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Kane MA, Birmingham KG, Yeoman B, Patel N, Sperinde H, Molley TG, Beri P, Tuler J, Kumar A, Klein S, Zare S, Wallace A, Katira P, Engler AJ. Adhesion strength of tumor cells predicts metastatic disease in vivo. Cell Rep 2025; 44:115359. [PMID: 40049163 PMCID: PMC12014391 DOI: 10.1016/j.celrep.2025.115359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/26/2024] [Accepted: 02/06/2025] [Indexed: 03/29/2025] Open
Abstract
Although only a fraction of tumor cells contribute to metastatic disease, no prognostic biomarkers currently exist to identify these cells. We show that a physical marker-adhesion strength-predicts metastatic potential in a mouse breast cancer model and that it may stratify human disease. Cells disseminating from murine mammary tumors are weakly adherent, and, when pre-sorted by adhesion, primary tumors created from strongly adherent cells exhibit fewer lung metastases than weakly adherent cells do. We demonstrate that admixed cancer lines can be separated by label-free adhesive signatures. When applied to murine metastatic tumors, adhesion retrospectively predicts metastatic disease with 100% specificity, 85% sensitivity, and area under the curve (AUC) of 0.94. Cells from human reduction mammoplasties have a higher adhesion strength versus resected human tumors, which may also be stratified between invasive and more indolent cancers. Thus, highly metastatic cells may have a distinct physical phenotype that may be a predictive marker of clinical outcomes.
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Affiliation(s)
- Madison A Kane
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | | | - Benjamin Yeoman
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Department of Mechanical Engineering, San Diego State University, San Diego, CA 92182, USA
| | - Neal Patel
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA
| | - Hayley Sperinde
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | - Thomas G Molley
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | - Pranjali Beri
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA
| | - Jeremy Tuler
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | - Aditya Kumar
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA
| | - Sarah Klein
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA
| | - Somaye Zare
- Department of Pathology, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA
| | - Anne Wallace
- Department of Surgery, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA
| | - Parag Katira
- Department of Mechanical Engineering, San Diego State University, San Diego, CA 92182, USA; Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA
| | - Adam J Engler
- Chien-Lay Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA; Department of Pathology, UC San Diego, La Jolla, CA 92093, USA; Department of Surgery, UC San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
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Szewczyk K, Jiang L, Khawaja H, Miranti CK, Zohar Y. Microfluidic Applications in Prostate Cancer Research. MICROMACHINES 2024; 15:1195. [PMID: 39459070 PMCID: PMC11509716 DOI: 10.3390/mi15101195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/13/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024]
Abstract
Prostate cancer is a disease in which cells in the prostate, a gland in the male reproductive system below the bladder, grow out of control and, among men, it is the second-most frequently diagnosed cancer (other than skin cancer). In recent years, prostate cancer death rate has stabilized and, currently, it is the second-most frequent cause of cancer death in men (after lung cancer). Most deaths occur due to metastasis, as cancer cells from the original tumor establish secondary tumors in distant organs. For a long time, classical cell cultures and animal models have been utilized in basic and applied scientific research, including clinical applications for many diseases, such as prostate cancer, since no better alternatives were available. Although helpful in dissecting cellular mechanisms, these models are poor predictors of physiological behavior mainly because of the lack of appropriate microenvironments. Microfluidics has emerged in the last two decades as a technology that could lead to a paradigm shift in life sciences and, in particular, controlling cancer. Microfluidic systems, such as organ-on-chips, have been assembled to mimic the critical functions of human organs. These microphysiological systems enable the long-term maintenance of cellular co-cultures in vitro to reconstitute in vivo tissue-level microenvironments, bridging the gap between traditional cell cultures and animal models. Several reviews on microfluidics for prostate cancer studies have been published focusing on technology advancement and disease progression. As metastatic castration-resistant prostate cancer remains a clinically challenging late-stage cancer, with no curative treatments, we expanded this review to cover recent microfluidic applications related to prostate cancer research. The review includes discussions of the roles of microfluidics in modeling the human prostate, prostate cancer initiation and development, as well as prostate cancer detection and therapy, highlighting potentially major contributions of microfluidics in the continuous march toward eradicating prostate cancer.
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Affiliation(s)
- Kailie Szewczyk
- Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721, USA; (K.S.); (L.J.)
| | - Linan Jiang
- Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721, USA; (K.S.); (L.J.)
| | - Hunain Khawaja
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724, USA;
| | - Cindy K. Miranti
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA;
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Yitshak Zohar
- Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721, USA; (K.S.); (L.J.)
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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Huang Z, Fu Y, Yang H, Zhou Y, Shi M, Li Q, Liu W, Liang J, Zhu L, Qin S, Hong H, Liu Y. Liquid biopsy in T-cell lymphoma: biomarker detection techniques and clinical application. Mol Cancer 2024; 23:36. [PMID: 38365716 PMCID: PMC10874034 DOI: 10.1186/s12943-024-01947-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/25/2024] [Indexed: 02/18/2024] Open
Abstract
T-cell lymphoma is a highly invasive tumor with significant heterogeneity. Invasive tissue biopsy is the gold standard for acquiring molecular data and categorizing lymphoma patients into genetic subtypes. However, surgical intervention is unfeasible for patients who are critically ill, have unresectable tumors, or demonstrate low compliance, making tissue biopsies inaccessible to these patients. A critical need for a minimally invasive approach in T-cell lymphoma is evident, particularly in the areas of early diagnosis, prognostic monitoring, treatment response, and drug resistance. Therefore, the clinical application of liquid biopsy techniques has gained significant attention in T-cell lymphoma. Moreover, liquid biopsy requires fewer samples, exhibits good reproducibility, and enables real-time monitoring at molecular levels, thereby facilitating personalized health care. In this review, we provide a comprehensive overview of the current liquid biopsy biomarkers used for T-cell lymphoma, focusing on circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), Epstein-Barr virus (EBV) DNA, antibodies, and cytokines. Additionally, we discuss their clinical application, detection methodologies, ongoing clinical trials, and the challenges faced in the field of liquid biopsy.
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Affiliation(s)
- Zongyao Huang
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yao Fu
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Hong Yang
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yehan Zhou
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Min Shi
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Qingyun Li
- Genecast Biotechnology Co., Ltd, Wuxi, 214104, China
| | - Weiping Liu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Junheng Liang
- Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Liuqing Zhu
- Nanjing Geneseeq Technology Inc., Nanjing, 210032, Jiangsu, China
| | - Sheng Qin
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
| | - Huangming Hong
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
| | - Yang Liu
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
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Chang JL, Huang CJ, Tsai YC, Chiang NJ, Huang YS, Hung SC, Shan YS, Lee GB. An integrated microfluidic system for automatic detection of cholangiocarcinoma cells from bile. LAB ON A CHIP 2024; 24:375-382. [PMID: 38126571 DOI: 10.1039/d3lc00862b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Cholangiocarcinoma (CCA) is an aggressive cancer that originates from the epithelial cells lining the bile ducts. Due to its location deep within the body and nonspecific symptoms in the early stages, it is often diagnosed at the advanced stage, thus leading to worse prognosis. Circulating tumor cells within liquid biopsies (i.e. blood) have been considered as promising biomarkers for CCA diagnosis, though current methods for profiling them are not satisfactory in terms of sensitivity and specificity. Herein we developed a new cancer cell probing and immuno-tracking assay known as "CAPTURE", which was performed on an integrated microfluidic system (IMS) to automate CCA diagnosis from bile with a sample amount of only 1 mL. The assay utilized magnetic beads surface-coated with two affinity reagents, a nucleic acid aptamer (HN16) and a glycosaminoglycan (SCH 45-mix), for capturing cancer cells in bile; the "gold standard" anti-epithelial cell adhesion molecule was used as a comparison. In a single-blind test of 54 CCA-positive (+) and 102 CCA-negative (-) clinical samples, sensitivities and specificities of 96 and 80%, respectively, were documented with the CAPTURE assay on-bench. An IMS composed of a centrifugal module for sample pretreatment and a CAPTURE module for cell capture and staining was integrated with a new "vertical integration module" for detecting cancer cells from bile without human intervention. Furthermore, a novel micro-tier structure within the centrifugal module was designed to block passage of gallbladder stones with diameters >1 mm, thereby preventing their interference during the subsequent CAPTURE assay. Improved sensitivity and specificity (100 & 83%, respectively) by using three affinity reagents were achieved on the IMS when using 26 clinical bile samples, confirming its clinical bio-applicability for CCA diagnosis. This approach could be therefore used for early-stage CCA diagnostics, ideally enabling effective treatment, as well as reducing potential for relapse.
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Affiliation(s)
- Jui-Lin Chang
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
| | - Chien-Jui Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Cheng Tsai
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Nai-Jung Chiang
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Yu-Shan Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | | | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Gwo-Bin Lee
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan
- Institute of NanoEngineering and MicroSystems, National Tsing Hua University, Hsinchu, Taiwan
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Shuai Y, Ma Z, Ju J, Wei T, Gao S, Kang Y, Yang Z, Wang X, Yue J, Yuan P. Liquid-based biomarkers in breast cancer: looking beyond the blood. J Transl Med 2023; 21:809. [PMID: 37957623 PMCID: PMC10644618 DOI: 10.1186/s12967-023-04660-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
In recent decades, using circulating tumor cell (CTC), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), exosomes and etc. as liquid biomarkers has received enormous attention in various tumors, including breast cancer (BC). To date, efforts in the area of liquid biopsy predominantly focus on the analysis of blood-based markers. It is worth noting that the identifications of markers from non-blood sources provide unique advantages beyond the blood and these alternative sources may be of great significance in offering supplementary information in certain settings. Here, we outline the latest advances in the analysis of non-blood biomarkers, predominantly including urine, saliva, cerebrospinal fluid, pleural fluid, stool and etc. The unique advantages of such testings, their current limitations and the appropriate use of non-blood assays and blood assays in different settings are further discussed. Finally, we propose to highlight the challenges of these alternative assays from basic to clinical implementation and explore the areas where more investigations are warranted to elucidate its potential utility.
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Affiliation(s)
- You Shuai
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhonghua Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Endoscopy, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jie Ju
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tong Wei
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Songlin Gao
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yikun Kang
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zixuan Yang
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xue Wang
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jian Yue
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Peng Yuan
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Huang Y, Wang H, Yue X, Li X. Bone serves as a transfer station for secondary dissemination of breast cancer. Bone Res 2023; 11:21. [PMID: 37085486 PMCID: PMC10121690 DOI: 10.1038/s41413-023-00260-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/28/2023] [Accepted: 03/22/2023] [Indexed: 04/23/2023] Open
Abstract
Metastasis is responsible for the majority of deaths among breast cancer patients. Although parallel polyclonal seeding has been shown to contribute to organ-specific metastasis, in the past decade, horizontal cross-metastatic seeding (metastasis-to-metastasis spreading) has also been demonstrated as a pattern of distant metastasis to multiple sites. Bone, as the most frequent first destination of breast cancer metastasis, has been demonstrated to facilitate the secondary dissemination of breast cancer cells. In this review, we summarize the clinical and experimental evidence that bone is a transfer station for the secondary dissemination of breast cancer. We also discuss the regulatory mechanisms of the bone microenvironment in secondary seeding of breast cancer, focusing on stemness regulation, quiescence-proliferation equilibrium regulation, epigenetic reprogramming and immune escape of cancer cells. Furthermore, we highlight future research perspectives and strategies for preventing secondary dissemination from bone.
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Affiliation(s)
- Yufan Huang
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Hongli Wang
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Xiaomin Yue
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
- Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Xiaoqing Li
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
- Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
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Vidlarova M, Rehulkova A, Stejskal P, Prokopova A, Slavik H, Hajduch M, Srovnal J. Recent Advances in Methods for Circulating Tumor Cell Detection. Int J Mol Sci 2023; 24:3902. [PMID: 36835311 PMCID: PMC9959336 DOI: 10.3390/ijms24043902] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/06/2023] [Accepted: 02/12/2023] [Indexed: 02/17/2023] Open
Abstract
Circulating tumor cells (CTCs) are released from primary tumors and transported through the body via blood or lymphatic vessels before settling to form micrometastases under suitable conditions. Accordingly, several studies have identified CTCs as a negative prognostic factor for survival in many types of cancer. CTCs also reflect the current heterogeneity and genetic and biological state of tumors; so, their study can provide valuable insights into tumor progression, cell senescence, and cancer dormancy. Diverse methods with differing specificity, utility, costs, and sensitivity have been developed for isolating and characterizing CTCs. Additionally, novel techniques with the potential to overcome the limitations of existing ones are being developed. This primary literature review describes the current and emerging methods for enriching, detecting, isolating, and characterizing CTCs.
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Affiliation(s)
- Monika Vidlarova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, 779 00 Olomouc, Czech Republic
- Laboratory of Experimental Medicine, University Hospital in Olomouc, 779 00 Olomouc, Czech Republic
| | - Alona Rehulkova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, 779 00 Olomouc, Czech Republic
- Laboratory of Experimental Medicine, University Hospital in Olomouc, 779 00 Olomouc, Czech Republic
| | - Pavel Stejskal
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, 779 00 Olomouc, Czech Republic
- Laboratory of Experimental Medicine, University Hospital in Olomouc, 779 00 Olomouc, Czech Republic
| | - Andrea Prokopova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, 779 00 Olomouc, Czech Republic
| | - Hanus Slavik
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, 67000 Strasbourg, France
| | - Marian Hajduch
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, 779 00 Olomouc, Czech Republic
- Laboratory of Experimental Medicine, University Hospital in Olomouc, 779 00 Olomouc, Czech Republic
| | - Josef Srovnal
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, 779 00 Olomouc, Czech Republic
- Laboratory of Experimental Medicine, University Hospital in Olomouc, 779 00 Olomouc, Czech Republic
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Ma S, Zhou M, Xu Y, Gu X, Zou M, Abudushalamu G, Yao Y, Fan X, Wu G. Clinical application and detection techniques of liquid biopsy in gastric cancer. Mol Cancer 2023; 22:7. [PMID: 36627698 PMCID: PMC9832643 DOI: 10.1186/s12943-023-01715-z] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/02/2023] [Indexed: 01/12/2023] Open
Abstract
Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology.
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Affiliation(s)
- Shuo Ma
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Meiling Zhou
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Yanhua Xu
- grid.452743.30000 0004 1788 4869Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, 225000 Jiangsu China
| | - Xinliang Gu
- grid.440642.00000 0004 0644 5481Department of Laboratory Medicine, Medical School, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001 Jiangsu China
| | - Mingyuan Zou
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Gulinaizhaer Abudushalamu
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Yuming Yao
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Xiaobo Fan
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Guoqiu Wu
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, 210009 Jiangsu China
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Danila DC. Liquid biopsy as a cancer biomarker-potential, and challenges. Cancer Biomark 2022. [DOI: 10.1016/b978-0-12-824302-2.00013-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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10
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Clinical Relevance of Circulating Tumor Cells in Prostate Cancer Management. Biomedicines 2021; 9:biomedicines9091179. [PMID: 34572366 PMCID: PMC8471111 DOI: 10.3390/biomedicines9091179] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/29/2021] [Accepted: 09/04/2021] [Indexed: 02/08/2023] Open
Abstract
Given the low specificity of the routinely used biomarker prostate-specific antigen, circulating tumor cell (CTC) enumeration seems to be particularly useful in the monitoring of prostate cancer. In this review, we focused on a few aspects of CTC enumeration in prostate malignancies: prognostic value in metastatic and non-metastatic tumors, role in the monitoring of treatment outcomes, use as a surrogate marker for survival, and other applications, mostly for research purposes. CTC enumeration, without a doubt, offers an attractive perspective in the management of prostate cancer. However, the vast majority of available data about the role of CTC in this malignancy originate from randomized studies of anticancer agents and do not necessarily translate into real-world clinical practice. Further, most studies on the application of CTC in prostate cancer patients were limited to advanced stages of this malignancy. Meanwhile, the role of CTC in the early stages of prostate cancer, in which some patients may present with occult disseminated disease, is still relatively poorly understood, and should thus be studied extensively. Other obstacles in the widespread application of CTC enumeration in routine clinical practice include considerable discrepancies in the number of cells determined with various commercially available systems.
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Park C, Abafogi AT, Ponnuvelu DV, Song I, Ko K, Park S. Enhanced Luminescent Detection of Circulating Tumor Cells by a 3D Printed Immunomagnetic Concentrator. BIOSENSORS 2021; 11:278. [PMID: 34436080 PMCID: PMC8391490 DOI: 10.3390/bios11080278] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022]
Abstract
Circulating tumor cells (CTCs) are an indicator of metastatic progression and relapse. Since non-CTC cells such as red blood cells outnumber CTCs in the blood, the separation and enrichment of CTCs is key to improving their detection sensitivity. The ATP luminescence assay can measure intracellular ATP to detect cells quickly but has not yet been used for CTC detection in the blood because extracellular ATP in the blood, derived from non-CTCs, interferes with the measurement. Herein, we report on the improvement of the ATP luminescence assay for the detection of CTCs by separating and concentrating CTCs in the blood using a 3D printed immunomagnetic concentrator (3DPIC). Because of its high-aspect-ratio structure and resistance to high flow rates, 3DPIC allows cancer cells in 10 mL to be concentrated 100 times within minutes. This enables the ATP luminescence assay to detect as low as 10 cells in blood, thereby being about 10 times more sensitive than when commercial kits are used for CTC concentration. This is the first time that the ATP luminescence assay was used for the detection of cancer cells in blood. These results demonstrate the feasibility of 3DPIC as a concentrator to improve the detection limit of the ATP luminescence assay for the detection of CTCs.
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Affiliation(s)
- Chanyong Park
- Department of Medical Device, Korea Institute of Machinery & Materials (KIMM), Daegu 42994, Korea;
| | - Abdurhaman Teyib Abafogi
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Korea; (A.T.A.); (D.V.P.)
| | - Dinesh Veeran Ponnuvelu
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Korea; (A.T.A.); (D.V.P.)
| | - Ilchan Song
- Department of Medicine, College of Medicine, Chung-Ang University, Seoul 06974, Korea; (I.S.); (K.K.)
| | - Kisung Ko
- Department of Medicine, College of Medicine, Chung-Ang University, Seoul 06974, Korea; (I.S.); (K.K.)
| | - Sungsu Park
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Korea; (A.T.A.); (D.V.P.)
- Department of Biomedical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Korea
- Institute of Quantum Biophysics (IQB), Sungkyunkwan University (SKKU), Suwon 16419, Korea
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12
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Hofbauer LC, Bozec A, Rauner M, Jakob F, Perner S, Pantel K. Novel approaches to target the microenvironment of bone metastasis. Nat Rev Clin Oncol 2021; 18:488-505. [PMID: 33875860 DOI: 10.1038/s41571-021-00499-9] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/08/2021] [Indexed: 02/07/2023]
Abstract
Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell-osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.
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Affiliation(s)
- Lorenz C Hofbauer
- University Center for Healthy Aging, Dresden University of Technology, Dresden, Germany. .,Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany. .,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) partner site Dresden, Dresden, Germany.
| | - Aline Bozec
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
| | - Martina Rauner
- University Center for Healthy Aging, Dresden University of Technology, Dresden, Germany.,Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany
| | - Franz Jakob
- Department of Orthopedic Surgery, Julius Maximilians University of Würzburg, Würzburg, Germany.,Department of Functional Materials in Medicine and Dentistry, Julius Maximilians University of Würzburg, Würzburg, Germany
| | - Sven Perner
- Institute of Pathology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.,Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Klaus Pantel
- Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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13
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Zhang W, Bado IL, Hu J, Wan YW, Wu L, Wang H, Gao Y, Jeong HH, Xu Z, Hao X, Lege BM, Al-Ouran R, Li L, Li J, Yu L, Singh S, Lo HC, Niu M, Liu J, Jiang W, Li Y, Wong STC, Cheng C, Liu Z, Zhang XHF. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 2021; 184:2471-2486.e20. [PMID: 33878291 PMCID: PMC8087656 DOI: 10.1016/j.cell.2021.03.011] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/30/2020] [Accepted: 03/04/2021] [Indexed: 12/22/2022]
Abstract
Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
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Affiliation(s)
- Weijie Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Igor L Bado
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jingyuan Hu
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ying-Wooi Wan
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ling Wu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hai Wang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yang Gao
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hyun-Hwan Jeong
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhan Xu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiaoxin Hao
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Bree M Lege
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rami Al-Ouran
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lucian Li
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jiasong Li
- Department of Systems Medicine and Bioengineering and Translational Biophotonics Laboratory, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Liqun Yu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Swarnima Singh
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hin Ching Lo
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Muchun Niu
- Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jun Liu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Weiyu Jiang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yi Li
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Stephen T C Wong
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Systems Medicine and Bioengineering and Translational Biophotonics Laboratory, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Chonghui Cheng
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhandong Liu
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
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14
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Lee LX, Li SC. Hunting down the dominating subclone of cancer stem cells as a potential new therapeutic target in multiple myeloma: An artificial intelligence perspective. World J Stem Cells 2020; 12:706-720. [PMID: 32952853 PMCID: PMC7477658 DOI: 10.4252/wjsc.v12.i8.706] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/08/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2023] Open
Abstract
The development of single-cell subclones, which can rapidly switch from dormant to dominant subclones, occur in the natural pathophysiology of multiple myeloma (MM) but is often "pressed" by the standard treatment of MM. These emerging subclones present a challenge, providing reservoirs for chemoresistant mutations. Technological advancement is required to track MM subclonal changes, as understanding MM's mechanism of evolution at the cellular level can prompt the development of new targeted ways of treating this disease. Current methods to study the evolution of subclones in MM rely on technologies capable of phenotypically and genotypically characterizing plasma cells, which include immunohistochemistry, flow cytometry, or cytogenetics. Still, all of these technologies may be limited by the sensitivity for picking up rare events. In contrast, more incisive methods such as RNA sequencing, comparative genomic hybridization, or whole-genome sequencing are not yet commonly used in clinical practice. Here we introduce the epidemiological diagnosis and prognosis of MM and review current methods for evaluating MM subclone evolution, such as minimal residual disease/multiparametric flow cytometry/next-generation sequencing, and their respective advantages and disadvantages. In addition, we propose our new single-cell method of evaluation to understand MM's mechanism of evolution at the molecular and cellular level and to prompt the development of new targeted ways of treating this disease, which has a broad prospect.
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Affiliation(s)
- Lisa X Lee
- Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, UCI Health, Orange, CA 92868, United States
| | - Shengwen Calvin Li
- Neuro-oncology and Stem Cell Research Laboratory, CHOC Children's Research Institute, Children's Hospital of Orange County, Orange, CA 92868, United States
- Department of Neurology, University of California-Irvine School of Medicine, Orange, CA 92868, United States.
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15
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Vafaei S, Roudi R, Madjd Z, Aref AR, Ebrahimi M. Potential theranostics of circulating tumor cells and tumor-derived exosomes application in colorectal cancer. Cancer Cell Int 2020; 20:288. [PMID: 32655320 PMCID: PMC7339440 DOI: 10.1186/s12935-020-01389-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/27/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND At the present time, colorectal cancer (CRC) is still known as a disease with a high mortality rate. Theranostics are flawless scenarios that link diagnosis with therapy, including precision medicine as a critical platform that relies on the development of biomarkers particularly "liquid biopsy". Circulating tumor cells (CTCs) and tumor-derived exosomes (TDEs) in a liquid biopsy approach are of substantial importance in comparison with traditional ones, which cannot generally be performed to determine the dynamics of the tumor due to its wide restriction of range. Thus, recent attempts has shifted towards minimally noninvasive methods. MAIN TEXT CTCs and TDEs, as significant signals emitted from the tumor microenvironment, which are also detectable in the blood, prove themselves to be promising novel biomarkers for cancer diagnosis, prognosis, and treatment response prediction. The therapeutic potential of them is still limited, and studies are at its infancy. One of the major challenges for the implementation of CTCs and TDEs which are new trends in translational medicine is the development of isolation and characterization; a standardizable approach. This review highlights and discusses the current challenges to find the bio fluids application in CRC early detection and clinical management. CONCLUSION Taken together, CTCs and TDEs as silent drivers of metastasis can serve in the management of cancer patient treatment and it is of the upmost importance to expand our insight into this subject. However, due to the limited data available from clinical trials, further validations are required before addressing their putative application in oncology.
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Affiliation(s)
- Somayeh Vafaei
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Raheleh Roudi
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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16
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Facile synthesis of 3D hierarchical micro-/nanostructures in capillaries for efficient capture of circulating tumor cells. J Colloid Interface Sci 2020; 575:108-118. [PMID: 32361043 DOI: 10.1016/j.jcis.2020.04.087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/06/2020] [Accepted: 04/20/2020] [Indexed: 01/28/2023]
Abstract
The efficient capture of rare circulating tumor cells (CTCs) with high viability is of great importance in cancer diagnosis. The integration of three-dimensional (3D) nanobiointerfaces with capillary flow channel platforms can efficiently improve CTC capture performance by providing abundant binding sites and increasing the likelihood of contact as samples flow through the microchannels. However, due to the complex preparation processes, facile synthesis of nanostructures for use as substrates in flow channels for biomedical applications is still challenging. To reduce the encapsulation steps in the fabricating of nanostructured flow channel devices, we chose the enclosed glass capillaries as flow channels and accomplished all the experiments in the microchannels, including 3D nanostructure synthesis, surface modification and capture/release of CTCs. In this work, we constructed a novel 3D Zn(OH)F/ZnO nanoforest array in capillaries for CTC isolation via a facile microfluidic wet chemistry method. Because of the abundant binding sites of the 3D Zn(OH)F/ZnO nanoforest array, the capture efficiency was remarkably enhanced compared with that of vertical nanowires (90.3% vs 69.1%). In addition, a high release efficiency and cell viability of released cells were achieved by grafting poly(N-isopropylacrylamide) (PNIPPAm). These results may provide evidence for a novel method to fabricate hierarchical 3D substrates with a combination of biomolecule recognition and topographical interaction for biomedical applications.
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17
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Panoptic View of Prognostic Models for Personalized Breast Cancer Management. Cancers (Basel) 2019; 11:cancers11091325. [PMID: 31500225 PMCID: PMC6770520 DOI: 10.3390/cancers11091325] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/03/2019] [Accepted: 09/05/2019] [Indexed: 12/12/2022] Open
Abstract
The efforts to personalize treatment for patients with breast cancer have led to a focus on the deeper characterization of genotypic and phenotypic heterogeneity among breast cancers. Traditional pathology utilizes microscopy to profile the morphologic features and organizational architecture of tumor tissue for predicting the course of disease, and is the first-line set of guiding tools for customizing treatment decision-making. Currently, clinicians use this information, combined with the disease stage, to predict patient prognosis to some extent. However, tumoral heterogeneity stubbornly persists among patient subgroups delineated by these clinicopathologic characteristics, as currently used methodologies in diagnostic pathology lack the capability to discern deeper genotypic and subtler phenotypic differences among individual patients. Recent advancements in molecular pathology, however, are poised to change this by joining forces with multiple-omics technologies (genomics, transcriptomics, epigenomics, proteomics, and metabolomics) that provide a wealth of data about the precise molecular complement of each patient's tumor. In addition, these technologies inform the drivers of disease aggressiveness, the determinants of therapeutic response, and new treatment targets in the individual patient. The tumor architecture information can be integrated with the knowledge of the detailed mutational, transcriptional, and proteomic phenotypes of cancer cells within individual tumors to derive a new level of biologic insight that enables powerful, data-driven patient stratification and customization of treatment for each patient, at each stage of the disease. This review summarizes the prognostic and predictive insights provided by commercially available gene expression-based tests and other multivariate or clinical -omics-based prognostic/predictive models currently under development, and proposes a more inclusive multiplatform approach to tackling the challenging heterogeneity of breast cancer to individualize its management. "The future is already here-it's just not very evenly distributed."-William Ford Gibson.
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18
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EMT and Stemness-Key Players in Pancreatic Cancer Stem Cells. Cancers (Basel) 2019; 11:cancers11081136. [PMID: 31398893 PMCID: PMC6721598 DOI: 10.3390/cancers11081136] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/01/2019] [Accepted: 08/06/2019] [Indexed: 12/15/2022] Open
Abstract
Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression.
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Tseng CC, Stanciauskas R, Zhang P, Woo D, Wu K, Kelly K, Gill PS, Yu M, Pinaud F, Lee AS. GRP78 regulates CD44v membrane homeostasis and cell spreading in tamoxifen-resistant breast cancer. Life Sci Alliance 2019; 2:e201900377. [PMID: 31416894 PMCID: PMC6696983 DOI: 10.26508/lsa.201900377] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 12/26/2022] Open
Abstract
GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.
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Affiliation(s)
- Chun-Chih Tseng
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Ramunas Stanciauskas
- Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Pu Zhang
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Dennis Woo
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kaijin Wu
- Department of Medicine/Division of Hematology, University of Southern California, Los Angeles, CA, USA
| | - Kevin Kelly
- Department of Medicine/Division of Hematology, University of Southern California, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Parkash S Gill
- Department of Pathology, University of Southern California, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Min Yu
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fabien Pinaud
- Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
- Department of Chemistry, University of Southern California, Los Angeles, CA, USA
- Department of Physics and Astronomy, University of Southern California, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Amy S Lee
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
- University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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Budna-Tukan J, Świerczewska M, Mazel M, Cieślikowski WA, Ida A, Jankowiak A, Antczak A, Nowicki M, Pantel K, Azria D, Zabel M, Alix-Panabières C. Analysis of Circulating Tumor Cells in Patients with Non-Metastatic High-Risk Prostate Cancer before and after Radiotherapy Using Three Different Enumeration Assays. Cancers (Basel) 2019; 11:cancers11060802. [PMID: 31185699 PMCID: PMC6627099 DOI: 10.3390/cancers11060802] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 05/28/2019] [Accepted: 06/06/2019] [Indexed: 12/14/2022] Open
Abstract
The characterization of circulating tumor cells (CTCs) can lead to a promising strategy for monitoring residual or relapsing prostate cancer (PCa) after local therapy. The aim of this study was to compare three innovative technologies for CTC enumeration in 131 high-risk patients with PCa, before and after radiotherapy, combined with androgen deprivation. The CTC number was tested using the FDA-cleared CellSearch® system, the dual fluoro-EPISPOT assay that only detects functional CTCs, and the in vivo CellCollector® technology. The highest percentage of CTC-positive patients was detected with the CellCollector® (48%) and dual fluoro-EPISPOT (42%) assays, while the CellSearch® system presented the lowest rate (14%). Although the concordance among methods was only 23%, the cumulative positivity rate was 79%. A matched-pair analysis of the samples before, and after, treatment suggested a trend toward a decrease in CTC count after treatment with all methods. CTC tended to be positivity correlated with age for the fluoro-EPISPOT assay and with PSA level from the data of three assays. Combining different CTC assays improved CTC detection rates in patients with non-metastatic high-risk PCa before and after treatment. Our findings do not support the hypothesis that radiotherapy leads to cancer cell release in the circulation.
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Affiliation(s)
- Joanna Budna-Tukan
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland.
| | - Monika Świerczewska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland.
| | - Martine Mazel
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, 34093 Montpellier, France.
| | | | - Agnieszka Ida
- Department of Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland.
| | - Agnieszka Jankowiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland.
| | - Andrzej Antczak
- Department of Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland.
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland.
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - David Azria
- Radiation Oncology Department, Montpellier Cancer Institute, 34298 Montpellier, France.
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland.
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland.
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, 34093 Montpellier, France.
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21
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Cai F, Cen C, Cai L, Falar Luis MA, Biskup E. Application of Circulation Tumor Cells Detection in Diagnosis and Treatment of Breast Tumors. Rejuvenation Res 2019; 22:498-502. [PMID: 30712469 DOI: 10.1089/rej.2018.2154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In recent years, the clinical application of circulating tumor cell (CTCs) detection has become one of the research hotspots in the field of precision medicine. CTCs detection is noninvasive, easy to obtain, can be repeatedly collected, and highly repeatable with other advantages. It not only can be a real-time comprehensive monitoring of cancer treatment but also can have a large number of applications, including early diagnosis of tumor, timely evaluation of efficacy, condition monitoring, resistance factor analysis, prognosis judgment, individualized treatment of tumors, drug guidance, and so on. At present, many large-scale clinical studies at home and abroad run through all stages of breast cancer diagnosis and treatment. For different treatment stages of breast cancer, the application value of CTCs detection is different. Compared with traditional detection methods, CTCs have advantages in dynamic monitoring of disease changes and efficacy evaluation in real-time. In the era of breast cancer classificational and individualized treatment, CTCs detection can provide patients with the most timely and optimized treatment plan.
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Affiliation(s)
- Fengfeng Cai
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Chunmei Cen
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Lu Cai
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Manuel Antonio Falar Luis
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Ewelina Biskup
- Shanghai University of Medicine and Health Sciences, Shanghai, P.R. China.,Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, Basel, Switzerland
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22
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Pallante P, Pisapia P, Bellevicine C, Malapelle U, Troncone G. Circulating Tumour Cells in Predictive Molecular Pathology: Focus on Drug-Sensitive Assays and 3D Culture. Acta Cytol 2019; 63:171-181. [PMID: 30759433 DOI: 10.1159/000496213] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022]
Abstract
Molecular cytopathology is a rapidly evolving field of cytopathology that provides biological information about the response to personalised therapy and about the prognosis of neoplasms diagnosed on cytological samples. Biomarkers such as circulating tumour cells and circulating tumour DNA are increasingly being evaluated in blood and in other body fluids. Such liquid biopsies are non-invasive, repeatable, and feasible also in patients with severe comorbidities. However, liquid biopsy may be challenging due to a low concentration of biomarkers. In such cases, biomarkers can be detected with highly sensitive molecular techniques, which in turn should be validated and integrated in a complex algorithm that includes tissue-based molecular assessments. The aim of this review is to provide the cytopathologist with practical information that is relevant to daily practice, particularly regarding the emerging role of circulating tumour cells in the field of predictive molecular pathology.
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Affiliation(s)
- Pierlorenzo Pallante
- Institute of Experimental Endocrinology and Oncology (IEOS) "G. Salvatore," National Research Council (CNR), Naples, Italy
| | - Pasquale Pisapia
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Claudio Bellevicine
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy,
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Samandari M, Julia MG, Rice A, Chronopoulos A, Del Rio Hernandez AE. Liquid biopsies for management of pancreatic cancer. Transl Res 2018; 201:98-127. [PMID: 30118658 DOI: 10.1016/j.trsl.2018.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/17/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
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Affiliation(s)
- Mohamadmahdi Samandari
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - María Gil Julia
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Antonios Chronopoulos
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Armando E Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
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24
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Gourdin T, Sonpavde G. Utility of cell-free nucleic acid and circulating tumor cell analyses in prostate cancer. Asian J Androl 2018; 20:230-237. [PMID: 29578115 PMCID: PMC5952476 DOI: 10.4103/aja.aja_1_18] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/28/2017] [Indexed: 12/25/2022] Open
Abstract
Prostate cancer is characterized by bone metastases and difficulty of objectively measuring disease burden. In this context, cell-free circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) quantitation and genomic profiling afford the ability to noninvasively and serially monitor the tumor. Recent data suggest that ctDNA and CTC quantitation are prognostic for survival. Indeed, CTC enumeration using the CellSearch® platform is validated as a prognostic factor and warrants consideration as a stratification factor in randomized trials. Changes in quantities of CTCs using CellSearch also are prognostic and may be employed to detect a signal of activity of new agents. Molecular profiling of both CTCs and ctDNA for androgen receptor (AR) variants has been associated with outcomes in the setting of novel androgen inhibitors. Serial profiling to detect the evolution of new alterations may inform drug development and help develop precision medicine. The costs of these assays and the small quantities in which they are detectable in blood are a limitation, and novel platforms are required to address this challenge. The presence of multiple platforms to assay CTCs and ctDNA also warrants the consideration of a mechanism to allow comparison of data across platforms. Further validation and the continued development and standardization of these promising modalities will facilitate their adoption in the clinic.
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Affiliation(s)
| | - Guru Sonpavde
- Dana Farber Cancer Institute, Genitourinary Oncology Section, Boston, MA 02215, USA
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Sharma S, Zhuang R, Long M, Pavlovic M, Kang Y, Ilyas A, Asghar W. Circulating tumor cell isolation, culture, and downstream molecular analysis. Biotechnol Adv 2018; 36:1063-1078. [PMID: 29559380 DOI: 10.1016/j.biotechadv.2018.03.007] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 03/07/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022]
Abstract
Circulating tumor cells (CTCs) are a major contributor of cancer metastases and hold a promising prognostic significance in cancer detection. Performing functional and molecular characterization of CTCs provides an in-depth knowledge about this lethal disease. Researchers are making efforts to design devices and develop assays for enumeration of CTCs with a high capture and detection efficiency from whole blood of cancer patients. The existing and on-going research on CTC isolation methods has revealed cell characteristics which are helpful in cancer monitoring and designing of targeted cancer treatments. In this review paper, a brief summary of existing CTC isolation methods is presented. We also discuss methods of detaching CTC from functionalized surfaces (functional assays/devices) and their further use for ex-vivo culturing that aid in studies regarding molecular properties that encourage metastatic seeding. In the clinical applications section, we discuss a number of cases that CTCs can play a key role for monitoring metastases, drug treatment response, and heterogeneity profiling regarding biomarkers and gene expression studies that bring treatment design further towards personalized medicine.
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Affiliation(s)
- Sandhya Sharma
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA; Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431, USA
| | - Rachel Zhuang
- Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431, USA
| | - Marisa Long
- Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431, USA
| | - Mirjana Pavlovic
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Yunqing Kang
- Department of Ocean & Mechanical Engineering, College of Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA; Department of Biomedical Science, College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Azhar Ilyas
- Department of Electrical & Computer Engineering, New York Institute of Technology, Old Westbury, NY 11568, USA
| | - Waseem Asghar
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA; Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431, USA; Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA.
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26
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El-Heliebi A, Hille C, Laxman N, Svedlund J, Haudum C, Ercan E, Kroneis T, Chen S, Smolle M, Rossmann C, Krzywkowski T, Ahlford A, Darai E, von Amsberg G, Alsdorf W, König F, Löhr M, de Kruijff I, Riethdorf S, Gorges TM, Pantel K, Bauernhofer T, Nilsson M, Sedlmayr P. In Situ Detection and Quantification of AR-V7, AR-FL, PSA, and KRAS Point Mutations in Circulating Tumor Cells. Clin Chem 2018; 64:536-546. [PMID: 29301749 DOI: 10.1373/clinchem.2017.281295] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 12/11/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms. METHODS We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wild-type (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients. RESULTS In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1-76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts. CONCLUSIONS Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices.
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Affiliation(s)
- Amin El-Heliebi
- Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria;
| | - Claudia Hille
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Navya Laxman
- Science for Life Laboratory, Department of Biophysics and Biochemistry, Stockholm University, Solna, Sweden
| | - Jessica Svedlund
- Science for Life Laboratory, Department of Biophysics and Biochemistry, Stockholm University, Solna, Sweden
| | - Christoph Haudum
- Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria
- Center for Biomarker Research in Medicine (CBmed); Graz, Austria
| | - Erkan Ercan
- Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria
| | - Thomas Kroneis
- Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria
| | - Shukun Chen
- Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria
| | - Maria Smolle
- Center for Biomarker Research in Medicine (CBmed); Graz, Austria
| | - Christopher Rossmann
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Tomasz Krzywkowski
- Science for Life Laboratory, Department of Biophysics and Biochemistry, Stockholm University, Solna, Sweden
| | - Annika Ahlford
- Science for Life Laboratory, Department of Biophysics and Biochemistry, Stockholm University, Solna, Sweden
- Devyser AB, Stockholm, Sweden
| | - Evangelia Darai
- Science for Life Laboratory, Department of Biophysics and Biochemistry, Stockholm University, Solna, Sweden
| | - Gunhild von Amsberg
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Winfried Alsdorf
- Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Matthias Löhr
- Center for Digestive Diseases, Karolinska University Hospital and Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Inge de Kruijff
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, the Netherlands
| | - Sabine Riethdorf
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias M Gorges
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Bauernhofer
- Center for Biomarker Research in Medicine (CBmed); Graz, Austria
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Mats Nilsson
- Science for Life Laboratory, Department of Biophysics and Biochemistry, Stockholm University, Solna, Sweden
| | - Peter Sedlmayr
- Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria
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Review: Microfluidics technologies for blood-based cancer liquid biopsies. Anal Chim Acta 2018; 1012:10-29. [PMID: 29475470 DOI: 10.1016/j.aca.2017.12.050] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 12/29/2017] [Accepted: 12/30/2017] [Indexed: 12/19/2022]
Abstract
Blood-based liquid biopsies provide a minimally invasive alternative to identify cellular and molecular signatures that can be used as biomarkers to detect early-stage cancer, predict disease progression, longitudinally monitor response to chemotherapeutic drugs, and provide personalized treatment options. Specific targets in blood that can be used for detailed molecular analysis to develop highly specific and sensitive biomarkers include circulating tumor cells (CTCs), exosomes shed from tumor cells, cell-free circulating tumor DNA (cfDNA), and circulating RNA. Given the low abundance of CTCs and other tumor-derived products in blood, clinical evaluation of liquid biopsies is extremely challenging. Microfluidics technologies for cellular and molecular separations have great potential to either outperform conventional methods or enable completely new approaches for efficient separation of targets from complex samples like blood. In this article, we provide a comprehensive overview of blood-based targets that can be used for analysis of cancer, review microfluidic technologies that are currently used for isolation of CTCs, tumor derived exosomes, cfDNA, and circulating RNA, and provide a detailed discussion regarding potential opportunities for microfluidics-based approaches in cancer diagnostics.
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Chiodi I, Scovassi AI, Mondello C. Circulating Molecular and Cellular Biomarkers in Cancer. TRANSLATIONAL TOXICOLOGY AND THERAPEUTICS: WINDOWS OF DEVELOPMENTAL SUSCEPTIBILITY IN REPRODUCTION AND CANCER 2017:607-656. [DOI: 10.1002/9781119023647.ch16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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29
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Maas M, Hegemann M, Rausch S, Bedke J, Stenzl A, Todenhöfer T. Circulating tumor cells and their role in prostate cancer. Asian J Androl 2017; 21:213572. [PMID: 28836508 PMCID: PMC6337952 DOI: 10.4103/aja.aja_29_17] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 06/02/2017] [Indexed: 12/28/2022] Open
Abstract
Circulating tumor cells (CTC) have become an important biomarker in patients with advanced prostate cancer. CTC count has been demonstrated to be a prognostic factor for overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In localized prostate cancer, a clear correlation between CTC counts and clinicopathological risk parameters and outcome has not been observed. Currently, the focus of research is shifting from CTC enumeration towards molecular characterization of CTC leading to the discovery of markers predicting treatment response. The role of androgen receptor splice variants expressed by CTC as markers of resistance to abiraterone and enzalutamide has been assessed by various studies. The identification of CTC markers predicting treatment response represents a key step to guide the selection of treatment (e.g., abiraterone/enzalutamide vs taxanes), particularly in patients with mCRPC. As an alternative to CTC, the analysis of circulating tumor DNA has been shown to enable a noninvasive disease characterization having high potential to promote precision oncology.
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Affiliation(s)
- Moritz Maas
- Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Straße 3, Tuebingen 72076, Germany
| | - Miriam Hegemann
- Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Straße 3, Tuebingen 72076, Germany
| | - Steffen Rausch
- Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Straße 3, Tuebingen 72076, Germany
| | - Jens Bedke
- Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Straße 3, Tuebingen 72076, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Straße 3, Tuebingen 72076, Germany
| | - Tilman Todenhöfer
- Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Straße 3, Tuebingen 72076, Germany
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30
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Jackson JM, Witek MA, Kamande JW, Soper SA. Materials and microfluidics: enabling the efficient isolation and analysis of circulating tumour cells. Chem Soc Rev 2017; 46:4245-4280. [PMID: 28632258 PMCID: PMC5576189 DOI: 10.1039/c7cs00016b] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We present a critical review of microfluidic technologies and material effects on the analyses of circulating tumour cells (CTCs) selected from the peripheral blood of cancer patients. CTCs are a minimally invasive source of clinical information that can be used to prognose patient outcome, monitor minimal residual disease, assess tumour resistance to therapeutic agents, and potentially screen individuals for the early diagnosis of cancer. The performance of CTC isolation technologies depends on microfluidic architectures, the underlying principles of isolation, and the choice of materials. We present a critical review of the fundamental principles used in these technologies and discuss their performance. We also give context to how CTC isolation technologies enable downstream analysis of selected CTCs in terms of detecting genetic mutations and gene expression that could be used to gain information that may affect patient outcome.
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31
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Chen S, El-Heliebi A, Kroneis T. Biological and Molecular Characterization of Circulating Tumor Cells: A Creative Strategy for Precision Medicine? Adv Clin Chem 2017; 82:71-103. [PMID: 28939214 DOI: 10.1016/bs.acc.2017.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Circulating tumor cells (CTCs) are a group of rare cells disseminated from either primary or metastatic tumors into the blood stream. CTCs are considered to be the precursor of cancer metastasis. As a critical component of liquid biopsies, CTCs are a unique tool to understand the formation of metastasis and a valuable source of information on intratumor heterogeneity. Much effort has been invested in technologies for the detection of CTCs because they are rare cells among the vast number of blood cells. Studies in various cancers have repeatedly demonstrated that increased CTC counts prior to or during treatment are significantly associated with poor outcomes. In the new era of precision medicine, the study of CTCs reaches far beyond detection and counting. The rapidly growing field of analytical platforms for rare-cell analysis allows in-depth characterization of CTCs at the bulk cell and single-cell level. Genetic profiling of CTCs may provide an insight into the real-time tumor status, may allow the monitoring and evaluation of treatment response in clinical routine, and may lead to the development of novel therapeutic targets as well.
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Affiliation(s)
- Shukun Chen
- Institute of Cell Biology, Histology & Embryology, Medical University of Graz, Graz, Austria.
| | - Amin El-Heliebi
- Institute of Cell Biology, Histology & Embryology, Medical University of Graz, Graz, Austria
| | - Thomas Kroneis
- Institute of Cell Biology, Histology & Embryology, Medical University of Graz, Graz, Austria
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Alix-Panabières C, Pantel K. Characterization of single circulating tumor cells. FEBS Lett 2017; 591:2241-2250. [DOI: 10.1002/1873-3468.12662] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 04/06/2017] [Accepted: 04/25/2017] [Indexed: 12/28/2022]
Affiliation(s)
- Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells (LCCRH); Department of Cell and Tissue Biopathology of Tumors; University Medical Centre; Montpellier France
- EA2415 - Help for Personalized Decision: Methodological Aspects; University Institute of Clinical Research (IURC); Montpellier University; France
| | - Klaus Pantel
- Department of Tumor Biology; Center of Experimental Medicine; University Cancer Center Hamburg; Germany
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33
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Zhang J, Fan ZH. A universal tumor cell isolation method enabled by fibrin-coated microchannels. Analyst 2017; 141:563-6. [PMID: 26568434 DOI: 10.1039/c5an01783a] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We report a simple but effective strategy to capture tumor cells using fibrin-immobilized microchannels. It is a universal method since it shows an ability to capture both epithelial and mesenchymal tumor cells. The cell capture efficiency is up to 90%.
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Affiliation(s)
- Jinling Zhang
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, PO Box 116250, Gainesville, Florida 32611, USA.
| | - Z Hugh Fan
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, PO Box 116250, Gainesville, Florida 32611, USA. and J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, P.O. Box 116131, Gainesville, FL 32611, USA
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Soler A, Cayrefourcq L, Mazel M, Alix-Panabières C. EpCAM-Independent Enrichment and Detection of Viable Circulating Tumor Cells Using the EPISPOT Assay. Methods Mol Biol 2017; 1634:263-276. [PMID: 28819858 DOI: 10.1007/978-1-4939-7144-2_22] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Identification and characterization of circulating tumor cells (CTCs) in peripheral blood can provide information on the direction and the efficacy of treatments. Current techniques such as CellSearch® are limited in differentiating between apoptotic and viable CTCs. In contrast, the fluorescent EPISPOT assay allows for the identification of viable cells by detecting proteins secreted/released/shed by functional single epithelial cancer cells. In addition, as CTCs are rare events, it is required to combine the EPISPOT assay with an enrichment step. In this article, the EPISPOT assay, as well as two technologies for enrichment of viable CTCs, RosetteSep™ and Parsortix™ techniques, will be presented and discussed in detail.
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MESH Headings
- Antibodies, Monoclonal/chemistry
- Antibodies, Monoclonal/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cell Count
- Cell Line, Tumor
- Cell Separation/instrumentation
- Cell Separation/methods
- Cell Survival
- Centrifugation, Density Gradient/methods
- Epithelial Cell Adhesion Molecule
- Equipment Design
- ErbB Receptors/genetics
- ErbB Receptors/immunology
- ErbB Receptors/metabolism
- Ficoll/chemistry
- Fluorescent Dyes/chemistry
- Humans
- Immunoassay
- Keratin-19/genetics
- Keratin-19/immunology
- Keratin-19/metabolism
- Microfluidic Analytical Techniques/instrumentation
- Neoplasms/blood
- Neoplasms/diagnosis
- Neoplasms/immunology
- Neoplasms/pathology
- Neoplastic Cells, Circulating/immunology
- Neoplastic Cells, Circulating/metabolism
- Neoplastic Cells, Circulating/pathology
- Protein Binding
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/immunology
- Receptor, ErbB-2/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/immunology
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Alexandra Soler
- Laboratory of Rare Human Circulating Cells (LCCRH), Department of Cellular and Tissular Biopathology of Tumors, University Medical Centre, Montpellier, France
- EA2415-Help for Personalized Decision: Methodological Aspects, University Institute of Clinical Research (IURC), Montpellier University, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France
| | - Laure Cayrefourcq
- Laboratory of Rare Human Circulating Cells (LCCRH), Department of Cellular and Tissular Biopathology of Tumors, University Medical Centre, Montpellier, France
- EA2415-Help for Personalized Decision: Methodological Aspects, University Institute of Clinical Research (IURC), Montpellier University, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France
| | - Martine Mazel
- Laboratory of Rare Human Circulating Cells (LCCRH), Department of Cellular and Tissular Biopathology of Tumors, University Medical Centre, Montpellier, France
- EA2415-Help for Personalized Decision: Methodological Aspects, University Institute of Clinical Research (IURC), Montpellier University, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells (LCCRH), Department of Cellular and Tissular Biopathology of Tumors, University Medical Centre, Montpellier, France.
- EA2415-Help for Personalized Decision: Methodological Aspects, University Institute of Clinical Research (IURC), Montpellier University, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France.
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Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients. Sci Rep 2016; 6:39736. [PMID: 28000772 PMCID: PMC5175156 DOI: 10.1038/srep39736] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/28/2016] [Indexed: 12/18/2022] Open
Abstract
The relevance of blood-based assays to monitor minimal residual disease (MRD) in non-metastatic prostate cancer (PCa) remains unclear. Proving that clinically relevant circulating tumor cells (CTCs) can be detected with available technologies could address this. This study aimed to improve CTC detection in non-metastatic PCa patients by combining three independent CTC assays: the CellSearch system, an in vivo CellCollector and the EPISPOT. Peripheral blood samples from high-risk PCa patients were screened for CTCs before and three months after radical prostatectomy (RP). Combining the results of both time points, CTCs were detected in 37%, 54.9% and 58.7% of patients using CellSearch, CellCollector and EPISPOT, respectively. The cumulative positivity rate of the three CTC assays was 81.3% (87/107) with 21.5% (23/107) of patients harboring ≥5 CTCs/7.5 ml blood. Matched pair analysis of 30 blood samples taken before and after surgery indicated a significant decrease in CTCs captured by the CellCollector from 66% before RP to 34% after therapy (p = 0.031). CTC detection by EPISPOT before RP significantly correlated with PSA serum values (p < 0.0001) and clinical tumor stage (p = 0.04), while the other assays showed no significant correlations. In conclusion, CTC-based liquid biopsies have the potential to monitor MRD in patients with non-metastatic prostate cancer.
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Hegemann M, Stenzl A, Bedke J, Chi KN, Black PC, Todenhöfer T. Liquid biopsy: ready to guide therapy in advanced prostate cancer? BJU Int 2016; 118:855-863. [PMID: 27430478 DOI: 10.1111/bju.13586] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The identification of molecular markers associated with response to specific therapy is a key step for the implementation of personalised treatment strategies in patients with metastatic prostate cancer. Only in a low proportion of patients biopsies of metastatic tissue are performed. Circulating tumour cells (CTC), cell-free DNA (cfDNA) and RNA offer the potential for non-invasive characterisation of disease and molecular stratification of patients. Furthermore, a 'liquid biopsy' approach permits longitudinal assessments, allowing sequential monitoring of response and progression and the potential to alter therapy based on observed molecular changes. In prostate cancer, CTC enumeration using the CellSearch© platform correlates with survival. Recent studies on the presence of androgen receptor (AR) variants in CTC have shown that such molecular characterisation of CTC provides a potential for identifying patients with resistance to agents that inhibit the androgen signalling axis, such as abiraterone and enzalutamide. New developments in CTC isolation, as well as in vitro and in vivo analysis of CTC will further promote the use of CTC as a tool for retrieving molecular information from advanced tumours in order to identify mechanisms of therapy resistance. In addition to CTC, nucleic acids such as RNA and cfDNA released by tumour cells into the peripheral blood contain important information on transcriptomic and genomic alterations in the tumours. Initial studies have shown that genomic alterations of the AR and other genes detected in CTC or cfDNA of patients with castration-resistant prostate cancer correlate with treatment outcomes to enzalutamide and abiraterone. Due to recent developments in high-throughput analysis techniques, it is likely that CTC, cfDNA and RNA will be an important component of personalised treatment strategies in the future.
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Affiliation(s)
- Miriam Hegemann
- Department of Urology, University Hospital, Tuebingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital, Tuebingen, Germany
| | - Jens Bedke
- Department of Urology, University Hospital, Tuebingen, Germany
| | - Kim N Chi
- Vancouver Prostate Centre, Vancouver, BC, Canada.,British Columbia Cancer Agency, Vancouver, BC, Canada
| | | | - Tilman Todenhöfer
- Department of Urology, University Hospital, Tuebingen, Germany.,Vancouver Prostate Centre, Vancouver, BC, Canada
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37
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Khoo BL, Grenci G, Jing T, Lim YB, Lee SC, Thiery JP, Han J, Lim CT. Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment. SCIENCE ADVANCES 2016; 2:e1600274. [PMID: 27453941 PMCID: PMC4956185 DOI: 10.1126/sciadv.1600274] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 06/14/2016] [Indexed: 05/08/2023]
Abstract
The lack of a robust anticancer drug screening system to monitor patients during treatment delays realization of personalized treatment. We demonstrate an efficient approach to evaluate drug response using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. Custom microfabricated tapered microwells were integrated with microfluidics to allow robust formation of CTC clusters without pre-enrichment and subsequent drug screening in situ. Rapid feedback after 2 weeks promotes immediate intervention upon detection of drug resistance or tolerance. The procedure was clinically validated with blood samples (n = 73) from 55 patients with early-stage, newly diagnosed, locally advanced, or refractory metastatic breast cancer. Twenty-four of these samples were used for drug evaluation. Cluster formation potential correlated inversely with increased drug concentration and therapeutic treatment. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment.
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Affiliation(s)
- Bee Luan Khoo
- BioSystems and Micromechanics (BioSyM) IRG, Singapore-MIT Alliance for Research and Technology (SMART) Centre, Singapore 138602, Singapore
| | - Gianluca Grenci
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
| | - Tengyang Jing
- BioSystems and Micromechanics (BioSyM) IRG, Singapore-MIT Alliance for Research and Technology (SMART) Centre, Singapore 138602, Singapore
- Department of Biomedical Engineering, National University of Singapore, 7 Engineering Drive 1, Singapore 117574, Singapore
| | - Ying Bena Lim
- Department of Biomedical Engineering, National University of Singapore, 7 Engineering Drive 1, Singapore 117574, Singapore
| | - Soo Chin Lee
- Department of Hematology-Oncology, National University Cancer Institute, National University Hospital, Singapore 119074, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Jean Paul Thiery
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Jongyoon Han
- BioSystems and Micromechanics (BioSyM) IRG, Singapore-MIT Alliance for Research and Technology (SMART) Centre, Singapore 138602, Singapore
- Department of Electrical Engineering and Computer Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Chwee Teck Lim
- BioSystems and Micromechanics (BioSyM) IRG, Singapore-MIT Alliance for Research and Technology (SMART) Centre, Singapore 138602, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
- Department of Biomedical Engineering, National University of Singapore, 7 Engineering Drive 1, Singapore 117574, Singapore
- Department of Mechanical Engineering, National University of Singapore, Singapore 117575, Singapore
- Corresponding author.
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38
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Khoo BL, Lee SC, Kumar P, Tan TZ, Warkiani ME, Ow SGW, Nandi S, Lim CT, Thiery JP. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget 2016; 6:15578-93. [PMID: 26008969 PMCID: PMC4558172 DOI: 10.18632/oncotarget.3903] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 04/24/2015] [Indexed: 12/22/2022] Open
Abstract
Circulating tumor cells (CTCs) are considered as surrogate markers for prognosticating and evaluating patient treatment responses. Here, 226 blood samples from 92 patients with breast cancer, including patients with newly diagnosed or metastatic refractory cancer, and 16 blood samples from healthy subjects were cultured in laser-ablated microwells. Clusters containing an increasing number of cytokeratin-positive (CK+) cells appeared after 2 weeks, while most blood cells disappeared with time. Cultures were heterogeneous and exhibited two distinct sub-populations of cells: 'Small' (≤ 25 μm; high nuclear/cytoplasmic ratio; CD45-) cells, comprising CTCs, and 'Large' (> 25 μm; low nuclear/cytoplasmic ratio; CD68+ or CD56+) cells, corresponding to macrophage and natural killer-like cells. The Small cell fraction also showed copy number increases in six target genes (FGFR1, Myc, CCND1, HER2, TOP2A and ZNF217) associated with breast cancer. These expanded CTCs exhibited different proportions of epithelial-mesenchymal phenotypes and were transferable for further expansion as spheroids in serum-free suspension or 3D cultures. Cluster formation was affected by the presence and duration of systemic therapy, and its persistence may reflect therapeutic resistance. This novel and advanced method estimates CTC clonal heterogeneity and can predict, within a relatively short time frame, patient responses to therapy.
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Affiliation(s)
- Bee Luan Khoo
- Mechanobiology Institute, National University of Singapore, Singapore
| | - Soo Chin Lee
- Department of Hematology-Oncology, National University Cancer Institute, National University Hospital, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Prashant Kumar
- Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Majid Ebrahimi Warkiani
- BioSystems and Micromechanics (BioSyM) IRG, Singapore-MIT Alliance for Research and Technology (SMART) Centre, Singapore.,School of Mechanical and Manufacturing Engineering, University of New South Wales, Sydney, Australia
| | - Samuel G W Ow
- Department of Hematology-Oncology, National University Cancer Institute, National University Hospital, Singapore
| | - Sayantani Nandi
- Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore
| | - Chwee Teck Lim
- Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.,BioSystems and Micromechanics (BioSyM) IRG, Singapore-MIT Alliance for Research and Technology (SMART) Centre, Singapore.,Department of Biomedical Engineering, National University of Singapore, Singapore.,Department of Mechanical Engineering, National University of Singapore, Singapore
| | - Jean Paul Thiery
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.,Department of Biochemistry Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Abstract
Isolation and analysis of cancer cells from body fluids have significant implications in diagnosis and therapeutic treatment of cancers. Circulating tumor cells (CTCs) are cancer cells circulating in the peripheral blood or spreading iatrogenically into blood vessels, which is an early step in the cascade of events leading to cancer metastasis. Therefore, CTCs can be used for diagnosing for therapeutic treatment, prognosing a given anticancer intervention, and estimating the risk of metastatic relapse. However, isolation of CTCs is a significant technological challenge due to their rarity and low recovery rate using traditional purification techniques. Recently microfluidic devices represent a promising platform for isolating cancer cells with high efficiency in processing complex cellular fluids, with simplicity, sensitivity, and throughput. This review summarizes recent methods of CTC isolation and analysis, as well as their applications in clinical studies.
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Affiliation(s)
- J Zhang
- University of Florida, Gainesville, FL, United States
| | - K Chen
- University of Florida, Gainesville, FL, United States
| | - Z H Fan
- University of Florida, Gainesville, FL, United States.
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40
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Pantel K, Speicher MR. The biology of circulating tumor cells. Oncogene 2016; 35:1216-24. [PMID: 26050619 DOI: 10.1038/onc.2015.192] [Citation(s) in RCA: 370] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 02/02/2015] [Accepted: 02/02/2015] [Indexed: 12/15/2022]
Abstract
Metastasis is a biologically complex process consisting of numerous stochastic events which may tremendously differ across various cancer types. Circulating tumor cells (CTCs) are cells that are shed from primary tumors and metastatic deposits into the blood stream. CTCs bear a tremendous potential to improve our understanding of steps involved in the metastatic cascade, starting from intravasation of tumor cells into the circulation until the formation of clinically detectable metastasis. These efforts were propelled by novel high-resolution approaches to dissect the genomes and transcriptomes of CTCs. Furthermore, capturing of viable CTCs has paved the way for innovative culturing technologies to study fundamental characteristics of CTCs such as invasiveness, their kinetics and responses to selection barriers, such as given therapies. Hence the study of CTCs is not only instrumental as a basic research tool, but also allows the serial monitoring of tumor genotypes and may therefore provide predictive and prognostic biomarkers for clinicians. Here, we review how CTCs have contributed to significant insights into the metastatic process and how they may be utilized in clinical practice.
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Affiliation(s)
- K Pantel
- Institute of Tumor Biology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - M R Speicher
- Institute of Human Genetics, Medical University of Graz, Graz, Austria
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41
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Lv Q, Gong L, Zhang T, Ye J, Chai L, Ni C, Mao Y. Prognostic value of circulating tumor cells in metastatic breast cancer: a systemic review and meta-analysis. Clin Transl Oncol 2016; 18:322-30. [PMID: 26260915 DOI: 10.1007/s12094-015-1372-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 07/28/2015] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Metastatic breast cancer (MBC) remains the main cause of cancer-related death, and the clinical significance and prognostic role of circulating tumor cells (CTCs) in metastatic breast cancer are still controversial. Here, we conducted a meta-analysis to clarify the correlation between CTCs and the clinicopathological features and prognosis of MBC. METHODS We performed a comprehensive search of Pubmed and the ISI Web of Science through December 2014. Only articles that focused on MBC patients and detected CTCs using the CellSearch system were included. The associations between CTCs and survival rate and clinicopathological parameters, including molecular pattern, metastatic region and treatment response, were evaluated. RESULTS This meta-analysis included 24 studies (3701 MBC patients), 13 prospective studies and 11 retrospective studies. We found that CTCs were more frequently detected with HER2 + primary tumors (pooled RR = 0.73, 95 % CI = 0.63-0.84). Additionally, higher CTC numbers indicated a worse treatment response (RR = 0.56, 95 % CI = 0.40-0.79), poorer PFS (RR = 0.64, 95 % CI = 0.56-0.73) and poorer OS (RR = 0.69, 95 % CI = 0.64-0.75) in MBC patients. CONCLUSION Based on these results, we propose that HER2 positivity could be a significant risk factor for the presence of CTCs. Additionally, CTCs have a significant prognostic value for MBC patients. Therefore, CTCs should be continually monitored to guide the treatment of MBC patients, especially those with HER2 + primary tumors.
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Affiliation(s)
- Q Lv
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - L Gong
- Department of Otorhinolaryngology, Affiliated Cixi Hospital of Wenzhou Medical College, Cixi, 315300, China
| | - T Zhang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - J Ye
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - L Chai
- Department of Otorhinolaryngology, First Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, 310003, China
| | - C Ni
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, 310004, China
| | - Y Mao
- Department of Otorhinolaryngology, First Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, 310003, China.
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42
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ANDERGASSEN ULRICH, KÖLBL ALEXANDRAC, MAHNER SVEN, JESCHKE UDO. Real-time RT-PCR systems for CTC detection from blood samples of breast cancer and gynaecological tumour patients (Review). Oncol Rep 2016; 35:1905-15. [DOI: 10.3892/or.2016.4608] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 11/15/2015] [Indexed: 11/06/2022] Open
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43
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Danila DC, Scher HI, Fleisher M. Circulating Tumor Cells as an Analytical Tool in the Management of Patients with Cancer. MANUAL OF MOLECULAR AND CLINICAL LABORATORY IMMUNOLOGY 2016:1051-1061. [DOI: 10.1128/9781555818722.ch111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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44
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Functional studies on circulating and disseminated tumor cells in carcinoma patients. Mol Oncol 2016; 10:443-9. [PMID: 26847851 DOI: 10.1016/j.molonc.2016.01.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 01/04/2016] [Indexed: 12/18/2022] Open
Abstract
Despite numerous clinical studies indicating the clinical relevance of circulating tumor cells (CTCs) in blood and disseminated tumor cells (DTCs) in the bone marrow of cancer patients, the functional properties of these cells are largely unknown. The focus of this review is to emphasize how functional studies on viable CTCs and DTCs can enlarge the spectrum of applications of "liquid biopsies". The low number of CTCs in the peripheral blood and DTCs in the bone marrow and the fact that carcinoma cells are difficult to culture are major challenges. Significant advances in the in vitro and in vivo expansion of CTCs and DTCs from cancer patients have been achieved, which enable us now to study the functional properties of these cells. Here, we discuss published data about functional studies on CTCs and DTCs using in vitro cultivation and in vivo xenograft models. Functional analyses on CTCs and DTCs offer the possibility to identify the metastasis-initiating cells. Moreover, CTC-derived cell lines and xenografts might point to new therapeutic targets and can be used for drug development.
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45
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Pantel K, Alix-Panabières C. Functional Studies on Viable Circulating Tumor Cells. Clin Chem 2015; 62:328-34. [PMID: 26637479 DOI: 10.1373/clinchem.2015.242537] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 10/19/2015] [Indexed: 01/14/2023]
Abstract
BACKGROUND Research on circulating tumor cells (CTCs) as new biomarkers has received great attention over the past decade. In particular, the capture and analysis of CTCs as "liquid biopsies" provides the possibility to avoid invasive tissue biopsies, with obvious implications in cancer diagnostics. CONTENT The focus of this review is to describe and discuss how functional studies on viable CTCs can enlarge the spectrum of applications of liquid biopsies, with emphasis on breast, prostate, colon, and lung cancer as the major tumor entities in industrialized countries. The low number of CTCs in the peripheral blood of most cancer patients makes challenging the in vitro culture of CTCs. Epithelial tumor cells are difficult to culture, even when starting with millions of tumor cells. Recently, several groups have achieved important advances in the in vitro and in vivo expansion of CTCs from cancer patients at very advanced stages with higher amounts of CTCs. Here, we present current technologies to enrich and detect viable human CTCs, including positive and negative enrichment strategies that are based on antigen expression and physical properties of CTCs. We also discuss published data about functional studies on CTCs that use in vitro and in vivo models. SUMMARY Functional analyses on CTCs offer the possibility to identify the biological properties of metastatic cells, including the identification of metastasis-initiating cells. Moreover, CTC-derived cell lines and xenografts might reveal new therapeutic targets and can be used for drug screening.
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Affiliation(s)
- Klaus Pantel
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells, Department of Cellular and Tissue Biopathology of Tumors, University Medical Centre, Montpellier, France; EA2415-Help for Personalized Decision: Methodological Aspects, University Institute of Clinical Research, Montpellier University, Montpellier, France.
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46
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周 彩. [Blood-based Tumor Markers in Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 18:770-80. [PMID: 26706955 PMCID: PMC6015179 DOI: 10.3779/j.issn.1009-3419.2015.12.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 10/28/2015] [Accepted: 10/30/2015] [Indexed: 11/12/2022]
Abstract
In recent years, "liquid biopsy" received enormous attention as a new detecting method. As a non-invasive tumor screening method, the applications of liquid biopsy include early detection, monitoring relapse, assessment of therapy and molecule expression in lung cancer. The main source of liquid biopsy comes from circulating tumor cells (CTCs), ctDNA, and so on. This review will explore the biological characteristics, detection technologies and clinical applications of CTCs, ctDNA and other tumor markers in lung cancer and summarize liquid biopsy which in accord with three important criteria of high sensitivity (high specificity), clinical utility and repeatability, especially a new method of ligand-targeted PCR (LT-PCR) that showed a high sensitivity of 67.2% in stage I lung cancer. We expect that "liquid biopsy" could be really explored from scientific research to clinical application.
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Affiliation(s)
- 彩存 周
- />200433 上海,上海市肺科医院肿瘤科Department of Oncology, Shanghai Pulmonary Hospital, Shanghai 200433, China
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47
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Alix-Panabières C, Pantel K. Liquid biopsy in cancer patients: advances in capturing viable CTCs for functional studies using the EPISPOT assay. Expert Rev Mol Diagn 2015; 15:1411-7. [PMID: 26390240 DOI: 10.1586/14737159.2015.1091729] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Circulating tumor cells (CTCs) in the blood of cancer patients have received increasing attention as new diagnostic tool enabling 'liquid biopsies'. In contrast to the wealth of descriptive studies demonstrating the clinical relevance of CTCs as biomarkers, the extremely low concentration of CTCs in the peripheral blood of most cancer patients challenges further functional studies. This article discusses the current possibilities to enrich and, in particular, detect viable CTCs with emphasis on the EPithelial ImmunoSPOT technology. This functional assay detects viable CTCs at the single-cell level and has been used on hundreds of patients with different tumor types including epithelial tumors (breast, prostate and colon cancer) and melanomas. Moreover, the article summarizes recent advances in the in vitro and in vivo expansion of CTCs from cancer patients. These functional analyses will contribute to identifying the biological properties of metastatic cells and reveal new therapeutic targets against disseminating cancer cells.
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Affiliation(s)
- Catherine Alix-Panabières
- a 1 Laboratory of Rare Human Circulating Cells (LCCRH), Department of Cellular and Tissular Biopathology of Tumors, University Medical Centre , Montpellier, France.,b 2 EA2415 - Help for Personalized Decision: Methodological Aspects, University Institute of Clinical Research (IURC), Montpellier University , Montpellier, France
| | - Klaus Pantel
- c 3 Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf , Hamburg, Germany
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48
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Ren C, Han C, Fu D, Wang D, Chen H, Chen Y, Shen M. Circulating tumor cells in breast cancer beyond the genotype of primary tumor for tailored therapy. Int J Cancer 2015; 138:1586-600. [PMID: 26178386 DOI: 10.1002/ijc.29679] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 06/30/2015] [Indexed: 12/21/2022]
Abstract
Although TNM staging based on tumor, node lymph status and metastasis status-is the most widely used method in the clinic to classify breast cancer (BC) and assess prognosis, it offers limited information for different BC subgroups. Circulating tumor cells (CTCs) are regarded as minimal residual disease and are proven to have a strong relationship with BC. Detection of ≥5 CTCs per 7.5 mL in peripheral blood predicts poor prognosis in metastatic BC irrespective of other clinical parameters, whereas, in early-stage BC, detection of CK19(+) CTCs are also associated with poor prognosis. Increasing data and clinical trials show that CTCs can improve prognostic accuracy and help tailor treatment for patients with BC. However, heterogeneous CTCs in the process of an epithelial-mesenchymal transition (EMT) in BC makes it a challenge to detect these rare cells. Moreover, the genotypic and phenotypic features of CTCs are different from primary BC tumors. Molecular analysis of CTCs in BC may benefit patients by identifying those amenable to tailored therapy. We propose that CTCs should be used alongside the TNM staging system and the genotype of primary tumor to guide tailored BC diagnosis and treatment.
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Affiliation(s)
- Chuanli Ren
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chongxu Han
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Deyuan Fu
- Breast Oncology Surgery, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Daxin Wang
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Hui Chen
- Geriatric Medicine Department, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Yong Chen
- Oncology Department, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Ming Shen
- Department of Physical Chemistry, Yangzhou University, Yangzhou, China
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49
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Abstract
Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.
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Affiliation(s)
- Simon A Joosse
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias M Gorges
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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50
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Li J, Gregory SG, Garcia-Blanco MA, Armstrong AJ. Using circulating tumor cells to inform on prostate cancer biology and clinical utility. Crit Rev Clin Lab Sci 2015; 52:191-210. [PMID: 26079252 DOI: 10.3109/10408363.2015.1023430] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Substantial advances in the molecular biology of prostate cancer have led to the approval of multiple new systemic agents to treat men with metastatic castration-resistant prostate cancer (mCRPC). These treatments encompass androgen receptor directed therapies, immunotherapies, bone targeting radiopharmaceuticals and cytotoxic chemotherapies. There is, however, great heterogeneity in the degree of patient benefit with these agents, thus fueling the need to develop predictive biomarkers that are able to rationally guide therapy. Circulating tumor cells (CTCs) have the potential to provide an assessment of tumor-specific biomarkers through a non-invasive, repeatable "liquid biopsy" of a patient's cancer at a given point in time. CTCs have been extensively studied in men with mCRPC, where CTC enumeration using the Cellsearch® method has been validated and FDA approved to be used in conjunction with other clinical parameters as a prognostic biomarker in metastatic prostate cancer. In addition to enumeration, more sophisticated molecular profiling of CTCs is now feasible and may provide more clinical utility as it may reflect tumor evolution within an individual particularly under the pressure of systemic therapies. Here, we review technologies used to detect and characterize CTCs, and the potential biological and clinical utility of CTC molecular profiling in men with metastatic prostate cancer.
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Affiliation(s)
- Jing Li
- a Duke Cancer Institute, Duke University Medical Center , Durham , NC , USA
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