] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Liquid biopsy is the analysis of materials shed by tumors into circulation, such as circulating tumor cells, nucleic acids, and extracellular vesicles (EVs), for the diagnosis and management of cancer. These assays have rapidly evolved with recent FDA approvals of single biomarkers in patients with advanced metastatic disease. However, they have lacked sensitivity or specificity as a diagnostic in early-stage cancer, primarily due to low concentrations in circulating plasma. EVs, membrane-enclosed nanoscale vesicles shed by tumor and other cells into circulation, are a promising liquid biopsy analyte owing to their protein and nucleic acid cargoes carried from their mother cells, their surface proteins specific to their cells of origin, and their higher concentrations over other noninvasive biomarkers across disease stages. Recently, the combination of EVs with non-EV biomarkers has driven improvements in sensitivity and accuracy; this has been fueled by the use of machine learning (ML) to algorithmically identify and combine multiple biomarkers into a composite biomarker for clinical prediction. This review presents an analysis of EV isolation methods, surveys approaches for and issues with using ML in multianalyte EV datasets, and describes best practices for bringing multianalyte liquid biopsy to clinical implementation. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 5 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Collapse
Affiliation(s)
- Andrew A Lin
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; .,Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Vivek Nimgaonkar
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
| | - David Issadore
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Erica L Carpenter
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
| |
Collapse
|
|
11
|
Ginghina O, Hudita A, Zamfir M, Spanu A, Mardare M, Bondoc I, Buburuzan L, Georgescu SE, Costache M, Negrei C, Nitipir C, Galateanu B. Liquid Biopsy and Artificial Intelligence as Tools to Detect Signatures of Colorectal Malignancies: A Modern Approach in Patient's Stratification. Front Oncol 2022; 12:856575. [PMID: 35356214 PMCID: PMC8959149 DOI: 10.3389/fonc.2022.856575] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/16/2022] [Indexed: 01/19/2023] Open
Abstract
Colorectal cancer (CRC) is the second most frequently diagnosed type of cancer and a major worldwide public health concern. Despite the global efforts in the development of modern therapeutic strategies, CRC prognosis is strongly correlated with the stage of the disease at diagnosis. Early detection of CRC has a huge impact in decreasing mortality while pre-lesion detection significantly reduces the incidence of the pathology. Even though the management of CRC patients is based on robust diagnostic methods such as serum tumor markers analysis, colonoscopy, histopathological analysis of tumor tissue, and imaging methods (computer tomography or magnetic resonance), these strategies still have many limitations and do not fully satisfy clinical needs due to their lack of sensitivity and/or specificity. Therefore, improvements of the current practice would substantially impact the management of CRC patients. In this view, liquid biopsy is a promising approach that could help clinicians screen for disease, stratify patients to the best treatment, and monitor treatment response and resistance mechanisms in the tumor in a regular and minimally invasive manner. Liquid biopsies allow the detection and analysis of different tumor-derived circulating markers such as cell-free nucleic acids (cfNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) in the bloodstream. The major advantage of this approach is its ability to trace and monitor the molecular profile of the patient's tumor and to predict personalized treatment in real-time. On the other hand, the prospective use of artificial intelligence (AI) in medicine holds great promise in oncology, for the diagnosis, treatment, and prognosis prediction of disease. AI has two main branches in the medical field: (i) a virtual branch that includes medical imaging, clinical assisted diagnosis, and treatment, as well as drug research, and (ii) a physical branch that includes surgical robots. This review summarizes findings relevant to liquid biopsy and AI in CRC for better management and stratification of CRC patients.
Collapse
Affiliation(s)
- Octav Ginghina
- Department II, University of Medicine and Pharmacy “Carol Davila” Bucharest, Bucharest, Romania
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Ariana Hudita
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Marius Zamfir
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Andrada Spanu
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Mara Mardare
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Irina Bondoc
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | | | - Sergiu Emil Georgescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Carolina Negrei
- Department of Toxicology, University of Medicine and Pharmacy “Carol Davila” Bucharest, Bucharest, Romania
| | - Cornelia Nitipir
- Department II, University of Medicine and Pharmacy “Carol Davila” Bucharest, Bucharest, Romania
- Department of Oncology, Elias University Emergency Hospital, Bucharest, Romania
| | - Bianca Galateanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| |
Collapse
|
|
12
|
Hosseini K, Ranjbar M, Pirpour Tazehkand A, Asgharian P, Montazersaheb S, Tarhriz V, Ghasemnejad T. Evaluation of exosomal non-coding RNAs in cancer using high-throughput sequencing. J Transl Med 2022; 20:30. [PMID: 35033106 PMCID: PMC8760667 DOI: 10.1186/s12967-022-03231-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Clinical oncologists need more reliable and non-invasive diagnostic and prognostic biomarkers to follow-up cancer patients. However, the existing biomarkers are often invasive and costly, emphasizing the need for the development of biomarkers to provide convenient and precise detection. Extracellular vesicles especially exosomes have recently been the focus of translational research to develop non-invasive and reliable biomarkers for several diseases such as cancers, suggesting as a valuable source of tumor markers. Exosomes are nano-sized extracellular vesicles secreted by various living cells that can be found in all body fluids including serum, urine, saliva, cerebrospinal fluid, and ascites. Different molecular and genetic contents of their origin such as nucleic acids, proteins, lipids, and glycans in a stable form make exosomes a promising approach for various cancers' diagnoses, prediction, and follow-up in a minimally invasive manner. Since exosomes are used by cancer cells for intercellular communication, they play a critical role in the disease process, highlighting the importance of their use as clinically relevant biomarkers. However, regardless of the advantages that exosome-based diagnostics have, they suffer from problems regarding their isolation, detection, and characterization of their contents. This study reviews the history and biogenesis of exosomes and discusses non-coding RNAs (ncRNAs) and their potential as tumor markers in different types of cancer, with a focus on next generation sequencing (NGS) as a detection method. Moreover, the advantages and challenges associated with exosome-based diagnostics are also presented.
Collapse
Affiliation(s)
- Kamran Hosseini
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Ranjbar
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Pirpour Tazehkand
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parina Asgharian
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
13
|
Abstract
Magnetic cell separation has become a key methodology for the isolation of target cell populations from biological suspensions, covering a wide spectrum of applications from diagnosis and therapy in biomedicine to environmental applications or fundamental research in biology. There now exists a great variety of commercially available separation instruments and reagents, which has permitted rapid dissemination of the technology. However, there is still an increasing demand for new tools and protocols which provide improved selectivity, yield and sensitivity of the separation process while reducing cost and providing a faster response. This review aims to introduce basic principles of magnetic cell separation for the neophyte, while giving an overview of recent research in the field, from the development of new cell labeling strategies to the design of integrated microfluidic cell sorters and of point-of-care platforms combining cell selection, capture, and downstream detection. Finally, we focus on clinical, industrial and environmental applications where magnetic cell separation strategies are amongst the most promising techniques to address the challenges of isolating rare cells.
Collapse
|
|
14
|
Amin R, Shukla A, Zhu JJ, Kim S, Wang P, Tian SZ, Tran AD, Paul D, Cappell SD, Burkett S, Liu H, Lee MP, Kruhlak MJ, Dwyer JE, Simpson RM, Hager GL, Ruan Y, Hunter KW. Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response. Nat Commun 2021; 12:7216. [PMID: 34903738 PMCID: PMC8669001 DOI: 10.1038/s41467-021-27451-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/16/2021] [Indexed: 12/26/2022] Open
Abstract
Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis. The involvement of nuclear pore proteins in cellular mechanosensing and metastasis is unclear. Here the authors identify that nuclear pore protein NUP210 promotes metastasis through the interaction with mechanotransducer LINC complex protein and chromatin to regulate mechanosensitive genes.
Collapse
Affiliation(s)
- Ruhul Amin
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
| | - Anjali Shukla
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | | | - Sohyoung Kim
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Ping Wang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Andy D Tran
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.,Confocal Microscopy Core Facility, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Debasish Paul
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Steven D Cappell
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Sandra Burkett
- Molecular Cytogenetics Core Facility, National Cancer Institute, NIH, Frederick, MD, USA
| | - Huaitian Liu
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.,High-Dimension Data Analysis Group, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Maxwell P Lee
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.,High-Dimension Data Analysis Group, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Michael J Kruhlak
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.,Confocal Microscopy Core Facility, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Jennifer E Dwyer
- Molecular Pathology Unit, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - R Mark Simpson
- Molecular Pathology Unit, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Gordon L Hager
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Yijun Ruan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Kent W Hunter
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
| |
Collapse
|
|
15
|
Openshaw MR, McVeigh TP. Non-invasive Technology Advances in Cancer-A Review of the Advances in the Liquid Biopsy for Endometrial and Ovarian Cancers. Front Digit Health 2021; 2:573010. [PMID: 34713045 PMCID: PMC8521848 DOI: 10.3389/fdgth.2020.573010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 11/19/2020] [Indexed: 01/02/2023] Open
Abstract
Improving cancer survival rates globally requires improvements in disease detection and monitoring, with the aim of improving early diagnosis and prediction of disease relapse. Traditional means of detecting and monitoring cancers rely largely on imaging and, where possible, blood-based protein biomarkers, many of which are non-specific. Treatments are being improved by identification of inherited and acquired genomic aberrations in tumors, some of which can be targeted by newly developed therapeutic interventions. Treatment of gynecological malignancy is progressively moving toward personalized therapy, as exemplified by application of PARP-inhibition for patients with BRCA-deficient tubo-ovarian cancers, or checkpoint inhibition in patients with mismatch repair-deficient disease. However, the more recent discovery of a group of biomarkers described under the umbrella term of “liquid biopsy” promises significant improvement in our ability to detect and monitor cancers. The term “liquid biopsy” is used to describe an array of tumor-derived material found in blood plasma and other bodily fluids such as ascites, pleural fluid, saliva, and urine. It includes circulating tumors cells (CTCs), circulating nucleic acids including DNA, messenger RNA and micro RNAs, and extracellular vesicles (EVs). In this review, we discuss recent advancements in liquid biopsy for biomarker detection to help in diagnosis, prognosis, and planning of treatment of ovarian and endometrial cancer.
Collapse
Affiliation(s)
- Mark R Openshaw
- Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Terri P McVeigh
- Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| |
Collapse
|
|
16
|
Clanchy FIL. Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy. Cancers (Basel) 2021; 13:824. [PMID: 33669307 PMCID: PMC7920076 DOI: 10.3390/cancers13040824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 02/12/2021] [Accepted: 02/13/2021] [Indexed: 12/13/2022] Open
Abstract
Sarcomas are mesenchymal tumours that often arise and develop as a result of chromosomal translocations, and for several forms of sarcoma the EWSR1 gene is a frequent translocation partner. Sarcomas are a rare form of malignancy, which arguably have a proportionally greater societal burden that their prevalence would suggest, as they are more common in young people, with survivors prone to lifelong disability. For most forms of sarcoma, histological diagnosis is confirmed by molecular techniques such as FISH or RT-PCR. Surveillance after surgical excision, or ablation by radiation or chemotherapy, has remained relatively unchanged for decades, but recent developments in molecular biology have accelerated the progress towards routine analysis of liquid biopsies of peripheral blood. The potential to detect evidence of residual disease or metastasis in the blood has been demonstrated by several groups but remains unrealized as a routine diagnostic for relapse during remission, for disease monitoring during treatment, and for the detection of occult, residual disease at the end of therapy. An update is provided on research relevant to the improvement of the early detection of relapse in sarcomas with EWSR1-associated translocations, in the contexts of biology, diagnosis, and liquid biopsy.
Collapse
Affiliation(s)
- Felix I. L. Clanchy
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, UK;
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7LD, UK
| |
Collapse
|
|
17
|
Liquid biopsy as a perioperative biomarker of digestive tract cancers: review of the literature. Surg Today 2020; 51:849-861. [PMID: 32979121 DOI: 10.1007/s00595-020-02148-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/10/2020] [Indexed: 10/23/2022]
Abstract
Tissue biopsies are the gold-standard for investigating the molecular characterization of tumors. However, a "solid" biopsy is an invasive procedure that cannot capture real-time tumor dynamics and may yield inaccurate information because of intratumoral heterogeneity. In this review, we summarize the current state of knowledge about surgical treatment-associated "liquid" biopsy for patients with digestive organ tumors. A liquid biopsy is a technique involving the sampling and testing of non-solid biological materials, including blood, urine, saliva, and ascites. Previous studies have reported the potential value of blood-based biomarkers, circulating tumor cells, and cell-free nucleic acids as facilitators of cancer treatment. The applications of a liquid biopsy in a cancer treatment setting include screening and early diagnosis, prognostication, and outcome and recurrence monitoring of cancer. This technique has also been suggested as a useful tool in personalized medicine. The transition to precision medicine is still in its early stages. Soon, however, liquid biopsy is likely to form the basis of patient selection for molecular targeted therapies, predictions regarding chemotherapy sensitivity, and real-time evaluations of therapeutic effects.
Collapse
|
|
18
|
Huaman J, Ogunwobi OO. Circulating Tumor Cell Migration Requires Fibronectin Acting through Integrin B1 or SLUG. Cells 2020; 9:cells9071594. [PMID: 32630254 PMCID: PMC7408126 DOI: 10.3390/cells9071594] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/27/2020] [Accepted: 06/30/2020] [Indexed: 01/16/2023] Open
Abstract
Fibronectin (FN1) is an extracellular matrix protein gaining increasing attention for its multifaceted roles in cancer progression. Using our recently established circulating tumor cell (CTC) lines, we had demonstrated increased FN1 expression and enhanced migration in CTC lines, in comparison to primary tumor cell lines. Whether increased FN1 expression is directly required for CTC migration, and the specific role of FN1’s regulation of integrin B1 (ITGB1) and SLUG (SNAI2) in CTC migration remains unclear. Here, for the first time, we report that the knockdown of FN1, ITGB1, or SLUG expression in CTCs leads to a significant decrease in CTC migration. Knocking down two or all three of these proteins simultaneously did not further inhibit migration. We observed a corresponding increase in CTC migration when recombinant FN1 was added to CTCs. This effect was significantly impeded by prior knockdown of ITGB1 or SLUG. Using knock down experiments and western blotting analysis, we confirmed FN1’s regulation of ITGB1 and SLUG to occur via two separate, independent pathways. Consequently, we can conclude that FN1-dependent enhanced migration of CTCs requires downstream signaling through either ITGB1 or SLUG and that FN1 regulation of ITGB1 and SLUG may have important implications for cancer progression and metastasis.
Collapse
Affiliation(s)
- Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, USA;
- Department of Biology, The Graduate Center of The City University of New York, New York, NY 10016, USA
| | - Olorunseun O. Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, USA;
- Department of Biology, The Graduate Center of The City University of New York, New York, NY 10016, USA
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Correspondence:
| |
Collapse
|
|
19
|
Chen L, Chen Y, Feng YL, Zhu Y, Wang LQ, Hu S, Cheng P. Tumor circulome in the liquid biopsies for digestive tract cancer diagnosis and prognosis. World J Clin Cases 2020; 8:2066-2080. [PMID: 32548136 PMCID: PMC7281040 DOI: 10.12998/wjcc.v8.i11.2066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/10/2020] [Accepted: 04/28/2020] [Indexed: 02/05/2023] Open
Abstract
Digestive tract cancer is one of the main diseases that endanger human health. At present, the early diagnosis of digestive tract tumors mainly depends on serology, imaging, endoscopy, and so on. Although tissue specimens are the gold standard for cancer diagnosis, with the rapid development of precision medicine in cancer, the demand for dynamic monitoring of tumor molecular characteristics has increased. Liquid biopsy involves the collection of body fluids via non-invasive approaches, and analyzes biological markers such as circulating tumor cells, circulating tumor DNA, circulating cell-free DNA, microRNAs, and exosomes. In recent years, liquid biopsy has become more and more important in the diagnosis and prognosis of cancer in clinical practice due to its convenience, non-invasiveness, high specificity and it overcomes temporal-spatial heterogeneity. Therefore, this review summarizes the current evidence on liquid biopsies in digestive tract cancers in relation to diagnosis and prognosis.
Collapse
Affiliation(s)
- Long Chen
- Department of Radiotherapy, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Yu Chen
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yuan-Ling Feng
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Yan Zhu
- Department of Respiratory, Shulan Hospital, Hangzhou 310004, Zhejiang Province, China
| | - Li-Quan Wang
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Shen Hu
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Pu Cheng
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310052, Zhejiang Province, China
| |
Collapse
|
|
20
|
Makler A, Asghar W. Exosomal biomarkers for cancer diagnosis and patient monitoring. Expert Rev Mol Diagn 2020; 20:387-400. [PMID: 32067543 PMCID: PMC7071954 DOI: 10.1080/14737159.2020.1731308] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/14/2020] [Indexed: 02/06/2023]
Abstract
Introduction: In recent years, extensive research has been conducted on using exosomes as biomarkers for cancer detection. Exosomes are 40-150 nm-sized extracellular vesicles released by all cell types, including tumor cells. Exosomes are stable in body fluids due to their lipid bilayer member and often contain DNA, RNA, and proteins. These exosomes can be harvested from blood, plasma, serum, urine, or saliva and analyzed for tumor-relevant mutations. Thus, exosomes provide an alternative to current methods of tumor detection.Areas covered: This review discusses the use of exosomal diagnostics in various tumor types as well as their examination in various clinical trials. The authors also discuss the limitations of exosome-based diagnostics in the clinical setting and provide examples of several studies in which the development and usage of microfluidic chips and nano-sensing devices have been utilized to address these obstacles.Expert commentary: In recent years, exosomes and their contents have exhibited potential as novel tumor detection markers despite the labor involved in their harvest and isolation. Despite this, much work is being done to optimize exosome capture and analysis. Thus, their roles as biomarkers in the clinical setting appear promising.
Collapse
Affiliation(s)
- Amy Makler
- Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431
| | - Waseem Asghar
- Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431
- Department of Biological Sciences (courtesy appointment), Florida Atlantic University, Boca Raton, FL 33431
| |
Collapse
|
|
21
|
Mao C, Deng B. [Research Advances in the Mechanism of Invasion and Metastasis of Circulating Tumor Cells in Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:189-195. [PMID: 32102136 PMCID: PMC7118339 DOI: 10.3779/j.issn.1009-3419.2020.03.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
近年来，随着液体活检技术兴起，循环肿瘤细胞（circulating tumor cell, CTC）在癌症患者的早期诊断、疗效评估及预后评价等方面显示出重要的价值。CTC的产生导致肿瘤发生远处转移及患者的预后不良。因此，阐明CTC的产生、进入循环系统及其免疫逃逸的机制尤为重要。目前，精准诊疗成为提高肺癌患者预后的重要努力方向。针对肺癌CTC有望为肺癌精准诊疗提供有力的理论依据与重要手段。现对上述热点问题的最新研究进展进行综述。
Collapse
Affiliation(s)
- Chunguo Mao
- Department of Thoracic Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Bo Deng
- Department of Thoracic Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| |
Collapse
|
|
22
|
The Prognostic Value of Circulating Tumor Cells in Asian Neuroendocrine Tumors. Sci Rep 2019; 9:19917. [PMID: 31882775 PMCID: PMC6934482 DOI: 10.1038/s41598-019-56539-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/08/2019] [Indexed: 01/14/2023] Open
Abstract
Circulating tumor cells (CTC) play important roles in various cancers; however, few studies have assessed their clinical utility in neuroendocrine tumors. This study aimed to prospectively evaluate the prognostic value of CTC counts in Asian patients with neuroendocrine tumors before and during anti-cancer therapy. Patients who were diagnosed with unresectable histological neuroendocrine tumors between September 2011 and September 2017 were enrolled. CTC testing was performed before and during anti-cancer therapy using a negative selection protocol. Chromogranin A levels were also assessed. Univariate and multivariate Cox’s proportional hazard model with forward LR model was performed to investigate the impact of independent factors on overall survival and progression-free survival. Kaplan–Meier method with log-rank tests were used to determine the difference among different clinicopathological signatures and CTC cutoff. The baseline CTC detection rate was 94.3% (33/35). CTC counts were associated with cancer stages (I-III vs. IV, P = 0.015), liver metastasis (P = 0.026), and neuroendocrine tumor grading (P = 0.03). The median progression-free survival and overall survivals were 12.3 and 30.4 months, respectively. In multivariate Cox regression model, neuroendocrine tumors grading and baseline CTC counts were both independent prognostic factors for progression-free survival (PFS, P = 0.005 and 0.015, respectively) and overall survival (OS, P = 0.018 and 0.023, respectively). In Kaplan-Meier analysis, lower baseline chromogranin A levels were associated with longer PFS (P = 0.024). Baseline CTC counts are associated with the clinicopathologic features of neuroendocrine tumors and are an independent prognostic factor for this malignancy.
Collapse
|
|
23
|
Buscail E, Alix-Panabières C, Quincy P, Cauvin T, Chauvet A, Degrandi O, Caumont C, Verdon S, Lamrissi I, Moranvillier I, Buscail C, Marty M, Laurent C, Vendrely V, Moreau-Gaudry F, Bedel A, Dabernat S, Chiche L. High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery. Cancers (Basel) 2019; 11:cancers11111656. [PMID: 31717747 PMCID: PMC6895804 DOI: 10.3390/cancers11111656] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/08/2023] Open
Abstract
PURPOSE Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. EXPERIMENTAL DESIGN Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. RESULTS Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. CONCLUSION This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.
Collapse
Affiliation(s)
- Etienne Buscail
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, EA2415 Montpellier, France;
| | - Pascaline Quincy
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Thomas Cauvin
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Alexandre Chauvet
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Olivier Degrandi
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Charline Caumont
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Séverine Verdon
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
| | - Isabelle Lamrissi
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Isabelle Moranvillier
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Camille Buscail
- Nutritional Epidemiology Research Team (EREN), Paris 13 University, U1153 INSERM, U1125 Institut national de la recherche agronomique (INRA), Conservatoire national des arts et métiers (CNAM), Paris Cité Epidemiology and Statistics Research Center (CRESS), 93017 Bobigny, France;
| | - Marion Marty
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
| | - Christophe Laurent
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Véronique Vendrely
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - François Moreau-Gaudry
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Aurélie Bedel
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| | - Sandrine Dabernat
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
- Correspondence: ; Tel.: +33-(0)5-5757-1374; Fax: +33-(0)5-5757-1374
| | - Laurence Chiche
- U1035 Institut National de la Santé et de la Recherche Médicale (INSERM), 33000 Bordeaux, France; (E.B.); (P.Q.); (T.C.); (A.C.); (O.D.); (I.L.); (I.M.); (C.L.); (V.V.); (F.M.-G.); (A.B.); (L.C.)
- Centre Hospitalier Universitaire (CHU) de Bordeaux, 33000 Bordeaux, France; (C.C.); (S.V.); (M.M.)
- Université de Bordeaux, 33076 Bordeaux, France
| |
Collapse
|
|
24
|
Vranes V, Rajković N, Li X, Plataniotis KN, Todorović Raković N, Milovanović J, Kanjer K, Radulovic M, Milošević NT. Size and Shape Filtering of Malignant Cell Clusters within Breast Tumors Identifies Scattered Individual Epithelial Cells as the Most Valuable Histomorphological Clue in the Prognosis of Distant Metastasis Risk. Cancers (Basel) 2019; 11:1615. [PMID: 31652628 PMCID: PMC6826383 DOI: 10.3390/cancers11101615] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 10/08/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022] Open
Abstract
Survival and life quality of breast cancer patients could be improved by more aggressive chemotherapy for those at high metastasis risk and less intense treatments for low-risk patients. Such personalized treatment cannot be currently achieved due to the insufficient reliability of metastasis risk prognosis. The purpose of this study was therefore, to identify novel histopathological prognostic markers of metastasis risk through exhaustive computational image analysis of 80 size and shape subsets of epithelial clusters in breast tumors. The group of 102 patients had a follow-up median of 12.3 years, without lymph node spread and systemic treatments. Epithelial cells were stained by the AE1/AE3 pan-cytokeratin antibody cocktail. The size and shape subsets of the stained epithelial cell clusters were defined in each image by use of the circularity and size filters and analyzed for prognostic performance. Epithelial areas with the optimal prognostic performance were uniformly small and round and could be recognized as individual epithelial cells scattered in tumor stroma. Their count achieved an area under the receiver operating characteristic curve (AUC) of 0.82, total area (AUC = 0.77), average size (AUC = 0.63), and circularity (AUC = 0.62). In conclusion, by use of computational image analysis as a hypothesis-free discovery tool, this study reveals the histomorphological marker with a high prognostic value that is simple and therefore easy to quantify by visual microscopy.
Collapse
Affiliation(s)
- Velicko Vranes
- Department of Basic and Environmental Science, Instituto Tecnológico de Santo Domingo (INTEC), Santo Domingo 10602, Dominican Republic.
| | - Nemanja Rajković
- Department of Biophysics, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
| | - Xingyu Li
- Multimedia Laboratory, The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, ON M5S 3G4, Canada.
| | - Konstantinos N Plataniotis
- Multimedia Laboratory, The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, ON M5S 3G4, Canada.
| | - Nataša Todorović Raković
- Department of Experimental Oncology, Institute for Oncology and Radiology, 11000 Belgrade, Serbia.
| | - Jelena Milovanović
- Department of Experimental Oncology, Institute for Oncology and Radiology, 11000 Belgrade, Serbia.
| | - Ksenija Kanjer
- Department of Experimental Oncology, Institute for Oncology and Radiology, 11000 Belgrade, Serbia.
| | - Marko Radulovic
- Department of Experimental Oncology, Institute for Oncology and Radiology, 11000 Belgrade, Serbia.
| | - Nebojša T Milošević
- Department of Basic and Environmental Science, Instituto Tecnológico de Santo Domingo (INTEC), Santo Domingo 10602, Dominican Republic.
- Department of Biophysics, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
| |
Collapse
|
|
25
|
Jin KT, Chen XY, Lan HR, Wang SB, Ying XJ, Abdi SM, Wang W, Hu ZM, Mou XZ. Current progress in the clinical use of circulating tumor cells as prognostic biomarkers. Cancer Cytopathol 2019; 127:739-749. [PMID: 31589381 DOI: 10.1002/cncy.22189] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/11/2022]
Abstract
The process of metastasis is characterized by the shedding of tumor cells into the bloodstream, where they are transported to other parts of the body to seed new tumors. These cells, known as circulating tumor cells (CTCs), have the potential to reveal much about an individual cancer case, and theoretically can aid in the prediction of outcomes and design of precision treatments. Recent advances in technology now allow for the robust and reproducible characterization of CTCs from a simple blood draw. Both the number of circulating cells and important molecular characteristics correlated with clinical phenotypes such as drug resistance can be obtained and used for real-time prognostic analysis. Molecular characterization can provide a snapshot of the activity of the main tumor (serving as a "liquid biopsy") and early warnings concerning changes such as the development of resistance, and aid in predicting the efficacy of different therapeutic approaches for treatment optimization. Herein, the authors review the current clinical use of CTCs as prognostic biomarkers for several different cancers. The quantification of CTCs can lead to more accurate staging and decision making regarding options such as adjuvant chemotherapy.
Collapse
Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Xiao-Yi Chen
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Shi-Bing Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xiao-Jiang Ying
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Siyad Mohamed Abdi
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Wei Wang
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Zhi-Ming Hu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| |
Collapse
|
|
26
|
Buscail E, Chiche L, Laurent C, Vendrely V, Denost Q, Denis J, Thumerel M, Lacorte JM, Bedel A, Moreau-Gaudry F, Dabernat S, Alix-Panabières C. Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells. Mol Oncol 2019; 13:1811-1826. [PMID: 31216108 PMCID: PMC6717761 DOI: 10.1002/1878-0261.12534] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/04/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022] Open
Abstract
Circulating tumor cell (CTC) detection and numeration are becoming part of the common clinical practice, especially for breast, colon, and prostate cancer. However, their paucity in peripheral blood samples is an obstacle for their identification. Several groups have tried to improve CTC recovery rate by developing highly sensitive cellular and molecular detection methods. However, CTCs are still difficult to detect in peripheral blood. Therefore, their recovery rate could be increased by obtaining blood samples from vessels close to the drainage territories of the invaded organ, when the anatomical situation is favorable. This approach has been tested mostly during tumor resection surgery, when the vessels nearest to the tumor are easily accessible. Moreover, radiological (including echo‐guided based and endovascular techniques) and/or endoscopic routes could be utilized to obtain CTC samples close to the tumor in a less invasive way than conventional biopsies. The purpose of this article is to summarize the available knowledge on CTC recovery from blood samples collected close to the tumor (i.e., in vessels located in the drainage area of the primary tumor or metastases). The relevance of such an approach for diagnostic and prognostic evaluations will be discussed, particularly for pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and non‐small‐cell lung cancer.
Collapse
Affiliation(s)
- Etienne Buscail
- INSERM U1035, Bordeaux, France.,CHU de Bordeaux, France.,Université de Bordeaux, France
| | - Laurence Chiche
- INSERM U1035, Bordeaux, France.,CHU de Bordeaux, France.,Université de Bordeaux, France
| | - Christophe Laurent
- INSERM U1035, Bordeaux, France.,CHU de Bordeaux, France.,Université de Bordeaux, France
| | - Véronique Vendrely
- INSERM U1035, Bordeaux, France.,CHU de Bordeaux, France.,Université de Bordeaux, France
| | | | - Jérôme Denis
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, France
| | | | - Jean-Marc Lacorte
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, France
| | - Aurélie Bedel
- INSERM U1035, Bordeaux, France.,CHU de Bordeaux, France.,Université de Bordeaux, France
| | | | - Sandrine Dabernat
- INSERM U1035, Bordeaux, France.,CHU de Bordeaux, France.,Université de Bordeaux, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, France.,Service de Biochimie Endocrinienne et Oncologie, Hôpital Pitié Salpêtrière Assistance Publique Hôpitaux de Paris, France
| |
Collapse
|
|
27
|
Huaman J, Naidoo M, Zang X, Ogunwobi OO. Fibronectin Regulation of Integrin B1 and SLUG in Circulating Tumor Cells. Cells 2019; 8:cells8060618. [PMID: 31226820 PMCID: PMC6627780 DOI: 10.3390/cells8060618] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 12/12/2022] Open
Abstract
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.
Collapse
Affiliation(s)
- Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, USA.
- Department of Biology, The Graduate Center of The City University of New York, New York, NY 10016, USA.
| | - Michelle Naidoo
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, USA.
- Department of Biology, The Graduate Center of The City University of New York, New York, NY 10016, USA.
| | - Xingxing Zang
- Departments of Microbiology and Immunology, and Medicine (Oncology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, USA.
- Department of Biology, The Graduate Center of The City University of New York, New York, NY 10016, USA.
- Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
| |
Collapse
|
|
28
|
Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, Ma GX, Nguyen MT. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293. [PMID: 31148900 PMCID: PMC6529884 DOI: 10.3748/wjg.v25.i19.2279] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/27/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
Collapse
Affiliation(s)
- Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Trisheena Harricharran
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Anna Galuza
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Oluwatoyin Odumuwagun
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Yin Tan
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Grace X Ma
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Minhhuyen T Nguyen
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
| |
Collapse
|
|
29
|
Gill NK, Ly C, Nyberg KD, Lee L, Qi D, Tofig B, Reis-Sobreiro M, Dorigo O, Rao J, Wiedemeyer R, Karlan B, Lawrenson K, Freeman MR, Damoiseaux R, Rowat AC. A scalable filtration method for high throughput screening based on cell deformability. LAB ON A CHIP 2019; 19:343-357. [PMID: 30566156 DOI: 10.1039/c8lc00922h] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Cell deformability is a label-free biomarker of cell state in physiological and disease contexts ranging from stem cell differentiation to cancer progression. Harnessing deformability as a phenotype for screening applications requires a method that can simultaneously measure the deformability of hundreds of cell samples and can interface with existing high throughput facilities. Here we present a scalable cell filtration device, which relies on the pressure-driven deformation of cells through a series of pillars that are separated by micron-scale gaps on the timescale of seconds: less deformable cells occlude the gaps more readily than more deformable cells, resulting in decreased filtrate volume which is measured using a plate reader. The key innovation in this method is that we design customized arrays of individual filtration devices in a standard 96-well format using soft lithography, which enables multiwell input samples and filtrate outputs to be processed with higher throughput using automated pipette arrays and plate readers. To validate high throughput filtration to detect changes in cell deformability, we show the differential filtration of human ovarian cancer cells that have acquired cisplatin-resistance, which is corroborated with cell stiffness measurements using quantitative deformability cytometry. We also demonstrate differences in the filtration of human cancer cell lines, including ovarian cancer cells that overexpress transcription factors (Snail, Slug), which are implicated in epithelial-to-mesenchymal transition; breast cancer cells (malignant versus benign); and prostate cancer cells (highly versus weekly metastatic). We additionally show how the filtration of ovarian cancer cells is affected by treatment with drugs known to perturb the cytoskeleton and the nucleus. Our results across multiple cancer cell types with both genetic and pharmacologic manipulations demonstrate the potential of this scalable filtration device to screen cells based on their deformability.
Collapse
Affiliation(s)
- Navjot Kaur Gill
- Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Tellez-Gabriel M, Cochonneau D, Cadé M, Jubellin C, Heymann MF, Heymann D. Circulating Tumor Cell-Derived Pre-Clinical Models for Personalized Medicine. Cancers (Basel) 2018; 11:cancers11010019. [PMID: 30586936 PMCID: PMC6356998 DOI: 10.3390/cancers11010019] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/17/2018] [Accepted: 12/20/2018] [Indexed: 12/19/2022] Open
Abstract
The main cause of death from cancer is associated with the development of metastases, resulting from the inability of current therapies to cure patients at metastatic stages. Generating preclinical models to better characterize the evolution of the disease is thus of utmost importance, in order to implement effective new cancer biomarkers and therapies. Circulating Tumor Cells (CTCs) are good candidates for generating preclinical models, making it possible to follow up the spatial and temporal heterogeneity of tumor tissues. This method is a non-invasive liquid biopsy that can be obtained at any stage of the disease. It partially summarizes the molecular heterogeneity of the corresponding tumors at a given time. Here, we discuss the CTC-derived models that have been generated so far, from simplified 2D cultures to the most complex CTC-derived explants (CDX models). We highlight the challenges and strengths of these preclinical tools, as well as some of the recent studies published using these models.
Collapse
Affiliation(s)
- Marta Tellez-Gabriel
- RNA and Molecular Pathology Research Group, Department of Medical Biology, The Artic University of Norway, N-9037 Tromsø, Norway.
| | - Denis Cochonneau
- LabCT, Institut de Cancérologie de l'Ouest, CRCINA, Université d'Angers, 44805 Saint Herblain CEDEX, France.
| | - Marie Cadé
- INSERM, European Associated Laboratory "Sarcoma Research Unit", University of Nantes, 44035 Nantes, France.
| | - Camille Jubellin
- INSERM, European Associated Laboratory "Sarcoma Research Unit", University of Nantes, 44035 Nantes, France.
| | - Marie-Françoise Heymann
- LabCT, Institut de Cancérologie de l'Ouest, CRCINA, Université d'Angers, 44805 Saint Herblain CEDEX, France.
| | - Dominique Heymann
- LabCT, Institut de Cancérologie de l'Ouest, CRCINA, Université d'Angers, 44805 Saint Herblain CEDEX, France.
- INSERM, European Associated Laboratory "Sarcoma Research Unit", University of Nantes, 44035 Nantes, France.
- Department of Oncology & Metabolism, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
| |
Collapse
|
|
31
|
Sobral-Filho RG, DeVorkin L, Macpherson S, Jirasek A, Lum JJ, Brolo AG. Ex Vivo Detection of Circulating Tumor Cells from Whole Blood by Direct Nanoparticle Visualization. ACS NANO 2018; 12:1902-1909. [PMID: 29401387 DOI: 10.1021/acsnano.7b08813] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The detection of circulating tumor cells (CTCs) from blood samples can predict prognosis, response to systemic chemotherapy, and metastatic spread of carcinoma. Therefore, approaches for CTC identification is an important aspect of current cancer research. Here, a method for the direct visualization of nanoparticle-coated CTCs under dark field illumination is presented. A metastatic breast cancer cell line (4T1) was transduced with a non-native target protein (Thy1.1). Positive 4T1-Thy1.1 cells incubated with antibody-coated metallic nanoshells appeared overly bright at low magnification, allowing a quick screening of samples and easy visual detection of even single isolated CTCs. The use of a nontransduced cell line as control creates the ideal scenario to evaluate nonspecific binding. A murine metastatic tumor model with the 4T1-Thy1.1 cell line was also implemented. Blood was drawn from mice over the course of one month, and CTCs were successfully detected in all positive subjects. This work validates the use of metallic nanoshells as labels for direct visualization of CTCs while providing guidelines to a systematic development of nanotechnology-based detection systems for CTCs.
Collapse
Affiliation(s)
- Regivaldo G Sobral-Filho
- Department of Chemistry, University of Victoria , 3800 Finnerty Road, Victoria, BC V8P 5C2, Canada
| | - Lindsay DeVorkin
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency-Vancouver Island Centre , 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
| | - Sarah Macpherson
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency-Vancouver Island Centre , 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
| | - Andrew Jirasek
- Department of Mathematics, Statistics, Physics and Computer Science, University of British Columbia Okanagan , 3187 University Way, Kelowna, BC V1V 1V7, Canada
| | - Julian J Lum
- Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency-Vancouver Island Centre , 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada
- Department of Biochemistry and Microbiology, University of Victoria , 3800 Finnerty Road, Victoria, BC V8P 5C2, Canada
| | - Alexandre G Brolo
- Department of Chemistry, University of Victoria , 3800 Finnerty Road, Victoria, BC V8P 5C2, Canada
| |
Collapse
|