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Sharma R, Yadav J, Bhat SA, Musayev A, Myrzagulova S, Sharma D, Padha N, Saini M, Tuli HS, Singh T. Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research. Mol Neurobiol 2025; 62:6423-6466. [PMID: 39804528 DOI: 10.1007/s12035-024-04680-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 12/20/2024] [Indexed: 03/29/2025]
Abstract
This review explores the current understanding and recent advancements in neuroblastoma, one of the most common extracranial solid pediatric cancers, accounting for ~ 15% of childhood cancer-related mortality. The hallmarks of NBL, including angiogenesis, metastasis, apoptosis resistance, cell cycle dysregulation, drug resistance, and responses to hypoxia and ROS, underscore its complex biology. The tumor microenvironment's significance in disease progression is acknowledged in this study, along with the pivotal role of cancer stem cells in sustaining tumor growth and heterogeneity. A number of molecular signatures are being studied in order to better understand the disease, with many of them serving as targets for the development of new therapeutics. This includes inhibitor therapies for NBL patients, which notably concentrate on ALK signaling, MDM2, PI3K/Akt/mTOR, Wnt, and RAS-MAPK pathways, along with regulators of epigenetic mechanisms. Additionally, this study offers an extensive understanding of the molecular therapies used, such as monoclonal antibodies and CAR-T therapy, focused on both preclinical and clinical studies. Radiation therapy's evolving role and the promise of stem cell transplantation-mediated interventions underscore the dynamic landscape of NBL treatment. This study has also emphasized the recent progress in the field of diagnosis, encompassing the adoption of artificial intelligence and liquid biopsy as a non-intrusive approach for early detection and ongoing monitoring of NBL. Furthermore, the integration of innovative treatment approaches such as CRISPR-Cas9, and cancer stem cell therapy has also been emphasized in this review.
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Affiliation(s)
- Rishabh Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Jaya Yadav
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Sajad Ahmad Bhat
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
- Department of Biochemistry, NIMS University, Rajasthan, Jaipur, 303121, India
| | - Abdugani Musayev
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
| | | | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
| | - Nipun Padha
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Department of Zoology, Cluster University of Jammu, Jammu, 180001, India
| | - Manju Saini
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India.
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, (INMAS-DRDO), New Delhi, Delhi, 110054, India.
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Salomon R, Razavi Bazaz S, Mutafopulos K, Gallego-Ortega D, Warkiani M, Weitz D, Jin D. Challenges in blood fractionation for cancer liquid biopsy: how can microfluidics assist? LAB ON A CHIP 2025; 25:1097-1127. [PMID: 39775440 DOI: 10.1039/d4lc00563e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Liquid biopsy provides a minimally invasive approach to characterise the molecular and phenotypic characteristics of a patient's individual tumour by detecting evidence of cancerous change in readily available body fluids, usually the blood. When applied at multiple points during the disease journey, it can be used to monitor a patient's response to treatment and to personalise clinical management based on changes in disease burden and molecular findings. Traditional liquid biopsy approaches such as quantitative PCR, have tended to look at only a few biomarkers, and are aimed at early detection of disease or disease relapse using predefined markers. With advances in the next generation sequencing (NGS) and single-cell genomics, simultaneous analysis of both circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) is now a real possibility. To realise this, however, we need to overcome issues with current blood collection and fractionation processes. These include overcoming the need to add a preservative to the collection tube or the need to rapidly send blood tubes to a centralised processing lab with the infrastructure required to fractionate and process the blood samples. This review focuses on outlining the current state of liquid biopsy and how microfluidic blood fractionation tools can be used in cancer liquid biopsy. We describe microfluidic devices that can separate plasma for ctDNA analysis, and devices that are important in isolating the cellular component(s) in liquid biopsy, i.e., individual CTCs and CTC clusters. To facilitate a better understanding of these devices, we propose a new categorisation system based on how these devices operate. The three categories being 1) solid Interaction devices, 2) fluid Interaction devices and 3) external force/active devices. Finally, we conclude that whilst some assays and some cancers are well suited to current microfluidic techniques, new tools are necessary to support broader, clinically relevant multiomic workflows in cancer liquid biopsy.
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Affiliation(s)
- Robert Salomon
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
| | - Sajad Razavi Bazaz
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
| | - Kirk Mutafopulos
- Department of Physics, Harvard University, Cambridge, MA, 02138, USA
| | - David Gallego-Ortega
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
- School of Clinical Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia
- Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Majid Warkiani
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia
| | - David Weitz
- Department of Physics, Harvard University, Cambridge, MA, 02138, USA
| | - Dayong Jin
- Institute for Biomedical Materials and Devices (IBMD)/Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007 Australia
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Singh J, Peters NJ, Avti P, Trehan A, Mahajan JK, Menon P, Bansal D, Kanojia RP. The Role of Liquid Biopsy in Neuroblastoma: A Scoping Review. J Pediatr Surg 2025; 60:161887. [PMID: 39294087 DOI: 10.1016/j.jpedsurg.2024.161887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/16/2024] [Accepted: 08/27/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Neuroblastoma (NBL), is the most common, non-CNS solid tumor of childhood. This disease presents with unique biological and clinical challenges necessitating accurate diagnosis, prognosis assessment, treatment, and vigilant monitoring. Liquid biopsy is an upcoming, innovative, and non-invasive diagnostic modality. It has the potential to detect tumors and perform therapeutic monitoring through the analysis of circulating biomarkers in blood, urine, saliva, and other bodily fluids. METHODOLOGY This scoping review offers an in-depth exploration, of the current landscape of liquid biopsy-based biomarkers in NBL. The review looks at the clinical implications, prevalent challenges, and future outlook of their clinical applications in NBL. The scoping review adhered to the guidelines of the PRISMA extension for scoping reviews, known as PRISMA-ScR, as the skeletal framework. The review involved comprehensive searches for liquid biopsy-based biomarkers in NBL across multiple databases, including PUBMED, EMBASE, SCOPUS, and WEB of Science, without restrictions. RESULTS The scoping review process uncovered a significant body of literature (n = 201) that underwent meticulous scrutiny, ultimately leading to the final selection of studies (n = 15). The liquid biopsy biomarkers included circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and other entities in bodily fluids. Their evaluation focused on associations with clinical outcomes such as overall survival, event-free survival, and risk stratification in NBL. CONCLUSION Our findings highlight the potential of liquid biopsy biomarkers to revolutionize NBL diagnosis and therapeutic monitoring. This rapidly evolving frontier in pediatric oncology suggests significant advancements in precision medicine for the management of NBL.
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Affiliation(s)
- Jitender Singh
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Nitin J Peters
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Pramod Avti
- Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Amita Trehan
- Pediatric Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - J K Mahajan
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Prema Menon
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Deepak Bansal
- Pediatric Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ravi Prakash Kanojia
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
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Song J, Ye X, Peng Q, Ying X, Xiao H. Circulating Tumor cells and multiple indicators combined to identify the risk of poorer prognosis in patients with resected non-small cell lung cancer. BMC Cancer 2024; 24:1491. [PMID: 39627742 PMCID: PMC11616275 DOI: 10.1186/s12885-024-13245-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Surgical resection is an important treatment option for patients with non-small cell lung cancer (NSCLC). However, recurrence and survival rates remain a cause of concern. To further improve prognosis, more studies have focused on liquid biopsy, which has significant value as a prognostic factor for defining the risk stratification of postoperative NSCLC patients. This study aimed to identify circulating tumor cells (CTCs) as biomarkers that indicate a poor prognosis, combined with multiple indicators to determine prognostic risks in advance and develop individualized treatment strategies. METHODS Between November 2015 and August 2018, 65 radical resected patients with NSCLC were analyzed. Preoperative CTCs were collected, and follow-up lasted until August 2023. Overall survival (OS) and disease-free survival (DFS) were the primary outcomes. RESULTS With an 11 CTC unit threshold, the high preoperative CTC level group had worse OS and DFS than the low-level group, suggesting that preoperative CTC levels have prognostic value. Time-dependent receiver operating characteristic (ROC) curves also showed satisfactory predictive efficiency of CTCs. Univariate analysis revealed that preoperative CTC levels were significantly associated with increasing risks for OS and DFS. Moreover, we combined CTCs and multiple indicators to provide a reference for a group at high risk of adverse outcomes. CONCLUSIONS CTCs serve as feasible biomarkers for predicting postoperative prognosis in NSCLC patients. The combination of hematological, radiological, and pathological features could be valuable tools to guide postoperative management and treatment decisions in these patients. A multimodal prognostic approach is important for the clinical evaluation of lung cancer.
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Affiliation(s)
- Jinghan Song
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiong Ye
- School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Qianqian Peng
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinnan Ying
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Xiao
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Janssen FW, Lak NSM, Janda CY, Kester LA, Meister MT, Merks JHM, van den Heuvel-Eibrink MM, van Noesel MM, Zsiros J, Tytgat GAM, Looijenga LHJ. A comprehensive overview of liquid biopsy applications in pediatric solid tumors. NPJ Precis Oncol 2024; 8:172. [PMID: 39097671 PMCID: PMC11297996 DOI: 10.1038/s41698-024-00657-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/15/2024] [Indexed: 08/05/2024] Open
Abstract
Liquid biopsies are emerging as an alternative source for pediatric cancer biomarkers with potential applications during all stages of patient care, from diagnosis to long-term follow-up. While developments within this field are reported, these mainly focus on dedicated items such as a specific liquid biopsy matrix, analyte, and/or single tumor type. To the best of our knowledge, a comprehensive overview is lacking. Here, we review the current state of liquid biopsy research for the most common non-central nervous system pediatric solid tumors. These include neuroblastoma, renal tumors, germ cell tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcomas, and liver tumors. Within this selection, we discuss the most important or recent studies involving liquid biopsy-based biomarkers, anticipated clinical applications, and the current challenges for success. Furthermore, we provide an overview of liquid biopsy-based biomarker publication output for each tumor type based on a comprehensive literature search between 1989 and 2023. Per study identified, we list the relevant liquid biopsy-based biomarkers, matrices (e.g., peripheral blood, bone marrow, or cerebrospinal fluid), analytes (e.g., circulating cell-free and tumor DNA, microRNAs, and circulating tumor cells), methods (e.g., digital droplet PCR and next-generation sequencing), the involved pediatric patient cohort, and proposed applications. As such, we identified 344 unique publications. Taken together, while the liquid biopsy field in pediatric oncology is still behind adult oncology, potentially relevant publications have increased over the last decade. Importantly, steps towards clinical implementation are rapidly gaining ground, notably through validation of liquid biopsy-based biomarkers in pediatric clinical trials.
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Affiliation(s)
| | | | | | | | - Michael T Meister
- Princess Máxima Center, Utrecht, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Johannes H M Merks
- Princess Máxima Center, Utrecht, the Netherlands
- Division of Imaging and Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Marry M van den Heuvel-Eibrink
- Princess Máxima Center, Utrecht, the Netherlands
- Wilhelmina Children's Hospital-Division of CHILDHEALTH, University Medical Center Utrech, University of Utrecht, Utrecht, the Netherlands
| | - Max M van Noesel
- Princess Máxima Center, Utrecht, the Netherlands
- Division of Imaging and Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | | | - Godelieve A M Tytgat
- Princess Máxima Center, Utrecht, the Netherlands
- Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Leendert H J Looijenga
- Princess Máxima Center, Utrecht, the Netherlands.
- Department of Pathology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
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Li Y, Jiang L, Chen Y, Li Y, Yuan J, Lu J, Zhang Z, Liu S, Feng X, Xiong J, Jiang Y, Zhang X, Li J, Shen L. Specific lineage transition of tumor-associated macrophages elicits immune evasion of ascitic tumor cells in gastric cancer with peritoneal metastasis. Gastric Cancer 2024; 27:519-538. [PMID: 38460015 PMCID: PMC11016508 DOI: 10.1007/s10120-024-01486-6] [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: 11/30/2023] [Accepted: 02/23/2024] [Indexed: 03/11/2024]
Abstract
BACKGROUND Gastric cancer with peritoneal metastasis (PM-GC), recognized as one of the deadliest cancers. However, whether and how the tumor cell-extrinsic tumor microenvironment (TME) is involved in the therapeutic failure remains unknown. Thus, this study systematically assessed the immunosuppressive tumor microenvironment in ascites from patients with PM-GC, and its contribution to dissemination and immune evasion of ascites-disseminated tumor cells (aDTCs). METHODS Sixty-three ascites and 43 peripheral blood (PB) samples from 51 patients with PM-GC were included in this study. aDTCs in ascites and circulating tumor cells (CTCs) in paired PB were immunophenotypically profiled. Using single-cell RNA transcriptional sequencing (scRNA-seq), crosstalk between aDTCs and the TME features of ascites was inspected. Further studies on the mechanism underlying aDTCs-immune cells crosstalk were performed on in vitro cultured aDTCs. RESULTS Immune cells in ascites interact with aDTCs, prompting their immune evasion. Specifically, we found that the tumor-associated macrophages (TAMs) in ascites underwent a continuum lineage transition from cathepsinhigh (CTShigh) to complement 1qhigh (C1Qhigh) TAM. CTShigh TAM initially attracted the metastatic tumor cells to ascites, thereafter, transitioning terminally to C1Qhigh TAM to trigger overproliferation and immune escape of aDTCs. Mechanistically, we demonstrated that C1Qhigh TAMs significantly enhanced the expression of PD-L1 and NECTIN2 on aDTCs, which was driven by the activation of the C1q-mediated complement pathway. CONCLUSIONS For the first time, we identified an immunosuppressive macrophage transition from CTShigh to C1Qhigh TAM in ascites from patients with PM-GC. This may contribute to developing potential TAM-targeted immunotherapies for PM-GC.
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Affiliation(s)
- Yilin Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lei Jiang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yanyan Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jiajia Yuan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jialin Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zizhen Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Shengde Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xujiao Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | | | - Yan Jiang
- Singleron Biotechnologies, Nanjing, China
| | - Xiaotian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jian Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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Singhto N, Pongphitcha P, Jinawath N, Hongeng S, Chutipongtanate S. Extracellular Vesicles for Childhood Cancer Liquid Biopsy. Cancers (Basel) 2024; 16:1681. [PMID: 38730633 PMCID: PMC11083250 DOI: 10.3390/cancers16091681] [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: 04/09/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Liquid biopsy involves the utilization of minimally invasive or noninvasive techniques to detect biomarkers in biofluids for disease diagnosis, monitoring, or guiding treatments. This approach is promising for the early diagnosis of childhood cancer, especially for brain tumors, where tissue biopsies are more challenging and cause late detection. Extracellular vesicles offer several characteristics that make them ideal resources for childhood cancer liquid biopsy. Extracellular vesicles are nanosized particles, primarily secreted by all cell types into body fluids such as blood and urine, and contain molecular cargos, i.e., lipids, proteins, and nucleic acids of original cells. Notably, the lipid bilayer-enclosed structure of extracellular vesicles protects their cargos from enzymatic degradation in the extracellular milieu. Proteins and nucleic acids of extracellular vesicles represent genetic alterations and molecular profiles of childhood cancer, thus serving as promising resources for precision medicine in cancer diagnosis, treatment monitoring, and prognosis prediction. This review evaluates the recent progress of extracellular vesicles as a liquid biopsy platform for various types of childhood cancer, discusses the mechanistic roles of molecular cargos in carcinogenesis and metastasis, and provides perspectives on extracellular vesicle-guided therapeutic intervention. Extracellular vesicle-based liquid biopsy for childhood cancer may ultimately contribute to improving patient outcomes.
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Affiliation(s)
- Nilubon Singhto
- Ramathibodi Comprehensive Cancer Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand;
| | - Pongpak Pongphitcha
- Bangkok Child Health Center, Bangkok Hospital Headquarters, Bangkok 10130, Thailand;
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand;
| | - Natini Jinawath
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand;
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan 10540, Thailand
- Integrative Computational Biosciences Center, Mahidol University, Nakon Pathom 73170, Thailand
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand;
| | - Somchai Chutipongtanate
- MILCH and Novel Therapeutics Laboratory, Division of Epidemiology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
- Extracellular Vesicle Working Group, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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8
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Pirone D, Montella A, Sirico D, Mugnano M, Del Giudice D, Kurelac I, Tirelli M, Iolascon A, Bianco V, Memmolo P, Capasso M, Miccio L, Ferraro P. Phenotyping neuroblastoma cells through intelligent scrutiny of stain-free biomarkers in holographic flow cytometry. APL Bioeng 2023; 7:036118. [PMID: 37753527 PMCID: PMC10519746 DOI: 10.1063/5.0159399] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/21/2023] [Indexed: 09/28/2023] Open
Abstract
To efficiently tackle certain tumor types, finding new biomarkers for rapid and complete phenotyping of cancer cells is highly demanded. This is especially the case for the most common pediatric solid tumor of the sympathetic nervous system, namely, neuroblastoma (NB). Liquid biopsy is in principle a very promising tool for this purpose, but usually enrichment and isolation of circulating tumor cells in such patients remain difficult due to the unavailability of universal NB cell-specific surface markers. Here, we show that rapid screening and phenotyping of NB cells through stain-free biomarkers supported by artificial intelligence is a viable route for liquid biopsy. We demonstrate the concept through a flow cytometry based on label-free holographic quantitative phase-contrast microscopy empowered by machine learning. In detail, we exploit a hierarchical decision scheme where at first level NB cells are classified from monocytes with 97.9% accuracy. Then we demonstrate that different phenotypes are discriminated within NB class. Indeed, for each cell classified as NB its belonging to one of four NB sub-populations (i.e., CHP212, SKNBE2, SHSY5Y, and SKNSH) is evaluated thus achieving accuracy in the range 73.6%-89.1%. The achieved results solve the realistic problem related to the identification circulating tumor cell, i.e., the possibility to recognize and detect tumor cells morphologically similar to blood cells, which is the core issue in liquid biopsy based on stain-free microscopy. The presented approach operates at lab-on-chip scale and emulates real-world scenarios, thus representing a future route for liquid biopsy by exploiting intelligent biomedical imaging.
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Affiliation(s)
| | | | - Daniele Sirico
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | - Martina Mugnano
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | - Danila Del Giudice
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | | | | | | | - Vittorio Bianco
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | - Pasquale Memmolo
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | - Mario Capasso
- Authors to whom correspondence should be addressed: and
| | - Lisa Miccio
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | - Pietro Ferraro
- CNR-ISASI, Institute of Applied Sciences and Intelligent Systems “E. Caianiello,” via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
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Kojima M, Harada T, Fukazawa T, Kurihara S, Touge R, Saeki I, Takahashi S, Hiyama E. Single-cell next-generation sequencing of circulating tumor cells in patients with neuroblastoma. Cancer Sci 2022; 114:1616-1624. [PMID: 36571449 PMCID: PMC10067419 DOI: 10.1111/cas.15707] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/04/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022] Open
Abstract
Circulating tumor cells (CTCs) derived from any tumor tissue could contribute to metastasis and resistance to cancer treatments. In this study, we performed single-cell next-generation sequencing of CTCs and evaluated their usefulness for characterizing tumor biology and the mechanisms of metastasis in neuroblastomas (NB). We aimed to isolate CTCs from 10 patients with NB at diagnosis before any treatments and four patients at relapse. GD2+ CD90+ CD45- CD235a- DAPI- cells were isolated as neuroblastoma CTCs using fluorescence-activated cell sorting. In five patients with advanced stages (M stage), DNA and RNA sequencing of CTCs at single-cell level were performed. NB CTCs were isolated from eight of the 10 patients at diagnosis and three of the four patients at relapse. More CTCs could be isolated from patients with advanced stages. In one patient, ALK mutation (p.F1174L), was identified in both tumor tissue and a CTC. In patients with MYCN amplification, this gene was amplified in 12 of 13 CTCs. Using single-cell RNA sequencing, angiogenesis-related and cell cycle-related genes together with CCND1 and TUBA1A genes were found to be upregulated in CTCs. In one patient, CTCs were divided into two subgroups showing different gene expression profiles. In one subgroup, cell cycle-related and proliferation-related genes were differentially upregulated compared with the other group. In conclusion, next-generation sequencing of CTCs at single-cell level might help to characterize the tumor biology and the mechanisms of metastasis in NB.
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Affiliation(s)
- Masato Kojima
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan.,Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
| | - Takanori Harada
- Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
| | - Takahiro Fukazawa
- Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
| | - Sho Kurihara
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryo Touge
- Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Isamu Saeki
- Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Shinya Takahashi
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eiso Hiyama
- Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan.,Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
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10
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Zhuo Z, Lin L, Miao L, Li M, He J. Advances in liquid biopsy in neuroblastoma. FUNDAMENTAL RESEARCH 2022; 2:903-917. [PMID: 38933377 PMCID: PMC11197818 DOI: 10.1016/j.fmre.2022.08.005] [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: 04/27/2022] [Revised: 07/18/2022] [Accepted: 08/09/2022] [Indexed: 10/15/2022] Open
Abstract
Even with intensive treatment of high-risk neuroblastoma (NB) patients, half of high-risk NB patients still relapse. New therapies targeting the biological characteristics of NB have important clinical value for the personalized treatment of NB. However, the current biological markers for NB are mainly analyzed by tissue biopsy. In recent years, circulating biomarkers of NB based on liquid biopsy have attracted more and more attention. This review summarizes the analytes and methods for liquid biopsy of NB. We focus on the application of liquid biopsy in the diagnosis, prognosis assessment, and monitoring of NB. Finally, we discuss the prospects and challenges of liquid biopsy in NB.
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Affiliation(s)
- Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
- Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Meng Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
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11
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Loh AHP, Angelina C, Wong MK, Tan SH, Sukhatme SA, Yeo T, Lim SB, Lee YT, Soh SY, Leung W, Chang KTE, Chua YW, Alkaff SMF, Lim TKH, Lim CT, Chen ZX. Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse. Front Oncol 2022; 12:939460. [PMID: 36176417 PMCID: PMC9513238 DOI: 10.3389/fonc.2022.939460] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes via NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.
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Affiliation(s)
- Amos H. P. Loh
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
| | - Clara Angelina
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Meng Kang Wong
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Sheng Hui Tan
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Sarvesh A. Sukhatme
- Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Trifanny Yeo
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Su Bin Lim
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| | - York Tien Lee
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
| | - Shui Yen Soh
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Wing Leung
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Kenneth T. E. Chang
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Yong Wei Chua
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Syed M. F. Alkaff
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Tony K. H. Lim
- Duke NUS Medical School, Singapore, Singapore
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Teck Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- Institute of Health Innovation and Technology, National University of Singapore, Singapore, Singapore
| | - Zhi Xiong Chen
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Cancer Institute, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- *Correspondence: Zhi Xiong Chen,
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12
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Yang R, Zheng S, Dong R. Circulating tumor cells in neuroblastoma: Current status and future perspectives. Cancer Med 2022; 12:7-19. [PMID: 35632981 PMCID: PMC9844658 DOI: 10.1002/cam4.4893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/09/2022] [Accepted: 05/15/2022] [Indexed: 01/26/2023] Open
Abstract
Neuroblastoma is the most common extracranial solid tumor in children, accounting for 10% to 20% of deaths of pediatric malignancies. Due to the poor prognosis and significant biological heterogeneity of neuroblastoma, it is essential to develop personalized therapeutics and monitor treatment response. Circulating tumor cells (CTCs), as one of the important analytes for liquid biopsy, could facilitate response assessment and outcome prediction for patients in a non-invasive way. Several methods and platforms have been used for the enrichment and detection of CTCs. The enumeration of CTCs counts and evaluation of tumor-specific mRNA transcript levels could provide prognostic information at diagnosis, during or after chemotherapy, and during the process of disease progression. So far, studies into neuroblastoma CTCs are only in the preliminary stages. The quality-controlled large prospective cohort studies are needed to evaluate the clinical significance and statistical rigor of CTC detection methods. Moreover, there remains a lot to be explored and investigated in genotyping characterization of neuroblastoma (NB) CTCs and construction of in-vitro or in-vivo functional models. CTCs and circulating tumor DNA (ctDNA) analysis will be complementary in understanding tumor heterogeneity and evolution over the course of therapy for patients with NB in the future.
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Affiliation(s)
- Ran Yang
- Department of Pediatric SurgeryChildren's Hospital of Fudan UniversityShanghaiChina
| | - Shan Zheng
- Department of Pediatric SurgeryChildren's Hospital of Fudan UniversityShanghaiChina
| | - Rui Dong
- Department of Pediatric SurgeryChildren's Hospital of Fudan UniversityShanghaiChina
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13
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Guo Z, Lin X, Hui Y, Wang J, Zhang Q, Kong F. Circulating Tumor Cell Identification Based on Deep Learning. Front Oncol 2022; 12:843879. [PMID: 35252012 PMCID: PMC8889528 DOI: 10.3389/fonc.2022.843879] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/21/2022] [Indexed: 12/18/2022] Open
Abstract
As a major reason for tumor metastasis, circulating tumor cell (CTC) is one of the critical biomarkers for cancer diagnosis and prognosis. On the one hand, CTC count is closely related to the prognosis of tumor patients; on the other hand, as a simple blood test with the advantages of safety, low cost and repeatability, CTC test has an important reference value in determining clinical results and studying the mechanism of drug resistance. However, the determination of CTC usually requires a big effort from pathologist and is also error-prone due to inexperience and fatigue. In this study, we developed a novel convolutional neural network (CNN) method to automatically detect CTCs in patients’ peripheral blood based on immunofluorescence in situ hybridization (imFISH) images. We collected the peripheral blood of 776 patients from Chifeng Municipal Hospital in China, and then used Cyttel to delete leukocytes and enrich CTCs. CTCs were identified by imFISH with CD45+, DAPI+ immunofluorescence staining and chromosome 8 centromeric probe (CEP8+). The sensitivity and specificity based on traditional CNN prediction were 95.3% and 91.7% respectively, and the sensitivity and specificity based on transfer learning were 97.2% and 94.0% respectively. The traditional CNN model and transfer learning method introduced in this paper can detect CTCs with high sensitivity, which has a certain clinical reference value for judging prognosis and diagnosing metastasis.
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Affiliation(s)
- Zhifeng Guo
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Xiaoxi Lin
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Yan Hui
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Jingchun Wang
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Qiuli Zhang
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Fanlong Kong
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
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14
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Li L, Chen F, Lin A, Wang D, Shi Y, Chen G. Detection of BRCA1/2 Mutation and Analysis of Clinicopathological Characteristics in 141 Cases of Ovarian Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:4854282. [PMID: 34721658 PMCID: PMC8554521 DOI: 10.1155/2021/4854282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/28/2021] [Indexed: 12/04/2022]
Abstract
Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are known biomarkers for hereditary ovarian cancer (OC). However, a comprehensive association study between BRCA1/2 mutation spectrum and clinicopathological characteristics in Chinese ovarian cancer patients has not been performed yet to our best knowledge. To fill in this gap, we collected BRCA1/2 sequencing data and clinical information of 141 OC patients from Fujian Cancer Hospital between April 2018 and March 2020. The clinical information includes the age of onset, FIGO staging, pathological types, serum 125 detection level, lymph node metastasis, distant metastasis, the expression of Ki67, and disease history of the patient and his/her family. We then studied their associations by software SciPy 1.0. As a result, we detected pathogenic and potentially pathogenic BRCA1/2 mutations in 27 out of 141 patients (19.15%). Among the 27 patients with mutations, the major type of mutation was frameshift, which was observed in 12 patients (44.4%). Most of the mutation sites were distributed on exons 10 and 11, accounting for 48.1% (13/27) and 22.2% (6/27), respectively. In terms of histological classification, high-grade serous adenocarcinoma accounted for 79.43% of the 141 samples. The BRCA1/2 mutation group was all high-grade serous adenocarcinoma, accounting for 24.1% (27/112) of this group. The incidence of pathogenic mutation in BRCA1 and BRCA2 was 15.7% (19/112) and 7.27% (8/112), respectively. Univariate analysis showed that there was no significant difference between patients with BRCA1/2 mutation and others in age-of-onset, FIGO stage, pathological types, serum CA125 level, lymph node metastasis, the expression of Ki67, and personal and family disease history. However, there are significant differences between patients with BRCA1/2 mutation and others in distant metastasis rate (P < 0.002). In addition, the BRCA1/2 mutation rate in 141 ovarian cancer patients was similar to those reported in other studies in China. Nearly one-quarter of high-grade serous carcinomas had BRCA1/2 mutations. In conclusion, our study indicated that patients with BRCA1/2 mutations were more likely to undergo distant metastasis, and BRCA1/2 mutation detection should be performed for patients with high-grade serous adenocarcinoma to guide the selection of clinical treatment options.
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Affiliation(s)
- Ling Li
- Department of Gynecological Oncology Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China
| | - Fangfang Chen
- Department of Molecular Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China
| | - An Lin
- Department of Gynecological Oncology Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China
| | - Di Wang
- Department of Molecular Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China
| | - Yi Shi
- Department of Molecular Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China
| | - Gang Chen
- Department of Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350014, China
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15
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Shawraba F, Hammoud H, Mrad Y, Saker Z, Fares Y, Harati H, Bahmad HF, Nabha S. Biomarkers in Neuroblastoma: An Insight into Their Potential Diagnostic and Prognostic Utilities. Curr Treat Options Oncol 2021; 22:102. [PMID: 34580780 DOI: 10.1007/s11864-021-00898-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2021] [Indexed: 12/23/2022]
Abstract
OPINION STATEMENT Neuroblastoma (NB) is a heterogeneous solid tumor of the pediatric population that originates from neural crest cells and affects the developing sympathetic nervous system. It is the most common neuroblastic tumor accounting for approximately 10% of all childhood cancers and 10-15% of pediatric tumor mortalities. The outcomes range from spontaneous tumor regression in low-risk groups to metastasis and death even after multimodal therapy in high-risk groups. Hence, the detection of NB at an early stage improves outcomes and provides a better prognosis for patients. Early detection and prognosis of NB depend on specific molecules termed biomarkers which can be tissue-specific or circulating. Certain biomarkers are employed in the classification of NB into different groups to improve the treatment and prognosis, and others can be used as therapeutic targets. Therefore, novel biomarker discovery is essential for the early detection of NB, predicting the course of the disease, and developing new targeted treatment strategies. In this review, we aim to summarize the literature pertinent to some important biomarkers of NB and discuss the prognostic role of these biomarkers as well as their potential role in targeted therapy.
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Affiliation(s)
- Fatima Shawraba
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Hussein Hammoud
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Yara Mrad
- Université Clermont Auvergne, Inserm, Neuro-Dol, Clermont-Ferrand, France
| | - Zahraa Saker
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Youssef Fares
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon.,Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Hayat Harati
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Hisham F Bahmad
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL, 33140, USA.
| | - Sanaa Nabha
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon.
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16
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Zhang W, Duan X, Zhang Z, Yang Z, Zhao C, Liang C, Liu Z, Cheng S, Zhang K. Combination of CT and telomerase+ circulating tumor cells improves diagnosis of small pulmonary nodules. JCI Insight 2021; 6:148182. [PMID: 33905377 PMCID: PMC8262359 DOI: 10.1172/jci.insight.148182] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/23/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early diagnosis and treatment are key to the long-term survival of lung cancer patients. Although CT has significantly contributed to the early diagnosis of lung cancer, there are still consequences of excessive or delayed treatment. By improving the sensitivity and specificity of circulating tumor cell (CTC) detection, a solution was proposed for differentiating benign from malignant pulmonary nodules. METHODS In this study, we used telomerase reverse transcriptase–based (TERT-based) CTC detection (TBCD) to distinguish benign from malignant pulmonary nodules < 2 cm and compared this method with the pathological diagnosis as the gold standard. FlowSight and FISH were used to confirm the CTCs detected by TBCD. RESULTS Our results suggest that CTCs based on TBCD can be used as independent biomarkers to distinguish benign from malignant nodules and are significantly superior to serum tumor markers. When the detection threshold was 1, the detection sensitivity and specificity of CTC diagnosis were 0.854 and 0.839, respectively. For pulmonary nodules ≤ 1 cm and 1–2 cm, the sensitivity and specificity of CTCs were both higher than 77%. Additionally, the diagnostic ability of CTC-assisted CT was compared by CT detection. The results show that CT combined with CTCs could significantly improve the differentiation ability of benign and malignant nodules in lung nodules < 2 cm and that the sensitivity and specificity could reach 0.899 and 0.839, respectively. CONCLUSION TBCD can effectively diagnose pulmonary nodules and be used as an effective auxiliary diagnostic scheme for CT diagnosis. FUNDING National Key Research and Development Project grant nos. 2019YFC1315700 and 2017YFC1308702, CAMS Initiative for Innovative Medicine grant no. 2017-I2M-1-005, and National Natural Science Foundation of China grant no. 81472013.
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Affiliation(s)
- Wen Zhang
- Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinchun Duan
- Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhenrong Zhang
- Department of General Thoracic Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Zhenrong Yang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changyun Zhao
- Chongqing Deepexam Biotechnology Co. Ltd., Chongqing, China
| | | | - Zhidong Liu
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Shujun Cheng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kaitai Zhang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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17
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Liquid biomarkers for the management of paediatric neuroblastoma: an approach to personalised and targeted cancer therapy. JOURNAL OF RADIOTHERAPY IN PRACTICE 2021. [DOI: 10.1017/s1460396920000102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AbstractBackground:Neuroblastoma is the most common extracranial solid tumour of infancy and accounts for about 6–10% of paediatric cancers. It has a biologically and clinically heterogeneous behaviour that ranges from spontaneous regression to cases of highly aggressive metastatic disease that could be unresponsive to standard therapy. In recent years, there have been several investigations into the development of various diagnostic, predictive and prognostic biomarkers towards personalised and targeted management of the disease.Materials and Methods:This paper reports on the review of current clinical and emerging biomarkers used in risk assessment, screening for early detection and diagnosis, prognostication and monitoring of the response of treatment of neuroblastoma in paediatric patients.Conclusions:Tumour markers can significantly improve diagnosis; however, the invasive, unpleasant and inconvenient nature of current tissue biopsies limits their applications, especially in paediatric patients. Therefore, the development of a non-invasive, reliable high accurate and personalised diagnostic tool capable of early detection and rapid response is the most promising step towards advanced cancer management from tumour diagnosis, therapy to patient monitoring and represents an important step towards the promise of precision, personalised and targeted medicine. Liquid biopsy assay with wide ranges of clinical applications is emerging to hold incredible potential for advancing cancer treatment and has greater promise for diagnostic purposes, identification and tracking of tumour-specific alterations during the course of the disease and to guide therapeutic decisions.
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18
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Jiang SS, Mao CG, Feng YG, Jiang B, Tao SL, Tan QY, Deng B. Circulating tumor cells with epithelial-mesenchymal transition markers as potential biomarkers for the diagnosis of lung cancer. World J Clin Cases 2021; 9:2721-2730. [PMID: 33969055 PMCID: PMC8058682 DOI: 10.12998/wjcc.v9.i12.2721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/19/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) can be clustered into three subtypes according to epithelial-mesenchymal transition (EMT) markers: CTCs with epithelial markers (E-CTCs), CTCs with mesenchymal markers (M-CTCs), and CTCs with both markers (E&M-CTCs). CTC detection has clinical implications in the diagnosis of lung cancer (LC). AIM To clarify the diagnostic value of CTCs categorized by EMT markers in LC. METHODS The study included 106 patients with lung adenocarcinoma, including 42 ground-glass opacities (GGO) and 64 solid lesions, who underwent surgery between July 2015 and December 2019. Eleven patients with benign tumors and seventeen healthy controls were included. CTCs in peripheral blood and associated EMT markers were detected preoperatively using the CanPatrolTM technique. The diagnostic power of CTCs for discriminating LC cases from controls was analyzed by the receiver operating characteristic (ROC) curve. The CytoploRare technique was used in 20 cases and 18 controls for validation, and Kappa values were calculated to evaluate consistency between techniques. RESULTS Of the 106 LC cases, 94 (89.6%) had at least one CTC. CTCs were detectable in 35 (83.3%) of 42 GGO cases. Total CTCs and E&M-CTCs were significantly more frequent in LC cases than in benign or healthy controls. The proportion of M-CTCs plus E&M-CTCs increased gradually from healthy controls, to benign controls, to LC cases. The area under the ROC curve of total CTCs and E&M-CTCs was > 0.8 and > 10.75, respectively. The combined sensitivity of total-CTCs and E&M-CTCs was 85.85% for LC patients (80.95% for GGO patients) and the specificity was 78.57%. The Kappa value was 0.415, indicating relative consistency between CanPatrolTM and CytoploRare. CONCLUSION CTC detection is valuable for distinguishing LC from controls, and particularly E&M-CTC detection warrants further study.
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Affiliation(s)
- Sha-Sha Jiang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Chun-Guo Mao
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Yong-Geng Feng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Bin Jiang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Shao-Lin Tao
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Qun-You Tan
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Bo Deng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
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19
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Gavin C, Geerts N, Cavanagh B, Haynes M, Reynolds CP, Loessner D, Ewald AJ, Piskareva O. Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix. Cancers (Basel) 2021; 13:736. [PMID: 33578855 PMCID: PMC7916632 DOI: 10.3390/cancers13040736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/30/2021] [Accepted: 02/04/2021] [Indexed: 02/06/2023] Open
Abstract
Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system. About half of the patients have metastatic disease at the time of diagnosis and a survival rate of less than 50%. Our understanding of the cellular processes promoting neuroblastoma metastases will be facilitated by the development of appropriate experimental models. In this study, we aimed to explore the invasion of neuroblastoma cells and organoids from patient-derived xenografts (PDXs) grown embedded in 3D extracellular matrix (ECM) hydrogels by time-lapse microscopy and quantitative image analysis. We found that the ECM composition influenced the growth, viability and local invasion of organoids. The ECM compositions induced distinct cell behaviours, with Matrigel being the preferred substratum for local organoid invasion. Organoid invasion was cell line- and PDX-dependent. We identified six distinct phenotypes in PDX-derived organoids. In contrast, NB cell lines were more phenotypically restricted in their invasion strategies, as organoids isolated from cell line-derived xenografts displayed a broader range of phenotypes compared to clonal cell line clusters. The addition of FBS and bFGF induced more aggressive cell behaviour and a broader range of phenotypes. In contrast, the repression of the prognostic neuroblastoma marker, MYCN, resulted in less aggressive cell behaviour. The combination of PDX organoids, real-time imaging and the novel 3D culture assays developed herein will enable rapid progress in elucidating the molecular mechanisms that control neuroblastoma invasion.
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Affiliation(s)
- Cian Gavin
- Cancer Bio-Engineering Group, Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland; (C.G.); (N.G.)
| | - Nele Geerts
- Cancer Bio-Engineering Group, Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland; (C.G.); (N.G.)
| | - Brenton Cavanagh
- Cellular and Molecular Imaging Core, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland;
| | - Meagan Haynes
- Center for Cell Dynamics, Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (M.H.); (A.J.E.)
| | - C. Patrick Reynolds
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79416, USA;
- Departments of Pediatrics and Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79416, USA
| | - Daniela Loessner
- Departments of Chemical Engineering and Materials Science and Engineering, Faculty of Engineering, Monash University, Melbourne, VIC 3800, Australia;
- Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3800, Australia
| | - Andrew J. Ewald
- Center for Cell Dynamics, Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (M.H.); (A.J.E.)
- Sidney Kimmel Comprehensive Cancer Center, Cancer Invasion and Metastasis Program, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Olga Piskareva
- Cancer Bio-Engineering Group, Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland; (C.G.); (N.G.)
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin D12 8MGH, Ireland
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20
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Zhao L, Wu X, Zheng J, Dong D. DNA methylome profiling of circulating tumor cells in lung cancer at single base-pair resolution. Oncogene 2021; 40:1884-1895. [PMID: 33564067 PMCID: PMC7946637 DOI: 10.1038/s41388-021-01657-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/14/2020] [Accepted: 01/13/2021] [Indexed: 01/30/2023]
Abstract
DNA methylation plays a pivotal role in regulating cellular processes, and altered DNA methylation pattern is a general hallmark of cancer. However, DNA methylome in circulating tumor cells (CTCs) is still a mystery due to the lack of proper analytical techniques. We introduced an efficient workflow, LCM-µWGBS, which can efficiently profile the DNA methylation of microdissected CTC samples. LCM-µWGBS combines the laser capture microdissection (LCM)-based CTC capture method and whole-genome bisulfite sequencing in very small CTC population (µWGBS) to gain insight into the DNA methylation landscape of CTCs. We herein profiled the DNA methylome of CTCs from lung cancer patients. Deriving from a comprehensive analysis of CTC methylome, a unique "CTC DNA methylation signature" that is distinct from primary lung cancer tissues was identified. Further analysis showed that promoter hypermethylation of epithelial genes is a hallmark of stable epithelial-mesenchymal transition process. Moreover, it has been suggested that CTCs are endowed with a stemness-related feature during dissemination and metastasis. This work constitutes a unique DNA methylation analysis of CTCs at single base-pair resolution, which might facilitate to propose noninvasive CTC DNA methylation biomarkers contributing to clinical diagnosis.
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Affiliation(s)
- Lei Zhao
- grid.417303.20000 0000 9927 0537Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu China ,grid.413389.4Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China ,grid.22069.3f0000 0004 0369 6365Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China
| | - Xiaohong Wu
- Department of General Surgery, Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200 Jiangsu China
| | - Junnian Zheng
- grid.417303.20000 0000 9927 0537Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu China ,grid.413389.4Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Dong Dong
- grid.417303.20000 0000 9927 0537Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu China ,grid.413389.4Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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21
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Song H, Hou X, Zeng M, Chen X, Chen X, Yang T, Xu F, Peng J, Peng Q, Cai X, Yu R. Traditional Chinese Medicine Li-Zhong-Tang accelerates the healing of indomethacin-induced gastric ulcers in rats by affecting TLR-2/MyD88 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2020; 259:112979. [PMID: 32442585 DOI: 10.1016/j.jep.2020.112979] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/25/2020] [Accepted: 05/11/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Li-Zhong-Tang (LZT) is a well-known Chinese herbal formulation first described in one of traditional Chinese medicine (TCM) scriptures, Treatise on Febrile Diseases. LZT has been commonly prescribed for the treatment of various gastrointestinal diseases for over 1800 years, and has demonstrated pronounced therapeutic effects on patients with gastric ulcers. AIM OF THE STUDY The present study aimed to scientifically evaluate protective effects of LZT on indomethacin (IND)-induced gastric injury in rats and to elucidate whether LZT exerts its gastro-protective effects via enhancing mucosal immunity by regulating TLR-2/MyD88 signaling pathway. MATERIAL AND METHODS Gastric ulcers were induced in male Sprague-Dawley (SD) rats with a single oral dose of 150 mg/kg IND. Ulcer index (UI) and curative index (CI) were evaluated. Histopathological examinations were performed and microscopic score (MS) was macroscopically calculated. The volume of gastric juice, free acidity, total acidity, and gastric pH was measured. The gastroprotective and inflammatory biomarkers including levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and malondialdehyde (MDA) were determined. Expression levels of TLR-2 and MyD88 mRNA were assessed by qRT-PCR. The expression, distribution, and co-localization of TLR-2 and MyD88 protein were determined by Western blot, immunohistochemistry, and immunofluorescence, respectively. RESULTS Induction of gastric ulcers in rats resulted in very significantly increased UI and elevated volume and acidity of gastric juice, which were markedly attenuated by LZT treatment. Microscopic examinations of the IND-induced gastric ulcers revealed severe gastric hemorrhagic necrosis, submucosal edema, and destruction of epithelial cells, which were significantly attenuated in LZT-treated rats. Moreover, treatment with LZT remarkably increased gastric mucosal levels of PGE2 and NO, and lowered highly elevated levels of TNF-α and MDA in gastric ulcerative rats. Mechanistically, LZT inhibited mRNA and protein expression of TLR-2 and MyD88 and enhanced immune function in gastric mucosa. Immunohistochemical analyses and immunofluorescent detection further confirmed a markedly decreased co-localization of TLR-2 and MyD88 protein in the gastric mucosa of LZT-treated rats as compared to that of gastric ulcerative rats. CONCLUSIONS These findings indicate that LZT alleviates serious gastric mucosal ulcerations induced by IND. Protective effects of LZT on gastric ulcers are believed to be associated with the intensification of the anti-oxidative defense system, mitigation of proinflammatory cytokines, stimulation of the production of cytoprotective mediators, and improvement of the mucosal immunity through TLR-2/MyD88 signaling pathway.
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Affiliation(s)
- Houpan Song
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Xueqin Hou
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai' an, Shandong, 271016, China.
| | - Meiyan Zeng
- Hunan Provincial Key Laboratory of Translational Research in TCM Prescriptions and Zheng, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Xiaojuan Chen
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Provincial Key Laboratory of Translational Research in TCM Prescriptions and Zheng, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Xinyi Chen
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Provincial Key Laboratory of Translational Research in TCM Prescriptions and Zheng, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Tao Yang
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Fuping Xu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
| | - Jun Peng
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Qinghua Peng
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Xiong Cai
- Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
| | - Rong Yu
- Hunan Provincial Key Laboratory of Translational Research in TCM Prescriptions and Zheng, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
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22
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He B, Lu Q, Lang J, Yu H, Peng C, Bing P, Li S, Zhou Q, Liang Y, Tian G. A New Method for CTC Images Recognition Based on Machine Learning. Front Bioeng Biotechnol 2020; 8:897. [PMID: 32850745 PMCID: PMC7423836 DOI: 10.3389/fbioe.2020.00897] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/13/2020] [Indexed: 12/18/2022] Open
Abstract
Circulating tumor cells (CTCs) derived from primary tumors and/or metastatic tumors are markers for tumor prognosis, and can also be used to monitor therapeutic efficacy and tumor recurrence. Circulating tumor cells enrichment and screening can be automated, but the final counting of CTCs currently requires manual intervention. This not only requires the participation of experienced pathologists, but also easily causes artificial misjudgment. Medical image recognition based on machine learning can effectively reduce the workload and improve the level of automation. So, we use machine learning to identify CTCs. First, we collected the CTC test results of 600 patients. After immunofluorescence staining, each picture presented a positive CTC cell nucleus and several negative controls. The images of CTCs were then segmented by image denoising, image filtering, edge detection, image expansion and contraction techniques using python’s openCV scheme. Subsequently, traditional image recognition methods and machine learning were used to identify CTCs. Machine learning algorithms are implemented using convolutional neural network deep learning networks for training. We took 2300 cells from 600 patients for training and testing. About 1300 cells were used for training and the others were used for testing. The sensitivity and specificity of recognition reached 90.3 and 91.3%, respectively. We will further revise our models, hoping to achieve a higher sensitivity and specificity.
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Affiliation(s)
- Binsheng He
- Academician Workstation, Changsha Medical University, Changsha, China
| | - Qingqing Lu
- Geneis (Beijing) Co., Ltd., Beijing, China.,Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Jidong Lang
- Geneis (Beijing) Co., Ltd., Beijing, China.,Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Hai Yu
- Geneis (Beijing) Co., Ltd., Beijing, China
| | - Chao Peng
- Geneis (Beijing) Co., Ltd., Beijing, China
| | - Pingping Bing
- Academician Workstation, Changsha Medical University, Changsha, China
| | - Shijun Li
- Department of Pathology, Chifeng Municipal Hospital, Chifeng, China
| | - Qiliang Zhou
- Academician Workstation, Changsha Medical University, Changsha, China
| | - Yuebin Liang
- Geneis (Beijing) Co., Ltd., Beijing, China.,Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Geng Tian
- Geneis (Beijing) Co., Ltd., Beijing, China.,Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
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23
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Zheng J, Ye X, Liu Y, Zhao Y, He M, Xiao H. The combination of CTCs and CEA can help guide the management of patients with SPNs suspected of being lung cancer. BMC Cancer 2020; 20:106. [PMID: 32041568 PMCID: PMC7011271 DOI: 10.1186/s12885-020-6524-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/08/2020] [Indexed: 12/15/2022] Open
Abstract
Objective Solitary pulmonary nodules (SPNs) is a common radiographic finding and require further evaluation because of the possibility of lung cancer. This study aimed to determine the sensitivity and specificity of circulating tumour cells (CTCs) as a marker for the diagnosis of SPNs and the integration of CTCs, carcinoembryonic antigen (CEA) and imaging findings to improve the sensitivity and specificity of diagnosis in patients with SPNs suspected of being lung cancer. Method For the serum biomarker assay, the concentration of CEA was measured by an automated electrochemiluminescence analyzer. CTCs were collected from 6 ml of blood by the SE i-FISH method, which detects the gene copy number in eight chromosomes and the tumour-associated antigen CK18. Results With a threshold of 6 CTC units, the method showed a sensitivity of 67.1% and a specificity of 56.5% in the diagnosis of NSCLC, especially in the upper lobe, in which the diagnostic strength was the highest (P < 0.01). CTCs, CEA and nodule type had the highest diagnostic efficacy (area under the curve, 0.827; 95% confidence interval, 0.752–0.901) in patients with SPNs being suspected lung cancer. Combining CTCs (cut-off value 12 units) with CEA (1.78 ng/ml), the method showed a sensitivity of 77.8% and a specificity of 90% in the diagnosis of NSCLC, especially in the upper lobe, subsolid nodules and nodules ≥8 mm. Conclusions Our results demonstrated that CTCs are feasible diagnostic biomarkers in patients with SPNs, especially in the upper lobe. Furthermore, CTCs combined with CEA showed higher diagnostic efficacy in the upper lobe, subsolid nodules and nodules ≥8 mm.
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Affiliation(s)
- Jian Zheng
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Xiong Ye
- College of Clinical Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
| | - Yanan Liu
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yuxia Zhao
- College of Clinical Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
| | - Mudan He
- Department of Respiratory and Critical Care Medicine, Shanghai First Hospital of Baoshan Branch, Shanghai, China
| | - Hui Xiao
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 85Wujin Road, Shanghai, 200080, China.
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24
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Jiang SS, Deng B, Feng YG, Qian K, Tan QY, Wang RW. Circulating tumor cells prior to initial treatment is an important prognostic factor of survival in non-small cell lung cancer: a meta-analysis and system review. BMC Pulm Med 2019; 19:262. [PMID: 31878900 PMCID: PMC6933689 DOI: 10.1186/s12890-019-1029-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 12/12/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Our study aimed to verify the prognostic value of circulating tumor cells (CTCs) prior to initial treatment on survival of non-small cell lung cancer (NSCLC) by using meta-analysis and system review of published studies. MATERIALS AND METHODS The PubMed, EMBASE and Cochrane Library were searched, respectively, to identify all studies that addressed the issues of CTCs prior to initial treatment and progression-free survival (PFS) and overall survival (OS). Finally, ten citations were included for analysis and assessment of publication bias by using review manager 5.3 statistical software and STATA 15.0. RESULTS Randomized model analyzing multivariate Cox Proportional Hazards Regression indicated that higher abundance of CTCs significantly predicts poorer prognosis of lung cancer cases basing both on PFS (Z = 2.31, P = 0.02) and OS of advanced cases (Z = 2.44, P = 0.01), and systematic study aslo indicated the similar results. CONCLUSION High CTCs prior to initial treatment can predict shorter PFS and OS in NSCLC, and further studies are warranted in the future.
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Affiliation(s)
- Sha-Sha Jiang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China
| | - Bo Deng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China.
| | - Yong-Geng Feng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China
| | - Kai Qian
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China
| | - Qun-You Tan
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China
| | - Ru-Wen Wang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People's Republic of China
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25
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Gao L, Lin P, Chen P, Gao R, Yang H, He Y, Chen J, Luo Y, Xu Q, Liang S, Gu J, Huang Z, Dang Y, Chen G. A novel risk signature that combines 10 long noncoding RNAs to predict neuroblastoma prognosis. J Cell Physiol 2019; 235:3823-3834. [PMID: 31612488 DOI: 10.1002/jcp.29277] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 09/27/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Li Gao
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Peng Lin
- Department of Ultrasound First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Peng Chen
- Department of Pediatric Surgery First calculated using the following formula Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Rui‐Zhi Gao
- Department of Ultrasound First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Hong Yang
- Department of Ultrasound First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Yun He
- Department of Ultrasound First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Jia‐Bo Chen
- Department of Pediatric Surgery First calculated using the following formula Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Yi‐Ge Luo
- Department of Pediatric Surgery First calculated using the following formula Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Qiong‐Qian Xu
- Department of Pediatric Surgery First calculated using the following formula Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Song‐Wu Liang
- Department of Pediatric Surgery First calculated using the following formula Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Jin‐Han Gu
- Department of Pediatric Surgery First calculated using the following formula Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Zhi‐Guang Huang
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Yi‐Wu Dang
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Gang Chen
- Department of Pathology First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
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26
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Zhang Y, Li J, Wang L, Meng P, Zhao J, Han P, Xia J, Xu J, Wang L, Shen F, Zheng A, Zhou F, Fan R. Clinical significance of detecting circulating tumor cells in patients with esophageal squamous cell carcinoma by EpCAM‑independent enrichment and immunostaining‑fluorescence in situ hybridization. Mol Med Rep 2019; 20:1551-1560. [PMID: 31257510 PMCID: PMC6625432 DOI: 10.3892/mmr.2019.10420] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 05/14/2019] [Indexed: 12/16/2022] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells present in the bloodstream, which originate from tumor sites, and are ultimately responsible for metastasis or relapse in several types of cancer. However, to the best of our knowledge, only a few studies have investigated these extremely rare cells in esophageal squamous cell carcinoma (ESCC). In the present study, 63 patients with ESCC and 50 healthy donors were recruited, and the potential clinical significance of CTCs was assessed using subtraction enrichment and immunostaining‑fluorescence in situ hybridization. Blood samples were collected at the following times: At first diagnosis, following neoadjuvant chemoradiotherapy, 24 h and 13 days post‑surgery, and every 3 months during follow‑up. Cytokeratin (CK)‑positive and clustered CTCs only accounted for 1% of total CTCs detected, whereas most CTCs were CK‑negative aneuploid cells. Patients with ESCC (n=63) had higher CTC counts compared with healthy donors (control group; n=50) (area under curve=0.807, median CTC count, 2 vs. 0). However, there was no statistical association between CTC counts and sex, age, pathological stage, tumor location, tumor depth or lymph node involvement (P>0.05). The association of tumor development with CTC status and other circulating biomarkers was monitored in patients for a further 2 years. The results revealed that a change in CTC counts between first diagnosis and 13 days post‑surgery (ΔCTC) of ≥2/7.5 ml peripheral blood could be applied for predicting progression‑free survival (hazard ratio, 3.922; 95% confidence interval, 0.907‑16.951; P<0.05) in patients with ESCC. In conclusion, ΔCTC evaluation may be a promising indicator for predicting tumor prognosis and the clinical efficacy of treatment in patients with ESCC.
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Affiliation(s)
- Yaowen Zhang
- The First Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Jian Li
- Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, Henan 455000, P.R. China
| | - Lu Wang
- Department of Medicine, Shanghai Zhangjiang Institute of Medical Innovation, Shanghai 201204, P.R. China
| | - Peng Meng
- Department of Medicine, Shanghai Zhangjiang Institute of Medical Innovation, Shanghai 201204, P.R. China
| | - Jiangman Zhao
- Department of Medicine, Shanghai Zhangjiang Institute of Medical Innovation, Shanghai 201204, P.R. China
| | - Peng Han
- Department of Pathology, Anyang Tumor Hospital, Anyang, Henan 455000, P.R. China
| | - Jin Xia
- The Fifth Department of Oncology, Anyang Tumor Hospital, Anyang, Henan 455000, P.R. China
| | - Jiangong Xu
- Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, Henan 455000, P.R. China
| | - Lidong Wang
- Henan Key Laboratory for Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Fangfang Shen
- The Key Laboratory for Tumor Translational Medicine, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Anping Zheng
- The First Department of Radiation Oncology, Anyang Tumor Hospital, Anyang, Henan 455000, P.R. China
| | - Fuyou Zhou
- Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, Henan 455000, P.R. China
| | - Ruitai Fan
- The First Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
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27
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Trigg RM, Shaw JA, Turner SD. Opportunities and challenges of circulating biomarkers in neuroblastoma. Open Biol 2019; 9:190056. [PMID: 31088252 PMCID: PMC6544987 DOI: 10.1098/rsob.190056] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/23/2019] [Indexed: 12/11/2022] Open
Abstract
Molecular analysis of nucleic acid and protein biomarkers is becoming increasingly common in paediatric oncology for diagnosis, risk stratification and molecularly targeted therapeutics. However, many current and emerging biomarkers are based on analysis of tumour tissue, which is obtained through invasive surgical procedures and in some cases may not be accessible. Over the past decade, there has been growing interest in the utility of circulating biomarkers such as cell-free nucleic acids, circulating tumour cells and extracellular vesicles as a so-called liquid biopsy of cancer. Here, we review the potential of emerging circulating biomarkers in the management of neuroblastoma and highlight challenges to their implementation in the clinic.
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Affiliation(s)
- Ricky M. Trigg
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Jacqui A. Shaw
- Leicester Cancer Research Centre, College of Life Sciences, University of Leicester, Leicester LE2 7LX, UK
| | - Suzanne D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK
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