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Rapanotti MC, Cugini E, Scioli MG, Cenci T, Anzillotti S, Puzzuoli M, Terrinoni A, Ferlosio A, De Luca A, Orlandi A. The Clinical Relevance of Epithelial-to-Mesenchymal Transition Hallmarks: A Cut-Off-Based Approach in Healthy and Cancerous Cell Lines. Int J Mol Sci 2025; 26:3617. [PMID: 40332096 PMCID: PMC12026647 DOI: 10.3390/ijms26083617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
The atypical activation of the epithelial-to-mesenchymal transition represents one of the main mechanisms driving cancer cell dissemination. It enables epithelial cancer cells to detach from the primary tumor mass and gain survival advantages in the bloodstream, significantly contributing to the spread of circulating tumor cells. Notably, epithelial-to-mesenchymal transition is not a binary process but rather leads to the formation of a wide range of cell subpopulations characterized by the simultaneous expression of both epithelial and mesenchymal markers. Therefore, analyzing the modulation of EMT hallmarks during the conversion from healthy cells to metastatic cancer cells, which acquire stem mesenchymal characteristics, is of particular interest. This study investigates the expression of a panel of epithelial-to-mesenchymal transition-related genes in healthy cells, primary and metastatic cancer cells, and in mesenchymal cell lines, derived from various tissues, including the lung, colon, pancreas, skin, and neuro-ectoderm, with the aim of identifying potential cut-off values for assessing cancer aggressiveness. Interestingly, we found that the expression levels of CDH1, which encodes the epithelial marker E-cadherin, CDH5, encoding vascular endothelial cadherin, and the epithelial-to-mesenchymal transition-transcription factor ZEB1, effectively distinguished primary from metastatic cancer cells. Additionally, our data suggest a tissue-specific signature in the modulation of epithelial-to-mesenchymal transition markers during cancer progression. Overall, our results underscore the importance of investigating epithelial-to-mesenchymal transition as a tissue-specific process to identify the most suitable markers acting as potential indicators of disease aggressiveness and therapeutic responsiveness.
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Affiliation(s)
- Maria Cristina Rapanotti
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Elisa Cugini
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
- Department of Laboratory Medicine, Tor Vergata University Hospital, 00133 Rome, Italy;
| | - Maria Giovanna Scioli
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Tonia Cenci
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Silvia Anzillotti
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Martina Puzzuoli
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Alessandro Terrinoni
- Department of Laboratory Medicine, Tor Vergata University Hospital, 00133 Rome, Italy;
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Amedeo Ferlosio
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Anastasia De Luca
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Augusto Orlandi
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
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Scholten D, El-Shennawy L, Jia Y, Zhang Y, Hyun E, Reduzzi C, Hoffmann AD, Almubarak HF, Tong F, Dashzeveg N, Sun Y, Squires JR, Lu J, Platanias LC, Wasserfall CH, Gradishar WJ, Cristofanilli M, Fang D, Liu H. Rare Subset of T Cells Form Heterotypic Clusters with Circulating Tumor Cells to Foster Cancer Metastasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.01.646421. [PMID: 40236049 PMCID: PMC11996511 DOI: 10.1101/2025.04.01.646421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
The immune ecosystem is central to maintaining effective defensive responses. However, how immune cells in the periphery blood interact with circulating tumor cells (CTCs) - seeds of metastasis - remains largely understudied. Here, our analysis of the blood specimens (N=1,529) from patients with advanced breast cancer revealed that over 75% of the CTC-positive blood specimens contained heterotypic CTC clusters with CD45 + white blood cells (WBCs). Detection of CTC-WBC clusters correlates with breast cancer subtypes (triple negative and luminal B), racial groups (Black), and decreased survival rates. Flow cytometry and ImageStream analyses revealed diverse WBC composition of heterotypic CTC-WBC clusters, including overrepresented T cells and underrepresented neutrophils. Most strikingly, a rare subset of CD4 and CD8 double positive T (DPT) cells showed an up to 140-fold enrichment in the CTC clusters versus its frequency in WBCs. DPT cells shared part of the profiles with CD4 + T cells and others with CD8 + T cells but exhibited unique features of T cell exhaustion and immune suppression with higher expression of TIM-3 and PD-1. Single-cell RNA sequencing and genetic perturbation studies further pinpointed the integrin VLA4 (α4β1) in DPT cells and its ligand VCAM1 in tumor cells as essential mediators of heterotypic WBC-CTC clusters. Neoadjuvant administration of anti-α4 (VLA4) neutralizing antibodies markedly blocked CTC-DPT cell clustering and inhibited metastasis for extended survival in preclinical mouse models in vivo . These findings uncover a pivotal role of rare DPT cells with immune suppressive features in fostering cancer dissemination through direct interactive clustering with CTCs. It lays a foundation for developing innovative biomarkers and therapeutic strategies to prevent and target cancer metastasis, ultimately benefiting cancer care. Brief summary Our findings uncover a fostering role of immune-suppressive T cells in contact with circulating tumor cells and identify therapeutic approaches to eliminate devastating cancer metastasis.
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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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Bates M, Mohamed BM, Lewis F, O'Toole S, O'Leary JJ. Biomarkers in high grade serous ovarian cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189224. [PMID: 39581234 DOI: 10.1016/j.bbcan.2024.189224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Faye Lewis
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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Fabisiewicz A, Szostakowska-Rodzos M, Grzybowska EA. Improving the Prognostic and Predictive Value of Circulating Tumor Cell Enumeration: Is Longitudinal Monitoring the Answer? Int J Mol Sci 2024; 25:10612. [PMID: 39408942 PMCID: PMC11476589 DOI: 10.3390/ijms251910612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
Circulating tumor cell (CTC) numbers in the blood of cancer patients can indicate the progression and invasiveness of tumors, and their prognostic and predictive value has been repeatedly demonstrated. However, the standard baseline CTC count at the beginning of treatment, while informative, is not completely reliable and may not adequately reflect the state of the disease. A growing number of studies indicate that the long-term monitoring of CTC numbers in the same patient provides more comprehensive prognostic data and should be incorporated into clinical practice, as a factor that contributes to therapeutic decisions. This review describes the current status of CTC enumeration as a prognostic and predictive factor, highlights the shortcomings of current solutions, and advocates for longitudinal CTC analysis as a more effective method of the evaluation of developing disease, treatment efficacy, and the long term-monitoring of the minimal residual disease. As evidenced by the described reports, the longitudinal monitoring of CTCs should provide a better and more sensitive prediction of the course of the disease, and its incorporation in clinical practice should be beneficial.
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Affiliation(s)
| | | | - Ewa A. Grzybowska
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland; (A.F.); (M.S.-R.)
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Schnoor B, Morris K, Kottana RK, Muldoon R, Barron J, Papa AL. Fibrinolytic Platelet Decoys Reduce Cancer Metastasis by Dissociating Circulating Tumor Cell Clusters. Adv Healthc Mater 2024; 13:e2304374. [PMID: 39075814 DOI: 10.1002/adhm.202304374] [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: 12/09/2023] [Revised: 07/07/2024] [Indexed: 07/31/2024]
Abstract
During metastasis, circulating tumor cells (CTCs) can travel in the bloodstream as individual cells or clusters, associated with fibrin and platelets. Clusters have a higher metastatic potential due to their increased ability to withstand shear stress and arrest in small vessels. Moreover, CTC-platelet interaction protects CTCs from shear stress and immune detection. The objective of this project is to develop a fibrinolytic platelet system to leverage platelet-CTC interactions and dissociate CTC clusters. For this approach, tissue plasminogen activator (tPA) is loaded onto two modified platelet systems: platelet Decoys and lyophilized platelets. The activities of the systems are characterized using a Förster Resonance Energy Transfer-based assay and an angiogenic assay. Furthermore, the ability of the system to dissociate cancer cell clusters in vitro is assessed using light transmission aggregometry. The data demonstrates that the fibrinolytic platelets can maintain tPA activity, interact with CTCs, and dissociate cancer cell clusters. Finally, fibrinolytic platelets are assessed in vivo, demonstrating a decreased tumor load and increased survival with tPA-Decoy treatment, which is selected as the optimal treatment based on favorable in vitro results and in vivo trials. Therefore, this fibrinolytic platelet approach is a promising method for leveraging platelet-CTC interactions to disperse CTC clusters and reduce metastasis.
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Affiliation(s)
- Brian Schnoor
- Department of Biomedical Engineering, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20052, USA
| | - Kenise Morris
- Department of Biomedical Engineering, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20052, USA
| | - Regina K Kottana
- Department of Biomedical Engineering, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20052, USA
| | - Rebekah Muldoon
- Department of Biomedical Engineering, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20052, USA
| | - Jaeden Barron
- Department of Biomedical Engineering, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20052, USA
| | - Anne-Laure Papa
- Department of Biomedical Engineering, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20052, USA
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Ashkarran AA, Lin Z, Rana J, Bumpers H, Sempere L, Mahmoudi M. Impact of Nanomedicine in Women's Metastatic Breast Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2301385. [PMID: 37269217 PMCID: PMC10693652 DOI: 10.1002/smll.202301385] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/16/2023] [Indexed: 06/04/2023]
Abstract
Metastatic breast cancer is responsible for 90% of mortalities among women suffering from various types of breast cancers. Traditional cancer treatments such as chemotherapy and radiation therapy can cause significant side effects and may not be effective in many cases. However, recent advances in nanomedicine have shown great promise in the treatment of metastatic breast cancer. For example, nanomedicine demonstrated robust capacity in detection of metastatic cancers at early stages (i.e., before the metastatic cells leave the initial tumor site), which gives clinicians a timely option to change their treatment process (for example, instead of endocrine therapy they may use chemotherapy). Here recent advances in nanomedicine technology in the identification and treatment of metastatic breast cancers are reviewed.
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Affiliation(s)
- Ali Akbar Ashkarran
- Department of Radiology and Precision Health Program, Michigan State University, East Lansing, MI, 48824, USA
| | - Zijin Lin
- Department of Radiology and Precision Health Program, Michigan State University, East Lansing, MI, 48824, USA
| | - Jatin Rana
- Division of Hematology and Oncology, Michigan State University, East Lansing, MI, 48824, USA
| | - Harvey Bumpers
- Department of Surgery, Michigan State University, East Lansing, MI, 48824, USA
| | - Lorenzo Sempere
- Department of Radiology and Precision Health Program, Michigan State University, East Lansing, MI, 48824, USA
| | - Morteza Mahmoudi
- Department of Radiology and Precision Health Program, Michigan State University, East Lansing, MI, 48824, USA
- Connors Center for Women's Health & Gender Biology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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Rapanotti MC, Cenci T, Scioli MG, Cugini E, Anzillotti S, Savino L, Coletta D, Di Raimondo C, Campione E, Roselli M, Bernardini S, Bianchi L, De Luca A, Ferlosio A, Orlandi A. Circulating Tumor Cells: Origin, Role, Current Applications, and Future Perspectives for Personalized Medicine. Biomedicines 2024; 12:2137. [PMID: 39335650 PMCID: PMC11429165 DOI: 10.3390/biomedicines12092137] [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: 07/08/2024] [Revised: 09/09/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized cancer management. In this review, we describe the current understanding of and advances in the clinical employment of CTCs. Although considered rare and fleeting, CTCs are now recognized as key players favoring the development of cancer metastasis and disease recurrence, particularly in malignant melanoma, lung, breast, and colorectal cancer patients. To date, the advancements in technology and the development of several successful approaches, also including immunomagnetic enrichment allow for a reliable and reproducible detection and characterization of CTCs. Those innovative methodologies improved the isolation, quantification, and characterization of CTCs from the blood of cancer patients, providing extremely useful evidence and new insights into the nature of the tumor, its epithelial/mesenchymal profile, and its potential resistance to therapy. In fact, in addition to their prognostic and predictive value, CTCs could serve as a valuable instrument for real-time monitoring of treatment response and disease recurrence, facilitating timely interventions and thus improving patient outcomes. However, despite their potential, several challenges hinder the widespread clinical utility of CTCs: (i) CTCs' rarity and heterogeneity pose technical limitations in isolation and characterization, as well as significant hurdles in their clinical implementation; (ii) it is mandatory to standardize CTC detection methods, optimize the sample processing techniques, and integrate them with existing diagnostic modalities; and (iii) the need for the development of new techniques, such as single-cell analysis platforms, to enhance the sensitivity and specificity of CTC detection, thereby facilitating their integration into routine clinical practice. In conclusion, CTCs represent a potential extraordinary tool in cancer diagnostics and therapeutics, offering unprecedented opportunities for personalized medicine and precision oncology. Moreover, their ability to provide real-time insights into tumor biology, treatment response, and disease progression underlines a great potential for their clinical application to improve patients' outcomes and advance our understanding of cancer biology.
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Affiliation(s)
- Maria Cristina Rapanotti
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
| | - Tonia Cenci
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
| | - Maria Giovanna Scioli
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
| | - Elisa Cugini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (E.C.)
| | - Silvia Anzillotti
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
| | - Luca Savino
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
| | - Deborah Coletta
- Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (D.C.); (M.R.)
| | - Cosimo Di Raimondo
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (E.C.); (L.B.)
| | - Elena Campione
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (E.C.); (L.B.)
| | - Mario Roselli
- Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (D.C.); (M.R.)
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (E.C.)
| | - Luca Bianchi
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (E.C.); (L.B.)
| | - Anastasia De Luca
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Amedeo Ferlosio
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
| | - Augusto Orlandi
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (T.C.); (M.G.S.); (S.A.); (L.S.); (A.F.); (A.O.)
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Hariri A, Mirian M, Khosravi A, Zarepour A, Iravani S, Zarrabi A. Intersecting pathways: The role of hybrid E/M cells and circulating tumor cells in cancer metastasis and drug resistance. Drug Resist Updat 2024; 76:101119. [PMID: 39111134 DOI: 10.1016/j.drup.2024.101119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 06/30/2024] [Accepted: 07/09/2024] [Indexed: 08/17/2024]
Abstract
Cancer metastasis and therapy resistance are intricately linked with the dynamics of Epithelial-Mesenchymal Transition (EMT) and Circulating Tumor Cells (CTCs). EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites. Concurrently, CTCs, which are detached from primary tumors and travel through the bloodstream, are crucial as potential biomarkers for cancer prognosis and therapeutic response. There is a significant interplay between EMT hybrid cells and CTCs, revealing a complex, bidirectional relationship that significantly influences metastatic progression and has a critical role in cancer drug resistance. This resistance is further influenced by the tumor microenvironment, with factors such as tumor-associated macrophages, cancer-associated fibroblasts, and hypoxic conditions driving EMT and contributing to therapeutic resistance. It is important to understand the molecular mechanisms of EMT, characteristics of EMT hybrid cells and CTCs, and their roles in both metastasis and drug resistance. This comprehensive understanding sheds light on the complexities of cancer metastasis and opens avenues for novel diagnostic approaches and targeted therapies and has significant advancements in combating cancer metastasis and overcoming drug resistance.
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Affiliation(s)
- Amirali Hariri
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran.
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Turkiye
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Siavash Iravani
- Independent Researcher, W Nazar ST, Boostan Ave, Isfahan, Iran.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkiye; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan.
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Highland B, Morrow WP, Arispe K, Beaty M, Maracaja D. Merkel Cell Carcinoma With Extensive Bone Marrow Metastasis and Peripheral Blood Involvement: A Case Report With Immunohistochemical and Mutational Studies. Appl Immunohistochem Mol Morphol 2024; 32:382-388. [PMID: 38990715 DOI: 10.1097/pai.0000000000001214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/05/2024] [Indexed: 07/13/2024]
Abstract
Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer of neuroendocrine origin that is typically associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet (UV) light. We report a case of relapsed MCC that presented with new symptoms of fatigue, back pain, and myeloid left shift identified during scheduled follow-up. The patient was found to have circulating neoplastic cells in the peripheral blood and bone marrow metastasis. Immunohistochemistry for synaptophysin, CD56, INSM-1, CK20, CD117 were positive, whereas CD34, TdT, Chromogranin, CD10, myeloperoxidase, CD3 and CD19 were negative. Flow cytometry of the peripheral blood confirmed the presence of an abnormal nonhematopoietic cell population expressing CD56 positivity. A next-generation sequencing (NGS) panel revealed the presence of variants in RB1, TP53, and other genes, some of which have not been previously described in MCC. This rare presentation highlights the challenges in the diagnosis and management of MCC.
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Affiliation(s)
| | | | - Karen Arispe
- Department of Pathology, Wake Forest School of Medicine
| | - Michael Beaty
- Department of Pathology, Wake Forest School of Medicine
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11
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Huh HD, Park HW. Emerging paradigms in cancer cell plasticity. BMB Rep 2024; 57:273-280. [PMID: 38627950 PMCID: PMC11214895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/09/2024] [Accepted: 04/05/2024] [Indexed: 06/28/2024] Open
Abstract
Cancer cells metastasize to distant organs by altering their characteristics within the tumor microenvironment (TME) to effectively overcome challenges during the multistep tumorigenesis. Plasticity endows cancer cell with the capacity to shift between different morphological states to invade, disseminate, and seed metastasis. The epithelial-to-mesenchymal transition (EMT) is a theory derived from tissue biopsy, which explains the acquisition of EMT transcription factors (TFs) that convey mesenchymal features during cancer migration and invasion. On the other hand, adherent-to-suspension transition (AST) is an emerging theory derived from liquid biopsy, which describes the acquisition of hematopoietic features by AST-TFs that reprograms anchorage dependency during the dissemination of circulating tumor cells (CTCs). The induction and plasticity of EMT and AST dynamically reprogram cell-cell interaction and cell-matrix interaction during cancer dissemination and colonization. Here, we review the mechanisms governing cellular plasticity of AST and EMT during the metastatic cascade and discuss therapeutic challenges posed by these two morphological adaptations to provide insights for establishing new therapeutic interventions. [BMB Reports 2024; 57(6): 273-280].
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Affiliation(s)
- Hyunbin D. Huh
- Department of Biochemistry, Brain Korea 21 Project, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hyun Woo Park
- Department of Biochemistry, Brain Korea 21 Project, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
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12
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Sayed ZS, Khattap MG, Madkour MA, Yasen NS, Elbary HA, Elsayed RA, Abdelkawy DA, Wadan AHS, Omar I, Nafady MH. Circulating tumor cells clusters and their role in Breast cancer metastasis; a review of literature. Discov Oncol 2024; 15:94. [PMID: 38557916 PMCID: PMC10984915 DOI: 10.1007/s12672-024-00949-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Breast cancer is a significant and deadly threat to women globally. Moreover, Breast cancer metastasis is a complicated process involving multiple biological stages, which is considered a substantial cause of death, where cancer cells spread from the original tumor to other organs in the body-representing the primary mortality factor. Circulating tumor cells (CTCs) are cancer cells detached from the primary or metastatic tumor and enter the bloodstream, allowing them to establish new metastatic sites. CTCs can travel alone or in groups called CTC clusters. Studies have shown that CTC clusters have more potential for metastasis and a poorer prognosis than individual CTCs in breast cancer patients. However, our understanding of CTC clusters' formation, structure, function, and detection is still limited. This review summarizes the current knowledge of CTC clusters' biological properties, isolation, and prognostic significance in breast cancer. It also highlights the challenges and future directions for research and clinical application of CTC clusters.
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Affiliation(s)
- Zeinab S Sayed
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | - Mohamed G Khattap
- Technology of Radiology and Medical Imaging Program, Faculty of Applied Health Sciences Technology, Galala University, Suez, 435611, Egypt
| | | | - Noha S Yasen
- Radiology and Imaging Technology Department, Faculty of Applied Health Science Technology, Delta University for Science and Technology, Gamasa, Al Mansurah, Egypt
| | - Hanan A Elbary
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | - Reem A Elsayed
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | - Dalia A Abdelkawy
- Faculty of Applied Medical Science, Misr University for Science and Technology, 26Th of July Corridor, 6Th of October, Giza Governorate, Postal Code: 77, Egypt
| | | | - Islam Omar
- Faculty of Pharmacy, South Valley University, Qena, Egypt
| | - Mohamed H Nafady
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
- Faculty of Applied Health Science Technology, Misr University for Science and Technology, 6th of october, Egypt.
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13
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Xie Q, Liu S, Zhang S, Liao L, Xiao Z, Wang S, Zhang P. Research progress on the multi-omics and survival status of circulating tumor cells. Clin Exp Med 2024; 24:49. [PMID: 38427120 PMCID: PMC10907490 DOI: 10.1007/s10238-024-01309-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/08/2024] [Indexed: 03/02/2024]
Abstract
In the dynamic process of metastasis, circulating tumor cells (CTCs) emanate from the primary solid tumor and subsequently acquire the capacity to disengage from the basement membrane, facilitating their infiltration into the vascular system via the interstitial tissue. Given the pivotal role of CTCs in the intricate hematogenous metastasis, they have emerged as an essential resource for a deeper comprehension of cancer metastasis while also serving as a cornerstone for the development of new indicators for early cancer screening and new therapeutic targets. In the epoch of precision medicine, as CTC enrichment and separation technologies continually advance and reach full fruition, the domain of CTC research has transcended the mere straightforward detection and quantification. The rapid advancement of CTC analysis platforms has presented a compelling opportunity for in-depth exploration of CTCs within the bloodstream. Here, we provide an overview of the current status and research significance of multi-omics studies on CTCs, including genomics, transcriptomics, proteomics, and metabolomics. These studies have contributed to uncovering the unique heterogeneity of CTCs and identifying potential metastatic targets as well as specific recognition sites. We also review the impact of various states of CTCs in the bloodstream on their metastatic potential, such as clustered CTCs, interactions with other blood components, and the phenotypic states of CTCs after undergoing epithelial-mesenchymal transition (EMT). Within this context, we also discuss the therapeutic implications and potential of CTCs.
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Affiliation(s)
- Qingming Xie
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Shilei Liu
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Sai Zhang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Liqiu Liao
- Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Zhi Xiao
- Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Shouman Wang
- Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
| | - Pengfei Zhang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
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14
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Grasset EM, Barillé-Nion S, Juin PP. Stress in the metastatic journey - the role of cell communication and clustering in breast cancer progression and treatment resistance. Dis Model Mech 2024; 17:dmm050542. [PMID: 38506114 PMCID: PMC10979546 DOI: 10.1242/dmm.050542] [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] [Indexed: 03/21/2024] Open
Abstract
Breast cancer stands as the most prevalent malignancy afflicting women. Despite significant advancements in its diagnosis and treatment, breast cancer metastasis continues to be a leading cause of mortality among women. To metastasize, cancer cells face numerous challenges: breaking away from the primary tumor, surviving in the circulation, establishing in a distant location, evading immune detection and, finally, thriving to initiate a new tumor. Each of these sequential steps requires cancer cells to adapt to a myriad of stressors and develop survival mechanisms. In addition, most patients with breast cancer undergo surgical removal of their primary tumor and have various therapeutic interventions designed to eradicate cancer cells. Despite this plethora of attacks and stresses, certain cancer cells not only manage to persist but also proliferate robustly, giving rise to substantial tumors that frequently culminate in the patient's demise. To enhance patient outcomes, there is an imperative need for a deeper understanding of the molecular and cellular mechanisms that empower cancer cells to not only survive but also expand. Herein, we delve into the intrinsic stresses that cancer cells encounter throughout the metastatic journey and the additional stresses induced by therapeutic interventions. We focus on elucidating the remarkable strategies adopted by cancer cells, such as cell-cell clustering and intricate cell-cell communication mechanisms, to ensure their survival.
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Affiliation(s)
- Eloïse M. Grasset
- Université de Nantes, INSERM, CNRS, CRCI2NA, 44000 Nantes, France
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, 44000 Nantes, France
| | - Sophie Barillé-Nion
- Université de Nantes, INSERM, CNRS, CRCI2NA, 44000 Nantes, France
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, 44000 Nantes, France
| | - Philippe P. Juin
- Université de Nantes, INSERM, CNRS, CRCI2NA, 44000 Nantes, France
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, 44000 Nantes, France
- Institut de Cancérologie de l'Ouest, 44805 Saint Herblain, France
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15
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Radhakrishnan V, Kaifi JT, Suvilesh KN. Circulating Tumor Cells: How Far Have We Come with Mining These Seeds of Metastasis? Cancers (Basel) 2024; 16:816. [PMID: 38398206 PMCID: PMC10887304 DOI: 10.3390/cancers16040816] [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: 01/10/2024] [Revised: 02/06/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells that slough off from the tumor and circulate in the peripheral blood and lymphatic system as micro metastases that eventually results in macro metastases. Through a simple blood draw, sensitive CTC detection from clinical samples has proven to be a useful tool for determining the prognosis of cancer. Recent technological developments now make it possible to detect CTCs reliably and repeatedly from a simple and straightforward blood test. Multicenter trials to assess the clinical value of CTCs have demonstrated the prognostic value of these cancer cells. Studies on CTCs have filled huge knowledge gap in understanding the process of metastasis since their identification in the late 19th century. However, these rare cancer cells have not been regularly used to tailor precision medicine and or identify novel druggable targets. In this review, we have attempted to summarize the milestones of CTC-based research from the time of identification to molecular characterization. Additionally, the need for a paradigm shift in dissecting these seeds of metastasis and the possible future avenues to improve CTC-based discoveries are also discussed.
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Affiliation(s)
- Vijay Radhakrishnan
- Department of Surgery, Ellis Fischel Cancer Center, Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA; (V.R.); (J.T.K.)
| | - Jussuf T. Kaifi
- Department of Surgery, Ellis Fischel Cancer Center, Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA; (V.R.); (J.T.K.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Kanve N. Suvilesh
- Department of Surgery, Ellis Fischel Cancer Center, Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA; (V.R.); (J.T.K.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
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16
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Hao YJ, Chang LW, Yang CY, Lo LC, Lin CP, Jian YW, Jiang JK, Tseng FG. The rare circulating tumor microemboli as a biomarker contributes to predicting early colorectal cancer recurrences after medical treatment. Transl Res 2024; 263:1-14. [PMID: 37558203 DOI: 10.1016/j.trsl.2023.07.011] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/03/2023] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Early prognosis of cancer recurrence remains difficult partially due to insufficient and ineffective screening biomarkers or regimes. This study evaluated the rare circulating tumor microemboli (CTM) from liquid biopsy individually and together with circulating tumor cells (CTCs) and serum CEA/CA19-9 in a panel, on early prediction of colorectal cancer (CRC) recurrence. Stained CTCs/CTM were detected by a microfluidic chip-based automatic rare-cell imaging platform. ROC, AUC, Kaplan-Meier survival, and Cox proportional hazard models regarding 4 selected biomarkers were analyzed. The relative risk, odds ratio, predictive accuracy, and positive/negative predictive value of biomarkers individually and in combination, to predict CRC recurrence were assessed and preliminarily validated. The EpCAM+Hochest+CD45- CTCs/CTM could be found in all cancer stages, where more recurrences were observed in late-stage cases. Significant correlations between CTCs/CTM with metastatic stages and clinical treatment were illustrated. CA19-9 and CTM could be seen as independent risk factors in patient survivals, while stratified patients by grouped biomarkers on the Kaplan-Meier analyses presented more significant differences in predicting CRC recurrences. By monitoring the panel of selected biomarkers, disease progressions of 4 CRC patients during follow-up visits after first treatments within 3 years were predicted successfully. This study unveiled the value of rare CTM on clinical studies and a panel of selected biomarkers on predicting CRC recurrences in patients at the early time after medical treatment, in which the CTM and serum CA19-9 could be applied in clinical surveillance and CRC management to improve the accuracy.
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Affiliation(s)
- Yun-Jie Hao
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Lu-Wey Chang
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chih-Yung Yang
- Department of Teaching and Research, Taipei City Hospital, Taipei, Taiwan; Commission for General Education, National United University, Miaoli, Taiwan; General Education Center, University of Taipei, Taipei, Taiwan
| | - Liang-Chuan Lo
- National Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang-Ming Chiao-Tung University, Taipei, Taiwan
| | - Chien-Ping Lin
- Department of Surgery, Division of Colorectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yuan-Wei Jian
- Department of Surgery, Division of Colorectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jeng-Kai Jiang
- Department of Surgery, Division of Colorectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fan-Gang Tseng
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan; Department of Chemistry, Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing-Hua University, Hsinchu, Taiwan; Research Center for Applied Sciences, Taipei, Taiwan.
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17
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Bohaumilitzky L, Gebert J, Doeberitz MVK, Kloor M, Ahadova A. Liquid biopsy-based early tumor and minimal residual disease detection : New perspectives for cancer predisposition syndromes. MED GENET-BERLIN 2023; 35:259-268. [PMID: 38835740 PMCID: PMC11006388 DOI: 10.1515/medgen-2023-2049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
Genetic predisposition is one of the major measurable cancer risk factors. Affected patients have an enhanced risk for cancer and require life-long surveillance. However, current screening measures are mostly invasive and only available for certain tumor types. Particularly in hereditary cancer syndromes, liquid biopsy, in addition to monitoring therapy response and assessing minimal residual disease, holds great potential for surveillance at the precancerous stage and potentially even diagnostics. Exploring these options and future clinical translation could help reduce cancer risk and mortality in high-risk individuals and enhance patients' adherence to tailored surveillance protocols.
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Affiliation(s)
- Lena Bohaumilitzky
- Institute of Pathology University Hospital Heidelberg Heidelberg Germany
- University Hospital Heidelberg Department of Applied Tumor Biology, Institute of Pathology Heidelberg Germany
| | - Johannes Gebert
- Institute of Pathology University Hospital Heidelberg Heidelberg Germany
- University Hospital Heidelberg Department of Applied Tumor Biology, Institute of Pathology Heidelberg Germany
| | - Magnus von Knebel Doeberitz
- Institute of Pathology University Hospital Heidelberg Heidelberg Germany
- University Hospital Heidelberg Department of Applied Tumor Biology, Institute of Pathology Heidelberg Germany
| | - Matthias Kloor
- Institute of Pathology University Hospital Heidelberg Heidelberg Germany
- University Hospital Heidelberg Department of Applied Tumor Biology, Institute of Pathology Heidelberg Germany
| | - Aysel Ahadova
- Institute of Pathology University Hospital Heidelberg Heidelberg Germany
- University Hospital Heidelberg Department of Applied Tumor Biology, Institute of Pathology Heidelberg Germany
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18
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Keup C, Kimmig R, Kasimir-Bauer S. The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management. Cancers (Basel) 2023; 15:5463. [PMID: 38001722 PMCID: PMC10670968 DOI: 10.3390/cancers15225463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of clinical decisions. Multi-cancer early detection tests utilizing blood are advancing but are not part of any clinical routine yet. Liquid biopsy analysis in the course of neoadjuvant therapy has potential for therapy (de)escalation.Minimal residual disease detection via serial cfDNA analysis is currently on its way. The prognostic value of blood analytes in early and metastatic BC is undisputable, but the value of these prognostic biomarkers for clinical management is controversial. An interventional trial confirmed a significant outcome benefit when therapy was changed in case of newly emerging cfDNA mutations under treatment and thus showed the clinical utility of cfDNA analysis for therapy monitoring. The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes' biology, lack of standards and difficulties in proving clinical utility.
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Affiliation(s)
- Corinna Keup
- Department of Gynecology and Obstetrics, University Hospital of Essen, 45147 Essen, Germany
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19
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Nguyen TNA, Huang PS, Chu PY, Hsieh CH, Wu MH. Recent Progress in Enhanced Cancer Diagnosis, Prognosis, and Monitoring Using a Combined Analysis of the Number of Circulating Tumor Cells (CTCs) and Other Clinical Parameters. Cancers (Basel) 2023; 15:5372. [PMID: 38001632 PMCID: PMC10670359 DOI: 10.3390/cancers15225372] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/05/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
Analysis of circulating tumor cells (CTCs) holds promise to diagnose cancer or monitor its development. Among the methods, counting CTC numbers in blood samples could be the simplest way to implement it. Nevertheless, its clinical utility has not yet been fully accepted. The reasons could be due to the rarity and heterogeneity of CTCs in blood samples that could lead to misleading results from assays only based on single CTC counts. To address this issue, a feasible direction is to combine the CTC counts with other clinical data for analysis. Recent studies have demonstrated the use of this new strategy for early detection and prognosis evaluation of cancers, or even for the distinguishment of cancers with different stages. Overall, this approach could pave a new path to improve the technical problems in the clinical applications of CTC counting techniques. In this review, the information relevant to CTCs, including their characteristics, clinical use of CTC counting, and technologies for CTC enrichment, were first introduced. This was followed by discussing the challenges and new perspectives of CTC counting techniques for clinical applications. Finally, the advantages and the recent progress in combining CTC counts with other clinical parameters for clinical applications have been discussed.
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Affiliation(s)
- Thi Ngoc Anh Nguyen
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan; (T.N.A.N.); (P.-S.H.); (P.-Y.C.)
| | - Po-Shuan Huang
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan; (T.N.A.N.); (P.-S.H.); (P.-Y.C.)
| | - Po-Yu Chu
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan; (T.N.A.N.); (P.-S.H.); (P.-Y.C.)
| | - Chia-Hsun Hsieh
- Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City 23652, Taiwan;
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan
| | - Min-Hsien Wu
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan; (T.N.A.N.); (P.-S.H.); (P.-Y.C.)
- Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City 23652, Taiwan;
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan
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20
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Yaghoubi Naei V, Bordhan P, Mirakhorli F, Khorrami M, Shrestha J, Nazari H, Kulasinghe A, Ebrahimi Warkiani M. Advances in novel strategies for isolation, characterization, and analysis of CTCs and ctDNA. Ther Adv Med Oncol 2023; 15:17588359231192401. [PMID: 37692363 PMCID: PMC10486235 DOI: 10.1177/17588359231192401] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 07/19/2023] [Indexed: 09/12/2023] Open
Abstract
Over the past decade, the detection and analysis of liquid biopsy biomarkers such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have advanced significantly. They have received recognition for their clinical usefulness in detecting cancer at an early stage, monitoring disease, and evaluating treatment response. The emergence of liquid biopsy has been a helpful development, as it offers a minimally invasive, rapid, real-time monitoring, and possible alternative to traditional tissue biopsies. In resource-limited settings, the ideal platform for liquid biopsy should not only extract more CTCs or ctDNA from a minimal sample volume but also accurately represent the molecular heterogeneity of the patient's disease. This review covers novel strategies and advancements in CTC and ctDNA-based liquid biopsy platforms, including microfluidic applications and comprehensive analysis of molecular complexity. We discuss these systems' operational principles and performance efficiencies, as well as future opportunities and challenges for their implementation in clinical settings. In addition, we emphasize the importance of integrated platforms that incorporate machine learning and artificial intelligence in accurate liquid biopsy detection systems, which can greatly improve cancer management and enable precision diagnostics.
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Affiliation(s)
- Vahid Yaghoubi Naei
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
- Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Pritam Bordhan
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
- Faculty of Science, Institute for Biomedical Materials & Devices, University of Technology Sydney, Australia
| | - Fatemeh Mirakhorli
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Motahare Khorrami
- Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jesus Shrestha
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Hojjatollah Nazari
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Arutha Kulasinghe
- Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, 1, Broadway, Ultimo New South Wales 2007, Australia
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21
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Munoz-Arcos LS, Nicolò E, Serafini MS, Gerratana L, Reduzzi C, Cristofanilli M. Latest advances in clinical studies of circulating tumor cells in early and metastatic breast cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 381:1-21. [PMID: 37739480 DOI: 10.1016/bs.ircmb.2023.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/24/2023]
Abstract
Circulating tumor cells (CTCs) have emerged as a promising biomarker in breast cancer, offering insights into disease progression and treatment response. While CTCs have demonstrated prognostic relevance in early breast cancer, more validation is required to establish optimal cut-off points. In metastatic breast cancer, the detection of CTCs using the Food and Drug Administration-approved CellSearch® system is a strong independent prognostic factor. However, mesenchymal CTCs and the Parsortix® PC1 system show promise as alternative detection methods. This chapter offers a comprehensive review of clinical studies on CTCs in breast cancer, emphasizing their prognostic and predictive value in different stages of the disease and provides insights into potential future directions in CTC research.
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Affiliation(s)
- Laura S Munoz-Arcos
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Eleonora Nicolò
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, United States; Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
| | - Mara S Serafini
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Lorenzo Gerratana
- Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Carolina Reduzzi
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Massimo Cristofanilli
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, United States.
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22
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Muraro E, Brisotto G. Circulating tumor cells and host immunity: A tricky liaison. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 381:131-157. [PMID: 37739482 DOI: 10.1016/bs.ircmb.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/24/2023]
Abstract
During their dissemination, circulating tumor cells (CTCs) steadily face the immune system, which is a key player in the whole metastatic cascade, from intravasation to the CTC colonization of distant sites. In this chapter, we will go through the description of immune cells involved in this controversial dialogue encompassing both the anti-tumor activity and the tumor-promoting and immunosuppressive function mediated by several circulating immune effectors as natural killer (NK) cells, CD4+ and CD8+ T lymphocytes, T helper 17, regulatory T cells, neutrophils, monocytes, macrophages, myeloid-derived suppressor cells, dendritic cells, and platelets. Then, we will report on the same interaction from the CTCs point of view, depicting the direct and indirect mechanisms of crosstalk with the above mentioned immune cells. Finally, we will report the recent literature evidence on the potential prognostic role of the integrated CTCs and immune cells monitoring in cancer patients management.
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Affiliation(s)
- Elena Muraro
- Immunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
| | - Giulia Brisotto
- Immunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
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23
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Pérez-González A, Bévant K, Blanpain C. Cancer cell plasticity during tumor progression, metastasis and response to therapy. NATURE CANCER 2023; 4:1063-1082. [PMID: 37537300 PMCID: PMC7615147 DOI: 10.1038/s43018-023-00595-y] [Citation(s) in RCA: 110] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 06/01/2023] [Indexed: 08/05/2023]
Abstract
Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
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Affiliation(s)
- Andrea Pérez-González
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Kevin Bévant
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium.
- WELBIO, ULB, Bruxelles, Belgium.
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24
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Torres JA, Brito ABC, Silva VSE, Messias IM, Braun AC, Ruano APC, Buim MEC, Carraro DM, Chinen LTD. CD47 Expression in Circulating Tumor Cells and Circulating Tumor Microemboli from Non-Small Cell Lung Cancer Patients Is a Poor Prognosis Factor. Int J Mol Sci 2023; 24:11958. [PMID: 37569332 PMCID: PMC10419161 DOI: 10.3390/ijms241511958] [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: 06/14/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Circulating tumor cells (CTCs) and/or circulating tumor microemboli (CTM) from non-small cell lung cancer (NSCLC) patients may be a non-invasive tool for prognosis, acting as liquid biopsy. CTCs interact with platelets through the transforming growth factor-β/transforming growth factor-β receptor type 1 (TGF-β/TGFβRI) forming clusters. CTCs also may express the Cluster of Differentiation 47 (CD47) protein, responsible for the inhibition of phagocytosis, the "don't eat me" signal to macrophages. OBJECTIVES To isolate, quantify and analyze CTCs/CTMs from metastatic NSCLC patients, identify TGFβRI/CD47 expression in CTCs/CTMs, and correlate with progression-free survival (PFS). METHODS Blood (10 mL) was collected at two time-points: T1 (before the beginning of any line of treatment; T2 (60 days after initial collection). CTCs were isolated using ISET®. Immunocytochemistry was conducted to evaluate TGFβRI/CD47 expression. RESULTS 45 patients were evaluated. CTCs were observed in 82.2% of patients at T1 (median: 1 CTC/mL; range: 0.33-11.33 CTCs/mL) and 94.5% at T2 (median: 1.33 CTC/mL; 0.33-9.67). CTMs were observed in 24.5% of patients and significantly associated with poor PFS (10 months vs. 17 months for those without clusters; p = 0.05) and disease progression (p = 0.017). CTMs CD47+ resulted in poor PFS (p = 0.041). TGFβRI expression in CTCs/CTMs was not associated with PFS. CONCLUSION In this study, we observed that CTC/CTM from NSCLC patients express the immune evasion markers TGFβRI/CD47. The presence of CTMs CD47+ is associated with poor PFS. This was the first study to investigate CD47 expression in CTCs/CTM of patients with NSCLC and its association with poor PFS.
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Affiliation(s)
| | | | - Virgilio Souza e Silva
- Department of Clinical Oncology, A.C. Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - Iara Monique Messias
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil; (J.A.T.)
| | - Alexcia Camila Braun
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil; (J.A.T.)
| | - Anna Paula Carreta Ruano
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil; (J.A.T.)
| | | | - Dirce Maria Carraro
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil; (J.A.T.)
| | - Ludmilla Thomé Domingos Chinen
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil; (J.A.T.)
- Translational Medicine Laboratory, Núcleo de Pesquisa e Ensino da Rede São Camilo, São Paulo 04014-002, Brazil
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25
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Baa AK, Sharma A, Bhaskar S, Biswas A, Thakar A, Kumar R, Jayant S, Aland G, D’Souza A, Jadhav V, Bharde A, Khandare J, Pramanik R. Role of circulating tumour cells (CTCs) in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Ecancermedicalscience 2023; 17:1578. [PMID: 37533950 PMCID: PMC10393317 DOI: 10.3332/ecancer.2023.1578] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Indexed: 08/04/2023] Open
Abstract
Background Liquid biopsy is emerging as a non-invasive tool, providing a personalized snapshot of a primary and metastatic tumour. It aids in detecting early metastasis, recurrence or resistance to the disease. We aimed to assess the role of circulating tumour cells (CTCs) as a predictive biomarker in recurrent/metastatic head and neck cancer (head and neck squamous cell carcinoma (HNSCC)). Methodology Thirty-five patients receiving palliative chemotherapy underwent blood sampling [2 mL in Ethylenediaminetetraacetic acid (EDTA) vial] at baseline and at 3 months intervals. The CTCs were isolated and evaluated using anti-epithelial cell adhesion molecule antibody-based enrichment using the OncoDiscover platform. Results CTCs isolated from 80% of patients (n = 28) showed the sensitivity of cell detection at the baseline and 3 months intervals. The median CTC count was 1/1.5 mL of blood and the concordance with clinic-radiological outcomes was 51.4%. The median CTC count (1 (range:0-4) to 0 (range:0-1)) declined at 3 months in responders, while the non-responders had an increase in levels (0 (range :0-2) to 1 (range :0-3)). Although CTCs positively correlated with progression-free survival (PFS) and overall survival (OS), the association of CTCs did not show a significant difference with these parameters (PFS: 6 months versus 4 months; hazard ratio: 0.68; 95% confidence interval (CI): 0.29-1.58, p = 0.323; OS: 10 months versus 8 months; hazard ratio: 0.54; 95% (CI):0.18-1.57 p = 0.216) between CTC positive and CTC negative patients at 3 months. Conclusion This study highlights the utility of CTC as a disease progression-monitoring tool in recurrent HNSCC patients. Our findings suggest the potential clinical utility of CTC and the need for exploration in upfront settings of the disease as well (NCT: CTRL/2020/02/023378).
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Affiliation(s)
- Annie Kanchan Baa
- Department of Medical Oncology, Dr B. R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Atul Sharma
- Department of Medical Oncology, Dr B. R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Suman Bhaskar
- Department of Radiation Oncology, Dr B. R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Ahitagni Biswas
- Department of Radiation Oncology, Dr B. R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Alok Thakar
- Department of Head and Neck Surgery, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Rajeev Kumar
- Department of Head and Neck Surgery, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Sreeja Jayant
- Actorius Innovations and Research, Pune 411057, India, and Actorius Innovations and Research Co., Simi Valley, CA 93063, USA
| | - Gourishankar Aland
- Actorius Innovations and Research, Pune 411057, India, and Actorius Innovations and Research Co., Simi Valley, CA 93063, USA
| | - Alain D’Souza
- Actorius Innovations and Research, Pune 411057, India, and Actorius Innovations and Research Co., Simi Valley, CA 93063, USA
| | - Vikas Jadhav
- Actorius Innovations and Research, Pune 411057, India, and Actorius Innovations and Research Co., Simi Valley, CA 93063, USA
| | - Atul Bharde
- Actorius Innovations and Research, Pune 411057, India, and Actorius Innovations and Research Co., Simi Valley, CA 93063, USA
| | - Jayant Khandare
- Actorius Innovations and Research, Pune 411057, India, and Actorius Innovations and Research Co., Simi Valley, CA 93063, USA
| | - Raja Pramanik
- Department of Medical Oncology, Dr B. R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110 029, India
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26
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Grašič Kuhar C, Silvester J, Mencinger M, Ovčariček T, Čemažar M, Miceska S, Modic Ž, Kuhar A, Jesenko T, Kloboves Prevodnik V. Association of Circulating Tumor Cells, Megakaryocytes and a High Immune-Inflammatory Environment in Metastatic Breast Cancer. Cancers (Basel) 2023; 15:3397. [PMID: 37444507 DOI: 10.3390/cancers15133397] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 06/25/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Liquid biopsy is becoming an important source of new biomarkers during the treatment of metastatic cancer patients. Using size-based microfluid technology, we isolated circulating tumor cells (CTCs) from metastatic breast cancer patients to evaluate their presence and cluster formation, as well as the presence of megakaryocytes and immune-inflammatory blood cells, and to correlate their presence with clinicopathological data and overall survival (OS). In total, 59 patients (median age 60.4 years) were included in the study: 62.7% luminal A/B-like, 20.3% HER2-positive, and 17% triple-negative. Our results showed that at least one CTC was present in 79.7% and ≥5 CTCs in 35.2% of the patients. CTC clusters were present in patients with ≥5 CTCs only (in 19.2% of them), and megakaryocytes were present in 52% of all patients. The presence of CTC clusters and megakaryocytes was positively associated with the CTC count. Patients with low pan-inflammatory value (PIV), low systemic immune-inflammatory index (SII), and low relative change from baseline (ΔPIV%, ΔSII%) were associated with significantly higher OS than their counterparts. ΔPIV%, the presence of infection in the last month, and a long duration of metastatic disease were identified as independent prognostic factors for OS. The interplay of CTCs, CTC clusters, megakaryocytes, and PIV needs to be further explored.
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Affiliation(s)
- Cvetka Grašič Kuhar
- Department Medical Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
- Faculty of Medicine Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Jernej Silvester
- Faculty of Medicine Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Marina Mencinger
- Department Medical Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Tanja Ovčariček
- Department Medical Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Maja Čemažar
- Department of Experimental Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
- Faculty of Health Sciences, University of Primorska, 6000 Izola, Slovenia
| | - Simona Miceska
- Faculty of Medicine Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
- Department of Cytopathology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Živa Modic
- Faculty of Medicine Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
- Department of Experimental Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Anamarija Kuhar
- Department of Cytopathology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Tanja Jesenko
- Faculty of Medicine Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
- Department of Experimental Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Veronika Kloboves Prevodnik
- Department of Cytopathology, Institute of Oncology, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Maribor, 2000 Ljubljana, Slovenia
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27
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Si H, Esquivel M, Mendoza Mendoza E, Roarty K. The covert symphony: cellular and molecular accomplices in breast cancer metastasis. Front Cell Dev Biol 2023; 11:1221784. [PMID: 37440925 PMCID: PMC10333702 DOI: 10.3389/fcell.2023.1221784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer has emerged as the most commonly diagnosed cancer and primary cause of cancer-related deaths among women worldwide. Although significant progress has been made in targeting the primary tumor, the effectiveness of systemic treatments to prevent metastasis remains limited. Metastatic disease continues to be the predominant factor leading to fatality in the majority of breast cancer patients. The existence of a prolonged latency period between initial treatment and eventual recurrence in certain patients indicates that tumors can both adapt to and interact with the systemic environment of the host, facilitating and sustaining the progression of the disease. In order to identify potential therapeutic interventions for metastasis, it will be crucial to gain a comprehensive framework surrounding the mechanisms driving the growth, survival, and spread of tumor cells, as well as their interaction with supporting cells of the microenvironment. This review aims to consolidate recent discoveries concerning critical aspects of breast cancer metastasis, encompassing the intricate network of cells, molecules, and physical factors that contribute to metastasis, as well as the molecular mechanisms governing cancer dormancy.
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Affiliation(s)
- Hongjiang Si
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Madelyn Esquivel
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Erika Mendoza Mendoza
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Kevin Roarty
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, United States
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28
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Schuster E, Dashzeveg N, Jia Y, Golam K, Zhang T, Hoffman A, Zhang Y, Zheng C, Ramos E, Taftaf R, Shennawy LE, Scholten D, Kitata RB, Adorno-Cruz V, Reduzzi C, Spahija S, Xu R, Siziopikou KP, Platanias LC, Shah A, Gradishar WJ, Cristofanilli M, Tsai CF, Shi T, Liu H. Computational ranking-assisted identification of Plexin-B2 in homotypic and heterotypic clustering of circulating tumor cells in breast cancer metastasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.10.536233. [PMID: 37090580 PMCID: PMC10120645 DOI: 10.1101/2023.04.10.536233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Metastasis is the cause of over 90% of all deaths associated with breast cancer, yet the strategies to predict cancer spreading based on primary tumor profiles and therefore prevent metastasis are egregiously limited. As rare precursor cells to metastasis, circulating tumor cells (CTCs) in multicellular clusters in the blood are 20-50 times more likely to produce viable metastasis than single CTCs. However, the molecular mechanisms underlying various CTC clusters, such as homotypic tumor cell clusters and heterotypic tumor-immune cell clusters, are yet to be fully elucidated. Combining machine learning-assisted computational ranking with experimental demonstration to assess cell adhesion candidates, we identified a transmembrane protein Plexin- B2 (PB2) as a new therapeutic target that drives the formation of both homotypic and heterotypic CTC clusters. High PB2 expression in human primary tumors predicts an unfavorable distant metastasis-free survival and is enriched in CTC clusters compared to single CTCs in advanced breast cancers. Loss of PB2 reduces formation of homotypic tumor cell clusters as well as heterotypic tumor-myeloid cell clusters in triple-negative breast cancer. Interactions between PB2 and its ligand Sema4C on tumor cells promote homotypic cluster formation, and PB2 binding with Sema4A on myeloid cells (monocytes) drives heterotypic CTC cluster formation, suggesting that metastasizing tumor cells hijack the PB2/Sema family axis to promote lung metastasis in breast cancer. Additionally, using a global proteomic analysis, we identified novel downstream effectors of the PB2 pathway associated with cancer stemness, cell cycling, and tumor cell clustering in breast cancer. Thus, PB2 is a novel therapeutic target for preventing new metastasis.
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29
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Mazzitelli C, Santini D, Corradini AG, Zamagni C, Trerè D, Montanaro L, Taffurelli M. Liquid Biopsy in the Management of Breast Cancer Patients: Where Are We Now and Where Are We Going. Diagnostics (Basel) 2023; 13:diagnostics13071241. [PMID: 37046459 PMCID: PMC10092978 DOI: 10.3390/diagnostics13071241] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Liquid biopsy (LB) is an emerging diagnostic tool that analyzes biomarkers in the blood (and possibly in other body fluids) to provide information about tumor genetics and response to therapy. This review article provides an overview of LB applications in human cancer with a focus on breast cancer patients. LB methods include circulating tumor cells and cell-free tumor products, such as circulating tumor DNA. LB has shown potential in detecting cancer at an early stage, monitoring tumor progression and recurrence, and predicting patient response to therapy. Several studies have demonstrated its clinical utility in breast cancer patients. However, there are limitations to LB, including the lack of standardized assays and the need for further validation. Future potential applications of LB include identifying the minimal residual disease, early detection of recurrence, and monitoring treatment response in various cancer types. LB represents a promising non-invasive diagnostic tool with potential applications in breast cancer diagnosis, treatment, and management. Further research is necessary to fully understand its clinical utility and overcome its current limitations.
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30
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Reimer F, Bryan S, Legler K, Karn T, Eppenberger-Castori S, Matschke J, Pereira-Veiga T, Wikman H, Witzel I, Müller V, Schmalfeldt B, Milde-Langosch K, Schumacher U, Stürken C, Oliveira-Ferrer L. The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients. Cancer Cell Int 2023; 23:47. [PMID: 36927383 PMCID: PMC10018948 DOI: 10.1186/s12935-023-02896-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND The disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer. METHODS We analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo. RESULTS We found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free-also in multivariate analysis-and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions. CONCLUSION We conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation.
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Affiliation(s)
- Francesca Reimer
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Sarah Bryan
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Karen Legler
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | | | | | - Jakob Matschke
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thais Pereira-Veiga
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Harriet Wikman
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Isabell Witzel
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Volkmar Müller
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Barbara Schmalfeldt
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Karin Milde-Langosch
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Udo Schumacher
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Experimental Anatomy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Stürken
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Experimental Anatomy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,MSH Medical School of Hamburg, University of Applied Sciences and Medical University, Hamburg, Germany
| | - Leticia Oliveira-Ferrer
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
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31
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Phenotypic Plasticity in Circulating Tumor Cells Is Associated with Poor Response to Therapy in Metastatic Breast Cancer Patients. Cancers (Basel) 2023; 15:cancers15051616. [PMID: 36900406 PMCID: PMC10000974 DOI: 10.3390/cancers15051616] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/03/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC counts decreased with therapy, and progressors had higher CTC counts than non-progressors. CTC count was prognostic primarily at the start of therapy in univariate and multivariate analyses but had less prognostic utility at 6 months to 1 year later. In contrast, gene expression, including both epithelial and mesenchymal markers, identified high-risk patients after 6-9 months of treatment, and progressors had a shift towards mesenchymal CTC gene expression on therapy. Cross-sectional analysis showed higher CTC-related gene expression in progressors 6-15 months after baseline. Furthermore, patients with higher CTC counts and CTC gene expression experienced more progression events. Longitudinal time-dependent multivariate analysis indicated that CTC count, triple-negative status, and CTC expression of FGFR1 significantly correlated with inferior progression-free survival while CTC count and triple-negative status correlated with inferior overall survival. This highlights the utility of protein-agnostic CTC enrichment and multimodality analysis to capture the heterogeneity of CTCs.
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Bates M, Mohamed BM, Ward MP, Kelly TE, O'Connor R, Malone V, Brooks R, Brooks D, Selemidis S, Martin C, O'Toole S, O'Leary JJ. Circulating tumour cells: The Good, the Bad and the Ugly. Biochim Biophys Acta Rev Cancer 2023; 1878:188863. [PMID: 36796527 DOI: 10.1016/j.bbcan.2023.188863] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/06/2023] [Accepted: 01/21/2023] [Indexed: 02/17/2023]
Abstract
This review is an overview of the current knowledge regarding circulating tumour cells (CTCs), which are potentially the most lethal type of cancer cell, and may be a key component of the metastatic cascade. The clinical utility of CTCs (the "Good"), includes their diagnostic, prognostic, and therapeutic potential. Conversely, their complex biology (the "Bad"), including the existence of CD45+/EpCAM+ CTCs, adds insult to injury regarding their isolation and identification, which in turn hampers their clinical translation. CTCs are capable of forming microemboli composed of both non-discrete phenotypic populations such as mesenchymal CTCs and homotypic and heterotypic clusters which are poised to interact with other cells in the circulation, including immune cells and platelets, which may increase their malignant potential. These microemboli (the "Ugly") represent a prognostically important CTC subset, however, phenotypic EMT/MET gradients bring additional complexities to an already challenging situation.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Mark P Ward
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Tanya E Kelly
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Roisin O'Connor
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Victoria Malone
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Robert Brooks
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Doug Brooks
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology, Bundoora, VIC 3083, Australia
| | - Cara Martin
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin 2, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
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Circulating Tumor Cell Detection by Liquid Biopsy during Early-Stage Endometrial Cancer Surgery: A Pilot Study. Biomolecules 2023; 13:biom13030428. [PMID: 36979364 PMCID: PMC10046537 DOI: 10.3390/biom13030428] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/16/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
The recurrence of non-metastatic endometrial carcinoma (EC) (6 to 21%) might be due to disseminated tumor cells. This feasibility study investigated whether circulating tumor cells (CTCs) were detectable in blood samples from the peripheral and ovarian veins of 10 patients undergoing laparoscopic resection of stage I-II EC between July 2019 and September 2021. CTCs were detected using the CellSearch® system (i) preoperatively (T0) in peripheral blood, (ii) after ovary suspensory ligament pediculation in ovarian vein blood (T1), and (iii) before colpotomy in peripheral blood (T2). CTCs were detected only in ovarian vein samples in 8/10 patients. The CTC median number did not differ with patient age (37 (min-max: 0–91) in <70-year-old vs. 11 (0–65) in ≥70 year-old women, p = 0.59), tumor grade (15 (0–72) for grade 1 vs. 15 (0–91) for grade 2, p = 0.97), FIGO stage (72 (27–91) vs. 2 (0–65) vs. 3 (0–6]) for stage IA, B, and II, respectively; p = 0.08), and tumor size (40 (2–72) for size < 30 mm vs. 4 (0–91) for size ≥ 30 mm, p = 0.39). Estrogen receptor-positive CTCs and CTC clusters were identified. The prognostic and therapeutic values of CTCs released during EC surgery need to be determined.
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Zhang Y, Zhang Z, Zheng D, Huang T, Fu Q, Liu Y. Label-Free Separation of Circulating Tumor Cells and Clusters by Alternating Frequency Acoustic Field in a Microfluidic Chip. Int J Mol Sci 2023; 24:ijms24043338. [PMID: 36834750 PMCID: PMC9964901 DOI: 10.3390/ijms24043338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/27/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Circulating tumor cells (CTCs) play an important role in the prognosis and efficacy evaluation of metastatic tumors. Since CTCs are present in very low concentrations in the blood and the phenotype is dynamically changing, it is a great challenge to achieve efficient separation while maintaining their viability. In this work, we designed an acoustofluidic microdevice for CTCs separation based on the differences in cell physical properties of size and compressibility. Efficient separation can be achieved with only one piece of piezoceramic working on alternating frequency mode. The separation principle was simulated by numerical calculation. Cancer cells from different tumor types were separated from peripheral blood mononuclear cells (PBMCs), with capture efficiency higher than 94% and a contamination rate of about 1% was obtained. Furthermore, this method was validated to have no negative effect on the viability of the separated cells. Finally, blood samples from patients with different cancer types and stages were tested, with measured concentrations of 36-166 CTCs per milliliter. Effective separation was achieved even when the size of CTCs is similar to that of PBMCs, which has the prospect of clinical application in cancer diagnosis and efficacy evaluation.
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Ko JMY, Lam KO, Kwong DLW, Wong IYH, Chan FSY, Wong CLY, Chan KK, Law TT, Chiu KWH, Lam CCS, Wong JC, Fong HCH, Choy FSF, Lo A, Law S, Lung ML. Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Cancers (Basel) 2023; 15:cancers15030832. [PMID: 36765790 PMCID: PMC9913330 DOI: 10.3390/cancers15030832] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/19/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
We aim to reveal the clinical significance and potential usefulness of dynamic monitoring of CTCs to track therapeutic responses and improve survival for advanced ESCC patients. Peripheral blood (PB) (n = 389) and azygos vein blood (AVB) (n = 13) samplings were recruited prospectively from 88 ESCC patients undergoing curative surgery from 2017 to 2022. Longitudinal CTC enumeration was performed with epithelial (EpCAM/pan-cytokeratins/MUC1) and mesenchymal (vimentin) markers at 12 serial timepoints at any of the pre-treatment, all of the post-treatments/pre-surgery, post-surgery follow-ups for 3-year, and relapse. Longitudinal real-time CTC analysis in PB and AVB suggests more CTCs are released early at pre-surgery and 3-month post-surgery into the circulation from the CTRT group compared to the up-front surgery group. High CTC levels at pre-treatments, 1-/3-month post-surgery, unfavorable changes of CTC levels between all post-treatment/pre-surgery and 1-month or 3-month post-surgery (Hazard Ratio (HR) = 6.662, p < 0.001), were independent prognosticators for curative treatment. The unfavorable pre-surgery CTC status was independent prognostic and predictive for neoadjuvant treatment efficacy (HR = 3.652, p = 0.035). The aggressive CTC clusters were more frequently observed in AVB compared to PB. Its role as an independent prognosticator with relapse was first reported in ESCC (HR = 2.539, p = 0.068). CTC clusters and longitudinal CTC monitoring provide useful prognostic information and potential predictive biomarkers to help guide clinicians in improving disease management.
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Affiliation(s)
- Josephine Mun Yee Ko
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
- Correspondence: (J.M.Y.K.); (S.L.); Tel.: +86-(852)-3917-6931 (J.M.Y.K.); +86-(852)-2255-4774 (S.L.); Fax: +86-(852)-2816-6279 (J.M.Y.K.); +86-(852)-2819-4221 (S.L.)
| | - Ka On Lam
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Dora Lai Wan Kwong
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Ian Yu-Hong Wong
- Department of Surgery, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Fion Siu-Yin Chan
- Department of Surgery, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Claudia Lai-Yin Wong
- Department of Surgery, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Kwan Kit Chan
- Department of Surgery, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Tsz Ting Law
- Department of Surgery, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Keith Wan Hang Chiu
- Department of Diagnostic Radiology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Candy Chi Shan Lam
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Jean Chrysei Wong
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Henry Chun Hung Fong
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Faith Sin Fai Choy
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Andy Lo
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
| | - Simon Law
- Department of Surgery, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
- Correspondence: (J.M.Y.K.); (S.L.); Tel.: +86-(852)-3917-6931 (J.M.Y.K.); +86-(852)-2255-4774 (S.L.); Fax: +86-(852)-2816-6279 (J.M.Y.K.); +86-(852)-2819-4221 (S.L.)
| | - Maria Li Lung
- Department of Clinical Oncology, School of Clinical Medicine, University of Hong Kong, Hong Kong, China
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Yamamoto A, Doak AE, Cheung KJ. Orchestration of Collective Migration and Metastasis by Tumor Cell Clusters. ANNUAL REVIEW OF PATHOLOGY 2023; 18:231-256. [PMID: 36207009 DOI: 10.1146/annurev-pathmechdis-031521-023557] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Metastatic dissemination has lethal consequences for cancer patients. Accruing evidence supports the hypothesis that tumor cells can migrate and metastasize as clusters of cells while maintaining contacts with one another. Collective metastasis enables tumor cells to colonize secondary sites more efficiently, resist cell death, and evade the immune system. On the other hand, tumor cell clusters face unique challenges for dissemination particularly during systemic dissemination. Here, we review recent progress toward understanding how tumor cell clusters overcome these disadvantages as well as mechanisms they utilize to gain advantages throughout the metastatic process. We consider useful models for studying collective metastasis and reflect on how the study of collective metastasis suggests new opportunities for eradicating and preventing metastatic disease.
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Affiliation(s)
- Ami Yamamoto
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Center, Seattle, Washington, USA; , , .,Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA
| | - Andrea E Doak
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Center, Seattle, Washington, USA; , , .,Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA
| | - Kevin J Cheung
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Center, Seattle, Washington, USA; , ,
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Zhao X, Qi Z, Gao Z, He H. High counting of circulating tumor cells in blood is not directly related to metastasis. Cytometry A 2023; 103:82-87. [PMID: 35912963 DOI: 10.1002/cyto.a.24672] [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: 04/15/2022] [Revised: 06/24/2022] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
Circulating tumor cells (CTCs) in blood flow have been believed as an essential biomarker of cancer. The technologies of in vitro and in vivo CTC enrichment and detection suggest although CTCs might play a role of "seed" in metastasis, only the minority of CTCs, probably in the form of CTC clusters, hold the potential to develop a tumor in organs. The detected amount of CTCs might be solely an indicator of tumor burden. To provide new insights into this argument, we take advantage of a safe drug to tune the pacemaker activity of a mouse tumor model to increase the heart rate for a period of time every day during the tumor development. We detect the CTCs in vivo by fast line scanning of a confocal microscope when the heart rate returns to the baseline and find the average CTC amount is significantly elevated in the drug-treated group but the metastases are even less than that of control. Our results imply the detected CTC counts in blood might not be directly related to metastasis.
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Affiliation(s)
- Xiaohui Zhao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Ziang Qi
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Ziao Gao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Hao He
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
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Hurtado P, Martínez-Pena I, Yepes-Rodríguez S, Bascoy-Otero M, Abuín C, Fernández-Santiago C, Sánchez L, López-López R, Piñeiro R. Modelling metastasis in zebrafish unveils regulatory interactions of cancer-associated fibroblasts with circulating tumour cells. Front Cell Dev Biol 2023; 11:1076432. [PMID: 36949770 PMCID: PMC10025339 DOI: 10.3389/fcell.2023.1076432] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
The dynamic intercommunication between tumour cells and cells from the microenvironment, such as cancer-associated fibroblast (CAFs), is a key factor driving breast cancer (BC) metastasis. Clusters of circulating tumour cells (CTCs), known to bare a higher efficiency at establishing metastases, are found in the blood of BC patients, often accompanied by CAFs in heterotypic CTC-clusters. Previously we have shown the utility of CTC-clusters models and the zebrafish embryo as a model of metastasis to understand the biology of breast cancer CTC-clusters. In this work, we use the zebrafish embryo to study the interactions between CTCs in homotypic clusters and CTC-CAFs in heterotypic CTC-clusters to identify potential pro-metastatic traits derived from CTC-CAF communication. We found that upon dissemination CAFs seem to exert a pro-survival and pro-proliferative effect on the CTCs, but only when CTCs and CAFs remain joined as cell clusters. Our data indicate that the clustering of CTC and CAF allows the establishment of physical interactions that when maintained over time favour the selection of CTCs with a higher capacity to survive and proliferate upon dissemination. Importantly, this effect seems to be dependent on the survival of disseminated CAFs and was not observed in the presence of normal fibroblasts. Moreover, we show that CAFs can exert regulatory effects on the CTCs without being involved in promoting tumour cell invasion. Lastly, we show that the physical communication between BC cells and CAFs leads to the production of soluble factors involved in BC cell survival and proliferation. These findings suggest the existence of a CAF-regulatory effect on CTC survival and proliferation sustained by cell-to-cell contacts and highlight the need to understand the molecular mechanisms that mediate the interaction between the CTCs and CAFs in clusters enhancing the metastatic capacity of CTCs.
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Affiliation(s)
- Pablo Hurtado
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain
| | - Inés Martínez-Pena
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain
| | - Sabrina Yepes-Rodríguez
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
| | - Miguel Bascoy-Otero
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
| | - Carmen Abuín
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
| | - Cristóbal Fernández-Santiago
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
| | - Laura Sánchez
- Departamento de Zoología, Genética y Antropología Física, Facultad de Veterinaria, Universidade de Santiago de Compostela, Lugo, Spain
| | - Rafael López-López
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain
- Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- Department of Oncology, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
- *Correspondence: Roberto Piñeiro, ; Rafael López-López,
| | - Roberto Piñeiro
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
- Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain
- *Correspondence: Roberto Piñeiro, ; Rafael López-López,
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Fridrichova I, Kalinkova L, Ciernikova S. Clinical Relevancy of Circulating Tumor Cells in Breast Cancer: Epithelial or Mesenchymal Characteristics, Single Cells or Clusters? Int J Mol Sci 2022; 23:12141. [PMID: 36292996 PMCID: PMC9603393 DOI: 10.3390/ijms232012141] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/05/2022] [Accepted: 10/07/2022] [Indexed: 07/30/2023] Open
Abstract
Metastatic breast cancer (MBC) is typically an incurable disease with high mortality rates; thus, early identification of metastatic features and disease recurrence through precise biomarkers is crucial. Circulating tumor cells (CTCs) consisting of heterogeneous subpopulations with different morphology and genetic, epigenetic, and gene expression profiles represent promising candidate biomarkers for metastatic potential. The experimentally verified role of epithelial-to-mesenchymal transition in cancer dissemination has not been clearly described in BC patients, but the stemness features of CTCs strongly contributes to metastatic potency. Single CTCs have been shown to be protected in the bloodstream against recognition by the immune system through impaired interactions with T lymphocytes and NK cells, while associations of heterotypic CTC clusters with platelets, leucocytes, neutrophils, tumor-associated macrophages, and fibroblasts improve their tumorigenic behavior. In addition to single CTC and CTC cluster characteristics, we reviewed CTC evaluation methods and clinical studies in early and metastatic BCs. The variable CTC tests were developed based on specific principles and strategies. However, CTC count and the presence of CTC clusters were shown to be most clinically relevant in existing clinical trials. Despite the known progress in CTC research and sampling of BC patients, implementation of CTCs and CTC clusters in routine diagnostic and treatment strategies still requires improvement in detection sensitivity and precise molecular characterizations, focused predominantly on the role of CTC clusters for their higher metastatic potency.
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Wang Z, Xu W, Yang Y, Gao G, Teng C, Ge Z, Zhang H, Yuan Z, Ding G, Wang Y, Li P, Xu Y, Li P, Hu Z, Zhang Z, Qu X. Impact of changing treatment strategy based on circulating tumor cells on postoperative survival of breast cancer. Front Oncol 2022; 12:1006909. [PMID: 36263206 PMCID: PMC9573986 DOI: 10.3389/fonc.2022.1006909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background We sought to explore the impact of changing treatment strategy based on circulating tumor cells (CTC) on postoperative survival of breast cancer. Methods We retrospectively analyzed records of patients who underwent surgery for early-stage breast cancer at Beijing Friendship Hospital from January 2016 to January 2018 and regularly underwent CTC examination after surgery. During the regular examination and CTC monitoring, the patients with positive CTC results and without distant metastasis had their treatment regimen changed. Results Of 109 patients who received CTC examination regularly after surgery, 61 (56.0%) were CTC-positive during postoperative follow-up, including 33 ER or PR-positive, and 28 ER and PR-negative patients. Of the 33 ER or PR-positive patients, 20 changed endocrine therapy drugs. Compared with those without replacement, those with changed endocrine therapy strategy had higher CTC clearance rates (90.0% vs. 53.8%, p=0.04) and significantly lower CTC-positive values (1.70 ± 1.72 vs. 0.62 ± 0.65, p = 0.04). Among the 28 patients who were CTC positive and ER and PR-negative, 11 used capecitabine. Compared with non-users, the capecitabine users had higher CTC clearance rates (100.0% vs. 52.9%, p=0.01) and more significant decrease in CTC-positive values (2.09 ± 1.14 vs. 0.82 ± 1.67, p=0.04). Disease-free survival (DFS) at 1, 3, and 5 years was significantly longer in those who changed treatment than in those who did not (respectively, 96.6% vs. 89.6%, 92.8% vs. 56.9%, 69.0% vs. 47.8%, p<0.01). By changing the treatment strategy, CTC-positive patients achieved DFS that was not significantly different from CTC-negative patients (95.0% vs. 97.7%, 77.5% vs. 82.9%, 57.6% vs. 59.9%, p=0.20). Conclusion Timely change of treatment strategy for breast cancer patients with positive CTC results after surgery may improve CTC clearance rate and DFS.
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Affiliation(s)
- Zihan Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wei Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yanlian Yang
- Chinese Academy of Sciences (CAS) Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Guoxuan Gao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Changsheng Teng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhicheng Ge
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Huiming Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhu Yuan
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guoqian Ding
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yang Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peixin Li
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yaqian Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ping Li
- Chinese Academy of Sciences (CAS) Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
| | - Zhiyuan Hu
- Chinese Academy of Sciences (CAS) Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- *Correspondence: Zhongtao Zhang, ; Xiang Qu,
| | - Xiang Qu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- *Correspondence: Zhongtao Zhang, ; Xiang Qu,
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Marles H, Biddle A. Cancer stem cell plasticity and its implications in the development of new clinical approaches for oral squamous cell carcinoma. Biochem Pharmacol 2022; 204:115212. [PMID: 35985402 DOI: 10.1016/j.bcp.2022.115212] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 11/25/2022]
Abstract
Oral squamous cell carcinoma (SCC) represents a major worldwide disease burden, with high rates of recurrence and metastatic spread following existing treatment methods. Populations of treatment resistant cancer stem cells (CSCs) are well characterised in oral SCC. These populations of CSCs engage the cellular programme known as epithelial mesenchymal transition (EMT) to enhance metastatic spread and therapeutic resistance. EMT is characterised by specific morphological changes and the expression of certain cell surface markers that represent a transition from an epithelial phenotype to a mesenchymal phenotype. This process is regulated by several cellular pathways that interact both horizontally and hierarchically. The cellular changes in EMT occur along a spectrum, with sub-populations of cells displaying both epithelial and mesenchymal features. The unique features of these CSCs in terms of their EMT state, cell surface markers and metabolism may offer new druggable targets. In addition, these features could be used to identify more aggressive disease states and the opportunity to personalise therapy depending on the presence of certain CSC sub-populations.
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Affiliation(s)
- Henry Marles
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Adrian Biddle
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.
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42
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Macaraniag C, Luan Q, Zhou J, Papautsky I. Microfluidic techniques for isolation, formation, and characterization of circulating tumor cells and clusters. APL Bioeng 2022; 6:031501. [PMID: 35856010 PMCID: PMC9288269 DOI: 10.1063/5.0093806] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/28/2022] [Indexed: 12/13/2022] Open
Abstract
Circulating tumor cell (CTC) clusters that are shed from the primary tumor into the bloodstream are associated with a poor prognosis, elevated metastatic potential, higher proliferation rate, and distinct molecular features compared to single CTCs. Studying CTC clusters may give us information on the differences in the genetic profiles, somatic mutations, and epigenetic changes in circulating cells compared to the primary tumor and metastatic sites. Microfluidic systems offer the means of studying CTC clusters through the ability to efficiently isolate these rare cells from the whole blood of patients in a liquid biopsy. Microfluidics can also be used to develop in vitro models of CTC clusters and make possible their characterization and analysis. Ultimately, microfluidic systems can offer the means to gather insight on the complexities of the metastatic process, the biology of cancer, and the potential for developing novel or personalized therapies. In this review, we aim to discuss the advantages and challenges of the existing microfluidic systems for working with CTC clusters. We hope that an improved understanding of the role microfluidics can play in isolation, formation, and characterization of CTC clusters, which can lead to increased sophistication of microfluidic platforms in cancer research.
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Affiliation(s)
- Celine Macaraniag
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Qiyue Luan
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Jian Zhou
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Ian Papautsky
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, Illinois 60607, USA
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Allegra A, Cancemi G, Mirabile G, Tonacci A, Musolino C, Gangemi S. Circulating Tumour Cells, Cell Free DNA and Tumour-Educated Platelets as Reliable Prognostic and Management Biomarkers for the Liquid Biopsy in Multiple Myeloma. Cancers (Basel) 2022; 14:cancers14174136. [PMID: 36077672 PMCID: PMC9454477 DOI: 10.3390/cancers14174136] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Even though the presently employed biomarkers in the detection and management of multiple myeloma are demonstrating encouraging results, the mortality percentage of the malignancy is still elevated. Thus, searching for new diagnostic or prognostic markers is pivotal. Liquid biopsy allows the examination of circulating tumour DNA, cell-free DNA, extracellular RNA, and cell free proteins, which are released into the bloodstream due to the breakdown of tumour cells or exosome delivery. Liquid biopsy can now be applied in clinical practice to diagnose, and monitor multiple myeloma, probably allowing a personalized treatment of the disease. Abstract Liquid biopsy is one of the fastest emerging fields in cancer evaluation. Circulating tumour cells and tumour-originated DNA in plasma have become the new targets for their possible employ in tumour diagnosis, and liquid biopsy can define tumour burden without invasive procedures. Multiple Myeloma, one of the most frequent hematologic tumors, has been the target of therapeutic progresses in the last few years. Bone marrow aspirate is the traditional tool for diagnosis, prognosis, and genetic evaluation in multiple myeloma patients. However, this painful procedure presents a relevant drawback for regular disease examination as it requires an invasive practice. Moreover, new data demonstrated that a sole bone marrow aspirate is incapable of expressing the multifaceted multiple myeloma genetic heterogeneity. In this review, we report the emerging usefulness of the assessment of circulating tumour cells, cell-free DNA, extracellular RNA, cell-free proteins, extracellular vesicles, and tumour-educated platelets to evaluate the changing mutational profile of multiple myeloma, as early markers of disease, reliable predictors of prognosis, and as useful tools to perform less invasive monitoring in multiple myeloma.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
- Correspondence:
| | - Gabriella Cancemi
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
| | - Giuseppe Mirabile
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
| | - Alessandro Tonacci
- Clinical Physiology Institute, National Research Council of Italy (IFC-CNR), 56124 Pisa, Italy
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
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Lu L, Hu W, Liu B, Yang T. Insights into Circulating Tumor Cell Clusters: A Barometer for Treatment Effects and Prognosis for Prostate Cancer Patients. Cancers (Basel) 2022; 14:cancers14163985. [PMID: 36010983 PMCID: PMC9406494 DOI: 10.3390/cancers14163985] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/09/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Circulating tumor cells (CTCs) are a promising biomarker for the risk of prostate cancer aggressiveness and metastasis and play a role in the processes of tumor migration and metastasis. CTC clusters, which have different physical and biological properties from individual CTCs, are collections of tumor cells and non-malignant cells, resulting in greater metastatic potential. Therefore, this review aims to summarize the current knowledge of CTC clusters in metastasis as well as related biological properties and to suggest possibilities for their usage in diagnostic and therapeutic practice. Abstract Prostate cancer (PCa) exhibits high cellular heterogeneity across patients. Therefore, there is an urgent need for more real-time and accurate detection methods, in both prognosis and treatment in clinical settings. Circulating tumor cell (CTC) clusters, a population of tumor cells and non-malignant cells in the blood of patients with tumors, are a promising non-invasive tool for screening PCa progression and identifying potential benefit groups. CTC clusters are associated with tumor metastasis and possess stem-like characteristics, which are likely attributable to epithelial–mesenchymal transition (EMT). Additionally, these biological properties of CTC clusters, particularly androgen receptor V7, have indicated the potential to reflect curative effects, guide treatment modalities, and predict prognosis in PCa patients. Here, we discuss the role of CTC clusters in the mechanisms underlying PCa metastasis and clinical applications, with the aim of informing more appropriate clinical decisions, and ultimately, improving the overall survival of PCa patients.
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Affiliation(s)
- Linyao Lu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Wei Hu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Bingli Liu
- Department of Orthopedics, Shanghai Pudong New Area People’s Hospital, Shanghai 201299, China
- Correspondence: (B.L.); (T.Y.); Tel./Fax: +86-21-2050-9000 (B.L.); +86-21-6803-6506 (T.Y.)
| | - Tao Yang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
- Correspondence: (B.L.); (T.Y.); Tel./Fax: +86-21-2050-9000 (B.L.); +86-21-6803-6506 (T.Y.)
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Chen Q, Zou J, He Y, Pan Y, Yang G, Zhao H, Huang Y, Zhao Y, Wang A, Chen W, Lu Y. A narrative review of circulating tumor cells clusters: A key morphology of cancer cells in circulation promote hematogenous metastasis. Front Oncol 2022; 12:944487. [PMID: 36059616 PMCID: PMC9434215 DOI: 10.3389/fonc.2022.944487] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/18/2022] [Indexed: 11/28/2022] Open
Abstract
Circulating tumor cells (CTCs) that survive in the blood are playing an important role in the metastasis process of tumor. In addition, they have become a tool for tumor diagnosis, prognosis and recurrence monitoring. CTCs can exist in the blood as individual cells or as clumps of aggregated cells. In recent years, more and more studies have shown that clustered CTCs have stronger metastasis ability compared to single CTCs. With the deepening of studies, scholars have found that cancer cells can combine not only with each other, but also with non-tumor cells present in the blood, such as neutrophils, platelets, etc. At the same time, it was confirmed that non-tumor cells bound to CTCs maintain the survival and proliferation of cancer cells through a variety of ways, thus promoting the occurrence and development of tumor. In this review, we collected information on tumorigenesis induced by CTC clusters to make a summary and a discussion about them. Although CTC clusters have recently been considered as a key role in the transition process, many characteristics of them remain to be deeply explored. A detailed understanding of their vulnerability can prospectively pave the way for new inhibitors for metastasis.
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Affiliation(s)
- Qiong Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jueyao Zou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yong He
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yanhong Pan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gejun Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Han Zhao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Huang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China
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Agnoletto C, Volinia S. Mitochondria dysfunction in circulating tumor cells. Front Oncol 2022; 12:947479. [PMID: 35992829 PMCID: PMC9386562 DOI: 10.3389/fonc.2022.947479] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/11/2022] [Indexed: 12/16/2022] Open
Abstract
Circulating tumor cells (CTCs) represent a subset of heterogeneous cells, which, once released from a tumor site, have the potential to give rise to metastasis in secondary sites. Recent research focused on the attempt to detect and characterize these rare cells in the circulation, and advancements in defining their molecular profile have been reported in diverse tumor species, with potential implications for clinical applications. Of note, metabolic alterations, involving mitochondria, have been implicated in the metastatic process, as key determinants in the transition of tumor cells to a mesenchymal or stemness-like phenotype, in drug resistance, and in induction of apoptosis. This review aimed to briefly analyse the most recent knowledge relative to mitochondria dysfunction in CTCs, and to envision implications of altered mitochondria in CTCs for a potential utility in clinics.
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Affiliation(s)
- Chiara Agnoletto
- Rete Oncologica Veneta (ROV), Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Stefano Volinia
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Biological and Chemical Research Centre (CNBCh UW), University of Warsaw, Warsaw, Poland
- Center of New Technologies, University of Warsaw, Warsaw, Poland
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Han J, Lu C, Shen M, Sun X, Mo X, Yang G. Fast, Reusable, Cell Uniformly Distributed Membrane Filtration Device for Separation of Circulating Tumor Cells. ACS OMEGA 2022; 7:20761-20767. [PMID: 35755342 PMCID: PMC9219081 DOI: 10.1021/acsomega.2c01153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/06/2022] [Indexed: 06/15/2023]
Abstract
Isolation of circulating tumor cells (CTCs) is of great significance for the diagnosis, prognosis, and treatment of metastatic cancer. Among CTC capture methods independent of antibodies, membrane filtration-based methods have the advantages of simplicity, rapidity, and high throughput but usually have problems such as clogging, high pressure drop, and impaired cell viability. In this study, we designed and tested a reusable device that used horizontal rotor and fluid-assisted separation to capture CTCs by centrifugal membrane filtration, achieving simple, fast, highly efficient, and viable cell capture on traditional centrifuge. The average capture efficiency was 95.8% for different types of cancer cells with >90% survival, and the removal of white blood cells can reach 99.72% under four times cleaning of the membrane after filtration. A further clinic demo was performed using the device to detect residual leukemic cells in patients; the results showed a 10-fold enrichment of the leukemic cells in peripheral blood samples. Taken together, the simple, robust, and efficient CTC capture device may have the potential for clinic routine detection and analysis of circulating tumor cells.
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Affiliation(s)
- Jintao Han
- State
Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871, China
| | - Chunyang Lu
- State
Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871, China
| | - Mengzhu Shen
- Beijing
Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University Institute of Hematology, Peking
University People’s Hospital, Beijing 100044, China
| | - Xiaoyi Sun
- State
Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871, China
| | - Xiaodong Mo
- Beijing
Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University Institute of Hematology, Peking
University People’s Hospital, Beijing 100044, China
| | - Gen Yang
- State
Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871, China
- Wenzhou
Institute, University of Chinese Academy
of Sciences, Wenzhou 352001, China
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Abu-Khalaf M, Wang C, Zhang Z, Luo R, Chong W, Silver DP, Fellin F, Jaslow R, Lopez A, Cescon T, Jiang W, Myers R, Wei Q, Li B, Cristofanilli M, Yang H. Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism. Cancers (Basel) 2022; 14:cancers14122872. [PMID: 35740538 PMCID: PMC9221535 DOI: 10.3390/cancers14122872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/02/2022] [Accepted: 06/07/2022] [Indexed: 02/01/2023] Open
Abstract
Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER+) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in RB1, CCNE1, FBXW7, EZH2, and ARID1A, but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings.
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Affiliation(s)
- Maysa Abu-Khalaf
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
- Correspondence: (M.A.-K.); (H.Y.); Tel.: +1-215-503-1195 (M.A.-K.); +1-215-503-6521 (H.Y.)
| | - Chun Wang
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Zhenchao Zhang
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Rui Luo
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Weelic Chong
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Daniel P. Silver
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Frederick Fellin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Rebecca Jaslow
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - AnaMaria Lopez
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Terrence Cescon
- Department of Hematology Oncology, Reading Hospital, West Reading, PA 19611, USA;
| | - Wei Jiang
- Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Ronald Myers
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
| | - Qiang Wei
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA; (Q.W.); (B.L.)
| | - Bingshan Li
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA; (Q.W.); (B.L.)
| | - Massimo Cristofanilli
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA;
| | - Hushan Yang
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (C.W.); (Z.Z.); (R.L.); (W.C.); (D.P.S.); (F.F.); (R.J.); (A.L.); (R.M.)
- Correspondence: (M.A.-K.); (H.Y.); Tel.: +1-215-503-1195 (M.A.-K.); +1-215-503-6521 (H.Y.)
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Hassan S, Blick T, Wood J, Thompson EW, Williams ED. Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models. Front Cell Dev Biol 2022; 10:858013. [PMID: 35493092 PMCID: PMC9043137 DOI: 10.3389/fcell.2022.858013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/09/2022] [Indexed: 11/17/2022] Open
Abstract
Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote EMP. We explored effects of castration on EMP in the tumours and circulating tumour cells (CTCs) of patient-derived xenograft (PDX)-bearing castrated mice using human-specific RT-qPCR assays and immunocytochemistry. Expression of prostate epithelial cell marker KLK3 was below detection in most tumours from castrated mice (62%, 23/37 mice), consistent with its known up-regulation by androgens. Endpoint tumour size after castration varied significantly in a PDX model-specific pattern; while most tumours were castration-sensitive (BM18, LuCaP70), the majority of LuCaP105 tumours continued to grow following castration. By contrast, LuCaP96 PDX showed a mixed response to castration. CTCs were detected in 33% of LuCaP105, 43% of BM18, 47% of LuCaP70, and 54% of LuCaP96 castrated mice using RPL32 mRNA measurement in plasma. When present, CTC numbers estimated using human RPL32 expression ranged from 1 to 458 CTCs per ml blood, similar to our previous observations in non-castrated mice. In contrast to their non-castrated counterparts, there was no relationship between tumour size and CTC burden in castrated mice. Unsupervised hierarchical clustering of the gene expression profiles of CTCs collected from castrated and non-castrated mice revealed distinct CTC sub-groups within the pooled population that were classified as having mesenchymal, epithelial, or EMP hybrid gene expression profiles. The epithelial signature was only found in CTCs from non-castrated mice. Hybrid and mesenchymal signatures were detected in CTCs from both castrated and non-castrated mice, with an emphasis towards mesenchymal phenotypes in castrated mice. Post-castration serum PSA levels were either below detection or very low for all the CTC positive samples highlighting the potential usefulness of CTCs for disease monitoring after androgen ablation therapy. In summary, our study of castration effects on prostate cancer PDX CTCs showed that CTCs were often detected in the castrate setting, even in mice with no palpable tumours, and demonstrated the superior ability of CTCs to reveal residual disease over the conventional clinical biomarker serum PSA.
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Affiliation(s)
- Sara Hassan
- Queensland University of Technology (QUT), Faculty of Health, School of Biomedical Sciences at Translational Research Institute (TRI), Brisbane, QLD, Australia
| | - Tony Blick
- Queensland University of Technology (QUT), Faculty of Health, School of Biomedical Sciences at Translational Research Institute (TRI), Brisbane, QLD, Australia
| | - Jack Wood
- Queensland University of Technology (QUT), Faculty of Health, School of Biomedical Sciences at Translational Research Institute (TRI), Brisbane, QLD, Australia
- Australian Prostate Cancer Research Centre, Queensland (APCRC-Q) and Queensland Bladder Cancer Initiative (QBCI), Brisbane, QLD, Australia
| | - Erik W. Thompson
- Queensland University of Technology (QUT), Faculty of Health, School of Biomedical Sciences at Translational Research Institute (TRI), Brisbane, QLD, Australia
| | - Elizabeth D. Williams
- Queensland University of Technology (QUT), Faculty of Health, School of Biomedical Sciences at Translational Research Institute (TRI), Brisbane, QLD, Australia
- Australian Prostate Cancer Research Centre, Queensland (APCRC-Q) and Queensland Bladder Cancer Initiative (QBCI), Brisbane, QLD, Australia
- *Correspondence: Elizabeth D. Williams,
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Richard V, Davey MG, Annuk H, Miller N, Kerin MJ. The double agents in liquid biopsy: promoter and informant biomarkers of early metastases in breast cancer. Mol Cancer 2022; 21:95. [PMID: 35379239 PMCID: PMC8978379 DOI: 10.1186/s12943-022-01506-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/10/2022] [Indexed: 02/08/2023] Open
Abstract
Breast cancer continues to be a major global problem with significant mortality associated with advanced stage and metastases at clinical presentation. However, several findings suggest that metastasis is indeed an early occurrence. The standard diagnostic techniques such as invasive core needle biopsy, serological protein marker assays, and non-invasive radiological imaging do not provide information about the presence and molecular profile of small fractions of early metastatic tumor cells which are prematurely dispersed in the circulatory system. These circulating tumor cells (CTCs) diverge from the primary tumors as clusters with a defined secretome comprised of circulating cell-free nucleic acids and small microRNAs (miRNAs). These circulatory biomarkers provide a blueprint of the mutational profile of the tumor burden and tumor associated alterations in the molecular signaling pathways involved in oncogenesis. Amidst the multitude of circulatory biomarkers, miRNAs serve as relatively stable and precise biomarkers in the blood for the early detection of CTCs, and promote step-wise disease progression by executing paracrine signaling that transforms the microenvironment to guide the metastatic CTCs to anchor at a conducive new organ. Random sampling of easily accessible patient blood or its serum/plasma derivatives and other bodily fluids collectively known as liquid biopsy (LB), forms an efficient alternative to tissue biopsies. In this review, we discuss in detail the divergence of early metastases as CTCs and the involvement of miRNAs as detectable blood-based diagnostic biomarkers that warrant a timely screening of cancer, serial monitoring of therapeutic response, and the dynamic molecular adaptations induced by miRNAs on CTCs in guiding primary and second-line systemic therapy.
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