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Yang W, Nguyen R, Safri F, Shiddiky MJA, Warkiani ME, George J, Qiao L. Liquid Biopsy in Hepatocellular Carcinoma: ctDNA as a Potential Biomarker for Diagnosis and Prognosis. Curr Oncol Rep 2025:10.1007/s11912-025-01681-3. [PMID: 40343687 DOI: 10.1007/s11912-025-01681-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2025] [Indexed: 05/11/2025]
Abstract
PURPOSE OF REVIEW Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with rising incidence and mortality. Early-stage HCC is often asymptomatic, and the lack of reliable early diagnostic markers leads to late-stage diagnosis with limited treatment options. Current treatment relies on tumour staging and patient status, but accurate staging requires invasive procedures that fail to capture tumour heterogeneity and progression. There is an urgent need for less invasive diagnostic strategies, such as liquid biopsy technologies, which allow for repeated sampling and real-time analysis of tumour dynamics. Liquid biopsies, including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), offer the potential to monitor recurrence, metastasis, and treatment responses, potentially transforming HCC clinical management by enabling earlier intervention and personalised treatment strategies. RECENT FINDINGS Recent studies emphasise the potential of ctDNA as a non-invasive biomarker by targeting DNA methylation for early HCC detection, enabling timely intervention and personalised treatment to improve patient outcomes. Comparative analyses have shown that ctDNA mutation testing outperforms alpha-fetoprotein (AFP), with a sensitivity of 85% and a specificity of 92%, compared to 60% sensitivity and 80% specificity for AFP. Additionally, profiling the ctDNA mutation landscape of 100 HCC patients has identified recurrent mutations in genes such as TP53, CTNNB1, and AXIN1. ctDNA appears to be a promising non-invasive biomarker in the clinical management of HCC patients, with the sensitivity and specificity improving by 41.67% and 15% respectively. The ctDNA mutations, particularly those targeting DNA methylation, highlight great potential for precision medicine, critical for early diagnosis and prognosis of HCC.
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Affiliation(s)
- William Yang
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Romario Nguyen
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Fatema Safri
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Muhammad J A Shiddiky
- Rural Health Research Institute (RHRI), Charles Sturt University, Orange, NSW, 2800, Australia
| | - Majid E Warkiani
- School of Biomedical Engineering, The University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
- Storr Liver Centre, Westmead Institute for Medical Research (WIMR), the University of Sydney, Westmead, NSW, 2145, Australia.
| | - Liang Qiao
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
- Storr Liver Centre, Westmead Institute for Medical Research (WIMR), the University of Sydney, Westmead, NSW, 2145, Australia.
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Park J, Lee YT, Agopian VG, Liu JS, Koltsova EK, You S, Zhu Y, Tseng HR, Yang JD. Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications. Clin Mol Hepatol 2025; 31:S255-S284. [PMID: 39604328 PMCID: PMC11925447 DOI: 10.3350/cmh.2024.0541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional's skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.
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Affiliation(s)
- Jaeho Park
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yi-Te Lee
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Vatche G. Agopian
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Jessica S Liu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Ekaterina K. Koltsova
- Smidt Heart Institute, Department of Medicine, Department of Biomedical Sciences, 8700 Beverly Blvd, Los Angeles, CA, USA
| | - Sungyong You
- Department of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Soleymani S, Naghib SM, Mozafari MR. Circulating Tumor Cells in Cancer Diagnosis, Therapy, and Theranostics Applications: An Overview of Emerging Materials and Technologies. Curr Pharm Des 2025; 31:674-690. [PMID: 39473210 DOI: 10.2174/0113816128328459241009191933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/06/2024] [Indexed: 04/11/2025]
Abstract
In recent years, immunotherapy, namely immune checkpoint inhibitor therapy, has significantly transformed the approach to treating various forms of cancer. Simultaneously, the adoption of clinical oncology has been sluggish due to the exorbitant expense of therapy, the adverse effects experienced by patients, and the inconsistency in treatment response among individuals. As a reaction, individualized methods utilizing predictive biomarkers have arisen as novel strategies for categorizing patients to achieve successful immunotherapy. Recently, the identification and examination of circulating tumor cells (CTCs) have gained attention as predictive indicators for the treatment of cancer patients undergoing chemotherapy and for personalized targeted therapy. CTCs have been found to exhibit immunological checkpoints in several types of solid tumors, which has contributed to our understanding of managing cancer immunotherapy. Circulating tumor cells (CTCs) present in the bloodstream have a crucial function in the formation of metastases. Nevertheless, the practical usefulness of existing CTC tests is mostly restricted by methodological limitations.
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Affiliation(s)
- Sina Soleymani
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Seyed Morteza Naghib
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - M R Mozafari
- Australasian Nanoscience and Nanotechnology Initiative (ANNI), Monash University LPO, Clayton, VIC 3168, Australia
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Hsu CM, Liu YC, Huang JF. Exploring Circulating Tumor Cells: Detection Methods and Biomarkers for Clinical Evaluation in Hepatocellular Carcinoma. J Clin Transl Hepatol 2024; 12:1020-1042. [PMID: 39649035 PMCID: PMC11622199 DOI: 10.14218/jcth.2024.00230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/13/2024] [Accepted: 09/25/2024] [Indexed: 12/10/2024] Open
Abstract
Circulating tumor cells (CTCs), originating from primary neoplastic tissues, infiltrate blood vessels, migrate through the bloodstream, and establish secondary tumor foci. The detection of CTCs holds significant promise for early-stage identification, diagnostic precision, therapeutic monitoring, and prognostic evaluation. It offers a non-invasive approach and has broad clinical relevance in cancer management. This comprehensive review primarily focused on CTCs as biomarkers in the diagnostic, therapeutic, and prognostic surveillance of hepatocellular carcinoma, compared their correlation with key clinical parameters and the identification of gene characteristics. It also highlighted current methodologies in CTC detection. Despite approval by the U.S. Food and Drug Administration for select malignancies, the comprehensive integration of CTCs into routine clinical practice requires procedural standardization and a deeper understanding of the underlying molecular intricacies. The challenges in CTC detection, including limited quantity, technical impediments, and cellular heterogeneity, call for concerted and further investigational efforts to advance precision in cancer diagnostics and prognostication, thus realizing the objectives of precise and personalized medicine.
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Affiliation(s)
- Chin-Mu Hsu
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Yi-Chang Liu
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Jee-Fu Huang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung
- Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung
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Zhou Z, Cai S, Zhou X, Zhao W, Sun J, Zhou Z, Yang Z, Li W, Wang Z, Zou H, Fu H, Wang X, Khoo BL, Yang M. Circulating Tumor Cells Culture: Methods, Challenges, and Clinical Applications. SMALL METHODS 2024:e2401026. [PMID: 39726345 DOI: 10.1002/smtd.202401026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 11/10/2024] [Indexed: 12/28/2024]
Abstract
Circulating tumor cells (CTCs) play a pivotal role in cancer metastasis and hold considerable potential for clinical diagnosis, therapeutic monitoring, and prognostic evaluation. Nevertheless, the limited quantity of CTCs in liquid biopsy samples poses challenges for comprehensive downstream analysis. In vitro culture of CTCs can effectively address the issue of insufficient CTC numbers. Furthermore, research based on CTC cell lines serves as a valuable complement to traditional cancer cell line-based research. While numerous reports exist on CTC in vitro culture and even the establishment of CTC cell lines, the methods used vary, leading to disparate culture outcomes. This review presents the developmental history and current status of CTC in vitro culture research. Additionally, the culture strategies applied in different methods and analyzed the impact of various steps on culture outcomes are compared. Overall, the review indicates that while the short-term culture of CTCs is relatively straightforward, long-term culture success has been achieved for various specific cancer types but still faces challenges. Further optimization of efficient and widely applicable culture strategies is needed. Additionally, ongoing applications of CTC in vitro culture are summarized, highlighting the potential of expanded CTCs for drug susceptibility testing and as therapeutic tools in personalized treatment.
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Affiliation(s)
- Zhengdong Zhou
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Songhua Cai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Xiaoyu Zhou
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Wei Zhao
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Jiayu Sun
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zhihang Zhou
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zihan Yang
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Wenxiu Li
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zhe Wang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Heng Zou
- Cellomics (Shenzhen) Limited, Shenzhen, 518118, China
| | - Huayang Fu
- Cellomics (Shenzhen) Limited, Shenzhen, 518118, China
| | - Xicheng Wang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Bee Luan Khoo
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Mengsu Yang
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
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6
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Büdeyri I, Guckelberger O, Oppermann E, Roy D, Sliwinski S, Becker F, Struecker B, Vogl TJ, Pascher A, Bechstein WO, Lorentzen A, Heikenwalder M, Juratli MA. Ezrin Polarization as a Diagnostic Marker for Circulating Tumor Cells in Hepatocellular Carcinoma. Cells 2024; 14:6. [PMID: 39791707 PMCID: PMC11720075 DOI: 10.3390/cells14010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 12/08/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide, with no precise method for early detection. Circulating tumor cells (CTCs) expressing the dynamic polarity of the cytoskeletal membrane protein, ezrin, have been proposed to play a crucial role in tumor progression and metastasis. This study investigated the diagnostic and prognostic potential of polarized circulating tumor cells (p-CTCs) in HCC patients. CTCs were isolated from the peripheral blood of 20 HCC patients and 18 patients with nonmalignant liver disease (NMLD) via an OncoQuick® kit and immunostained with Ezrin-Alexa Fluor 488®, CD146-PE, and CD45-APC. A fluorescence microscopy was then performed for analysis. The HCC group exhibited significantly higher levels of p-CTCs, with median values of 0.56 p-CTCs/mL, compared to 0.02 p-CTCs/mL (p = 0.03) in the NMLD group. CTCs were detected in 95% of the HCC patients, with a sensitivity of 95% and specificity of 89%. p-CTCs were present in 75% of the HCC patients, with a sensitivity of 75% and a specificity of 94%. Higher p-CTC counts were associated with the significantly longer overall survival in HCC patients (p = 0.05). These findings suggest that p-CTCs could serve as valuable diagnostic and prognostic markers for HCC. The incorporation of p-CTCs into diagnostic strategies could enhance therapeutic decision-making and improve patient outcomes.
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Affiliation(s)
- Ibrahim Büdeyri
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Olaf Guckelberger
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Elsie Oppermann
- Department of General, Visceral and Transplant Surgery, Frankfurt University Hospital, 60596 Frankfurt, Germany
| | - Dhruvajyoti Roy
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Svenja Sliwinski
- Department of General, Visceral and Transplant Surgery, Frankfurt University Hospital, 60596 Frankfurt, Germany
| | - Felix Becker
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Benjamin Struecker
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Thomas J. Vogl
- Department of Diagnostic and Interventional Radiology, Frankfurt University Hospital, Goethe University, 60596 Frankfurt, Germany
| | - Andreas Pascher
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
| | - Wolf O. Bechstein
- Department of General, Visceral and Transplant Surgery, Frankfurt University Hospital, 60596 Frankfurt, Germany
| | - Anna Lorentzen
- Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mazen A. Juratli
- Department of General, Visceral and Transplant Surgery, University Hospital Muenster, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany; (I.B.)
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Liu C, Cai Y, Mou S. Liquid biopsy in lung cancer: The role of circulating tumor cells in diagnosis, treatment, and prognosis. Biomed Pharmacother 2024; 181:117726. [PMID: 39612860 DOI: 10.1016/j.biopha.2024.117726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2024] Open
Abstract
Despite numerous therapeutic advancements, such as immune checkpoint inhibitors, lung cancer continues to be the leading cause of cancer-related mortality. Therefore, the identification of cancer at an early stage is becoming a significant subject in contemporary oncology. Despite significant advancements in early detection tactics in recent decades, they continue to provide challenges because of the inconspicuous symptoms observed during the early stages of the primary tumor. Presently, tumor biomarkers and imaging techniques are extensively employed across different forms of cancer. Nevertheless, every approach has its own set of constraints. In certain instances, the detriments outweigh the advantages. Hence, there is an urgent need to enhance early detection methods. Currently, liquid biopsy is considered more flexible and not intrusive method in comparison to conventional test for early detection. Circulating tumor cells (CTCs) are crucial components of liquid biopsy and have a pivotal function in the spread and formation of secondary tumors. These indicators show great promise in the early identification of cancer. This study presents a comprehensive examination of the methodologies employed for the isolation and enrichment of circulating tumor cells (CTCs) in lung cancer. Additionally, it explores the formation of clusters of CTCs, which have a pivotal function in facilitating the effective dissemination of cancer to distant organs. In addition, we discuss the importance of CTCs in the detection, treatment, and prognosis of lung cancer.
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Affiliation(s)
- Chibo Liu
- Department of Clinical Laboratory, Taizhou Municipal Hospital, Taizhou, Zhejiang, China.
| | - Yanqun Cai
- Department of Clinical Laboratory, Taizhou Municipal Hospital, Taizhou, Zhejiang, China
| | - Sihua Mou
- Department of Clinical Laboratory, Taizhou Municipal Hospital, Taizhou, Zhejiang, China.
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Tu J, Wang B, Wang X, Huo K, Hu W, Zhang R, Li J, Zhu S, Liang Q, Han S. Current status and new directions for hepatocellular carcinoma diagnosis. LIVER RESEARCH 2024; 8:218-236. [PMID: 39958920 PMCID: PMC11771281 DOI: 10.1016/j.livres.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/17/2024] [Accepted: 12/01/2024] [Indexed: 02/18/2025]
Abstract
Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) accounting for approximately 75%-85% of cases. Most patients present with moderately advanced disease, while those with advanced HCC face limited and ineffective treatment options. Despite diagnostic efforts, no ideal tumor marker exists to date, highlighting the urgent clinical need for improved early detection of HCC. A key research objective is the development of assays that target specific pathways involved in HCC progression. This review explores the pathological origin and development of HCC, providing insights into the mechanistic rationale, clinical statistics, and the advantages and limitations of commonly used diagnostic tumor markers. Additionally, it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies. This review aims to summarize existing markers and investigate new ones, providing a basis for subsequent research.
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Affiliation(s)
- Jinqi Tu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Bo Wang
- Animal Experimental Center, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Kugeng Huo
- Cyagen Biosciences (Guangzhou) Inc., Guangzhou, Guangdong, China
| | - Wanting Hu
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Rongli Zhang
- Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qionglin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Shuxin Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
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Chan YT, Zhang C, Wu J, Lu P, Xu L, Yuan H, Feng Y, Chen ZS, Wang N. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma. Mol Cancer 2024; 23:189. [PMID: 39242496 PMCID: PMC11378508 DOI: 10.1186/s12943-024-02101-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024] Open
Abstract
Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheng Zhang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Junyu Wu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Pengde Lu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lin Xu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hongchao Yuan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhe-Sheng Chen
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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Sayed ZS, Khattap MG, Madkour MA, Yasen NS, Elbary HA, Elsayed RA, Abdelkawy DA, Wadan AHS, Omar I, Nafady MH. Circulating tumor cells clusters and their role in Breast cancer metastasis; a review of literature. Discov Oncol 2024; 15:94. [PMID: 38557916 PMCID: PMC10984915 DOI: 10.1007/s12672-024-00949-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Breast cancer is a significant and deadly threat to women globally. Moreover, Breast cancer metastasis is a complicated process involving multiple biological stages, which is considered a substantial cause of death, where cancer cells spread from the original tumor to other organs in the body-representing the primary mortality factor. Circulating tumor cells (CTCs) are cancer cells detached from the primary or metastatic tumor and enter the bloodstream, allowing them to establish new metastatic sites. CTCs can travel alone or in groups called CTC clusters. Studies have shown that CTC clusters have more potential for metastasis and a poorer prognosis than individual CTCs in breast cancer patients. However, our understanding of CTC clusters' formation, structure, function, and detection is still limited. This review summarizes the current knowledge of CTC clusters' biological properties, isolation, and prognostic significance in breast cancer. It also highlights the challenges and future directions for research and clinical application of CTC clusters.
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Affiliation(s)
- Zeinab S Sayed
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | - Mohamed G Khattap
- Technology of Radiology and Medical Imaging Program, Faculty of Applied Health Sciences Technology, Galala University, Suez, 435611, Egypt
| | | | - Noha S Yasen
- Radiology and Imaging Technology Department, Faculty of Applied Health Science Technology, Delta University for Science and Technology, Gamasa, Al Mansurah, Egypt
| | - Hanan A Elbary
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | - Reem A Elsayed
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | - Dalia A Abdelkawy
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | | | - Islam Omar
- Faculty of Pharmacy, South Valley University, Qena, Egypt
| | - Mohamed H Nafady
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
- Faculty of Applied Health Science Technology, Misr University for Science and Technology, 6th of october, Egypt.
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11
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Salehi M, Lavasani ZM, Keshavarz Alikhani H, Shokouhian B, Hassan M, Najimi M, Vosough M. Circulating Tumor Cells as a Promising Tool for Early Detection of Hepatocellular Carcinoma. Cells 2023; 12:2260. [PMID: 37759483 PMCID: PMC10527869 DOI: 10.3390/cells12182260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/27/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Liver cancer is a significant contributor to the cancer burden, and its incidence rates have recently increased in almost all countries. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the second leading cause of cancer-related deaths worldwide. Because of the late diagnosis and lack of efficient therapeutic modality for advanced stages of HCC, the death rate continues to increase by ~2-3% per year. Circulating tumor cells (CTCs) are promising tools for early diagnosis, precise prognosis, and follow-up of therapeutic responses. They can be considered to be an innovative biomarker for the early detection of tumors and targeted molecular therapy. In this review, we briefly discuss the novel materials and technologies applied for the practical isolation and detection of CTCs in HCC. Also, the clinical value of CTC detection in HCC is highlighted.
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Affiliation(s)
- Mahsa Salehi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
| | - Zohre Miri Lavasani
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran;
| | - Hani Keshavarz Alikhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
| | - Bahare Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 171 77 Stockholm, Sweden;
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, B-1200 Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 171 77 Stockholm, Sweden;
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12
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Shaik MR, Sagar PR, Shaik NA, Randhawa N. Liquid Biopsy in Hepatocellular Carcinoma: The Significance of Circulating Tumor Cells in Diagnosis, Prognosis, and Treatment Monitoring. Int J Mol Sci 2023; 24:10644. [PMID: 37445822 DOI: 10.3390/ijms241310644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor outcomes when diagnosed at an advanced stage. Current curative treatments are most effective in early-stage HCC, highlighting the importance of early diagnosis and intervention. However, existing diagnostic methods, such as radiological imaging, alpha-fetoprotein (AFP) testing, and biopsy, have limitations that hinder early diagnosis. AFP elevation is absent in a significant portion of tumors, and imaging may have low sensitivity for smaller tumors or in the presence of cirrhosis. Additionally, as our understanding of the molecular pathogenesis of HCC grows, there is an increasing need for molecular information about the tumors. Biopsy, although informative, is invasive and may not always be feasible depending on tumor location. In this context, liquid biopsy technology has emerged as a promising approach for early diagnosis, enabling molecular characterization and genetic profiling of tumors. This technique involves analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or tumor-derived exosomes. CTCs are cancer cells shed from the primary tumor or metastatic sites and circulate in the bloodstream. Their presence not only allows for early detection but also provides insights into tumor metastasis and recurrence. By detecting CTCs in peripheral blood, real-time tumor-related information at the DNA, RNA, and protein levels can be obtained. This article provides an overview of CTCs and explores their clinical significance for early detection, prognosis, treatment selection, and monitoring treatment response in HCC, citing relevant literature.
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Affiliation(s)
- Mohammed Rifat Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | - Prem Raj Sagar
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | - Nishat Anjum Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
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13
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Li S, Xin K, Pan S, Wang Y, Zheng J, Li Z, Liu X, Liu B, Xu Z, Chen X. Blood-based liquid biopsy: insights into early detection, prediction, and treatment monitoring of bladder cancer. Cell Mol Biol Lett 2023; 28:28. [PMID: 37016296 PMCID: PMC10074703 DOI: 10.1186/s11658-023-00442-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Bladder cancer (BC) is a clinical challenge worldwide with late clinical presentation, poor prognosis, and low survival rates. Traditional cystoscopy and tissue biopsy are routine methods for the diagnosis, prognosis, and monitoring of BC. However, due to the heterogeneity and limitations of tumors, such as aggressiveness, high cost, and limited applicability of longitudinal surveillance, the identification of tumor markers has attracted significant attention in BC. Over the past decade, liquid biopsies (e.g., blood) have proven to be highly efficient methods for the discovery of BC biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into the peripheral circulation and allows serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers are being extensively studied and have shown promising results in clinical applications of BC, including early detection, detection of microscopic residual disease, prediction of recurrence, and response to therapy. Therefore, in this review, we aim to provide an update on various novel blood-based liquid biopsy markers and review the advantages and current limitations of liquid biopsy in BC therapy. The role of blood-based circulating tumor cells, circulating tumor DNA, cell-free RNA, exosomes, metabolomics, and proteomics in diagnosis, prognosis, and treatment monitoring, and their applicability to the personalized management of BC, are highlighted.
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Affiliation(s)
- Shijie Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Kerong Xin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Shen Pan
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Yang Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, Liaoning, People's Republic of China
| | - Jianyi Zheng
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Zeyu Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Xuefeng Liu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China
| | - Bitian Liu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China.
| | - Zhenqun Xu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China.
| | - Xiaonan Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People's Republic of China.
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14
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Zhou Z, Xu X, Liu Y, Liu Q, Zhang W, Wang K, Wang J, Yin Y. Liquid Biopsy in Hepatocellular Carcinoma. Methods Mol Biol 2023; 2695:213-225. [PMID: 37450121 DOI: 10.1007/978-1-0716-3346-5_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly neoplasms with a poor prognosis. Due to the significant tumor heterogeneity of HCC, alpha-fetoprotein (AFP) or liver biopsy has not yet met the clinical needs in terms of early diagnosis or determining prognosis. In recent years, liquid biopsy techniques that analyze tumor by-products released into the circulation have shown great potential. Its ability to monitor tumors in real time and respond to their global characteristics is expected to improve the management of HCC patients clinically. This review discusses some of the findings of a liquid biopsy in terms of diagnosis and prognosis of HCC.
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Affiliation(s)
- Zheyu Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoliang Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qiaoyu Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Kun Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jincheng Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yin Yin
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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15
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Labgaa I. Editorial: The impact of liquid biopsies in the management of liver cancer. Front Oncol 2022; 12:1083355. [DOI: 10.3389/fonc.2022.1083355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022] Open
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16
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Schlosser S, Tümen D, Volz B, Neumeyer K, Egler N, Kunst C, Tews HC, Schmid S, Kandulski A, Müller M, Gülow K. HCC biomarkers - state of the old and outlook to future promising biomarkers and their potential in everyday clinical practice. Front Oncol 2022; 12:1016952. [PMID: 36518320 PMCID: PMC9742592 DOI: 10.3389/fonc.2022.1016952] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Management of HCC depends on reliable biomarkers for screening, diagnosis, and monitoring of the disease, as well as predicting response towards therapy and safety. To date, imaging has been the established standard technique in the diagnosis and follow-up of HCC. However, imaging techniques have their limitations, especially in the early detection of HCC. Therefore, there is an urgent need for reliable, non/minimal invasive biomarkers. To date, alpha-fetoprotein (AFP) is the only serum biomarker used in clinical practice for the management of HCC. However, AFP is of relatively rather low quality in terms of specificity and sensitivity. Liquid biopsies as a source for biomarkers have become the focus of clinical research. Our review highlights alternative biomarkers derived from liquid biopsies, including circulating tumor cells, proteins, circulating nucleic acids, and exosomes, and their potential for clinical application. Using defined combinations of different biomarkers will open new perspectives for diagnosing, treating, and monitoring HCC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
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17
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Roa-Colomo A, López Garrido MÁ, Molina-Vallejo P, Rojas A, Sanchez MG, Aranda-García V, Salmeron J, Romero-Gomez M, Muntane J, Padillo J, Alamo JM, Lorente JA, Serrano MJ, Garrido-Navas MC. Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception. Front Mol Biosci 2022; 9:1074277. [PMID: 36518850 PMCID: PMC9742249 DOI: 10.3389/fmolb.2022.1074277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/16/2022] [Indexed: 09/24/2023] Open
Abstract
Purpose: Lack of diagnostic and prognostic biomarkers in hepatocellular carcinoma impedes stratifying patients based on their risk of developing cancer. The aim of this study was to evaluate phenotypic and genetic heterogeneity of circulating epithelial cells (CECs) based on asialoglycoprotein receptor 1 (ASGR1) and miR-122-5p expression as potential diagnostic and prognostic tools in patients with hepatocellular carcinoma (HCC) and liver cirrhosis (LC). Methods: Peripheral blood samples were extracted from LC and HCC patients at different disease stages. CECs were isolated using positive immunomagnetic selection. Genetic and phenotypic characterization was validated by double immunocytochemistry for cytokeratin (CK) and ASGR1 or by in situ hybridization with miR-122-5p and CECs were visualized by confocal microscopy. Results: The presence of CECs increased HCC risk by 2.58-fold, however, this was only significant for patients with previous LC (p = 0.028) and not for those without prior LC (p = 0.23). Furthermore, the number of CECs lacking ASGR1 expression correlated significantly with HCC incidence and absence of miR-122-5p expression (p = 0.014; r = 0.23). Finally, overall survival was significantly greater for patients at earlier cancer stages (p = 0.018), but this difference was only maintained in the group with the presence of CECs (p = 0.021) whereas progression-free survival was influenced by the absence of ASGR1 expression. Conclusion: Identification and characterization of CECs by ASGR1 and/or miR-122-5p expression may be used as a risk-stratification tool in LC patients, as it was shown to be an independent prognostic and risk-stratification marker in LC and early disease stage HCC patients.
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Affiliation(s)
- Amparo Roa-Colomo
- Clinical Medicine and Public Health Doctoral Program, University of Granada, Granada, Spain
- Gastroenterology and Hepatology Department, San Cecilio University Hospital, Granada, Spain
| | | | - Pilar Molina-Vallejo
- Genyo-Centro Pfizer-Universidad De Granada-Junta De Andalucía De Genómica e Investigación Oncológica, Granada, Spain
| | - Angela Rojas
- Seliver Group, Institute of Biomedicine of Seville (IBiS)/ Hospital Universitario Virgen Del Rocío/CSIC/Universidad De Sevilla, Seville, Spain
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Mercedes González Sanchez
- Gastroenterology and Hepatology Department, Virgen De Las Nieves University Hospital, Granada, Spain
| | - Violeta Aranda-García
- Statistician at Fundación para la Investigación Biosanitaria Andalucía Oriental Alejandro Otero (FIBAO), Hospital Virgen de las Nieves, Granada, Spain
| | - Javier Salmeron
- Gastroenterology and Hepatology Department, San Cecilio University Hospital, Granada, Spain
| | - Manuel Romero-Gomez
- Seliver Group, Institute of Biomedicine of Seville (IBiS)/ Hospital Universitario Virgen Del Rocío/CSIC/Universidad De Sevilla, Seville, Spain
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Jordi Muntane
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Madrid, Spain
- Institute of Biomedicine of Seville (IBiS), Hospital University Virgen del Rocío/CSIC/University of Seville, Seville, Spain
- Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain
| | - Javier Padillo
- General and Gastrointestinal Surgery Division, Virgen del Rocío University Hospital, Sevilla, Spain
| | - Jose María Alamo
- General and Gastrointestinal Surgery Division, Virgen del Rocío University Hospital, Sevilla, Spain
| | - Jose A. Lorente
- Genyo-Centro Pfizer-Universidad De Granada-Junta De Andalucía De Genómica e Investigación Oncológica, Granada, Spain
- Legal Medicine Department, Medicine School, University of Granada, Granada, Spain
| | - María José Serrano
- Genyo-Centro Pfizer-Universidad De Granada-Junta De Andalucía De Genómica e Investigación Oncológica, Granada, Spain
- Comprehensive Oncology Division, Clinical University Hospital, Virgen de las Nieves-IBS, Granada, Spain
- Department of Pathological Anatomy, Faculty of Medicine, University of Granada, Granada, Spain
| | - M. Carmen Garrido-Navas
- Genyo-Centro Pfizer-Universidad De Granada-Junta De Andalucía De Genómica e Investigación Oncológica, Granada, Spain
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18
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Pallozzi M, Di Tommaso N, Maccauro V, Santopaolo F, Gasbarrini A, Ponziani FR, Pompili M. Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives. Cancers (Basel) 2022; 14:cancers14194631. [PMID: 36230554 PMCID: PMC9559710 DOI: 10.3390/cancers14194631] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The search for non-invasive biomarkers is a hot topic in modern oncology, since a tissue biopsy has significant limitations in terms of cost and invasiveness. The treatment perspectives have been significantly improved after the approval of immunotherapy for patients with hepatocellular carcinoma; therefore, the quick identification of responders is crucial to define the best therapeutic strategy. In this review, the current knowledge on the available non-invasive biomarkers of the response to immunotherapy is described. Abstract The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients’ outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.
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Affiliation(s)
- Maria Pallozzi
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Natalia Di Tommaso
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Valeria Maccauro
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: (F.R.P.); (M.P.)
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: (F.R.P.); (M.P.)
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19
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Gonvers S, Tabrizian P, Melloul E, Dormond O, Schwartz M, Demartines N, Labgaa I. Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma? Front Oncol 2022; 12:940473. [PMID: 36033451 PMCID: PMC9402935 DOI: 10.3389/fonc.2022.940473] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Liver transplant (LT) is the most favorable treatment option for patients with early stage hepatocellular carcinoma (HCC). Numerous attempts have been pursued to establish eligibility criteria and select HCC patients for LT, leading to various systems that essentially integrate clinico-morphological variables. Lacking of sufficient granularity to recapitulate the biological complexity of the disease, all these alternatives display substantial limitations and are thus undeniably imperfect. Liquid biopsy, defined as the molecular analysis of circulating analytes released by a cancer into the bloodstream, was revealed as an incomparable tool in the management of cancers, including HCC. It appears as an ideal candidate to refine selection criteria of LT in HCC. The present comprehensive review analyzed the available literature on this topic. Data in the field, however, remain scarce with only 17 studies. Although rare, these studies provided important and encouraging findings highlighting notable prognostic values and supporting the contribution of liquid biopsy in this specific clinical scenario. These results underpinned the critical and urgent need to intensify and accelerate research on liquid biopsy, in order to determine whether and how liquid biopsy may be integrated in the decision-making of LT in HCC.
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Affiliation(s)
- Stéphanie Gonvers
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Parissa Tabrizian
- Recanati Miller Transplant Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, United States
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Olivier Dormond
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Myron Schwartz
- Recanati Miller Transplant Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, United States
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Ismail Labgaa
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
- *Correspondence: Ismail Labgaa,
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20
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Luo K, Wang X, Zhang X, Liu Z, Huang S, Li R. The Value of Circulating Tumor Cells in the Prognosis and Treatment of Pancreatic Cancer. Front Oncol 2022; 12:933645. [PMID: 35860591 PMCID: PMC9293050 DOI: 10.3389/fonc.2022.933645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/31/2022] [Indexed: 12/21/2022] Open
Abstract
In the past few decades, tumor diagnosis and treatment theory have developed in a variety of directions. The number of people dying from pancreatic cancer increases while the mortality rate of other common tumors decreases. Traditional imaging methods show the boundaries of pancreatic tumor, but they are not sufficient to judge early micrometastasis. Although carcinoembryonic antigen (CEA) and carbohydrate antigen19-9 (CA19-9) have the obvious advantages of simplicity and minimal invasiveness, these biomarkers obviously lack sensitivity and specificity. Circulating tumor cells (CTCs) have attracted attention as a non-invasive, dynamic, and real-time liquid biopsy technique for analyzing tumor characteristics. With the continuous development of new CTCs enrichment technologies, substantial progress has been made in the basic research of CTCs clinical application prospects. In many metastatic cancers, CTCs have been studied as an independent prognostic factor. This article reviews the research progress of CTCs in the treatment and prognosis of pancreatic cancer.
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21
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Teng PC, Agopian VG, Lin TY, You S, Zhu Y, Tseng HR, Yang JD. Circulating tumor cells: A step toward precision medicine in hepatocellular carcinoma. J Gastroenterol Hepatol 2022; 37:1179-1190. [PMID: 35543075 PMCID: PMC9271591 DOI: 10.1111/jgh.15886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/02/2022] [Indexed: 12/09/2022]
Abstract
Serum alpha-fetoprotein and radiologic imaging are the most commonly used tests for early diagnosis and dynamic monitoring of treatment response in hepatocellular carcinoma (HCC). However, the accuracy of these tests is limited, and they may not reflect the underlying biology of the tumor. Thus, developing highly accurate novel HCC biomarkers reflecting tumor biology is a clinically unmet need. Circulating tumor cells (CTCs) have long been proposed as a noninvasive biomarker in clinical oncology. Most CTC assays utilize immunoaffinity-based, size-based, and/or enrichment-free mechanisms followed by immunocytochemical staining to characterize CTCs. The prognostic value of HCC CTC enumeration has been extensively validated. Subsets of CTCs expressing mesenchymal markers are also reported to have clinical significance. In addition, researchers have been devoting their efforts to molecular characterizations of CTCs (e.g. genetics and transcriptomics) as molecular profiling can offer a more accurate readout and provide biological insights. As new molecular profiling techniques, such as digital polymerase chain reaction, are developed to detect minimal amounts of DNA/RNA, several research groups have established HCC CTC digital scoring systems to quantify clinically relevant gene panels. Given the versatility of CTCs to provide intact molecular and functional data that reflects the underlying tumor, CTCs have great potential as a noninvasive biomarker in HCC. Large-scale, prospective studies for HCC CTCs with a standardized protocol are necessary for successful clinical translation.
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Affiliation(s)
- Pai-Chi Teng
- Department of Education and Research, Taipei City Hospital Renai Branch, Taipei, Taiwan,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Vatche G. Agopian
- Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA,Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Ting-Yi Lin
- Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taiwan,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Sungyong You
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA,Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Ju Dong Yang
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA,corresponding author (Dr. Ju Dong Yang):
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22
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Garrido Castillo LN, Mejean A, Vielh P, Anract J, Decina A, Nalpas B, Benali-Furet N, Desitter I, Paterlini-Bréchot P. Predictive Value of Circulating Tumor Cells Detected by ISET® in Patients with Non-Metastatic Prostate Cancer Undergoing Radical Prostatectomy. Life (Basel) 2022; 12:life12020165. [PMID: 35207452 PMCID: PMC8877346 DOI: 10.3390/life12020165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
There is an unmet need for reliable biomarkers to predict prostate cancer recurrence after prostatectomy in order to better guide the choice of surgical treatment. We have evaluated the predictive value of the preoperative detection of Circulating Tumor Cells (CTC) for prostate cancer recurrence after surgery. A cohort of 108 patients with non-metastatic prostate adenocarcinoma undergoing radical prostatectomy was tested for the presence of CTC before prostatectomy using ISET®. Disease recurrence was assessed by the increase in serum PSA level after prostatectomy. The following factors were assessed for statistical association with prostate cancer recurrence: the presence of CTC, serum PSA, Gleason score, and pT stage using univariate and multivariate analyses, with a mean follow-up of 34.9 months. Prostate cancer recurrence was significantly associated with the presence of at least 1 CTC at the preoperative time point (p < 0.001; Predictive value = 0.83). Conversely, the absence of prostate cancer recurrence was significantly associated with the lack of CTC detection at diagnosis (Predictive value = 1). Our multivariate analysis shows that only CTC presence is an independent risk factor associated with prostate cancer recurrence after prostatectomy (p < 0.001). Our results suggest that CTC detection by ISET® before surgery is an interesting candidate predictive marker for cancer recurrence in patients with non-metastatic PCa.
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Affiliation(s)
- Laura Nalleli Garrido Castillo
- Institut Necker Enfants Malades (INEM), INSERM U1151, Faculté de Médecine, Université de Paris, 75015 Paris, France; (L.N.G.C.); (J.A.)
- INSERM U807, Faculté de Médecine, Université de Paris, 75015 Paris, France;
| | - Arnaud Mejean
- Service d’Urologie, Hôpital Européen Georges Pompidou, 75015 Paris, France;
| | - Philippe Vielh
- Medipath and American Hospital of Paris, 92200 Paris, France;
| | - Julien Anract
- Institut Necker Enfants Malades (INEM), INSERM U1151, Faculté de Médecine, Université de Paris, 75015 Paris, France; (L.N.G.C.); (J.A.)
- Service d’Urologie, Hôpital Cochin, 75005 Paris, France
| | | | - Bertrand Nalpas
- Service d’addictologie, Université de Montpellier, 34090 Montpellier, France;
| | | | | | - Patrizia Paterlini-Bréchot
- Institut Necker Enfants Malades (INEM), INSERM U1151, Faculté de Médecine, Université de Paris, 75015 Paris, France; (L.N.G.C.); (J.A.)
- Rarecells Diagnostics, 75280 Paris, France; (A.D.); (I.D.)
- Laboratoires de Biochimie Hôpital Necker-Enfants Malades, 75015 Paris, France
- Correspondence:
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23
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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24
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Tan P, Grundy L, Makary P, Eng KH, Ramsay G, Bekheit M. The value of liquid biopsy in the diagnosis and staging of hepatocellular carcinoma: a systematic review. Transl Gastroenterol Hepatol 2021; 6:54. [PMID: 34805576 PMCID: PMC8573369 DOI: 10.21037/tgh.2020.01.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Blood-borne tumour markers in the form of circulating tumour cells (CTCs) are of intense research interest in the diagnostic and prognostic work-up of hepatocellular carcinoma (HCC). METHODS This is a meta-analysis. Using a PICO strategy, adults with HCC was the population, with the individual CTCs as the intervention and comparators. The primary outcome was the sensitivity and specificity of HCC detection with tumour specific single gene methylation alteration. Secondary outcomes were the comparison using specific assay methods and the effect of early vs. late stages on CTC positivity. We included patients with HCC who had samples taken from peripheral blood and had sufficient data to assess the outcome data. ASSIA, Cochrane library, EMbase, Medline, PubMed and the knowledge network Scotland were systematically searched with appropriate Mesh terms employed. The quality assessment of diagnostic accuracy studies (QUADAS) was used to ensure quality of data. Statistical analysis was performed using the 'Rev Man' meta-analysis soft ward for Windows. RESULTS The review included 36 studies, with a total of 5,853 patients. Here, we found that AFP has the highest overall diagnostic performance. The average Youden index amongst all CTC was 0.46 with a mode and median of 0.5 with highest of 0.87 and lowest of 0.01. CONCLUSIONS The available literature provides weak evidence that there is potential in the use of CTC, however the lack of a standardised procedure in the study of CTC contribute to the lack of consensus of use. Future research should include large scaled, standardized studies for the diagnostic accuracy of CTCs.
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Affiliation(s)
- Poh Tan
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Lisa Grundy
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Peter Makary
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
| | | | - George Ramsay
- Rowette institute of Health Sciences, Medical School, University of Aberdeen, Aberdeen, UK
| | - Mohamed Bekheit
- Department of General Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
- Department of Surgery, El Kabbary Hospital, Alexandria, Egypt
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25
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Sanches SM, Braun AC, Calsavara VF, Barbosa PNVP, Chinen LTD. Comparison of hormonal receptor expression and HER2 status between circulating tumor cells and breast cancer metastases. Clinics (Sao Paulo) 2021; 76:e2971. [PMID: 34644733 PMCID: PMC8478133 DOI: 10.6061/clinics/2021/e2971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 08/19/2021] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES Breast cancer (BC) is the most common neoplasm in women. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status as there are discrepancies in these patterns between primary tumors and metastases in up to 40% of the cases. Circulating tumor cells (CTCs) are related to BC outcomes and could potentially be an alternative to the invasive procedures of metastasis rebiopsy. ISET® technology is not currently employed to detect CTCs in patients with BC. Emerging data support that the characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-β plays a role in BC progression and invasiveness. Thus, in this study, we aimed to compare ER, PR, and HER2 expression in primary tumors, CTCs, and metastases and evaluate TGF-β type 1 receptor (TGF-β RI) expression in CTCs as prognostic factor for progression free survival (PFS) and overall survival (OS). METHODS This prospective study was conducted at the A.C. Camargo Cancer Center, Brazil. Blood samples were processed in ISET® (Isolation by SizE of Tumors, Rarecells, France) before computed tomography-guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases (medical records). RESULTS Of the 39 patients initially included, 27 underwent both biopsies of metastases and blood collection and were considered for analysis. The concordance rates for ER, PR, and HER2 expression between primary tumors and metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern of protein expression in all triple-negative (TN) tumors (92.5%, 81.5% and 96.2% respectively) (p<0.0001) was observed. When metastases/CTCs were classified as TN/non-TN, CTCs showed high specificity (93%), accuracy (84.2%), and negative predictive value (88%). The median OS of patients without TGF-β RI expression in CTCs was 42.6 versus 20.8 months for TGF-β RI expression-positive ones (p>0.05). CONCLUSION The role of CTCs detected by ISET has not yet been established in BC. Here, we suggest that this methodology may be useful to evaluate metastasis in non-TN cases as well as TGF-β RI expression in CTCs, which may impact patient survival. Due to sample limitations, future studies must focus on specific BC subtypes and an expansion of the cohort.
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26
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Curtin J, Wong G, Wang W, Thomson P, Lam AK, Choi SW. A comparison of two methods for the detection of circulating tumour cells in patients with oral cavity cancer. J Oral Pathol Med 2021; 51:249-255. [PMID: 34586677 DOI: 10.1111/jop.13240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 09/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Circulating tumour cells (CTCs) detected in patient blood samples are relevant as diagnostic and prognostic markers offering insights into tumour behaviour and guiding treatment of cancer at an individualised level. The aim of this study was to ascertain the feasibility of detecting CTCs in oral squamous cell carcinoma (OSCC) using two different methods so as to determine the optimal method for the study of this cancer. METHODS Comparison of the numbers of CTCs, circulating tumour micro-emboli (CTMs) and circulating tumour endothelial cells (CTECs), was undertaken in forty clinical samples of oral squamous cell carcinoma (OSCC) determined by filtration (ISET® ) and in situ fluorescent immunostaining (i-FISH, Cytelligen® ) immunostaining and in situ hybridisation. RESULTS i-FISH detected CTCs in 80% of samples compared with 40% of samples analysed by microfiltration. i-FISH detected CTCs in a further 40% of samples in which microfiltration did not detect CTCs. No CTC clusters were detected by microfiltration while i-FISH detected CTM in 12.5% of samples. i-FISH analysis detected CTECs in 20/40 samples. CONCLUSION These results highlight significant differences in detection of CTCs, CTM and CTECs between i-FISH and microfiltration when applied to OSCC samples, suggesting that technologies capable of detecting circulating aneuploid cells more accurately detect CTCs. i-FISH also detected CTM and CTEC not detected using ISET® . With proven prognostic relevance in adenocarcinomas, accurate enumeration of CTCs, CTMs and CTECs may be a clinically useful tool in the management of OSCC and may aid in the reduction of false-negative diagnoses.
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Affiliation(s)
- Justin Curtin
- School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia
| | - Gordon Wong
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong, Hong Kong
| | - Weilan Wang
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, Hong Kong
| | - Peter Thomson
- College of Medicine and Dentistry, James Cook University, Brisbane, QLD, Australia
| | - Alfred K Lam
- School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia
| | - Siu-Wai Choi
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, Hong Kong
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27
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Maravelia P, Silva DN, Rovesti G, Chrobok M, Stål P, Lu YC, Pasetto A. Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy. Cancers (Basel) 2021; 13:4334. [PMID: 34503144 PMCID: PMC8431414 DOI: 10.3390/cancers13174334] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/21/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.
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Affiliation(s)
- Panagiota Maravelia
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
| | - Daniela Nascimento Silva
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
| | - Giulia Rovesti
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Michael Chrobok
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
| | - Per Stål
- Unit of Gastroenterology and Hepatology, Department of Medicine/Huddinge, Karolinska Institutet, Department of Upper GI Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden;
| | - Yong-Chen Lu
- Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Anna Pasetto
- Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden; (D.N.S.); (G.R.); (M.C.)
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28
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Wrenn E, Huang Y, Cheung K. Collective metastasis: coordinating the multicellular voyage. Clin Exp Metastasis 2021; 38:373-399. [PMID: 34254215 PMCID: PMC8346286 DOI: 10.1007/s10585-021-10111-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/14/2021] [Indexed: 12/16/2022]
Abstract
The metastatic process is arduous. Cancer cells must escape the confines of the primary tumor, make their way into and travel through the circulation, then survive and proliferate in unfavorable microenvironments. A key question is how cancer cells overcome these multiple barriers to orchestrate distant organ colonization. Accumulating evidence in human patients and animal models supports the hypothesis that clusters of tumor cells can complete the entire metastatic journey in a process referred to as collective metastasis. Here we highlight recent studies unraveling how multicellular coordination, via both physical and biochemical coupling of cells, induces cooperative properties advantageous for the completion of metastasis. We discuss conceptual challenges and unique mechanisms arising from collective dissemination that are distinct from single cell-based metastasis. Finally, we consider how the dissection of molecular transitions regulating collective metastasis could offer potential insight into cancer therapy.
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Affiliation(s)
- Emma Wrenn
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, 98195, USA
| | - Yin Huang
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | - Kevin Cheung
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
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29
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Pelizzaro F, Cardin R, Penzo B, Pinto E, Vitale A, Cillo U, Russo FP, Farinati F. Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now? Cancers (Basel) 2021; 13:2274. [PMID: 34068786 PMCID: PMC8126224 DOI: 10.3390/cancers13092274] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Romilda Cardin
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Barbara Penzo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Elisa Pinto
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
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30
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Nathanson SD, Detmar M, Padera TP, Yates LR, Welch DR, Beadnell TC, Scheid AD, Wrenn ED, Cheung K. Mechanisms of breast cancer metastasis. Clin Exp Metastasis 2021; 39:117-137. [PMID: 33950409 PMCID: PMC8568733 DOI: 10.1007/s10585-021-10090-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/20/2021] [Indexed: 02/06/2023]
Abstract
Invasive breast cancer tends to metastasize to lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth of the disease in the breast/chest wall, and at metastatic sites, initially by surgery alone, then by a combination of surgery with radiation, and later by adding systemic treatments in the form of chemotherapy, hormone manipulation, targeted therapy, immunotherapy and other treatments aimed at inhibiting the proliferation of cancer cells. It would be valuable for us to know how breast cancer metastasizes; such knowledge would likely encourage the development of therapies that focus on mechanisms of metastasis and might even allow us to avoid toxic therapies that are currently used for this disease. For example, if we had a drug that targeted a gene that is critical for metastasis, we might even be able to cure a vast majority of patients with breast cancer. By bringing together scientists with expertise in molecular aspects of breast cancer metastasis, and those with expertise in the mechanical aspects of metastasis, this paper probes interesting aspects of the metastasis cascade, further enlightening us in our efforts to improve the outcome from breast cancer treatments.
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Affiliation(s)
- S David Nathanson
- Department of Surgery, Henry Ford Cancer Institute, 2799 W Grand Boulevard, Detroit, MI, USA.
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Timothy P Padera
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Danny R Welch
- Department of Cancer Biology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, KS, USA
| | - Thomas C Beadnell
- Department of Cancer Biology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, KS, USA
| | - Adam D Scheid
- Department of Cancer Biology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, KS, USA
| | - Emma D Wrenn
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA
| | - Kevin Cheung
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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31
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Ge Z, Helmijr JCA, Jansen MPHM, Boor PPC, Noordam L, Peppelenbosch M, Kwekkeboom J, Kraan J, Sprengers D. Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma. Transl Oncol 2021; 14:101073. [PMID: 33915518 PMCID: PMC8100622 DOI: 10.1016/j.tranon.2021.101073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/17/2021] [Accepted: 03/08/2021] [Indexed: 12/24/2022] Open
Abstract
In paired analysis CTCs were detected in 27% and ctDNA in 77% of HCC patients. The TERT promoter mutation C228T was present in all patients with one or more ctDNA mutations, or detectable CTCs. CtDNA (or TERT C228T) positivity was associated with macrovascular invasion and poor survival of advanced HCC patients. Background and aims Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients. Methods Twenty-six mostly advanced HCC patients were enrolled. 30 mL peripheral blood from each patient was obtained. CellSearch system was used for CTC detection. A sequencing panel covering 14 cancer-relevant genes was used to identify oncogenic mutations. TERT promoter C228T and C250T mutations were determined by droplet digital PCR. Results CTCs were detected in 27% (7/26) of subjects but at low numbers (median: 2 cells, range: 1–15 cells) and ctDNA in 77% (20/26) of patients. Mutations in ctDNA were identified in several genes: TERT promoter C228T (77%, 20/26), TP53 (23%, 6/26), CTNNB1 (12%, 3/26), PIK3CA (12%, 3/26) and NRAS (4%, 1/26). The TERT C228T mutation was present in all patients with one or more ctDNA mutations, or detectable CTCs. The TERT C228T and TP53 mutations detected in ctDNA were present at higher levels in matched primary HCC tumor tissue. The maximal variant allele frequency (VAF) of ctDNA was linearly correlated with largest tumor size and AFP level (Log10). CtDNA (or TERT C228T) positivity was associated with macrovascular invasion, and positivity of ctDNA (or TERT C228T) or CTCs (≥ 2) correlated with poor patient survival. Conclusions Oncogenic mutations could be detected in ctDNA from advanced HCC patients. CtDNA analysis may serve as a promising liquid biopsy to identify druggable mutations.
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Affiliation(s)
- Zhouhong Ge
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jean C A Helmijr
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maurice P H M Jansen
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Patrick P C Boor
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Lisanne Noordam
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Maikel Peppelenbosch
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jaap Kwekkeboom
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jaco Kraan
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Dave Sprengers
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
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Local Anesthetics and Recurrence after Cancer Surgery-What's New? A Narrative Review. J Clin Med 2021; 10:jcm10040719. [PMID: 33670434 PMCID: PMC7918400 DOI: 10.3390/jcm10040719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/27/2021] [Accepted: 02/08/2021] [Indexed: 12/16/2022] Open
Abstract
The perioperative use of regional anesthesia and local anesthetics is part of almost every anesthesiologist’s daily clinical practice. Retrospective analyses and results from experimental studies pointed towards a potential beneficial effect of the local anesthetics regarding outcome—i.e., overall and/or recurrence-free survival—in patients undergoing cancer surgery. The perioperative period, where the anesthesiologist is responsible for the patients, might be crucial for the further course of the disease, as circulating tumor cells (shed from the primary tumor into the patient’s bloodstream) might form new micro-metastases independent of complete tumor removal. Due to their strong anti-inflammatory properties, local anesthetics might have a certain impact on these circulating tumor cells, either via direct or indirect measures, for example via blunting the inflammatory stress response as induced by the surgical stimulus. This narrative review highlights the foundation of these principles, features recent experimental and clinical data and provides an outlook regarding current and potential future research activities.
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Labgaa I, Villanueva A, Dormond O, Demartines N, Melloul E. The Role of Liquid Biopsy in Hepatocellular Carcinoma Prognostication. Cancers (Basel) 2021; 13:cancers13040659. [PMID: 33562173 PMCID: PMC7914891 DOI: 10.3390/cancers13040659] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the deadliest cancer. Clinical guidelines for the management of HCC endorse algorithms deriving from clinical variables whose performances to prognosticate HCC is limited. Liquid biopsy is the molecular analysis of tumor by-products released into the bloodstream. It offers minimally-invasive access to circulating analytes like DNA, RNA, exosomes and cells. This technology demonstrated promising results for various applications in cancers, including prognostication. This review aimed to provide a comprehensive overview of the contribution of liquid biopsy in HCC prognostication. The results suggested that liquid biopsy may be a polyvalent and valuable tool to prognosticate HCC. Abstract Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications and scores that use clinical variables, such as the Barcelona Clinic Liver Cancer (BCLC) classification. These algorithms are unlikely to fully recapitulate the genomic complexity of HCC. Integrating molecular readouts on a patient-basis, following a precision-medicine perspective, might be an option to refine prognostic systems. The limited access to HCC tissue samples is an important limitation to these approaches but it could be partially circumvented by using liquid biopsy. This concept consists of the molecular analysis of products derived from a solid tumor and released into biological fluids, mostly into the bloodstream. It offers an easy and minimally-invasive access to DNA, RNA, extracellular vesicles and cells that can be analyzed with next-generation sequencing (NGS) technologies. This review aims to investigate the potential contributions of liquid biopsy in HCC prognostication. The results identified prognostic values for each of the components of liquid biopsy, suggesting that this technology may help refine HCC prognostication.
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Affiliation(s)
- Ismail Labgaa
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Olivier Dormond
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
- Correspondence:
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland; (I.L.); (O.D.); (E.M.)
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Ahn JC, Teng PC, Chen PJ, Posadas E, Tseng HR, Lu SC, Yang JD. Detection of Circulating Tumor Cells and Their Implications as a Biomarker for Diagnosis, Prognostication, and Therapeutic Monitoring in Hepatocellular Carcinoma. Hepatology 2021; 73:422-436. [PMID: 32017145 PMCID: PMC8183673 DOI: 10.1002/hep.31165] [Citation(s) in RCA: 231] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/28/2020] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of worldwide cancer-related morbidity and mortality. Poor prognosis of HCC is attributed primarily to tumor presentation at an advanced stage when there is no effective treatment to achieve the long term survival of patients. Currently available tests such as alpha-fetoprotein have limited accuracy as a diagnostic or prognostic biomarker for HCC. Liver biopsy provides tissue that can reveal tumor biology but it is not used routinely due to its invasiveness and risk of tumor seeding, especially in early-stage patients. Liver biopsy is also limited in revealing comprehensive tumor biology due to intratumoral heterogeneity. There is a clear need for new biomarkers to improve HCC detection, prognostication, prediction of treatment response, and disease monitoring with treatment. Liquid biopsy could be an effective method of early detection and management of HCC. Circulating tumor cells (CTCs) are cancer cells in circulation derived from the original tumor or metastatic foci, and their measurement by liquid biopsy represents a great potential in facilitating the implementation of precision medicine in patients with HCC. CTCs can be detected by a simple peripheral blood draw and potentially show global features of tumor characteristics. Various CTC detection platforms using immunoaffinity and biophysical properties have been developed to identify and capture CTCs with high efficiency. Quantitative abundance of CTCs, as well as biological characteristics and genomic heterogeneity among the CTCs, can predict disease prognosis and response to therapy in patients with HCC. This review article will discuss the currently available technologies for CTC detection and isolation, their utility in the clinical management of HCC patients, their limitations, and future directions of research.
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Affiliation(s)
- Joseph C Ahn
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55904, United States
| | - Pai-Chi Teng
- Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Pin-Jung Chen
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA 90095, United States
| | - Edwin Posadas
- Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States,Translational Oncology Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States,Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Hsian-Rong Tseng
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA 90095, United States
| | - Shelly C. Lu
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States,Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Ju Dong Yang
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States,Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States,Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
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Chen VL, Xu D, Wicha MS, Lok AS, Parikh ND. Utility of Liquid Biopsy Analysis in Detection of Hepatocellular Carcinoma, Determination of Prognosis, and Disease Monitoring: A Systematic Review. Clin Gastroenterol Hepatol 2020; 18:2879-2902.e9. [PMID: 32289533 PMCID: PMC7554087 DOI: 10.1016/j.cgh.2020.04.019] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 03/31/2020] [Accepted: 04/03/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Liquid biopsies, or blood samples, can be analyzed to detect circulating tumor cells (CTCs), cell-free DNA (cfDNA), and extracellular vesicles, which might identify patients with hepatocellular carcinoma (HCC) or help determine their prognoses. We performed a systematic review of studies of analyses of liquid biopsies from patients with HCC and their comparisons with other biomarkers. METHODS We performed a systematic review of original studies published before December 1, 2019. We included studies that compared liquid biopsies alone and in combination with other biomarkers for the detection of HCC, performed multivariate analyses of the accuracy of liquid biopsy analysis in determining patient prognoses, or evaluated the utility of liquid biopsy analysis in monitoring treatment response. RESULTS Our final analysis included 112 studies: 67 on detection, 46 on determining prognosis, and 25 on treatment monitoring or selection. Ten studies evaluated assays that characterized cfDNA for detection of HCC in combination with measurement of α-fetoprotein (AFP)-these studies found that the combined measurement of cfDNA and AFP more accurately identified patients with HCC than measurement of AFP alone. Six studies evaluated assays for extracellular vesicles and 2 studies evaluated assays for CTC in detection of HCC, with and without other biomarkers-most of these studies found that detection of CTCs or extracellular vesicles with AFP more accurately identified patients with HCC than measurement of AFP alone. Detection of CTCs before surgery was associated with HCC recurrence after resection in 13 of 14 studies; cfDNA and extracellular vesicles have been studied less frequently as prognostic factors. Changes in CTC numbers before vs after treatment more accurately identify patients with HCC recurrence than pretreatment counts alone, and measurements of cfDNA can identify patients with disease recurrence or progression before changes can be detected by imaging. We found little evidence that analyses of liquid biopsies can aid in the selection of treatment for HCC. Quality assessment showed risk of bias in studies of HCC detection and determination of prognosis. CONCLUSIONS In a systematic review of 112 studies of the accuracy of liquid biopsy analysis, we found that assays for CTCs and cfDNA might aid in determining patient prognoses and monitoring HCC, and assays for cfDNA might aid in HCC detection, but there is a risk of bias in these studies. Studies must be standardized before we can assess the clinical utility of liquid biopsy analysis in the detection and management of patients with HCC.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
| | - Dabo Xu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Max S Wicha
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
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Quan Y, Chen K, Xiang N, Ni Z. A single-view field filter device for rare tumor cell filtration and enumeration. Electrophoresis 2020; 41:2000-2006. [PMID: 32767389 DOI: 10.1002/elps.202000176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/27/2020] [Accepted: 08/03/2020] [Indexed: 12/11/2022]
Abstract
In this work, we demonstrate a single-view field filter (SVFF) device for the efficient filtration and enumeration of rare tumor cells in the blood. In our device, the track-etched membrane is integrated within a low-cost polymer-film microfluidic chip, and multiplex microfiltration chambers are designed. Our device permits the performing of multiple sample tests on a single membrane and the dynamical observation of the entire filtration process in a single field of view. To characterize the device performance, our device is first tested using tumor cells, and three different cell behaviors are observed during the filtration process. Finally, we successfully apply our device for the separation of rare tumor cells from the lysed blood samples at various flow rates. The recovery rates of 93.3, 87.6, and 84.1% can be respectively achieved at the throughputs of 50, 100, and 150 μL/min. Our single-view field filter (SVFF) device offers the advantages of label-free filtration, efficient enumeration, easy integration, and low cost, and holds the potential to be used as an efficient tool for the filtration and enumeration of rare cells.
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Affiliation(s)
- Yunlin Quan
- School of Mechanical Engineering, and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, P. R. China
| | - Ke Chen
- School of Mechanical Engineering, and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, P. R. China
| | - Nan Xiang
- School of Mechanical Engineering, and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, P. R. China
| | - Zhonghua Ni
- School of Mechanical Engineering, and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, P. R. China
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Chen M, Xu K, Li B, Wang N, Zhang Q, Chen L, Zhang D, Yang L, Xu Z, Xu H. HMGA1 Regulates the Stem Cell-Like Properties of Circulating Tumor Cells from GIST Patients via Wnt/β-Catenin Pathway. Onco Targets Ther 2020; 13:4943-4956. [PMID: 32606726 PMCID: PMC7296980 DOI: 10.2147/ott.s249063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/06/2020] [Indexed: 12/21/2022] Open
Abstract
Background Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the digestive system. Circulating tumor cells (CTCs) have been proven to be critical in the recurrence and metastasis of diseases; however, the characteristics of CTCs of GIST are still unclear. Methods We sorted out and verified the validity of CTCs from peripheral blood of gastrointestinal stromal tumor (GIST) patients with or without heterochronous liver metastasis using flow cytometry (FCM). Differential genes were analyzed between the GIST patients with and without liver metastasis using next-generation sequencing (NGS). Results The preliminary study on the characteristics of CTCs revealed that CTCs of GIST patients with heterochronous liver metastasis had stronger stem cell-like properties (SC-like properties) than CTCs of those without liver metastasis. Furthermore, NGS followed with a series of assays revealed that HMGA1 played a critical role in regulating the SC-like properties of CTCs. Mechanistically, HMGA1 could activate Wnt/β-catenin pathway in vitro and vivo. Moreover, we found that the expression level of HMGA1 in CTCs was an independent risk factor probably influencing the prognosis of GIST patients. Conclusion Our findings indicate the significant role of HMGA1 in SC-like properties, IM resistance and eventually hepatic metastasis formation of CTCs. Targeting HMGA1 in CTCs may be a therapeutic strategy for GIST patients with hepatic metastasis.
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Affiliation(s)
- Ming Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Kangjing Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Nuofan Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Qiang Zhang
- Department of Gastrointestinal Surgery, The Second People's Hospital of Lianyungang, Lianyungang, Jiangsu 222000, People's Republic of China
| | - Liang Chen
- Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, People's Republic of China
| | - Diancai Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Li Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China
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Chen L, Chen Y, Feng YL, Zhu Y, Wang LQ, Hu S, Cheng P. Tumor circulome in the liquid biopsies for digestive tract cancer diagnosis and prognosis. World J Clin Cases 2020; 8:2066-2080. [PMID: 32548136 PMCID: PMC7281040 DOI: 10.12998/wjcc.v8.i11.2066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/10/2020] [Accepted: 04/28/2020] [Indexed: 02/05/2023] Open
Abstract
Digestive tract cancer is one of the main diseases that endanger human health. At present, the early diagnosis of digestive tract tumors mainly depends on serology, imaging, endoscopy, and so on. Although tissue specimens are the gold standard for cancer diagnosis, with the rapid development of precision medicine in cancer, the demand for dynamic monitoring of tumor molecular characteristics has increased. Liquid biopsy involves the collection of body fluids via non-invasive approaches, and analyzes biological markers such as circulating tumor cells, circulating tumor DNA, circulating cell-free DNA, microRNAs, and exosomes. In recent years, liquid biopsy has become more and more important in the diagnosis and prognosis of cancer in clinical practice due to its convenience, non-invasiveness, high specificity and it overcomes temporal-spatial heterogeneity. Therefore, this review summarizes the current evidence on liquid biopsies in digestive tract cancers in relation to diagnosis and prognosis.
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Affiliation(s)
- Long Chen
- Department of Radiotherapy, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Yu Chen
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yuan-Ling Feng
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Yan Zhu
- Department of Respiratory, Shulan Hospital, Hangzhou 310004, Zhejiang Province, China
| | - Li-Quan Wang
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Shen Hu
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Pu Cheng
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310052, Zhejiang Province, China
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Nagai M, Sho M, Akahori T, Nakagawa K, Nakamura K. Application of liquid biopsy for surgical management of pancreatic cancer. Ann Gastroenterol Surg 2020; 4:216-223. [PMID: 32490335 PMCID: PMC7240145 DOI: 10.1002/ags3.12317] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/19/2019] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Although drug development over the past decade has gradually improved the prognosis of PDAC, the prognosis remains extremely poor. The predominant determinant of a poor prognosis is that patients are already at the advanced stage when they are diagnosed. Therefore, it is essential to detect early-stage PDAC to ensure a good prognosis. However, in general, being asymptomatic at the early stage makes the detection of early-stage PDAC very difficult. Recently, much attention has been focused on the utility of a liquid biopsy as a biomarker. Theoretically, early-stage tumors can be detected even under asymptomatic conditions. A number of studies on liquid biopsies have been reported so far. Several biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCS), and exosomes, are used in liquid biopsies, with the potential to be applied to the clinical setting. Each biomarker is reported to have different utilities, such as the detection of early-stage disease, the differential diagnosis of PDAC from other types of pancreatic tumors, the prediction of the prognosis or risk of recurrence, and monitoring the treatment response. In this review, we focus on ctDNA, CTCS, and exosomes as representative liquid biopsy biomarkers and describe the specific functions of each biomarker in the treatment of PDAC. Furthermore, we discuss the application of liquid biopsies, especially for the surgical management of PDAC.
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Affiliation(s)
- Minako Nagai
- Department of Surgery Nara Medical University Kashihara Japan
| | - Masayuki Sho
- Department of Surgery Nara Medical University Kashihara Japan
| | | | - Kenji Nakagawa
- Department of Surgery Nara Medical University Kashihara Japan
| | - Kota Nakamura
- Department of Surgery Nara Medical University Kashihara Japan
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Relevance of CTC Clusters in Breast Cancer Metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1220:93-115. [PMID: 32304082 DOI: 10.1007/978-3-030-35805-1_7] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Metastasis is the major cause of mortality in patients with breast cancer; however, the mechanisms of tumor cell dissemination and metastasis formation are not well established yet. The study of circulating tumour cells (CTCs), the metastatic precursors of distant disease, may help in this search. CTCs can be found in the blood of cancer patients as single cells or as tumor cell aggregates, known as CTC clusters. CTC clusters have differential biological features such as an enhanced survival and metastatic potential, and they hold great promises for the evaluation of prognosis, diagnosis and therapy of the metastatic cancer. The analysis of CTC clusters offers new insights into the mechanism of metastasis and can guide towards the development of new diagnostic and therapeutic strategies to suppress cancer metastasis. This has become possible thanks to the development of improved technologies for detection of CTCs and CTC clusters. However, more efficient methods are needed in order to address important questions regarding the metastatic potential of CTC and future clinical applications. In this chapter, we explore the current knowledge on the role of CTC clusters in breast cancer metastasis, their origin, metastatic advantages and clinical importance.
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Bai T, Mai R, Ye J, Chen J, Qi L, Tang J, Wei M, Zhang L, Chen Z, Tang Z, Li L, Wu F. Circulating tumor cells and CXCR4 in the prognosis of hepatocellular carcinoma. Transl Cancer Res 2020; 9:1384-1394. [PMID: 35117486 PMCID: PMC8798757 DOI: 10.21037/tcr.2020.01.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 12/26/2019] [Indexed: 11/17/2022]
Abstract
Background This study was to determine circulating tumor cells (CTCs) and the expression of CXC chemokine receptor type 4 (CXCR4) in primary hepatocellular carcinoma (HCC) and the relationships with prognosis. Methods We used an advanced CanPatrolTM CTC-enrichment technique to collect CTCs for isolation and characterization from blood samples. The RNA in situ hybridization (RNA-ISH) method, which is based on branched DNA (bDNA) signal amplification technology, was used to determine the expression of CXCR4 according to epithelial-mesenchymal transition (EMT) markers in 99 patients with primary liver cancer in blood samples pre-operatively. The relationship between the EMT markers and HCC was determined. Results The positive rates of CTCs and CXCR4 were 89.9% and 58.8%, respectively. CTCs were positively correlated with the Barcelona clinic liver cancer (BCLC) staging, tumor diameter and number, envelope, microsatellite damage, portal vein thrombosis, alpha-fetoprotein (AFP), and hepatitis B DNA, and negatively correlated with Edmondson grade. There were significant differences in the expression of CXCR4 between interstitial CTCs and mixed CTCs. A total of 99 patients underwent CTCs testing prior to surgery. The tumor-free survival time of HCC patients with interstitial CTCs <1 (13.3 months) was significantly longer than patients with interstitial CTCs ≥1 (5.0 months) pre-operatively. Conclusions CTC-positivity was shown to be associated with HCC and can be used as an independent prognostic factor for HCC. High CXCR4 protein expression was more common in mixed CTCs.
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Affiliation(s)
- Tao Bai
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Rongyun Mai
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Lunan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Juan Tang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Meng Wei
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Lianda Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Zhiwei Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Zhihong Tang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
| | - Feixiang Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.,Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning 530021, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning 530021, China
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Cytomorphological Characterization of Individual Metastatic Tumor Cells from Gastrointestinal Cancer Patient Lymph Nodes with Imaging Flow Cytometry. GASTROINTESTINAL DISORDERS 2019. [DOI: 10.3390/gidisord1040030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The presence or absence of tumor cells within patient lymph nodes is an important prognostic indicator in a number of cancer types and an essential element of the staging process. However, patients with the same pathological stage will not necessarily have the same outcome. Therefore, additional factors may aid in identifying patients at a greater risk of developing metastasis. In this proof of principle study, initially, spiked tumor cells in rat lymph nodes were used to mimic a node with a small cancer deposit. Next, human lymph nodes were obtained from cancer patients for morphological characterization. Nodes were dissociated with a manual tissue homogenizer and stained with fluorescent antibodies against CD45 and Pan-Cytokeratin and then imaging flow cytometry (AMNIS ImageStreamX Mark II) was performed. We show here that imaging flow cytometry can be used for the detection and characterization of small numbers of cancer cells in lymph nodes and we also demonstrate the phenotypical and morphological characterization of cancer cells in gastrointestinal cancer patient lymph nodes. When used in addition to conventional histological techniques, this high throughput detection of tumor cells in lymph nodes may offer additional information assisting in the staging process with therapeutic and prognostic applications.
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Snow A, Chen D, Lang JE. The current status of the clinical utility of liquid biopsies in cancer. Expert Rev Mol Diagn 2019; 19:1031-1041. [PMID: 31482746 DOI: 10.1080/14737159.2019.1664290] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Liquid biopsies have attracted considerable attention as potential diagnostic, prognostic, predictive, and screening assays in oncology. The term liquid biopsies include circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in the blood. While many liquid biopsy technologies are under active investigation, relatively few liquid biopsy assays have been proven to serve as a diagnostic surrogate for biopsies of metastatic disease as predictive biomarkers to guide the selection of therapy in the clinic. Areas covered: The objective of this review is to highlight the status of liquid biopsies in solid tumors in the oncology literature with attention to proven utility as diagnostic surrogates for macrometastases. Expert opinion: Carefully designed clinical-translational studies are needed to establish the diagnostic accuracy and clinical utility of liquid biopsy biomarkers in oncology. Investigators must fully consider relevant pre-analytical variables, assay sensitivity, bioinformatics considerations as well as the clinical utility of rare event profiling in the context of the normal blood background. Future liquid biopsy research should address the concern that not all DNA mutations are expressed and should provide the means to discover potential therapeutic targets in metastatic patients via a minimally invasive blood draw.
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Affiliation(s)
- Anson Snow
- Department of Surgery, University of Southern California Norris Comprehensive Cancer Center , Los Angeles , CA , USA
| | - Denaly Chen
- Department of Medicine, University of Southern California Norris Comprehensive Cancer Center , Los Angeles , CA , USA
| | - Julie E Lang
- Department of Surgery, University of Southern California Norris Comprehensive Cancer Center , Los Angeles , CA , USA
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Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Mol Cancer 2019; 18:114. [PMID: 31269959 PMCID: PMC6607541 DOI: 10.1186/s12943-019-1043-x] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Due to latent liver disease, late diagnosis, and nonresponse to systemic treatments, surgical resection and/or biopsy specimens are still generally considered as the gold standard by clinicians for clinical decision-making until now. Since the conventional tissue biopsy is invasive and contains small tissue samples, it is unable to represent tumor heterogeneity or monitor dynamic tumor progression. Therefore, it is imperative to find a new less invasive or noninvasive diagnostic strategy to detect HCC at an early stage and to monitor HCC recurrence. Over the past years, a new diagnostic concept known as “liquid biopsy” has emerged with substantial attention. Liquid biopsy is noninvasive and allows repeated analyses to monitor tumor recurrence, metastasis or treatment responses in real time. With the advanced development of new molecular techniques, HCC circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) detection have achieved interesting and encouraging results. In this review, we focus on the clinical applications of CTCs and ctDNA as key components of liquid biopsy in HCC patients.
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45
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Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, Ma GX, Nguyen MT. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293. [PMID: 31148900 PMCID: PMC6529884 DOI: 10.3748/wjg.v25.i19.2279] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/27/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
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Affiliation(s)
- Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Trisheena Harricharran
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Anna Galuza
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Oluwatoyin Odumuwagun
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Yin Tan
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Grace X Ma
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Minhhuyen T Nguyen
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
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Abstract
The clinical utility of tissue biopsies in cancer management will continue to expand, especially with the evolving role of targeted therapies. "Liquid biopsy" refers to testing a patient's biofluid samples such as blood or urine to detect tumor-derived molecules and cells that can be used diagnostically and prognostically in the assessment of cancer. Many proof-of-concept and pilot studies have shown the clinical potential of liquid biopsies as diagnostic and prognostic markers which would provide a surrogate for the conventional "solid biopsy". In this review, we focus on three methods of liquid biopsy-circulating tumor cells, extracellular vesicles, and circulating tumor DNA-to provide a landscape view of their clinical applicability in cancer management and research.
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Affiliation(s)
- Matthew Scarlotta
- 1 Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Cem Simsek
- 2 Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Amy K Kim
- 2 Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
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Potential Utility of Liquid Biopsy as a Diagnostic and Prognostic Tool for the Assessment of Solid Tumors: Implications in the Precision Oncology. J Clin Med 2019; 8:jcm8030373. [PMID: 30889786 PMCID: PMC6463095 DOI: 10.3390/jcm8030373] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/24/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
Abstract
Liquid biopsy is a technique that utilizes circulating biomarkers in the body fluids of cancer patients to provide information regarding the genetic landscape of the cancer. It is emerging as an alternative and complementary diagnostic and prognostic tool to surgical biopsy in oncology. Liquid biopsy focuses on the detection and isolation of circulating tumor cells, circulating tumor DNA and exosomes, as a source of genomic and proteomic information in cancer patients. Liquid biopsy is expected to provide the necessary acceleratory force for the implementation of precision oncology in clinical settings by contributing an enhanced understanding of tumor heterogeneity and permitting the dynamic monitoring of treatment responses and genomic variations. However, widespread implementation of liquid biopsy based biomarker-driven therapy in the clinical practice is still in its infancy. Technological advancements have resolved many of the hurdles faced in the liquid biopsy methodologies but sufficient clinical and technical validation for specificity and sensitivity has not yet been attained for routine clinical implementation. This article provides a comprehensive review of the clinical utility of liquid biopsy and its effectiveness as an important diagnostic and prognostic tool in colorectal, breast, hepatocellular, gastric and lung carcinomas which were the five leading cancer related mortalities in 2018.
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48
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Rostami P, Kashaninejad N, Moshksayan K, Saidi MS, Firoozabadi B, Nguyen NT. Novel approaches in cancer management with circulating tumor cell clusters. JOURNAL OF SCIENCE: ADVANCED MATERIALS AND DEVICES 2019; 4:1-18. [DOI: 10.1016/j.jsamd.2019.01.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Amado V, Rodríguez-Perálvarez M, Ferrín G, De la Mata M. Selecting patients with hepatocellular carcinoma for liver transplantation: incorporating tumor biology criteria. J Hepatocell Carcinoma 2018; 6:1-10. [PMID: 30613572 PMCID: PMC6306074 DOI: 10.2147/jhc.s174549] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the optimal therapeutic option for patients with liver cirrhosis and hepatocellular carcinoma (HCC). Due to universal donor shortage, only the patients with limited tumor burden (under the so-called Milan criteria) are considered as potential candidates for LT in most institutions. It is expected that in the near future, more liver grafts will be available for patients with HCC due to the implementation of new direct antivirals against hepatitis C, leaving a prone scenario to consider expanding Milan criteria. A moderate expansion of Milan criteria could be implemented without increasing the risk of tumor recurrence if patients with favorable biological behavior are carefully selected. Incorporating information regarding tumor biology in the decision-making algorithm would result in a more rational use of LT in patients with HCC. In the present review, surrogate markers of tumor biology are critically evaluated as potential tools to be combined with existing radiological criteria. In addition, the current state of liquid biopsy is discussed, as this cutting-edge technology may reshape the management of HCC in the upcoming years.
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Affiliation(s)
- Víctor Amado
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Gustavo Ferrín
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
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50
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Li J, Han X, Yu X, Xu Z, Yang G, Liu B, Xiu P. Clinical applications of liquid biopsy as prognostic and predictive biomarkers in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:213. [PMID: 30176913 PMCID: PMC6122633 DOI: 10.1186/s13046-018-0893-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/25/2018] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant disease with a poor prognosis and high mortality due to a low early diagnosis rate, resistance to systemic treatments and progression to late-stage liver disease. Owing to limitations in the detection of HCC and the lack of awareness of healthcare systems, fewer than 40% of HCC patients are eligible for surgery due to advanced stages of the disease at the time of diagnosis and the occurrence of multiple lesions in the cirrhotic or fibrotic liver. At present, the updated American Association for the Study of Liver Disease (AASLD) guidelines no longer recommend alpha-fetoprotein (AFP) testing as a part of diagnostic evaluation. Thus, it is imperative to establish a novel diagnostic strategy with high sensitivity and reliability to monitor risk factors to detect HCC at an early stage. In recent years, “liquid biopsy,” (including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA)), has emerged as a technique for the characterization of circulating cells, providing a strong basis for the individualized treatment of patients. As a noninvasive detection method, liquid biopsy is expected to play an important role in the early diagnosis, dynamic monitoring of cancer patients and drug screening. In this review, we will focus on the clinical applications, recent studies and future prospects of liquid biopsy, particularly focusing on HCC.
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Affiliation(s)
- Jie Li
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Xu Han
- Department of Hepatobiliary Surgery, Zibo Central Hospital, Zibo, 255000, Shandong, China
| | - Xiaona Yu
- Department of General Medicine, Weifang Rongfu Military Hospital, Weifang, 261000, Shandong, China
| | - Zongzhen Xu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Guangsheng Yang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Bingqi Liu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Peng Xiu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China.
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