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Valladares-Ayerbes M, Toledano-Fonseca M, Graña B, Jimenez-Fonseca P, Pulido-Cortijo G, Gil S, Sastre J, Salud A, Rivera F, Salgado M, García-Alfonso P, López López R, Guillén-Ponce C, Rodríguez-Ariza A, Vieitez JM, Díaz-Rubio E, Aranda E. Associations of blood RNA biomarkers and circulating tumour cells in patients with previously untreated metastatic colorectal cancer. BMC Cancer 2025; 25:743. [PMID: 40259317 PMCID: PMC12013160 DOI: 10.1186/s12885-025-14098-9] [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: 07/05/2024] [Accepted: 04/07/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND In patients with metastatic colorectal cancer, analysis of the number of basal circulating tumour cells (bCTCs) has been shown to be a strong prognostic indicator. In this study, we aim to explore the potential associations between whole blood mRNA and microRNA expression profiles and bCTC counts, tumour mutations and prognosis in untreated metastatic colorectal cancer patients. METHODS A total of 151 patients previously screened for inclusion in two clinical trials (VISNÚ1 and VISNÚ2) were enrolled in this study. Real-time quantitative PCR (qPCR) analyses were performed to determine the whole blood expression of selected RNAs (mRNAs and microRNAs) involved in the metastatic process. The CellSearch system was used to enumerate circulating tumour cells. The primary objective was to correlate RNA expression with the number of bCTCs, while the secondary objectives were to investigate the relationship between the levels of circulating RNA biomarkers in whole blood and the clinical, pathological, and molecular characteristics and prognosis of patients with metastatic colorectal cancer. RESULTS bCTC count was significantly associated with AGR2 mRNA in the entire cohort of 151 patients. AGR2, ADAR1 and LGR5 were associated with the number of bCTC, both in the subgroup with bCTC ≥ 3 and in the subgroup with native RAS/BRAF/PIK3 CA tumours. In patients with RAS/BRAF/PIK3 CA mutations no correlations with bCTC were detected, but an upregulation of miR-224-5p and the stemness marker LGR5 and a downregulation of immune regulatory CD274 were found. Lower levels of miR-106a-5p/miR-26a-5p were associated with shorter overall survival, with independent statistical significance in the multivariate analysis. CONCLUSIONS A correlation was identified between the levels of a subset of whole blood RNAs, including AGR2, ADAR1, and LGR5, and the number of bCTC and RAS/BRAF/PIK3 CA mutational status. Furthermore, another set of whole blood RNAs, specifically miR-106a-5p and miR-26a-5p, was found to be associated with poor prognosis. This may be helpful for risk stratification. TRIAL REGISTRATION Clinical Trials Gov. NCT01640405 and NCT01640444. Registered on 13 June 2012. https://clinicaltrials.gov/ .
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Affiliation(s)
- Manuel Valladares-Ayerbes
- Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina (IBIS), Seville, Spain.
| | - Marta Toledano-Fonseca
- Department of Medical Oncology, IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Begoña Graña
- Department of Medical Oncology, Instituto de Investigación Biomédica (INIBIC), Hospital Universitario de A Coruña, A Coruña, Spain
| | - Paula Jimenez-Fonseca
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Gema Pulido-Cortijo
- Department of Medical Oncology, IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Silvia Gil
- Department of Medical Oncology, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Javier Sastre
- Department of Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación (IdISSC), Universidad Complutense, Madrid, Spain
| | - Antonieta Salud
- Department of Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida, Spain
| | - Fernando Rivera
- Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - Mercedes Salgado
- Department of Medical Oncology, Complejo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Pilar García-Alfonso
- Department of Medical Oncology, Hospital Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain
| | - Rafael López López
- Department of Medical Oncology and Translational Medical Oncology Group, Hospital Clínico Universitario, Instituto de Investigación Sanitaria de Santiago (IDIS), CIBERONC, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
| | - Carmen Guillén-Ponce
- Department of Medical Oncology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
| | - Antonio Rodríguez-Ariza
- Department of Medical Oncology, IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Jose Mª Vieitez
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Eduardo Díaz-Rubio
- Department of Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación (IdISSC), Universidad Complutense, Madrid, Spain
| | - Enrique Aranda
- Department of Medical Oncology, IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
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Chang CH, Tsai CC, Tsai FM, Chu TY, Hsu PC, Kuo CY. EpCAM Signaling in Oral Cancer Stem Cells: Implications for Metastasis, Tumorigenicity, and Therapeutic Strategies. Curr Issues Mol Biol 2025; 47:123. [PMID: 39996844 PMCID: PMC11854592 DOI: 10.3390/cimb47020123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/08/2025] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
Oral cancer, a subtype of head and neck cancer, poses significant global health challenges owing to its late diagnosis and high metastatic potential. The epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein, has emerged as a critical player in cancer biology, particularly in oral cancer stem cells (CSCs). This review highlights the multifaceted roles of EPCAM in regulating oral cancer metastasis, tumorigenicity, and resistance to therapy. EpCAM influences key pathways, including Wnt/β-catenin and EGFR, modulating CSC self-renewal, epithelial-to-mesenchymal transition (EMT), and immune evasion. Moreover, EpCAM has been implicated in metabolic reprogramming, epigenetic regulation, and crosstalk with other signaling pathways. Advances in EpCAM-targeting strategies, such as monoclonal antibodies, chimeric antigen receptor (CAR) T/NK cell therapies, and aptamer-based systems hold promise for personalized cancer therapies. However, challenges remain in understanding the precise mechanism of EpCAM in CSC biology and its translation into clinical applications. This review highlights the need for further investigation into the role of EPCAM in oral CSCs and its potential as a therapeutic target to improve patient outcomes.
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Affiliation(s)
- Chuan-Hsin Chang
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Chung-Che Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Fu-Ming Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Tin-Yi Chu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
| | - Po-Chih Hsu
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
- Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-H.C.); (C.-C.T.); (F.-M.T.); (T.-Y.C.)
- Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
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Yadav M, Sharma A, Patne K, Tabasum S, Suryavanshi J, Rawat L, Machaalani M, Eid M, Singh RP, Choueiri TK, Pal S, Sabarwal A. AXL signaling in cancer: from molecular insights to targeted therapies. Signal Transduct Target Ther 2025; 10:37. [PMID: 39924521 PMCID: PMC11808115 DOI: 10.1038/s41392-024-02121-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/02/2024] [Accepted: 12/19/2024] [Indexed: 02/11/2025] Open
Abstract
AXL, a member of the TAM receptor family, has emerged as a potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, and inflammatory responses. Beyond oncology, AXL also facilitates viral infections, including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology. In preclinical models, small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential. This review primarily focuses on the induction, regulation and biological functions of AXL in mediating these tumor-promoting pathways. We discuss a range of therapeutic strategies, including recently developed small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates (ADCs), anti-AXL-CAR, and combination therapies. These interventions are being examined in both preclinical and clinical studies, offering the potential for improved drug sensitivity and therapeutic efficacy. We further discuss the mechanisms of acquired therapeutic resistance, particularly the crosstalk between AXL and other critical receptor tyrosine kinases (RTKs) such as c-MET, EGFR, HER2/HER3, VEGFR, PDGFR, and FLT3. Finally, we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.
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Affiliation(s)
- Monika Yadav
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
- Laboratory of Nanotechnology and Chemical Biology, Regional Center for Biotechnology, Faridabad, Haryana, India
| | - Akansha Sharma
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ketki Patne
- Chromatin Remodeling Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Saba Tabasum
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jyoti Suryavanshi
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA
| | - Laxminarayan Rawat
- Harvard Medical School, Boston, MA, USA
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
| | - Marc Machaalani
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Marc Eid
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
| | - Toni K Choueiri
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Soumitro Pal
- Harvard Medical School, Boston, MA, USA.
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
| | - Akash Sabarwal
- Harvard Medical School, Boston, MA, USA.
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
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Zhang X, Miao J, Song Y, Zhang J, Miao M. Review on effects and mechanisms of plant-derived natural products against breast cancer bone metastasis. Heliyon 2024; 10:e37894. [PMID: 39318810 PMCID: PMC11420494 DOI: 10.1016/j.heliyon.2024.e37894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/16/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024] Open
Abstract
Bone metastasis is the prevalent form of metastasis in breast cancer, resulting in severe pain, pathological fractures, nerve compression, hypercalcemia, and other complications that significantly impair patients' quality of life. The infiltration and colonization of breast cancer (BC) cells in bone tissue disrupt the delicate balance between osteoblasts and osteoclasts within the bone microenvironment, initiating a vicious cycle of bone metastasis. Once bone metastasis occurs, conventional medical therapy with bone-modifying agents is commonly used to alleviate bone-related complications and improve patients' quality of life. However, the utilization of bone-modifying agents may cause severe drug-related adverse effects. Plant-derived natural products such as terpenoids, alkaloids, coumarins, and phenols have anti-tumor, anti-inflammatory, and anti-angiogenic pharmacological properties with minimal side effects. Certain natural products that exhibit both anti-breast cancer and anti-bone metastasis effects are potential therapeutic agents for breast cancer bone metastasis (BCBM). This article reviewed the effects of plant-derived natural products against BCBM and their mechanisms to provide a reference for the research and development of drugs related to BCBM.
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Affiliation(s)
- Xiaolei Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Jinxin Miao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Yagang Song
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Jiawen Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Mingsan Miao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
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Chen K, He Y, Wang W, Yuan X, Carbone DP, Yang F. Development of new techniques and clinical applications of liquid biopsy in lung cancer management. Sci Bull (Beijing) 2024; 69:1556-1568. [PMID: 38641511 DOI: 10.1016/j.scib.2024.03.062] [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: 09/25/2023] [Revised: 12/12/2023] [Accepted: 01/17/2024] [Indexed: 04/21/2024]
Abstract
Lung cancer is an exceedingly malignant tumor reported as having the highest morbidity and mortality of any cancer worldwide, thus posing a great threat to global health. Despite the growing demand for precision medicine, current methods for early clinical detection, treatment and prognosis monitoring in lung cancer are hampered by certain bottlenecks. Studies have found that during the formation and development of a tumor, molecular substances carrying tumor-related genetic information can be released into body fluids. Liquid biopsy (LB), a method for detecting these tumor-related markers in body fluids, maybe a way to make progress in these bottlenecks. In recent years, LB technology has undergone rapid advancements. Therefore, this review will provide information on technical updates to LB and its potential clinical applications, evaluate its effectiveness for specific applications, discuss the existing limitations of LB, and present a look forward to possible future clinical applications. Specifically, this paper will introduce technical updates from the prospectives of engineering breakthroughs in the detection of membrane-based LB biomarkers and other improvements in sequencing technology. Additionally, it will summarize the latest applications of liquid biopsy for the early detection, diagnosis, treatment, and prognosis of lung cancer. We will present the interconnectedness of clinical and laboratory issues and the interplay of technology and application in LB today.
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Affiliation(s)
- Kezhong Chen
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing 100044, China; Peking University People's Hospital Thoracic Oncology Institute & Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Beijing 100044, China
| | - Yue He
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing 100044, China; Peking University People's Hospital Thoracic Oncology Institute & Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Beijing 100044, China
| | - Wenxiang Wang
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing 100044, China; Peking University People's Hospital Thoracic Oncology Institute & Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Beijing 100044, China
| | - Xiaoqiu Yuan
- Peking University Health Science Center, Beijing 100191, China
| | - David P Carbone
- Thoracic Oncology Center, Ohio State University, Columbus 43026, USA.
| | - Fan Yang
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing 100044, China; Peking University People's Hospital Thoracic Oncology Institute & Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Beijing 100044, China.
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Hassanzadeh-Barforoushi A, Tukova A, Nadalini A, Inglis DW, Chang-Hao Tsao S, Wang Y. Microfluidic-SERS Technologies for CTC: A Perspective on Clinical Translation. ACS APPLIED MATERIALS & INTERFACES 2024. [PMID: 38652011 DOI: 10.1021/acsami.4c01158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
Enumeration and phenotypic profiling of circulating tumor cells (CTCs) provide critical information for clinical diagnosis and treatment monitoring in cancer. To achieve this goal, an integrated system is needed to efficiently isolate CTCs from patient samples and sensitively evaluate their phenotypes. Such integration would comprise a high-throughput single-cell processing unit for the isolation and manipulation of CTCs and a sensitive and multiplexed quantitation unit to detect clinically relevant signals from these cells. Surface-enhanced Raman scattering (SERS) has been used as an analytical method for molecular profiling and in vitro cancer diagnosis. More recently, its multiplexing capability and power to create distinct molecular signatures against their targets have garnered attention. Here, we share our insights into the combined power of microfluidics and SERS in realizing CTC isolation, enumeration, and detection from a clinical translation perspective. We highlight the key operational factors in CTC microfluidic processing and SERS detection from patient samples. We further discuss microfluidic-SERS integration and its clinical utility as a paradigm shift in clinical CTC-based cancer diagnosis and prognostication. Finally, we summarize the challenges and attempt to look forward to what lies ahead of us in potentially translating the technique into real clinical applications.
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Affiliation(s)
- Amin Hassanzadeh-Barforoushi
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - Anastasiia Tukova
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - Audrey Nadalini
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - David W Inglis
- School of Engineering, Faculty of Science and Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - Simon Chang-Hao Tsao
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
- Department of Surgery, Austin Health, University of Melbourne, Heidelberg, Victoria 3084, Australia
| | - Yuling Wang
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
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Sawai K, Goi T, Kimura Y, Koneri K. Presence of CD44v9-Expressing Cancer Stem Cells in Circulating Tumor Cells and Effects of Carcinoembryonic Antigen Levels on the Prognosis of Colorectal Cancer. Cancers (Basel) 2024; 16:1556. [PMID: 38672639 PMCID: PMC11048819 DOI: 10.3390/cancers16081556] [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: 03/21/2024] [Revised: 04/15/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells released from the primary tumor into the bloodstream, and contain cancer stem cells that influence tumor survival, recurrence, and metastasis. Here, we investigated CD44v9 expression in CTCs and impact of preoperative carcinoembryonic antigen (CEA) levels on colorectal cancer (CRC) prognosis. We analyzed the expression of CD44v9 mRNA in CTCs using reverse transcription-polymerase chain reaction and preoperative CEA levels in blood samples obtained from 300 patients with CRC. Subsequently, we evaluated the association of CD44v9 expression and CEA levels with clinicopathological factors. CD44v9 mRNA was expressed in 31.3% of the patients, and was significantly associated with liver metastasis. Patients with positive CD44v9 expression had a lower 5-year survival rate (62.3%) than those with negative CD44v9 expression (82.8%, p < 0.001). Cox regression analysis identified CD44v9 expression and high CEA levels (≥5 ng/mL) as poor prognostic factors, while negative CD44v9 expression and low CEA levels (<5 ng/mL) were associated with favorable prognosis (hazard ratio = 0.285, p = 0.006). These results suggest that a combination of CD44v9 mRNA expression in CTCs and serum CEA levels could serve as a valuable prognostic marker for CRC, potentially enhancing the accuracy of prognosis predictions.
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Affiliation(s)
- Katsuji Sawai
- First Department of Surgery, University of Fukui, Fukui 910-1193, Japan; (T.G.); (Y.K.); (K.K.)
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Xu J, Zhao Y, Chen Z, Wei L. Clinical Application of Different Liquid Biopsy Components in Hepatocellular Carcinoma. J Pers Med 2024; 14:420. [PMID: 38673047 PMCID: PMC11051574 DOI: 10.3390/jpm14040420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/26/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, usually occurring in the background of chronic liver disease. HCC lethality rate is in the third highest place in the world. Patients with HCC have concealed early symptoms and possess a high-level of heterogeneity. Once diagnosed, most of the tumors are in advanced stages and have a poor prognosis. The sensitivity and specificity of existing detection modalities and protocols are suboptimal. HCC calls for more sophisticated and individualized therapeutic regimens. Liquid biopsy is non-invasive, repeatable, unaffected by location, and can be monitored dynamically. It has emerged as a useable aid in achieving precision malignant tumor treatment. Circulating tumor cells (CTCs), circulating nucleic acids, exosomes and tumor-educated platelets are the commonest components of a liquid biopsy. It possesses the theoretical ability to conquer the high heterogeneity and the difficulty of early detection for HCC patients. In this review, we summarize the common enrichment techniques and the clinical applications in HCC for different liquid biopsy components. Tumor recurrence after HCC-related liver transplantation is more insidious and difficult to treat. The clinical use of liquid biopsy in HCC-related liver transplantation is also summarized in this review.
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Affiliation(s)
| | | | | | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China; (J.X.); (Y.Z.); (Z.C.)
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Giudice E, Huang TT, Nair JR, Zurcher G, McCoy A, Nousome D, Radke MR, Swisher EM, Lipkowitz S, Ibanez K, Donohue D, Malys T, Lee MJ, Redd B, Levy E, Rastogi S, Sato N, Trepel JB, Lee JM. The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial. Nat Commun 2024; 15:2805. [PMID: 38555285 PMCID: PMC10981752 DOI: 10.1038/s41467-024-47215-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 03/25/2024] [Indexed: 04/02/2024] Open
Abstract
The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.
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Affiliation(s)
- Elena Giudice
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
- Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | - Tzu-Ting Huang
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Jayakumar R Nair
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Grant Zurcher
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Ann McCoy
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Darryl Nousome
- Center for Cancer Research Collaborative Bioinformatics Resource, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Marc R Radke
- Department of Ob/Gyn, University of Washington, Seattle, WA, 98195, USA
| | | | - Stanley Lipkowitz
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Kristen Ibanez
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Duncan Donohue
- Statistical Consulting and Scientific Programming Group, Computer and Statistical Services, Data Management Services, Inc. (a BRMI company), NCI, Frederick, MD, 21702, USA
| | - Tyler Malys
- Statistical Consulting and Scientific Programming Group, Computer and Statistical Services, Data Management Services, Inc. (a BRMI company), NCI, Frederick, MD, 21702, USA
| | - Min-Jung Lee
- Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Bernadette Redd
- Clinical Image Processing Service, Department of Radiology and Imaging Sciences, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Elliot Levy
- Interventional Radiology, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Shraddha Rastogi
- Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Nahoko Sato
- Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Jane B Trepel
- Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD, 20892, USA
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
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10
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Tariki MS, Barberan CCG, Torres JA, Ruano APC, Ferreira Costa DDJ, Braun AC, da Silva Alves V, de Cássio Zequi S, da Costa WH, Fay AP, Torrezan G, Carraro DM, Domingos Chinen LT. Circulating tumor cells as a predictor and prognostic tool for metastatic clear cell renal carcinoma: An immunocytochemistry and genomic analysis. Pathol Res Pract 2024; 253:154918. [PMID: 37995423 DOI: 10.1016/j.prp.2023.154918] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Treatment of metastatic clear cell renal carcinoma (mccRCC) has changed dramatically over the past 20 years, without improvement in the development of biomarkers. Recently, circulating tumor cells (CTCs) have been validated as a prognostic and predictive tool for many solid tumors. OBJECTIVE We evaluated CTCs in blood samples obtained from patients diagnosed with mccRCC. Comparisons of CTC counts, protein expression profiling, and DNA mutants were made in relation to overall survival and progression-free survival. METHODS CTCs were isolated from 10 mL blood samples using the ISET® system (Isolation by SizE of Tumor Cells; Rarecells, France) and counted. Protein expression was evaluated in immunocytochemistry assays. DNA mutations were identified with next generation sequencing (NGS). RESULTS Blood samples (10 mL) were collected from 12 patients with mccRCC before the start of first-line systemic therapy, and again 30 and 60 days after the start of treatment. All 12 patients had CTCs detected at baseline (median, 1.5 CTCs/mL; range: 0.25-7.75). Patients with CTC counts greater than the median had two or more metastatic sites and exhibited worse progression-free survival (19.7 months) compared to those with CTC counts less than the median (31.1 months). Disease progression was observed in 7/12 patients during the study. Five of these patients had baseline CTC counts greater than the median, one had higher CTC levels at the second blood collection, and one patient had CTCs present at 1 CTC/mL which positively stained for PD-L1, N-cadherin, VEGF, and SETD2. CTC DNA from six patients with worse outcomes was subjected to NGS. However, no conclusions could be made due to the low variant allele frequencies. CONCLUSION Detection of CTCs in patients with mccRCC receiving first-line treatment is a feasible tool with prognostic potential since increased numbers of CTCs were found to be associated with metastasis and disease progression.
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Affiliation(s)
- Milena Shizue Tariki
- Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo 01509-900, Brazil.
| | | | | | | | | | - Alexcia Camila Braun
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil
| | | | - Stenio de Cássio Zequi
- Department of Urology, Fundação Antônio Prudente, A.C. Camargo Cancer Center, São Paulo 01509-900, Brazil; National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo 01509-900, Brazil; Graduate School, Department of Surgery, Division of Urology, São Paulo Federal University, São Paulo 04024-002, Brazil
| | - Walter Henriques da Costa
- Department of Urology, Fundação Antônio Prudente, A.C. Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - André P Fay
- PUCRS School of Medicine, Rio Grande do Sul 90619-900, Brazil
| | - Giovana Torrezan
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil
| | - Dirce M Carraro
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil
| | - Ludmilla T Domingos Chinen
- International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil; Associação Beneficente Síria, HCor, São Paulo 04004-030, Brazil; Hospital Amaral Carvalho, Jaú, São Paulo 17210-080, Brazil
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11
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Thomsen AR, Sahlmann J, Bronsert P, Schilling O, Poensgen F, May AM, Timme-Bronsert S, Grosu AL, Vaupel P, Gebbers JO, Multhoff G, Lüchtenborg AM. Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer. Front Oncol 2023; 13:1275222. [PMID: 38169879 PMCID: PMC10759986 DOI: 10.3389/fonc.2023.1275222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/20/2023] [Indexed: 01/05/2024] Open
Abstract
Introduction Breast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study. Methods and analyses Patients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated. Registration The study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).
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Affiliation(s)
- Andreas R. Thomsen
- Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany
| | - Jörg Sahlmann
- Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Bronsert
- Tumorbank Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Oliver Schilling
- German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany
- Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Felicia Poensgen
- Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Pediatric Department, Black Forest Baar Clinic, Villingen-Schwenningen, Germany
| | - Annette M. May
- Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Medizinisches Versorgungszentrum Laaff, Freiburg, Germany
| | - Sylvia Timme-Bronsert
- German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany
- Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany
| | - Peter Vaupel
- Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany
| | - Jan-Olaf Gebbers
- Department of Pathology, Working Group Digital Pathology, University of Berne, Bern, Switzerland
| | - Gabriele Multhoff
- Center for Translational Cancer Research, Klinikum rechts der Isar, Department of Radiation Oncology, Technical University Munich (TUM), Munich, Germany
| | - Anne-Marie Lüchtenborg
- Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany
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12
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Xie J, Hu B, Gong Y, He S, Lin J, Huang Q, Cheng J. A comparative study on ctDNA and tumor DNA mutations in lung cancer and benign cases with a high number of CTCs and CTECs. J Transl Med 2023; 21:873. [PMID: 38041139 PMCID: PMC10691057 DOI: 10.1186/s12967-023-04746-8] [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: 07/10/2023] [Accepted: 11/21/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Liquid biopsy provides a non-invasive approach that enables detecting circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) using blood specimens and theoretically benefits early finding primary tumor or monitoring treatment response as well as tumor recurrence. Despite many studies on these novel biomarkers, their clinical relevance remains controversial. This study aims to investigate the correlation between ctDNA, CTCs, and circulating tumor-derived endothelial cells (CTECs) while also evaluating whether mutation profiling in ctDNA is consistent with that in tumor tissue from lung cancer patients. These findings will help the evaluation and utilization of these approaches in clinical practice. METHODS 104 participants (49 with lung cancer and 31 with benign lesions) underwent CTCs and CTECs detection using integrating subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) strategy. The circulating cell-free DNA (cfDNA) concentration was measured and the mutational profiles of ctDNA were examined by Roche AVENIO ctDNA Expanded Kit (targeted total of 77 genes) by next generation sequencing (NGS) in 28 patients (20 with lung cancer and 8 with benign lesions) with highest numbers of CTCs and CTECs. Mutation validation in matched tumor tissue DNA was then performed in 9 patients with ctDNA mutations using a customized xGen pan-solid tumor kit (targeted total of 474 genes) by NGS. RESULTS The sensitivity and specificity of total number of CTCs and CTECs for the diagnosis of NSCLC were 67.3% and 77.6% [AUC (95%CI): 0.815 (0.722-0.907)], 83.9% and 77.4% [AUC (95%CI): 0.739 (0.618-0.860)]. The concentration of cfDNA in plasma was statistically correlated with the size of the primary tumor (r = 0.430, P = 0.022) and CYFRA 21-1 (r = 0.411, P = 0.041), but not with the numbers of CTCs and CTECs. In this study, mutations were found to be poorly consistent between ctDNA and tumor DNA (tDNA) in patients, even when numerous CTCs and CTECs were present. CONCLUSION Detection of CTCs and CTECs could be the potential adjunct tool for the early finding of lung cancer. The cfDNA levels are associated with the tumor burden, rather than the CTCs or CTECs counts. Moreover, the poorly consistent mutations between ctDNA and tDNA require further exploration.
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Affiliation(s)
- Jianzhu Xie
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Binjie Hu
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanping Gong
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sijia He
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Lin
- Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Huang
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jin Cheng
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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13
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Paglia EB, Baldin EKK, Freitas GP, Santiago TSA, Neto JBMR, Silva JVL, Carvalho HF, Beppu MM. Circulating Tumor Cells Adhesion: Application in Biosensors. BIOSENSORS 2023; 13:882. [PMID: 37754116 PMCID: PMC10526177 DOI: 10.3390/bios13090882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/23/2023] [Accepted: 09/01/2023] [Indexed: 09/28/2023]
Abstract
The early and non-invasive diagnosis of tumor diseases has been widely investigated by the scientific community focusing on the development of sensors/biomarkers that act as a way of recognizing the adhesion of circulating tumor cells (CTCs). As a challenge in this area, strategies for CTCs capture and enrichment currently require improvements in the sensors/biomarker's selectivity. This can be achieved by understanding the biological recognition factors for different cancer cell lines and also by understanding the interaction between surface parameters and the affinity between macromolecules and the cell surface. To overcome some of these concerns, electrochemical sensors have been used as precise, fast-response, and low-cost transduction platforms for application in cytosensors. Additionally, distinct materials, geometries, and technologies have been investigated to improve the sensitivity and specificity properties of the support electrode that will transform biochemical events into electrical signals. This review identifies novel approaches regarding the application of different specific biomarkers (CD44, Integrins, and EpCAm) for capturing CTCs. These biomarkers can be applied in electrochemical biosensors as a cytodetection strategy for diagnosis of cancerous diseases.
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Affiliation(s)
- Eduarda B. Paglia
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
| | - Estela K. K. Baldin
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
- Renato Archer Information Technology Center, Campinas 13069-901, Brazil;
| | - Gabriela P. Freitas
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
- Renato Archer Information Technology Center, Campinas 13069-901, Brazil;
| | - Thalyta S. A. Santiago
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
| | - João B. M. R. Neto
- Technology Center, Federal University of Alagoas, Maceió 57072-900, Brazil;
| | - Jorge V. L. Silva
- Renato Archer Information Technology Center, Campinas 13069-901, Brazil;
| | - Hernandes F. Carvalho
- Institute of Biology, Department of Structural and Functional Biology, University of Campinas, Campinas 13083-864, Brazil;
| | - Marisa M. Beppu
- School of Chemical Engineering, Department of Process and Product Development, University of Campinas, Campinas 13083-852, Brazil; (E.B.P.); (E.K.K.B.); (G.P.F.); (T.S.A.S.)
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14
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Bevere M, Masetto F, Carazzolo ME, Bettega A, Gkountakos A, Scarpa A, Simbolo M. An Overview of Circulating Biomarkers in Neuroendocrine Neoplasms: A Clinical Guide. Diagnostics (Basel) 2023; 13:2820. [PMID: 37685358 PMCID: PMC10486716 DOI: 10.3390/diagnostics13172820] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/14/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of diseases that are characterized by different behavior and clinical manifestations. The diagnosis and management of this group of tumors are challenging due to tumor complexity and lack of precise and widely validated biomarkers. Indeed, the current circulating mono-analyte biomarkers (such as chromogranin A) are ineffective in describing such complex tumors due to their poor sensitivity and specificity. In contrast, multi-analytical circulating biomarkers (including NETest) are emerging as more effective tools to determine the real-time profile of the disease, both in terms of accurate diagnosis and effective treatment. In this review, we will analyze the capabilities and limitations of different circulating biomarkers focusing on three relevant questions: (1) accurate and early diagnosis; (2) monitoring of disease progression and response to therapy; and (3) detection of early relapse.
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Affiliation(s)
- Michele Bevere
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Francesca Masetto
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Maria Elena Carazzolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Alice Bettega
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Anastasios Gkountakos
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Aldo Scarpa
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
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15
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Xanthopoulos A, Samt AK, Guder C, Taylor N, Roberts E, Herf H, Messner V, Trill A, Holzmann KLK, Kiechle M, Seifert-Klauss V, Zschaeck S, Schatka I, Tauber R, Schmidt R, Enste K, Pockley AG, Lobinger D, Multhoff G. Hsp70-A Universal Biomarker for Predicting Therapeutic Failure in Human Female Cancers and a Target for CTC Isolation in Advanced Cancers. Biomedicines 2023; 11:2276. [PMID: 37626772 PMCID: PMC10452093 DOI: 10.3390/biomedicines11082276] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/02/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Heat shock protein 70 (Hsp70) is frequently overexpressed in many different tumor types. However, Hsp70 has also been shown to be selectively presented on the plasma membrane of tumor cells, but not normal cells, and this membrane form of Hsp70 (mHsp70) could be considered a universal tumor biomarker. Since viable, mHsp70-positive tumor cells actively release Hsp70 in lipid micro-vesicles, we investigated the utility of Hsp70 in circulation as a universal tumor biomarker and its potential as an early predictive marker of therapeutic failure. We have also evaluated mHsp70 as a target for the isolation and enumeration of circulating tumor cells (CTCs) in patients with different tumor entities. Circulating vesicular Hsp70 levels were measured in the peripheral blood of tumor patients with the compHsp70 ELISA. CTCs were isolated using cmHsp70.1 and EpCAM monoclonal antibody (mAb)-based bead approaches and characterized by immunohistochemistry using cytokeratin and CD45-specific antibodies. In two out of 35 patients exhibiting therapeutic failure two years after initial diagnosis of non-metastatic breast cancer, progressively increasing levels of circulating Hsp70 had already been observed during therapy, whereas levels in patients without subsequent recurrence remained unaltered. With regards to CTC isolation from patients with different tumors, an Hsp70 mAb-based selection system appears superior to an EpCAM mAb-based approach. Extracellular and mHsp70 can therefore serve as a predictive biomarker for therapeutic failure in early-stage tumors and as a target for the isolation of CTCs in various tumor diseases.
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Affiliation(s)
- Alexia Xanthopoulos
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Ann-Kathrin Samt
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Christiane Guder
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Nicholas Taylor
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Erika Roberts
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Hannah Herf
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Verena Messner
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Anskar Trill
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Katharina Larissa Kreszentia Holzmann
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
| | - Marion Kiechle
- Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (M.K.); (V.S.-K.)
| | - Vanadin Seifert-Klauss
- Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (M.K.); (V.S.-K.)
| | - Sebastian Zschaeck
- Department of Radiation Oncology and Radiotherapy, Charité Berlin, 10117 Berlin, Germany;
| | - Imke Schatka
- Department of Nuclear Medicine, Charité Berlin, 10117 Berlin, Germany;
| | - Robert Tauber
- Department of Urology, Klinkum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany;
| | - Robert Schmidt
- Krankenhaus für Naturheilweisen, 81545 Munich, Germany; (R.S.); (K.E.)
| | - Katrin Enste
- Krankenhaus für Naturheilweisen, 81545 Munich, Germany; (R.S.); (K.E.)
| | - Alan Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK;
| | - Dominik Lobinger
- Department of Thoracic Surgery, München Klinik Bogenhausen, Lehrkrankenhaus der TU München, 81925 Munich, Germany;
| | - Gabriele Multhoff
- Center for Translational Cancer Research TU München (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (A.X.); (A.-K.S.); (C.G.); (N.T.); (E.R.); (H.H.); (V.M.); (A.T.)
- Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany
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16
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Welter L, Zheng S, Setayesh SM, Morikado M, Agrawal A, Nevarez R, Naghdloo A, Pore M, Higa N, Kolatkar A, Thiele JA, Sharma P, Moore HCF, Richer JK, Elias A, Pienta KJ, Zurita AJ, Gross ME, Shishido SN, Hicks J, Velasco CR, Kuhn P. Cell State and Cell Type: Deconvoluting Circulating Tumor Cell Populations in Liquid Biopsies by Multi-Omics. Cancers (Basel) 2023; 15:3949. [PMID: 37568766 PMCID: PMC10417732 DOI: 10.3390/cancers15153949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Bi-directional crosstalk between the tumor and the tumor microenvironment (TME) has been shown to increase the rate of tumor evolution and to play a key role in neoplastic progression, therapeutic resistance, and a patient's overall survival. Here, we set out to use a comprehensive liquid-biopsy analysis to study cancer and specific TME cells in circulation and their association with disease status. Cytokeratin+, CD45- circulating rare cells (CRCs) from nine breast and four prostate cancer patients were characterized through morphometrics, single-cell copy number analysis, and targeted multiplexed proteomics to delineate cancer cell lineage from other rare cells originating in the TME. We show that we can detect epithelial circulating tumor cells (EPI.CTC), CTCs undergoing epithelial-to-mesenchymal transition (EMT.CTC) and circulating endothelial cells (CECs) using a universal rare event detection platform (HDSCA). Longitudinal analysis of an index patient finds that CTCs are present at the time of disease progression, while CECs are predominately present at the time of stable disease. In a small cohort of prostate and breast cancer patients, we find high inter-patient and temporal intra-patient variability in the expression of tissue specific markers such as ER, HER2, AR, PSA and PSMA and EpCAM. Our study stresses the importance of the multi-omic characterization of circulating rare cells in patients with breast and prostate carcinomas, specifically highlighting overlapping and cell type defining proteo-genomic characteristics of CTCs and CECs.
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Affiliation(s)
- Lisa Welter
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
- Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Serena Zheng
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Sonia Maryam Setayesh
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
- Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Michael Morikado
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Arushi Agrawal
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Rafael Nevarez
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Amin Naghdloo
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
- Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Milind Pore
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Nikki Higa
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Anand Kolatkar
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Jana-Aletta Thiele
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Priyanka Sharma
- University of Kansas Medical Center, Westwood, KS 66205, USA;
| | - Halle C. F. Moore
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA;
| | - Jennifer K. Richer
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.R.); (A.E.)
| | - Anthony Elias
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (J.K.R.); (A.E.)
| | - Kenneth J. Pienta
- The Cancer Ecology Center, Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA;
| | - Amado J. Zurita
- Department of Genitourinary Medical Oncology, MD Anderson, Houston, TX 77230, USA;
| | - Mitchell E. Gross
- Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA 90064, USA;
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Stephanie N. Shishido
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - James Hicks
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
- Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Carmen Ruiz Velasco
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
| | - Peter Kuhn
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA; (L.W.); (S.Z.); (S.M.S.); (M.M.); (A.A.); (R.N.); (A.N.); (M.P.); (N.H.); (A.K.); (J.-A.T.); (S.N.S.); (C.R.V.)
- Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA
- Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
- Catherine & Joseph Aresty Department of Urology, Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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17
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Orrapin S, Thongkumkoon P, Udomruk S, Moonmuang S, Sutthitthasakul S, Yongpitakwattana P, Pruksakorn D, Chaiyawat P. Deciphering the Biology of Circulating Tumor Cells through Single-Cell RNA Sequencing: Implications for Precision Medicine in Cancer. Int J Mol Sci 2023; 24:12337. [PMID: 37569711 PMCID: PMC10418766 DOI: 10.3390/ijms241512337] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Circulating tumor cells (CTCs) hold unique biological characteristics that directly involve them in hematogenous dissemination. Studying CTCs systematically is technically challenging due to their extreme rarity and heterogeneity and the lack of specific markers to specify metastasis-initiating CTCs. With cutting-edge technology, single-cell RNA sequencing (scRNA-seq) provides insights into the biology of metastatic processes driven by CTCs. Transcriptomics analysis of single CTCs can decipher tumor heterogeneity and phenotypic plasticity for exploring promising novel therapeutic targets. The integrated approach provides a perspective on the mechanisms underlying tumor development and interrogates CTCs interactions with other blood cell types, particularly those of the immune system. This review aims to comprehensively describe the current study on CTC transcriptomic analysis through scRNA-seq technology. We emphasize the workflow for scRNA-seq analysis of CTCs, including enrichment, single cell isolation, and bioinformatic tools applied for this purpose. Furthermore, we elucidated the translational knowledge from the transcriptomic profile of individual CTCs and the biology of cancer metastasis for developing effective therapeutics through targeting key pathways in CTCs.
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Affiliation(s)
- Santhasiri Orrapin
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Patcharawadee Thongkumkoon
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Sasimol Udomruk
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
| | - Sutpirat Moonmuang
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Songphon Sutthitthasakul
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Petlada Yongpitakwattana
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
| | - Dumnoensun Pruksakorn
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
- Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
| | - Parunya Chaiyawat
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.O.); (P.T.); (S.U.); (S.M.); (S.S.); (P.Y.); (D.P.)
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand
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18
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Zaky W, Ragoonanan D, Batth I, Dao L, Wang J, Xia X, Daw NC, Gill JB, Khatua S, Li S. Automated Capture and Analysis of Circulating Tumor Cells in Pediatric, Adolescent and Young Adult Patients with Central Nervous System Tumors. Cancers (Basel) 2023; 15:3853. [PMID: 37568669 PMCID: PMC10417345 DOI: 10.3390/cancers15153853] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Tumors of the central nervous system (CNS) are the most common and lethal childhood malignancy. Detection of residual disease and longitudinal monitoring of treatment response in patients are challenging and rely on serial imaging. This current standard of care fails to detect microscopic disease or provide molecular characteristics of residual tumors. As such, there is dire need for minimally invasive liquid biopsy techniques. We have previously shown the high specificity of using cell surface vimentin (CSV) to identify circulating tumor cells (CTCs) from patients bearing various types of cancers. Here, we describe the first report of CTCs captured from peripheral blood samples in 58 pediatric CNS tumor patients. In this study, we used a CSV-coated cell capture chip, the Abnova CytoQuest automated CTC isolation system, to boost the CTC capture from pediatric patients with CNS tumors. We successfully isolated CTCs in six glioma patients using immunostaining of histone H3 lysine27-to-methionine (H3K27M) mutations which are highly expressed by this tumor. We show that CSV is a viable marker for CNS CTC isolation and that this is a feasible method for detecting microscopic disease. Larger-scale studies focusing on CTCs in pediatric CNS tumors to explore their diagnostic and prognostic value are warranted.
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Affiliation(s)
- Wafik Zaky
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Dristhi Ragoonanan
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Izhar Batth
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Long Dao
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Jian Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xueqing Xia
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Najat C. Daw
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Jonathan B. Gill
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Soumen Khatua
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
| | - Shulin Li
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77023, USA
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19
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Rapanotti MC, Cugini E, Campione E, Di Raimondo C, Costanza G, Rossi P, Ferlosio A, Bernardini S, Orlandi A, De Luca A, Bianchi L. Epithelial-to-Mesenchymal Transition Gene Signature in Circulating Melanoma Cells: Biological and Clinical Relevance. Int J Mol Sci 2023; 24:11792. [PMID: 37511550 PMCID: PMC10380315 DOI: 10.3390/ijms241411792] [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: 06/28/2023] [Revised: 07/14/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The most promising method for monitoring patients with minimal morbidity is the detection of circulating melanoma cells (CMCs). We have shown that CD45-CD146+ABCB5+ CMCs identify a rare primitive stem/mesenchymal CMCs population associated with disease progression. The epithelial-to-mesenchymal transition (EMT) confers cancer cells a hybrid epithelial/mesenchymal phenotype promoting metastatization. Thus, we investigated the potential clinical value of the EMT gene signature of these primitive CMCs. A reliable quantitative real-time polymerase chain reaction (qRT-PCR) protocol was settled up using tumor cell lines RNA dilutions. Afterwards, immune-magnetically isolated CMCs from advanced melanoma patients, at onset and at the first checkpoint (following immune or targeted therapy), were tested for the level of EMT hallmarks and EMT transcription factor genes. Despite the small cohort of patients, we obtained promising results. Indeed, we observed a deep gene rewiring of the EMT investigated genes: in particular we found that the EMT gene signature of isolated CMCs correlated with patients' clinical outcomes. In conclusion, We established a reliable qRT-PCR protocol with high sensitivity and specificity to characterize the gene expression of isolated CMCs. To our knowledge, this is the first evidence demonstrating the impact of immune or targeted therapies on EMT hallmark gene expressions in CMCs from advanced melanoma patients.
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Affiliation(s)
- Maria Cristina Rapanotti
- Department of Anatomic Pathology, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
| | - Elisa Cugini
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
| | - Elena Campione
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Cosimo Di Raimondo
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Gaetana Costanza
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
| | - Piero Rossi
- Surgery Division, Department of Surgery Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Amedeo Ferlosio
- Department of Anatomic Pathology, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
| | - Sergio Bernardini
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
| | - Augusto Orlandi
- Department of Anatomic Pathology, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
| | - Anastasia De Luca
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Luca Bianchi
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
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20
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Chen H, Osman SY, Moose DL, Vanneste M, Anderson JL, Henry MD, Anand RK. Quantification of capture efficiency, purity, and single-cell isolation in the recovery of circulating melanoma cells from peripheral blood by dielectrophoresis. LAB ON A CHIP 2023; 23:2586-2600. [PMID: 37185977 PMCID: PMC10228177 DOI: 10.1039/d2lc01113a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/31/2023] [Indexed: 05/17/2023]
Abstract
This paper describes a dielectrophoretic method for selection of circulating melanoma cells (CMCs), which lack reliable identifying surface antigens and are extremely rare in blood. This platform captures CMCs individually by dielectrophoresis (DEP) at an array of wireless bipolar electrodes (BPEs) aligned to overlying nanoliter-scale chambers, which isolate each cell for subsequent on-chip single-cell analysis. To determine the best conditions to employ for CMC isolation in this DEP-BPE platform, the static and dynamic dielectrophoretic response of established melanoma cell lines, melanoma cells from patient-derived xenografts (PDX) and peripheral blood mononuclear cells (PBMCs) were evaluated as a function of frequency using two established DEP platforms. Further, PBMCs derived from patients with advanced melanoma were compared with those from healthy controls. The results of this evaluation reveal that each DEP method requires a distinct frequency to achieve capture of melanoma cells and that the distribution of dielectric properties of PBMCs is more broadly varied in and among patients versus healthy controls. Based on this evaluation, we conclude that 50 kHz provides the highest capture efficiency on our DEP-BPE platform while maintaining a low rate of capture of unwanted PBMCs. We further quantified the efficiency of single-cell capture on the DEP-BPE platform and found that the efficiency diminished beyond around 25% chamber occupancy, thereby informing the minimum array size that is required. Importantly, the capture efficiency of the DEP-BPE platform for melanoma cells when using optimized conditions matched the performance predicted by our analysis. Finally, isolation of melanoma cells from contrived (spike-in) and clinical samples on our platform using optimized conditions was demonstrated. The capture and individual isolation of CMCs, confirmed by post-capture labeling, from patient-derived samples suggests the potential of this platform for clinical application.
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Affiliation(s)
- Han Chen
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
| | - Sommer Y Osman
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
| | - Devon L Moose
- Departments of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA
| | - Marion Vanneste
- Departments of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA
| | - Jared L Anderson
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
| | - Michael D Henry
- Departments of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA
- Pathology, Urology and Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Robbyn K Anand
- Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
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21
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Zhang X, Li L, Zhang M, Zhang L, Liu S, Guo J, Jiang N, Peng Q, Wang J, Ding S. Intelligent recognition of CTCs from gallbladder cancer by ultrasensitive electrochemical cytosensor and diagnosis of chemotherapeutic resistance. Biosens Bioelectron 2023; 228:115183. [PMID: 36905863 DOI: 10.1016/j.bios.2023.115183] [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: 11/26/2022] [Revised: 02/21/2023] [Accepted: 02/25/2023] [Indexed: 03/03/2023]
Abstract
Gallbladder carcinoma (GBC) is one of most aggressive and lethal malignancies. Early diagnosis of GBC is crucial for determining appropriate treatment and improving chances of cure. Chemotherapy represents the main therapeutic regimen for unresectable GBC patients to inhibit tumor growth & metastasis. But, chemoresistance is the major cause of GBC recurrence. Thus, there is an urgent need to explore potentially non-invasive and point-of-care approaches to screen GBC and monitor their chemoresistance. Herein, we established an electrochemical cytosensor to specifically detect circulating tumor cells (CTCs) and their chemoresistance. Trilayer of CdSe/ZnS quantum dots (QDs) were cladded upon SiO2 nanoparticles (NPs), forming Tri-QDs/PEI@SiO2 electrochemical probes. Upon conjugation of anti-ENPP1, the electrochemical probes were able to specifically label captured CTCs from GBC. The detection of CTCs and chemoresistance were realized by square wave anodic stripping voltammetric (SWASV) responses to anodic stripping current of Cd 2+ ion when cadmium in electrochemical probes was dissolved and eventually electrodeposited on bismuth film-modified glassy carbon electrode (BFE). Taking use of this cytosensor, one ensured the screening of GBC and limit of detection for CTCs approaches to ～10 cells/mL. Furthermore, by monitoring phenotypic changes of CTCs after drug treatment, the diagnosis of chemoresistance was achieved by our cytosensor.
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Affiliation(s)
- Xiuzhen Zhang
- School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Lu Li
- School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Mi Zhang
- Department of Neurosurgery, Children's Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - La Zhang
- Department of Hepatobiliary Surgery, Chongqing Medical University, Chongqing, 400016, PR China
| | - Shanshan Liu
- Department of Hepatobiliary Surgery, Chongqing Medical University, Chongqing, 400016, PR China
| | - Jiao Guo
- School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Ning Jiang
- Department of Pathology, Chongqing Medical University, Chongqing, 400016, PR China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, PR China; Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
| | - Qiling Peng
- School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, PR China.
| | - Jianwei Wang
- School of Basic Medical Science, Chongqing Medical University, Chongqing, 400016, PR China.
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, PR China
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22
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Geometric tumor embolic budding characterizes inflammatory breast cancer. Breast Cancer Res Treat 2023; 197:461-478. [PMID: 36473978 PMCID: PMC9734724 DOI: 10.1007/s10549-022-06819-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery. METHODS This study combines experimental studies with two different IBC xenografts with image algorithmic studies utilizing human tissue microarrays (TMAs) of IBC vs non-IBC cases to support a novel hypothesis to explain IBC's sina qua non signature of florid lymphovascular emboli. RESULTS In the human TMAs, compared to tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which show that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really sets IBC apart is the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers indicate geometric or exponential differences between IBC and non-IBC. In the experimental xenograft studies, Mary-X gives rise to tight spheroids in vitro which exhibit dynamic budding into smaller daughter spheroids whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into smaller daughter emboli in vivo. The mechanism that regulates this involves the generation of E-cad/NTF1, a calpain-mediated cleavage 100 kDa product of 120 kDa full length membrane E-cadherin. Inhibiting this calpain-mediated cleavage of E-cadherin by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides that both penetrate the cell membrane and mimic either the cleavage site or the binding site on E-cadherin, inhibits the generation of E-cad/NTF1 in a dose-dependent manner, reduces spheroid compactness and decreases budding. CONCLUSION Since E-cad/NFT1 retains the p120ctn binding site but loses the α-and β-catenin sites, promoting its 360° distribution around the cell's membrane, the vacilating levels of this molecule trigger budding of both the spheroids as well as the emboli. Recurrent and geometric budding of parental emboli into daughter emboli then would account for the plethora of emboli seen in IBC.
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23
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Noubissi Nzeteu GA, Geismann C, Arlt A, Hoogwater FJH, Nijkamp MW, Meyer NH, Bockhorn M. Role of Epithelial-to-Mesenchymal Transition for the Generation of Circulating Tumors Cells and Cancer Cell Dissemination. Cancers (Basel) 2022; 14:5483. [PMID: 36428576 PMCID: PMC9688619 DOI: 10.3390/cancers14225483] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/24/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Tumor-related death is primarily caused by metastasis; consequently, understanding, preventing, and treating metastasis is essential to improving clinical outcomes. Metastasis is mainly governed by the dissemination of tumor cells in the systemic circulation: so-called circulating tumor cells (CTCs). CTCs typically arise from epithelial tumor cells that undergo epithelial-to-mesenchymal transition (EMT), resulting in the loss of cell-cell adhesions and polarity, and the reorganization of the cytoskeleton. Various oncogenic factors can induce EMT, among them the transforming growth factor (TGF)-β, as well as Wnt and Notch signaling pathways. This entails the activation of numerous transcription factors, including ZEB, TWIST, and Snail proteins, acting as transcriptional repressors of epithelial markers, such as E-cadherin and inducers of mesenchymal markers such as vimentin. These genetic and phenotypic changes ultimately facilitate cancer cell migration. However, to successfully form distant metastases, CTCs must primarily withstand the hostile environment of circulation. This includes adaption to shear stress, avoiding being trapped by coagulation and surviving attacks of the immune system. Several applications of CTCs, from cancer diagnosis and screening to monitoring and even guided therapy, seek their way into clinical practice. This review describes the process leading to tumor metastasis, from the generation of CTCs in primary tumors to their dissemination into distant organs, as well as the importance of subtyping CTCs to improve personalized and targeted cancer therapy.
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Affiliation(s)
- Gaetan Aime Noubissi Nzeteu
- University Hospital of General and Visceral Surgery, Department of Human Medicine, University of Oldenburg and Klinikum Oldenburg, 26129 Oldenburg, Germany
| | - Claudia Geismann
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24118 Kiel, Germany
| | - Alexander Arlt
- Department for Gastroenterology and Hepatology, University Hospital Oldenburg, Klinikum Oldenburg AöR, European Medical School (EMS), 26133 Oldenburg, Germany
| | - Frederik J. H. Hoogwater
- Section of HPB Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Maarten W. Nijkamp
- Section of HPB Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - N. Helge Meyer
- University Hospital of General and Visceral Surgery, Department of Human Medicine, University of Oldenburg and Klinikum Oldenburg, 26129 Oldenburg, Germany
| | - Maximilian Bockhorn
- University Hospital of General and Visceral Surgery, Department of Human Medicine, University of Oldenburg and Klinikum Oldenburg, 26129 Oldenburg, Germany
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Jia L, Zhen X, Chen L, Feng Q, Yuan W, Bu Y, Wang S, Xie X. Bioinspired nano-plate-coral platform enabled efficient detection of circulating tumor cells via the synergistic capture of multivalent aptamer and tumor cell membrane. J Colloid Interface Sci 2022; 631:55-65. [DOI: 10.1016/j.jcis.2022.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/31/2022] [Accepted: 11/06/2022] [Indexed: 11/10/2022]
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Payne K, Brooks J, Batis N, Taylor G, Nankivell P, Mehanna H. Characterizing the epithelial-mesenchymal transition status of circulating tumor cells in head and neck squamous cell carcinoma. Head Neck 2022; 44:2545-2554. [PMID: 35932094 PMCID: PMC9804280 DOI: 10.1002/hed.27167] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/08/2022] [Accepted: 07/19/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs), in particular those undergoing an epithelial-mesenchymal transition (EMT), are a promising source of biomarkers in head and neck squamous cell carcinoma (HNSCC). Our aim was to validate a protocol using microfluidic enrichment (Parsortix platform) with flow-cytometry CTC characterization. METHOD Blood samples from 20 treatment naïve HNSCC patients underwent Parsortix enrichment and flow cytometry analysis to quantify CTCs and identify epithelial or EMT subgroups-correlated to clinical outcomes and EMT gene-expression in tumor tissue. RESULTS CTCs were detected in 65% of patients (mean count 4 CTCs/ml). CTCs correlated with advanced disease (p = 0.0121), but not T or N classification. Epithelial or EMT CTCs did not correlate with progression-free or overall survival. Tumor mesenchymal gene-expression did not correlate with CTC EMT expression (p = 0.347). DISCUSSION Microfluidic enrichment and flow cytometry successfully characterizes EMT CTCs in HNSCC. The lack of association between tumor and CTC EMT profile suggests CTCs may undergo an adaptive EMT in response to stimuli within the circulation.
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Affiliation(s)
- Karl Payne
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
| | - Jill Brooks
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
| | - Nikolaos Batis
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
| | - Graham Taylor
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Paul Nankivell
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
| | - Hisham Mehanna
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
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Smolkova B, Kataki A, Earl J, Ruz-Caracuel I, Cihova M, Urbanova M, Buocikova V, Tamargo S, Rovite V, Niedra H, Schrader J, Kohl Y. Liquid biopsy and preclinical tools for advancing diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2022; 180:103865. [PMID: 36334880 DOI: 10.1016/j.critrevonc.2022.103865] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
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Xie X, Li Y, Lian S, Lu Y, Jia L. Cancer metastasis chemoprevention prevents circulating tumour cells from germination. Signal Transduct Target Ther 2022; 7:341. [PMID: 36184654 PMCID: PMC9526788 DOI: 10.1038/s41392-022-01174-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 04/19/2022] [Accepted: 08/31/2022] [Indexed: 11/09/2022] Open
Abstract
The war against cancer traces back to the signature event half-a-century ago when the US National Cancer Act was signed into law. The cancer crusade costs trillions with disappointing returns, teasing the possibility of a new breakthrough. Cure for cancer post-metastases still seems tantalisingly out of reach. Once metastasized, cancer-related death is extremely difficult, if not impossible, to be reversed. Here we present cancer pre-metastasis chemoprevention strategy that can prevent circulating tumour cells (CTCs) from initiating metastases safely and effectively, and is disparate from the traditional cancer chemotherapy and cancer chemoprevention. Deep learning of the biology of CTCs and their disseminating organotropism, complexity of their adhesion to endothelial niche reveals that if the adhesion of CTCs to their metastasis niche (the first and the most important part in cancer metastatic cascade) can be pharmaceutically interrupted, the lethal metastatic cascade could be prevented from getting initiated. We analyse the key inflammatory and adhesive factors contributing to CTC adhesion/germination, provide pharmacological fundamentals for abortifacients to intervene CTC adhesion to the distant metastasis sites. The adhesion/inhibition ratio (AIR) is defined for selecting the best cancer metastasis chemopreventive candidates. The successful development of such new therapeutic modalities for cancer metastasis chemoprevention has great potential to revolutionise the current ineffective post-metastasis treatments.
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Affiliation(s)
- Xiaodong Xie
- College of Materials and Chemical Engineering, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Yumei Li
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Shu Lian
- College of Materials and Chemical Engineering, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Yusheng Lu
- College of Materials and Chemical Engineering, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Lee Jia
- College of Materials and Chemical Engineering, Minjiang University, Fuzhou, Fujian, 350108, China. .,Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, 350116, China.
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Kobayashi S, Sugasaki A, Yamamoto Y, Shigenoi Y, Udaka A, Yamamoto A, Tanaka M. Enrichment of Cancer Cells Based on Antibody-Free Selective Cell Adhesion. ACS Biomater Sci Eng 2022; 8:4547-4556. [PMID: 36153975 DOI: 10.1021/acsbiomaterials.2c00662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Blood-compatible and cell-adhering polymer materials are extremely useful for regenerative medicine and disease diagnosis. (Meth)acryl polymers with high hydrophilicity have been widely used in industries, and attempts to apply these polymers in the medical field are frequently reported. We focused on crosslinked polymer films prepared using bifunctional monomers, which are widely used as coating materials, and attempted to alter the cell adhesion behavior while maintaining blood compatibility by changing the chemical structure of the crosslinker. Four bifunctional monomers were studied, three of which were found to be blood-compatible polymers and to suppress platelet adhesion. The adhesion behavior of cancer cells to polymer films varied; moreover, the cancer model cells MCF-7 [EpCAM(+)] and MDA-MB-231 [EpCAM (-)], with different expression levels of epithelial cell adhesion molecule (EpCAM), showed distinct adhesion behavior for each material. We suggest that a combination of these materials has the potential to selectively capture and enrich highly metastatic cancer cells.
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Affiliation(s)
- Shingo Kobayashi
- Institute for Materials Chemistry and Engineering, Kyushu University, CE41 744 Motooka, Nishi-ku, Fukuoka819-0395, Japan
| | - Atsushi Sugasaki
- Synthetic Organic Chemistry Laboratories, FUJIFILM Corporation, 4000 Kawashiri, Yoshida-cho, Haibara-gun, Shizuoka421-0396, Japan
| | - Yosuke Yamamoto
- Synthetic Organic Chemistry Laboratories, FUJIFILM Corporation, 577 Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa258-0022, Japan
| | - Yuta Shigenoi
- Electronic Materials Research Laboratories, FUJIFILM Corporation, 4000 Kawashiri, Yoshida-cho, Haibara-gun, Shizuoka421-0396, Japan
| | - Airi Udaka
- Institute for Materials Chemistry and Engineering, Kyushu University, CE41 744 Motooka, Nishi-ku, Fukuoka819-0395, Japan
| | - Aki Yamamoto
- Institute for Materials Chemistry and Engineering, Kyushu University, CE41 744 Motooka, Nishi-ku, Fukuoka819-0395, Japan
| | - Masaru Tanaka
- Institute for Materials Chemistry and Engineering, Kyushu University, CE41 744 Motooka, Nishi-ku, Fukuoka819-0395, Japan
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29
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Loh AHP, Angelina C, Wong MK, Tan SH, Sukhatme SA, Yeo T, Lim SB, Lee YT, Soh SY, Leung W, Chang KTE, Chua YW, Alkaff SMF, Lim TKH, Lim CT, Chen ZX. Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse. Front Oncol 2022; 12:939460. [PMID: 36176417 PMCID: PMC9513238 DOI: 10.3389/fonc.2022.939460] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes via NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.
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Affiliation(s)
- Amos H. P. Loh
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
| | - Clara Angelina
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Meng Kang Wong
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Sheng Hui Tan
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Sarvesh A. Sukhatme
- Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Trifanny Yeo
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Su Bin Lim
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| | - York Tien Lee
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
| | - Shui Yen Soh
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Wing Leung
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Paediatric Subspecialties Haematology/Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Kenneth T. E. Chang
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Duke NUS Medical School, Singapore, Singapore
- Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Yong Wei Chua
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Syed M. F. Alkaff
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Tony K. H. Lim
- Duke NUS Medical School, Singapore, Singapore
- Department of Anatomic Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Teck Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
- Institute of Health Innovation and Technology, National University of Singapore, Singapore, Singapore
| | - Zhi Xiong Chen
- VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Cancer Institute, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- *Correspondence: Zhi Xiong Chen,
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30
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Deng Z, Wu S, Wang Y, Shi D. Circulating tumor cell isolation for cancer diagnosis and prognosis. EBioMedicine 2022; 83:104237. [PMID: 36041264 PMCID: PMC9440384 DOI: 10.1016/j.ebiom.2022.104237] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 11/03/2022] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that shed from the primary tumor and intravasate into the peripheral blood circulation system responsible for metastasis. Sensitive detection of CTCs from clinical samples can serve as an effective tool in cancer diagnosis and prognosis through liquid biopsy. Current CTC detection technologies mainly reply on the biomarker-mediated platforms including magnetic beads, microfluidic chips or size-sensitive microfiltration which can compromise detection sensitivity due to tumor heterogeneity. A more sensitive, biomarker independent CTCs isolation technique has been recently developed with the surface-charged superparamagnetic nanoprobe capable of different EMT subpopulation CTC capture from 1 mL clinical blood. In this review, this new strategy is compared with the conventional techniques on biomarker specificity, impact of protein corona, effect of glycolysis on cell surface charge, and accurate CTC identification. Correlations between CTC enumeration and molecular profiling in clinical blood and cancer prognosis are provided for clinical cancer management.
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Affiliation(s)
- Zicheng Deng
- The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH 45221, USA; Center for Lung Regenerative Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Shengming Wu
- The Institute for Translational Nanomedicine Shanghai East Hospital, The Institute for Biomedical Engineering and Nano Science, School of Medicine Tongji University, Shanghai 200092, PR China
| | - Yilong Wang
- The Institute for Translational Nanomedicine Shanghai East Hospital, The Institute for Biomedical Engineering and Nano Science, School of Medicine Tongji University, Shanghai 200092, PR China.
| | - Donglu Shi
- The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH 45221, USA.
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31
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Malla R, Puvalachetty K, Vempati RK, Marni R, Merchant N, Nagaraju GP. Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis. Clin Breast Cancer 2022; 22:507-514. [PMID: 35688785 DOI: 10.1016/j.clbc.2022.05.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/23/2022] [Accepted: 05/15/2022] [Indexed: 12/16/2022]
Abstract
Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.
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Affiliation(s)
- RamaRao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Kiran Puvalachetty
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Rahul K Vempati
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Rakshmitha Marni
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Neha Merchant
- Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, School of medicine, University of Alabama, Birmingham, Birmingham, AL.
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Alberti A, Lorini L, Ravanelli M, Perri F, Vinches M, Rondi P, Romani C, Bossi P. New Challenges in Evaluating Outcomes after Immunotherapy in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma. Vaccines (Basel) 2022; 10:vaccines10060885. [PMID: 35746493 PMCID: PMC9228441 DOI: 10.3390/vaccines10060885] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/16/2022] [Accepted: 05/28/2022] [Indexed: 01/04/2023] Open
Abstract
In many recurrent and/or metastatic cancers, the advent of immunotherapy opens up new scenarios of treatment response, with new phenomena, such as pseudoprogression and hyperprogression. Because of this, different immune-related response criteria have been developed, and new therapeutic strategies adopted, such as treatment beyond progression. Moreover, the role of progression-free survival as a surrogate has been questioned, and new surrogate endpoint hypotheses have arisen. A proper understanding of radiological imaging, an assessment of the biological events triggered by therapy, and the clinical evolution of the lesions and of the patient performance status are all factors that should be considered to guide the oncologist’s treatment choice. The primary aim of this article is to discuss how all these concepts apply to recurrent/metastatic head and neck squamous cell carcinoma patients when treated with immunotherapy.
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Affiliation(s)
- Andrea Alberti
- Medical Oncology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy; (A.A.); (L.L.)
| | - Luigi Lorini
- Medical Oncology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy; (A.A.); (L.L.)
| | - Marco Ravanelli
- Radiology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy; (M.R.); (P.R.)
| | - Francesco Perri
- Medical and Experimental Head and Neck Oncology Unit, INT IRCCS Foundation G Pascale, 80131 Naples, Italy;
| | - Marie Vinches
- Medical Oncology Department, Institut Régional du Cancer de Montpellier (ICM), 34090 Montpellier, France;
| | - Paolo Rondi
- Radiology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy; (M.R.); (P.R.)
| | - Chiara Romani
- Angelo Nocivelli Institute of Molecular Medicine, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy;
| | - Paolo Bossi
- Medical Oncology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy; (A.A.); (L.L.)
- Correspondence:
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33
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Mehraj U, Mushtaq U, Mir MA, Saleem A, Macha MA, Lone MN, Hamid A, Zargar MA, Ahmad SM, Wani NA. Chemokines in Triple-Negative Breast Cancer Heterogeneity: New Challenges for Clinical Implications. Semin Cancer Biol 2022; 86:769-783. [PMID: 35278636 DOI: 10.1016/j.semcancer.2022.03.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
Abstract
Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the door for developing difficult-to-treat TNBC treatment options.
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Affiliation(s)
- Umar Mehraj
- Department of Bioresources, School of Life Sciences, University of Kashmir, Srinagar, Jammu & Kashmir India
| | - Umer Mushtaq
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Manzoor A Mir
- Department of Bioresources, School of Life Sciences, University of Kashmir, Srinagar, Jammu & Kashmir India
| | - Afnan Saleem
- Division of Animal Biotechnology Faculty of Veterinary Sciences and Animal Husbandry, Shuhama Sher-e- Kashmir University of Agricultural Sciences and Technology-Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology Awantipora, Jammu & Kashmir, India
| | - Mohammad Nadeem Lone
- Department of Chemistry, School of Physical & Chemical Sciences, Central University of Kashmir, Ganderbal J & K, India
| | - Abid Hamid
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Mohammed A Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology Faculty of Veterinary Sciences and Animal Husbandry, Shuhama Sher-e- Kashmir University of Agricultural Sciences and Technology-Kashmir, India
| | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
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Guo Z, Lin X, Hui Y, Wang J, Zhang Q, Kong F. Circulating Tumor Cell Identification Based on Deep Learning. Front Oncol 2022; 12:843879. [PMID: 35252012 PMCID: PMC8889528 DOI: 10.3389/fonc.2022.843879] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/21/2022] [Indexed: 12/18/2022] Open
Abstract
As a major reason for tumor metastasis, circulating tumor cell (CTC) is one of the critical biomarkers for cancer diagnosis and prognosis. On the one hand, CTC count is closely related to the prognosis of tumor patients; on the other hand, as a simple blood test with the advantages of safety, low cost and repeatability, CTC test has an important reference value in determining clinical results and studying the mechanism of drug resistance. However, the determination of CTC usually requires a big effort from pathologist and is also error-prone due to inexperience and fatigue. In this study, we developed a novel convolutional neural network (CNN) method to automatically detect CTCs in patients’ peripheral blood based on immunofluorescence in situ hybridization (imFISH) images. We collected the peripheral blood of 776 patients from Chifeng Municipal Hospital in China, and then used Cyttel to delete leukocytes and enrich CTCs. CTCs were identified by imFISH with CD45+, DAPI+ immunofluorescence staining and chromosome 8 centromeric probe (CEP8+). The sensitivity and specificity based on traditional CNN prediction were 95.3% and 91.7% respectively, and the sensitivity and specificity based on transfer learning were 97.2% and 94.0% respectively. The traditional CNN model and transfer learning method introduced in this paper can detect CTCs with high sensitivity, which has a certain clinical reference value for judging prognosis and diagnosing metastasis.
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Affiliation(s)
- Zhifeng Guo
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Xiaoxi Lin
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Yan Hui
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Jingchun Wang
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Qiuli Zhang
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
| | - Fanlong Kong
- Department of Oncology, Chifeng Municipal Hospital, Chifeng, China
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Chen L, Luo S, Ge Z, Fan C, Yang Y, Li Q, Zhang Y. Unbiased Enrichment of Circulating Tumor Cells Via DNAzyme-Catalyzed Proximal Protein Biotinylation. NANO LETTERS 2022; 22:1618-1625. [PMID: 35156821 DOI: 10.1021/acs.nanolett.1c04583] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Circulating tumor cells (CTCs) are noninvasive biomarkers with great potential for assessing neoplastic diseases. However, the enrichment bias toward heterogeneous CTCs remains to be minimized. Herein, a DNAzyme-catalyzed proximal protein biotinylation (DPPB) strategy is established for unbiased CTCs enrichment, employing DNA-framework-based, aptamer-coupled DNAzymes that bind to the surface marker of CTCs and subsequently biotinylated membrane proteins in situ. The DNA framework enables the construction of multivalent DNAzyme and serves as steric hindrance to avoid undesired interaction between DNAzymes and aptamer, leading to efficient binding and biotinylation. Compared with a biotinylated-aptamer strategy, fivefold lower bias of cell subpopulations was achieved by DPPB before and after capture, which enabled a 4.6-fold performance for CTCs analysis in clinic blood samples. DPPB is envisioned to offer a new solution for CTC-based cancer diagnostics.
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Affiliation(s)
- Liang Chen
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
| | - Shihua Luo
- Department of Traumatology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Zhilei Ge
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Chunhai Fan
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Qian Li
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuanqing Zhang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
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Kim H, Heo CM, Oh J, Chung HH, Lee EM, Park J, Lee SH, Lee KH, Lee KT, Lee JK, Cho YK, Park JK. Clinical significance of circulating tumor cells after chemotherapy in unresectable pancreatic ductal adenocarcinoma. Transl Oncol 2022; 16:101321. [PMID: 34954457 PMCID: PMC8718659 DOI: 10.1016/j.tranon.2021.101321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/01/2022] Open
Abstract
Circulating tumor cells (CTCs) have emerged as liquid biopsy biomarker providing non-invasive assessment of cancer progression and biology. We investigated whether longitudinal analysis of CTCs could monitor disease progression, response to chemotherapy, and survival in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). A total of 52 patients with PDAC were prospectively enrolled in this study. Peripheral blood samples were serially collected at the time of diagnosis and after chemotherapy with clinical assessments. CTCs were isolated through a centrifugal microfluidic disc, enumerated with immunostaining against Epithelial cell adhesion molecule (EpCAM), Cytokeratin (CK), Plectin-1 and CD45, and identified by an automated imaging system. One or more CTCs were detected in 84.62% patients with unresectable PDAC at the time of diagnosis. CTC numbers were not statistically different across tumor sizes, location and metastatic sites. The absolute number of CTCs after chemotherapy was inversely related to overall survival (OS), and the decreased number of CTCs after chemotherapy was significantly associated with longer OS in patients with PDAC. Identifying CTCs and monitoring CTC changes after chemotherapy could be a useful prognostic marker for survival in patients with unresectable PDACs.
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Affiliation(s)
- Hyemin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; Medical Research Institute, Sungkyunkwan University School of Medicine, Seoul 06351 Republic of Korea
| | - Chan Mi Heo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Jinmyeong Oh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Hwe Hoon Chung
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Eun Mi Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Juhee Park
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea; Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Se-Hoon Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea
| | - Kwang Hyuck Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Kyu Taek Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Jong Kyun Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
| | - Yoon-Kyoung Cho
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea; Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Joo Kyung Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea.
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Identification of Key Genes and Pathways Involved in Circulating Tumor Cells in Colorectal Cancer. Anal Cell Pathol 2022; 2022:9943571. [PMID: 35127345 PMCID: PMC8813301 DOI: 10.1155/2022/9943571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 11/28/2021] [Accepted: 12/22/2021] [Indexed: 12/26/2022] Open
Abstract
Background. Characterization of the features associated with circulating tumor cells (CTCs) is one of major interests for predicting clinical outcome of colorectal cancer (CRC) patients. However, the molecular features of CTCs remain largely unclear. Methods. For identification of key genes and pathways, GSE31023, contained CTCs from six metastatic CRC patients and three controls, was retrieved for differentially expressed gene (DEG) analysis. Protein-protein interaction networks of DEGs were constructed. Hub genes from the network were prognostic analyzed, as well as the association with tumor-infiltrating immune cells. Results. 1353 DEGs were identified between the CTC and control groups, with 403 genes upregulated and 950 downregulated. 32 pathways were significantly enriched in KEGG, with ribosome pathway as top. The top 10 hub genes were included, including eukaryotic translation elongation factor 2 (EEF2), ribosomal protein S2 (RPS2), ribosomal protein S5 (RPS5), ribosomal protein L3 (RPL3), ribosomal protein S3 (RPS3), ribosomal protein S14 (RPS14), ribosomal protein SA (RPSA), eukaryotic translation elongation factor 1 alpha 1 (EEF1A1), ribosomal protein S15a (RPS15A), and ribosomal protein L4 (RPL4). The correlation between CD4+ T cells and RPS14 (
) was the highest in colon cancer while CD8+ T and RPS2 (
) was the highest in rectal cancer. Conclusion. This study identified potential role of ribosome pathway in CTC, providing further insightful therapeutic targets and biomarkers for CRC.
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Abstract
Magnetic cell separation has become a key methodology for the isolation of target cell populations from biological suspensions, covering a wide spectrum of applications from diagnosis and therapy in biomedicine to environmental applications or fundamental research in biology. There now exists a great variety of commercially available separation instruments and reagents, which has permitted rapid dissemination of the technology. However, there is still an increasing demand for new tools and protocols which provide improved selectivity, yield and sensitivity of the separation process while reducing cost and providing a faster response. This review aims to introduce basic principles of magnetic cell separation for the neophyte, while giving an overview of recent research in the field, from the development of new cell labeling strategies to the design of integrated microfluidic cell sorters and of point-of-care platforms combining cell selection, capture, and downstream detection. Finally, we focus on clinical, industrial and environmental applications where magnetic cell separation strategies are amongst the most promising techniques to address the challenges of isolating rare cells.
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Janjua KA, Shahzad R, Shehzad A. Development of Novel Cancer Biomarkers for Diagnosis and Prognosis. CANCER BIOMARKERS IN DIAGNOSIS AND THERAPEUTICS 2022:277-343. [DOI: 10.1007/978-981-16-5759-7_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Methods for the Detection of Circulating Biomarkers in Cancer Patients. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1379:525-552. [DOI: 10.1007/978-3-031-04039-9_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Sharifianjazi F, Jafari Rad A, Bakhtiari A, Niazvand F, Esmaeilkhanian A, Bazli L, Abniki M, Irani M, Moghanian A. Biosensors and nanotechnology for cancer diagnosis (lung and bronchus, breast, prostate, and colon): a systematic review. Biomed Mater 2021; 17. [PMID: 34891145 DOI: 10.1088/1748-605x/ac41fd] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 12/10/2021] [Indexed: 12/22/2022]
Abstract
The second cause of death in the world has been reported to be cancer, and it has been on the rise in recent years. As a result of the difficulties of cancer detection and its treatment, the survival rate of patients is unclear. The early detection of cancer is an important issue for its therapy. Cancer detection based on biomarkers may effectively enhance the early detection and subsequent treatment. Nanomaterial-based nanobiosensors for cancer biomarkers are excellent tools for the molecular detection and diagnosis of disease. This review reports the latest advancement and attainment in applying nanoparticles to the detection of cancer biomarkers. In this paper, the recent advances in the application of common nanomaterials like graphene, carbon nanotubes, Au, Ag, Pt, and Fe3O4together with newly emerged nanoparticles such as quantum dots, upconversion nanoparticles, inorganics (ZnO, MoS2), and metal-organic frameworks for the diagnosis of biomarkers related to lung, prostate, breast, and colon cancer are highlighted. Finally, the challenges, outlook, and closing remarks are given.
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Affiliation(s)
| | - Azadeh Jafari Rad
- Department of Chemistry, Islamic Azad University, Omidiyeh Branch, Omidiyeh, Iran
| | | | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | | | - Leila Bazli
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran, Iran
| | - Milad Abniki
- Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran
| | - Mohammad Irani
- Dentistry Clinical Research Development Unit, Alborz University of Medical Sciences, Karaj, Iran
| | - Amirhossein Moghanian
- Department of Materials Engineering, Imam Khomeini International University, Qazvin 34149-16818, Iran
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Hakim M, Khorasheh F, Alemzadeh I, Vossoughi M. A new insight to deformability correlation of circulating tumor cells with metastatic behavior by application of a new deformability-based microfluidic chip. Anal Chim Acta 2021; 1186:339115. [PMID: 34756251 DOI: 10.1016/j.aca.2021.339115] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/18/2022]
Abstract
Isolation and characterization of circulating tumor cells (CTCs) found in blood samples of cancer patients have been considered as a reliable source for cancer prognosis and diagnosis. A new continuous microfluidic platform has been designed in this investigation for simultaneous capture and characterization of CTCs based on their deformability. The deformability-based chip (D-Chip) consists of two sections of separation and characterization where slanted weirs with a gap of 7 μm were considered. Although sometimes CTCs and leukocytes have the same size, the deformability differs in such a way that can be exploited for enrichment purposes. MCF7 and MDA-MB-231 cell lines were used for the initial evaluation of the D-Chip performance. In the separation section, cancer cells were isolated based on deformability differences with an efficiency of higher than 93% (∼average capturing capacity of 2085 out of 2200 cancer cells ml-1) and with significantly high purity (15-40 WBCs ml-1; ∼5 log depletion of WBCs). Cancer cells were categorized based on the deformability difference in the characterization section. Subsequently, 15 clinical blood samples from breast cancer patients were analyzed by the D-Chip. Suggest 'The chip detected CTCs in all patient samples, processed the blood sample at a high throughput of 5.3 ml/h, and properly categorized CTCs based on deformability differences. Further characterization showed that the highly deformable breast cancer CTCs in our patient samples also showed higher potential of metastasis in support of a broader correlation between deformability of CTCs and metastatic behavior.
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Affiliation(s)
- Maziar Hakim
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Farhad Khorasheh
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Iran Alemzadeh
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Manouchehr Vossoughi
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran.
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Xie J, Ruan Z, Zheng J, Gong Y, Wang Y, Hu B, Cheng J, Huang Q. Detection of circulating rare cells benefitted the diagnosis of malignant solitary pulmonary nodules. J Cancer Res Clin Oncol 2021; 148:2681-2692. [PMID: 34791530 DOI: 10.1007/s00432-021-03852-8] [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: 08/21/2021] [Accepted: 11/05/2021] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Solitary pulmonary nodules (SPNs) are challenging in differentiating between benignancy and malignancy. Therefore, more effective non-invasive biomarkers are urgently needed. The purpose of this investigation was to examine whether circulating rare cells (CRCs) could facilitate the differentiation between benign and malignant SPNs as well as its sensitivity and specificity. METHODS 164 patients diagnosed with SPNs, 24 healthy volunteers, and 25 patients diagnosed with advanced-stage lung cancer were included. CT/PET-CT images, serum tumor markers, and biopsy results were collected. The CRCs were examined using subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) and their relationship with malignant or benign SPNs was analyzed. RESULTS The total CRC numbers from patients with malignant SPNs diagnosed by biopsy were significantly greater compared to those with benign SPNs (P < 0.0001), but not significantly different from patients with advanced lung cancer (P > 0.05). The total CRCs, with a cut-off value of 21.5 units, showed 67.6% sensitivity and 73.3% specificity [area under curve (AUC) 95% CI, 0.778 (0.666-0.889)] in discriminating benign and malignant SPNs and the triploid CRCs exhibited a high positive likelihood ratio of 8.4, which suggested that CRCs appeared to have a distinct advantage in discriminating benign and malignant SPNs compared to CT/PET-CT images and serum tumor markers and could be a potential screening indicator for lung cancer in the high-risk population. CONCLUSIONS SE-iFISH could effectively detect CRCs including circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) and the detection of CRCs could benefit the differentiation of patients with benign and malignant SPNs.
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Affiliation(s)
- Jianzhu Xie
- Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng Ruan
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Zheng
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanping Gong
- Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yulan Wang
- Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Binjie Hu
- Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin Cheng
- Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qian Huang
- Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Gribko A, Stiefel J, Liebetanz L, Nagel SM, Künzel J, Wandrey M, Hagemann J, Stauber RH, Freese C, Gül D. IsoMAG-An Automated System for the Immunomagnetic Isolation of Squamous Cell Carcinoma-Derived Circulating Tumor Cells. Diagnostics (Basel) 2021; 11:2040. [PMID: 34829387 PMCID: PMC8623084 DOI: 10.3390/diagnostics11112040] [Citation(s) in RCA: 4] [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: 09/20/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND detailed information about circulating tumor cells (CTCs) as an indicator of therapy response and cancer metastasis is crucial not only for basic research but also for diagnostics and therapeutic approaches. Here, we showcase a newly developed IsoMAG IMS system with an optimized protocol for fully automated immunomagnetic enrichment of CTCs, also revealing rare CTC subpopulations. METHODS using different squamous cell carcinoma cell lines, we developed an isolation protocol exploiting highly efficient EpCAM-targeting magnetic beads for automated CTC enrichment by the IsoMAG IMS system. By FACS analysis, we analyzed white blood contamination usually preventing further downstream analysis of enriched cells. RESULTS 1 µm magnetic beads with tosyl-activated hydrophobic surface properties were found to be optimal for automated CTC enrichment. More than 86.5% and 95% of spiked cancer cells were recovered from both cell culture media or human blood employing our developed protocol. In addition, contamination with white blood cells was minimized to about 1200 cells starting from 7.5 mL blood. Finally, we showed that the system is applicable for HNSCC patient samples and characterized isolated CTCs by immunostaining using a panel of tumor markers. CONCLUSION Herein, we demonstrate that the IsoMAG system allows the detection and isolation of CTCs from HNSCC patient blood for disease monitoring in a fully-automated process with a significant leukocyte count reduction. Future developments seek to integrate the IsoMAG IMS system into an automated microfluidic-based isolation workflow to further facilitate single CTC detection also in clinical routine.
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Affiliation(s)
- Alena Gribko
- Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; (A.G.); (S.M.N.); (M.W.); (J.H.); (R.H.S.)
| | - Janis Stiefel
- Fraunhofer Institute for Microengineering and Microsystems IMM, Carl-Zeiss-Str. 18-20, 55129 Mainz, Germany; (J.S.); (L.L.)
| | - Lana Liebetanz
- Fraunhofer Institute for Microengineering and Microsystems IMM, Carl-Zeiss-Str. 18-20, 55129 Mainz, Germany; (J.S.); (L.L.)
| | - Sophie Madeleine Nagel
- Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; (A.G.); (S.M.N.); (M.W.); (J.H.); (R.H.S.)
| | - Julian Künzel
- Department of Otorhinolaryngology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany;
| | - Madita Wandrey
- Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; (A.G.); (S.M.N.); (M.W.); (J.H.); (R.H.S.)
| | - Jan Hagemann
- Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; (A.G.); (S.M.N.); (M.W.); (J.H.); (R.H.S.)
| | - Roland H. Stauber
- Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; (A.G.); (S.M.N.); (M.W.); (J.H.); (R.H.S.)
| | - Christian Freese
- Fraunhofer Institute for Microengineering and Microsystems IMM, Carl-Zeiss-Str. 18-20, 55129 Mainz, Germany; (J.S.); (L.L.)
| | - Désirée Gül
- Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; (A.G.); (S.M.N.); (M.W.); (J.H.); (R.H.S.)
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Patel DA, Blay J. Seeding metastases: The role and clinical utility of circulating tumour cells. Tumour Biol 2021; 43:285-306. [PMID: 34690152 DOI: 10.3233/tub-210001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for various solid cancers. Enumeration of CTCs from blood is becoming a common practice in informing prognosis and may guide therapy decisions. It is further recognized that enumeration alone does not capture perspective on the heterogeneity of tumours and varying functional abilities of the CTCs to interact with the secondary microenvironment. Characterizing the isolated CTCs further, in particular assessing their functional abilities, can track molecular changes in the disease progress. As a step towards identifying a suite of functional features of CTCs that could aid in clinical decisions, developing a CTC isolation technique based on extracellular matrix (ECM) interactions may provide a more solid foundation for isolating the cells of interest. Techniques based on size, charge, density, and single biomarkers are not sufficient as they underutilize other characteristics of cancer cells. The ability of cancer cells to interact with ECM proteins presents an opportunity to utilize their full character in capturing, and also allows assessment of the features that reveal how cells might behave at secondary sites during metastasis. This article will review some common techniques and recent advances in CTC capture technologies. It will further explore the heterogeneity of the CTC population, challenges they experience in their metastatic journey, and the advantages of utilizing an ECM-based platform for CTC capture. Lastly, we will discuss how tailored ECM approaches may present an optimal platform to capture an influential heterogeneous population of CTCs.
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Affiliation(s)
- Deep A Patel
- School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
| | - Jonathan Blay
- School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.,Department of Pathology, Dalhousie University, Halifax, NS, Canada
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Han SY, Park SH, Ko HS, Jang A, Seo HI, Lee SJ, Kim GH, Kim DU. Vimentin-Positive Circulating Tumor Cells as Diagnostic and Prognostic Biomarkers in Patients with Biliary Tract Cancer. J Clin Med 2021; 10:4435. [PMID: 34640452 PMCID: PMC8509386 DOI: 10.3390/jcm10194435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/16/2022] Open
Abstract
Biliary tract cancer (BTC) has poor prognosis; thus, early diagnosis is important to decrease mortality. Although vimentin-positive circulating tumor cells (V-CTCs) are a good candidate for diagnostic and prognostic biomarkers, studies on the topic are limited. We aimed to evaluate the diagnostic efficacy of V-CTCs between BTC and benign biliary disease (BBD) and determine the prognostic value of V-CTCs in BTC patients. We recruited 69 participants who had BTCs and BBDs from a single tertiary referral center. We analyzed CTCs and V-CTCs in peripheral blood using the CD-PRIMETM system. Seven patients were excluded due to a technical failure of CTC detection. CTCs were detected in all 62 patients. CTC count > 40/mL blood (55.8% vs. 20%, p = 0.039), V-CTC count > 15/mL blood (57.7% vs. 10%, p = 0.005), and V-CTC/CTC ratio > 40% (48.1% vs. 10%, p = 0.025) were significantly different between BTCs and BBDs. Two or more of these three parameters (61.5% vs. 10%, p = 0.002) increased the accuracy. A combination of CTC markers with CA19-9 and biopsy increased the accuracy (90.4% vs. 10%, p = 0.000). V-CTC > 50/mL blood was a significant factor affecting survival (140 (66.6-213.3) vs. 253 (163.9-342.1) days, p = 0.008). V-CTC could be a potential biomarker for early diagnosis and predicting prognosis in patients with BTC.
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Affiliation(s)
- Sung Yong Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Sung Hee Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Hyun Suk Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Aelee Jang
- Department of Nursing, University of Ulsan, Ulsan 44610, Korea;
| | - Hyung Il Seo
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea;
| | - So Jeong Lee
- Department of Pathology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea;
| | - Gwang Ha Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
| | - Dong Uk Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University College of Medicine, Busan 49241, Korea; (S.Y.H.); (S.H.P.); (H.S.K.); (G.H.K.)
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Xing C, Li Y, Ding C, Wang S, Zhang H, Chen L, Li P, Dai M. CD44+ Circulating Tumor Endothelial Cells Indicate Poor Prognosis in Pancreatic Ductal Adenocarcinoma After Radical Surgery: A Pilot Study. Cancer Manag Res 2021; 13:4417-4431. [PMID: 34103996 PMCID: PMC8179744 DOI: 10.2147/cmar.s309115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/15/2021] [Indexed: 12/12/2022] Open
Abstract
Background Circulating tumor endothelial cells (CTECs) are cells that originate from tumor endothelial cells (TECs) of blood vessels and are shed into peripheral blood. Some studies have shown that CTECs are associated with tumor angiogenesis, growth and indicate prognosis in patients with malignant solid tumor. However, the role of CTECs especially the phenotype of CTECs in pancreatic adenocarcinoma (PDAC) is still not clear. We investigated the relationship between CTECs and patients’ prognosis. Methods A total of 73 patients with resectable PDAC were enrolled in our research and underwent radical surgery. Peripheral venous blood samples were collected before surgery, on postoperative day (POD) 7 and on postoperative month (POM) 1, respectively. We used integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform to identify and enumerate CTECs. Immunofluorescence was used to identify CTECs expressing CD44 and vimentin. Results In patients with early tumor recurrence (DFS< 6 months), the preoperative CD44+ CTEC levels showed significantly higher (P = 0.023). Univariate and multivariate analysis showed that history of diabetes [HR 2.656 (1.194–5.908), P = 0.017], numbers of positive lymph nodes [HR 1.871 (1.388–2.522), P < 0.001], preoperative numbers of CD44+ CTECs [HR 1.216 (1.064–1.390), P = 0.004], and POM1 CA19-9 level [HR 1.002 (1.001–1.002), P < 0.001] were independent prognostic factors for DFS. Conclusion The detection of CD44+CTECs in patients with resectable PDAC preoperatively could be an independent predictor of shorter DFS after radical surgery.
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Affiliation(s)
- Cheng Xing
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Yatong Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Cheng Ding
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Shunda Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Hanyu Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Lixin Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Pengyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People's Republic of China
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Dall'Olio FG, Gelsomino F, Conci N, Marcolin L, De Giglio A, Grilli G, Sperandi F, Fontana F, Terracciano M, Fragomeno B, Tober N, Manferrari G, Brocchi S, Golfieri R, Fiorentino M, Ardizzoni A. PD-L1 Expression in Circulating Tumor Cells as a Promising Prognostic Biomarker in Advanced Non-small-cell Lung Cancer Treated with Immune Checkpoint Inhibitors. Clin Lung Cancer 2021; 22:423-431. [PMID: 33849808 DOI: 10.1016/j.cllc.2021.03.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/23/2021] [Accepted: 03/04/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Circulating tumor cells (CTCs) are a promising source of biological information in cancer. Data correlating PD-L1 expression in CTCs with patients' response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are still lacking. METHODS This is a prospective single-center cohort study enrolling patients with advanced NSCLC. CTCs were identified and counted with the CellSearch system. PD-L1 expression on CTCs was assessed with phycoerythrin-conjugated anti-human PD-L1 antibody, clone MIH3 (BioLegend, USA). Primary endpoint was the correlation between the CTCs PD-L1 expression and overall survival (OS). Among secondary objectives, we evaluated the correlation between PD-L1 expression on CTCs and matched tumor tissue and the correlation of CTC number and baseline tumor size (BTS). RESULTS Thirty-nine patients treated with anti-PD-1/PD-L1 agents as second- or third-line therapy were enrolled. Patients were divided into 3 groups: no CTC detectable (CTCnull, n = 15), PD-L1 positive CTC (CTCpos, n = 13), and PD-L1 negative CTC (CTCneg, n = 11). Median OS in patients with CTCneg was 2.2 months, 95% confidence interval (CI), 0.8-3.6 (reference) versus 3.7 months, 95% CI, 0.1-7.5 (hazard ratio [HR] 0.33; 95% CI, 0.13-0.83; P = .019) in patients with CTCpos versus 16.0 months, 95% CI, 2.2-29.8 (HR 0.17; 95% CI, 0.06-0.45; P< .001) in patients with CTCnull. No correlation was found between PD-L1 expression on CTCs and on tumor tissue. CTC number was correlated with BTS. CONCLUSION PD-L1 expression on CTCs is a promising biomarker in patients with NSCLC treated with ICIs. Further validation as predictive biomarker is needed.
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Affiliation(s)
- Filippo G Dall'Olio
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Francesco Gelsomino
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nicole Conci
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Laura Marcolin
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea De Giglio
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giada Grilli
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Sperandi
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | | | - Benedetta Fragomeno
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nastassja Tober
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giulia Manferrari
- Department of Genetics, Environment, and Evolution (GEE), University College London, London, United Kingdom
| | - Stefano Brocchi
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Rita Golfieri
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Michelangelo Fiorentino
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Andrea Ardizzoni
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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The Mechanical Fingerprint of Circulating Tumor Cells (CTCs) in Breast Cancer Patients. Cancers (Basel) 2021; 13:cancers13051119. [PMID: 33807790 PMCID: PMC7961579 DOI: 10.3390/cancers13051119] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/17/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Detection of circulating tumor cells (CTCs) in the blood of cancer patients is a challenging issue, since they adapt to the biochemical and physical landscape of the bloodstream. We approached the issue of CTC identification on a biophysical level. For the first time, we recorded the mechanical deformation profiles of potential CTCs, which were isolated from the blood of breast cancer patients, at the force regime of the deforming blood flow. Mechanical fingerprints of CTCs were significantly different from healthy white blood cells. We used machine learning to further evaluate the differences and identify discrimination criteria. Our results suggest that mechanical characterization of CTCs at low forces is a promising path towards CTC detection. Abstract Circulating tumor cells (CTCs) are a potential predictive surrogate marker for disease monitoring. Due to the sparse knowledge about their phenotype and its changes during cancer progression and treatment response, CTC isolation remains challenging. Here we focused on the mechanical characterization of circulating non-hematopoietic cells from breast cancer patients to evaluate its utility for CTC detection. For proof of premise, we used healthy peripheral blood mononuclear cells (PBMCs), human MDA-MB 231 breast cancer cells and human HL-60 leukemia cells to create a CTC model system. For translational experiments CD45 negative cells—possible CTCs—were isolated from blood samples of patients with mamma carcinoma. Cells were mechanically characterized in the optical stretcher (OS). Active and passive cell mechanical data were related with physiological descriptors by a random forest (RF) classifier to identify cell type specific properties. Cancer cells were well distinguishable from PBMC in cell line tests. Analysis of clinical samples revealed that in PBMC the elliptic deformation was significantly increased compared to non-hematopoietic cells. Interestingly, non-hematopoietic cells showed significantly higher shape restoration. Based on Kelvin–Voigt modeling, the RF algorithm revealed that elliptic deformation and shape restoration were crucial parameters and that the OS discriminated non-hematopoietic cells from PBMC with an accuracy of 0.69, a sensitivity of 0.74, and specificity of 0.63. The CD45 negative cell population in the blood of breast cancer patients is mechanically distinguishable from healthy PBMC. Together with cell morphology, the mechanical fingerprint might be an appropriate tool for marker-free CTC detection.
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Huang C, Lin X, He J, Liu N. Enrichment and detection method for the prognostic value of circulating tumor cells in ovarian cancer: A meta-analysis. Gynecol Oncol 2021; 161:613-620. [PMID: 33674144 DOI: 10.1016/j.ygyno.2021.02.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Recent studies have revealed that circulating tumor cells (CTCs) might predict bad prognosis, but the results were conflicting. Sampling time, treatment, enrichment method and detection method also varied. We aimed to evaluate whether patients with CTCs in peripheral blood have bad survival outcomes with consideration of the above four aspects. METHODS Relevant studies were searched on Pubmed, Embase and the Cochrane Library. Studies of CTCs involving survival data available were identified for a systematic review and meta-analysis. HRs and 95% CIs for PFS and OS were extracted directly or from the Kaplan-Meier survival curves by the Engauge Digitizer v4.1. Subgroup analyses were performed to evaluate the effect of sampling time, treatment, enrichment method and detection method. RESULTS Two clinical trials and thirteen retrospective studies with a total of 1285 patients were included. CTCs significantly correlated with OS (HR = 1.77, 95%CI:1.42-2.21, p < 0.00001 and PFS (HR = 1.53, 95%CI:1.26-1.86, p < 0.0001). Subgroup analyses showed that CTCs were significant associated with OS in the "Pre-therapy" subgroup (HR = 1.79, 95%CI:1.43-2.24, p < 0.00001), the "Surgery" group (HR = 1.82, 95%CI:1.42-2.33, p < 0.00001), and the "RT-PCR"subgroup (HR = 2.29, 95%CI:1.53-3.42, p < 0.0001). While for enrichment method, CTCs significantly correlated with OS in the"Physical method" subgroup (HR = 1.94, 95%CI:1.21-3.09, p = 0.006) and the "Immunological method" subgroup (HR = 1.84, 95%CI:1.37-2.48, p < 0.0001). CONCLUSIONS The presence of CTCs prior to the treatment indicated worse OS and PFS and CTCs might be predictive biomarker for ovarian cancer patients . CTCs detected using RT-PCR seem to be associated with poorer OS and PFS in patients with ovarian cancer.
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Affiliation(s)
- Chengying Huang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoli Lin
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinmei He
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Nan Liu
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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