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Skovborg G, Svejsø FH, Müller C, Jensen BN, Jensen JG, Majidi SE, Matthiesen CL, Chen M. Replication of patient specific circulating tumor cells on a microfibrous filter for drug screening. NANOSCALE 2025. [PMID: 40242908 DOI: 10.1039/d4nr05294c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Personalized medicine in cancer treatment has the potential to enhance therapeutic efficacy while simultaneously reducing adverse effects. Molecular characterization of circulating tumor cells (CTCs) offers invaluable insight into metastatic tumor heterogeneity, making them a perfect candidate for metastatic cancer drug screening. However, they are extremely rare. This study presents the development of melt-electrowritten membrane filters designed for the capture, culture, and drug testing of CTCs. By varying the collector speeds, filters with optimized pore sizes and polymer densities were produced, enabling selective capture of CTCs while minimizing co-capture of white blood cells. Biocompatibility tests showed that the filter supported the proliferation of multiple cancer cell lines. The filter successfully captured and cultured colorectal cancer patient-derived CTC44 and CTC45 cells, which formed 3D clusters observable over several weeks. Drug testing with chemotherapeutic agents 5-fluorouracil/oxaliplatin (FOX) and 5-fluorouracil/irinotecan (FIRI) revealed that CTCs in 3D clusters on the filters exhibited significantly higher drug resistance compared to 2D monolayers. These findings demonstrate the potential of the filter as a versatile platform for studying CTC biology and for screening anticancer drugs, providing a more physiologically relevant environment than traditional 2D cultures.
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Affiliation(s)
- Grith Skovborg
- Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DK-8000, Denmark.
| | - Frederik Høbjerg Svejsø
- Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DK-8000, Denmark.
| | - Christoph Müller
- Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DK-8000, Denmark.
| | | | - Jesper Godrim Jensen
- Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DK-8000, Denmark.
| | - Sara Egsgaard Majidi
- Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DK-8000, Denmark.
| | | | - Menglin Chen
- Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DK-8000, Denmark.
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Yan H, Zhang Y, Shi Y, Ding J, Su H, Su W, Wang Y, Mao Y, Khattab TA, Al-Qahtani SD, Abdulla A, Jiang L, Ding X. Combining CD64 and CD123 Biomarkers for Sepsis Early Diagnosis and Severity Assessment via PD-L1 Antibody Affinity Microfluidic (PAAM) Chip in Trace Clinical Samples. Anal Chem 2025; 97:7928-7937. [PMID: 40177943 DOI: 10.1021/acs.analchem.4c07123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Sepsis, a lethal organ dysfunction caused by a dysregulated host response to infection, is the leading cause of worldwide in-hospital mortality. However, the early diagnostic methods for sepsis are still urgent for guiding accurate antibiotic usage and improving the survival rate of the patients. Herein, we constructed a PD-L1 antibody affinity microfluidic (PAAM) chip for early sepsis diagnosis and severity assessment. The chip was used to capture PD-L1-expressing leukocytes from whole blood samples obtained from healthy control (HC) volunteers (n = 15) and sepsis patients on day 1 (D1) and day 7 (D7) (n = 20), and there was a statistically significant difference between HC and sepsis patients (p < 0.0001), and the AUC was 0.96. However, there was no significant difference in the number of cells captured on-chip between sepsis patients on D1 and D7 (p = 0.16). Therefore, we performed immunofluorescence staining of PD-L1, CD64, and CD123 on the chip. The results showed that the combination of PD-L1, CD64, and CD123 for sepsis diagnosis had an AUC of 0.98, and there was a significant difference in PD-L1+/CD64+/CD123+ leukocytes between sepsis patients on D1 and on D7 (p < 0.0001). In conclusion, we found that the combination of multiple biomarkers was more precise and dependable for sepsis diagnosis and severity assessment.
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Affiliation(s)
- Haoni Yan
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Yan Zhang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Yujie Shi
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Jiahui Ding
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Hengxing Su
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China
| | - Wenqiong Su
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Yan Wang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Yanfei Mao
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Tawfik A Khattab
- Dyeing, Printing and Auxiliaries Department, Textile Research and Technology Institute National Research Centre, Cairo 12622, Egypt
| | - Salhah D Al-Qahtani
- Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Aynur Abdulla
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Xianting Ding
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
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Le MCN, Chen D, Smith KA, Tran DD, Fan ZH. Microfluidic isolation and release of live disseminated breast tumor cells in bone marrow. PLoS One 2025; 20:e0319392. [PMID: 40073025 PMCID: PMC11902295 DOI: 10.1371/journal.pone.0319392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 01/31/2025] [Indexed: 03/14/2025] Open
Abstract
Breast cancer represents a significant therapeutic challenge due to its aggressive nature and resistance to treatment. A major cause of treatment failure in breast cancer is the presence of rare, low-proliferative disseminated tumor cells (DTCs) in distant organs including the bone marrow. This study introduced a microfluidic-based approach to improve the immunodetection and isolation of these rare DTCs for downstream analysis, with an emphasis on optimizing immunocapture, release, and enrichment methods of live DTCs as compared to the standard approach for blood-borne circulating tumor cells (CTCs). EGFR (epidermal growth factor receptor) and EpCAM (epithelial cell adhesion molecule), two key cell surface markers in breast cancer, were validated as efficient cell capture targets for DTCs within microfluidic chambers. Furthermore, we demonstrated that a combination of 0.25% trypsin and impulse was the most effective for releasing captured cells, maintaining high viability, and preserving essential cellular characteristics. Using a metastatic mouse breast cancer model, we achieved a 47.9-fold enrichment of live DTCs. Analysis of blood and bone marrow samples obtained from a breast cancer patient with minimal residual disease at two timepoints revealed a reduction in CTCs and an increase in DTCs following adjuvant chemotherapy. This observation suggested a potential dynamic interplay between CTCs and DTCs in response to therapy. Our results underscore the potential of the microfluidic approach in enhancing DTC detection and shed light on the importance of monitoring both CTCs and DTCs in breast cancer prognosis and treatment response assessment.
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Affiliation(s)
- Minh-Chau N. Le
- Department of Mechanical and Aerospace Engineering, Interdisciplinary Microsystems Group, Gainesville, Florida, United States of America
| | - Dongjiang Chen
- Division of Neuro-Oncology, USC Keck Brain Tumor Center, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America
| | - Kierstin A. Smith
- Department of Mechanical and Aerospace Engineering, Interdisciplinary Microsystems Group, Gainesville, Florida, United States of America
| | - David D. Tran
- Division of Neuro-Oncology, USC Keck Brain Tumor Center, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America
| | - Z. Hugh Fan
- Department of Mechanical and Aerospace Engineering, Interdisciplinary Microsystems Group, Gainesville, Florida, United States of America
- J. Crayton Pruitt Family Department of Biomedical Engineering, GainesvilleFlorida, United States of America
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Janjua D, Chaudhary A, Joshi U, Tripathi T, Bharti AC. Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis. Biochim Biophys Acta Rev Cancer 2025; 1880:189236. [PMID: 39662757 DOI: 10.1016/j.bbcan.2024.189236] [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: 09/17/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/13/2024]
Abstract
Circulating tumor cells (CTCs) are shed from primary tumors and travel through the body via circulation, eventually settling to form micrometastases under favorable conditions. Numerous studies have identified CTCs as a negative prognostic indicator for survival across various cancer types. CTCs mirror the current heterogeneity and genetic and biological state of tumors, making their study invaluable for understanding tumor progression, cell senescence, and cancer dormancy. However, their isolation and characterization still poses a major challenge that limits their clinical translation. A wide array of methods, each with different levels of specificity, utility, cost, and sensitivity, have been developed to isolate and characterize CTCs. Moreover, innovative techniques are emerging to address the limitations of existing methods. In this review, we provide insights into CTC biology addressing spectra of markers employed for molecular analysis and functional characterization. It also emphasizes current label-dependent and label-independent isolation procedures, addressing their strengths and limitations. SIGNIFICANCE: A comprehensive overview of CTC biology, their molecular and functional characterization, along with their current clinical utility will help in understanding the present-day extent to which the clinical potential of CTCs is getting tapped in personalized medicine.
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Affiliation(s)
- Divya Janjua
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Apoorva Chaudhary
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Udit Joshi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India.
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Xiao J, Mukherji R, Sidarous G, Suguru S, Noel M, Weinberg BA, He A, Agarwal S. Longitudinal Circulating Tumor Cell Collection, Culture, and Characterization in Pancreatic Adenocarcinomas. Cancers (Basel) 2025; 17:355. [PMID: 39941724 PMCID: PMC11815863 DOI: 10.3390/cancers17030355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES Pancreatic adenocarcinoma (PDAC) remains one of the most lethal cancers, with limited advancements in treatment efficacy due to high rates of chemoresistance. Circulating tumor cells (CTCs) derived from liquid biopsies offer a non-invasive approach to monitoring tumor evolution and identifying molecular mechanisms of resistance. This study aims to longitudinally collect, culture, and characterize CTCs from PDAC patients to elucidate resistance mechanisms and tumor-specific gene expression profiles. METHODS Blood samples from 10 PDAC patients were collected across different treatment stages, yielding 16 CTC cultures. Differential gene expression, pathway dysregulation, and protein-protein interaction studies were utilized, highlighting patient-specific and disease progression-associated changes. Longitudinal comparisons within five patients provided further insights into dynamic molecular changes associated with therapeutic resistance. RESULTS CTC cultures exhibited the activation of key pathways implicated in PDAC progression and resistance, including TNFα/NF-kB, hedgehog signaling, and the epithelial-to-mesenchymal transition. Longitudinal samples revealed dynamic changes in signaling pathways, highlighting upregulated mechanisms of chemoresistance, including PI3K/Akt/mTOR and TGF-β pathways. Additionally, protein-protein interaction analysis emphasized the role of the immune system in PDAC progression and therapy response. Patient-specific gene expression patterns therefore suggest potential applications for precision medicine. CONCLUSIONS This proof-of-concept study demonstrates the feasibility of longitudinally capturing and analyzing CTCs from PDAC patients. The findings provide critical insights into molecular drivers of chemoresistance and highlight the potential of CTC profiling to inform personalized therapeutic strategies. Future large-scale studies are warranted to validate these findings and further explore CTC-based approaches in PDAC management.
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Affiliation(s)
- Jerry Xiao
- Department of Tumor Biology, Georgetown University, Washington, DC 20057, USA
- Department of Internal Medicine, University of California San Francisco, San Francisco, CA 94115, USA
| | - Reetu Mukherji
- Department of Hematology/Oncology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - George Sidarous
- Department of Internal Medicine, Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - Shravanthy Suguru
- Department of Pathology, Georgetown University, Washington, DC 20057, USA
| | - Marcus Noel
- Department of Hematology/Oncology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - Benjamin A. Weinberg
- Department of Hematology/Oncology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - Aiwu He
- Department of Hematology/Oncology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - Seema Agarwal
- Department of Pathology, Georgetown University, Washington, DC 20057, USA
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Zhang Y, Wang B, Cai J, Yang Y, Tang C, Zheng X, Li H, Xu F. Enrichment and separation technology for evaluation of circulating tumor cells. Talanta 2025; 282:127025. [PMID: 39406084 DOI: 10.1016/j.talanta.2024.127025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 11/20/2024]
Abstract
Circulating tumor cells (CTCs) are tumor cells that exist in human peripheral blood, which could spread to other tissues or organs via the blood circulation system and develop into metastatic foci, leading to tumor recurrence or metastasis in postoperative patients and thereby increasing the mortality of malignant tumor patients. Evaluation of CTC levels can be used for tumor metastasis prediction, prognosis evaluation, drug exploitation, individualized treatment, liquid biopsy, etc., which exhibit outstanding clinical application prospects. In recent years, accurately capturing and analyzing CTCs has become a research hotspot in the early diagnosis and precise treatment of tumors. This review summarized various enrichment and isolation technologies for evaluating CTCs based on the design principle and discussed the challenges and perspectives in this field.
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Affiliation(s)
- Yanjun Zhang
- The Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Bing Wang
- The Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Junwen Cai
- The Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yuting Yang
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Chen Tang
- The Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xiaoqun Zheng
- The Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China; Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Haidong Li
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, School of Bioengineering, Dalian University of Technology, Dalian, 116024, China; Provincial Key Laboratory of Interdisciplinary Medical Engineering for Gastrointestinal Carcinoma, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital & Institute), Shenyang, 110000, China
| | - Feng Xu
- The Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
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Zhou Z, Cai S, Zhou X, Zhao W, Sun J, Zhou Z, Yang Z, Li W, Wang Z, Zou H, Fu H, Wang X, Khoo BL, Yang M. Circulating Tumor Cells Culture: Methods, Challenges, and Clinical Applications. SMALL METHODS 2024:e2401026. [PMID: 39726345 DOI: 10.1002/smtd.202401026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 11/10/2024] [Indexed: 12/28/2024]
Abstract
Circulating tumor cells (CTCs) play a pivotal role in cancer metastasis and hold considerable potential for clinical diagnosis, therapeutic monitoring, and prognostic evaluation. Nevertheless, the limited quantity of CTCs in liquid biopsy samples poses challenges for comprehensive downstream analysis. In vitro culture of CTCs can effectively address the issue of insufficient CTC numbers. Furthermore, research based on CTC cell lines serves as a valuable complement to traditional cancer cell line-based research. While numerous reports exist on CTC in vitro culture and even the establishment of CTC cell lines, the methods used vary, leading to disparate culture outcomes. This review presents the developmental history and current status of CTC in vitro culture research. Additionally, the culture strategies applied in different methods and analyzed the impact of various steps on culture outcomes are compared. Overall, the review indicates that while the short-term culture of CTCs is relatively straightforward, long-term culture success has been achieved for various specific cancer types but still faces challenges. Further optimization of efficient and widely applicable culture strategies is needed. Additionally, ongoing applications of CTC in vitro culture are summarized, highlighting the potential of expanded CTCs for drug susceptibility testing and as therapeutic tools in personalized treatment.
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Affiliation(s)
- Zhengdong Zhou
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Songhua Cai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Xiaoyu Zhou
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Wei Zhao
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Jiayu Sun
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zhihang Zhou
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zihan Yang
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Wenxiu Li
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zhe Wang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Heng Zou
- Cellomics (Shenzhen) Limited, Shenzhen, 518118, China
| | - Huayang Fu
- Cellomics (Shenzhen) Limited, Shenzhen, 518118, China
| | - Xicheng Wang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Bee Luan Khoo
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Mengsu Yang
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
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Yun Y, Kim S, Lee SN, Cho HY, Choi JW. Nanomaterial-based detection of circulating tumor cells and circulating cancer stem cells for cancer immunotherapy. NANO CONVERGENCE 2024; 11:56. [PMID: 39671082 PMCID: PMC11645384 DOI: 10.1186/s40580-024-00466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024]
Abstract
Nanomaterials have emerged as transformative tools for detecting circulating tumor cells (CTCs) and circulating cancer stem cells (CCSCs), significantly enhancing cancer diagnostics and immunotherapy. Nanomaterials, including those composed of gold, magnetic materials, and silica, have enhanced the sensitivity, specificity, and efficiency of isolating these rare cells from blood. These developments are of paramount importance for the early detection of cancer and for providing real-time insights into metastasis and treatment resistance, which are essential for the development of personalized immunotherapies. The combination of nanomaterial-based platforms with phenotyping techniques, such as Raman spectroscopy and microfluidics, enables researchers to enhance immunotherapy protocols targeting specific CTC and CCSC markers. Nanomaterials also facilitate the targeted delivery of immunotherapeutic agents, including immune checkpoint inhibitors and therapeutic antibodies, directly to tumor cells. This synergistic approach has the potential to enhance therapeutic efficacy and mitigate the risk of metastasis and relapse. In conclusion, this review critically examines the use of nanomaterial-driven detection systems for detecting CTCs and CCSCs, their application in immunotherapy, and suggests future directions, highlighting their potential to transform the integration of diagnostics and treatment, thereby paving the way for more precise and personalized cancer therapies.
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Affiliation(s)
- Yeochan Yun
- Department of Bio and Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea
| | - Seewoo Kim
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea
| | - Sang-Nam Lee
- Uniance Gene Inc., 273, Digital-ro, Guro-gu, Seoul, 08381, Republic of Korea.
| | - Hyeon-Yeol Cho
- Department of Bio and Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea.
| | - Jeong-Woo Choi
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea.
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9
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Kinane DF, Gabert J, Xynopoulos G, Guzeldemir‐Akcakanat E. Strategic approaches in oral squamous cell carcinoma diagnostics using liquid biopsy. Periodontol 2000 2024; 96:316-328. [PMID: 38676371 PMCID: PMC11579816 DOI: 10.1111/prd.12567] [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: 11/01/2023] [Revised: 02/06/2024] [Accepted: 03/23/2024] [Indexed: 04/28/2024]
Abstract
Liquid biopsy is a noninvasive diagnostic technique used for monitoring cancer utilizing specific genetic biomarkers present in bodily fluids, such as blood, saliva, or urine. These analyses employ multiple biomolecular sources including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes (that contain DNA fragments) to detect genetic biomarkers that can predict, disclose, and/or monitor cancers. Levels of these biomarkers can inform on the presence of cancer, its genetic characteristics, and its potential treatment response and also provide predictive genetic predisposition information for specific cancers including oral squamous cell carcinomas (OSCC). Liquid biopsies can aid cancer management as they offer real-time dynamic information on the response to say chemotherapy or radiotherapy and recurrence following surgical excision. Unlike traditional tissue biopsies, which are invasive with a degree of morbidity and require specific tumor location sampling, liquid biopsies are noninvasive and can be repeated frequently. For oral squamous cell carcinoma, on which this review focuses, liquid biopsy of blood or saliva can be valuable in predicting susceptibility, providing early detection, and monitoring the disease's progression and response to therapy. This review gives a general narrative overview of the technology, its current medical usage, and advantages and disadvantages compared with current techniques and discusses a range of current potential biomarkers for disclosing OSCC and predicting its risk. Oral squamous cell carcinoma is all too often detected in the late stages. In future, liquid biopsy may provide an effective screening process such that cancers including OSCC will be detected in the early stages rather than later when prognosis is poor and morbidity and debilitation are greater. In this screening process, periodontists and hygienists have a critical role in that they are adept in examining mucosa, they see patients with shared risk factors for periodontitis and OSCC, namely smoking and poor oral hygiene, and they see patients frequently such that OSCC examinations should be a routine part of the recall visit. With this additional screening manpower, oral medicine and oral surgery colleagues will detect OSCC earlier and this coupled with new techniques such as liquid biopsy may greatly decrease global morbidity in OSCC.
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Affiliation(s)
- Denis F. Kinane
- Department of Periodontology, Dental SchoolUniversity BernBernSwitzerland
- ExpressTestCignpost Diagnostics Ltd.FarnboroughUnited Kingdom
| | | | | | - Esra Guzeldemir‐Akcakanat
- Department of Periodontology, Faculty of DentistryKocaeli UniversityİzmitTurkey
- College of Dental MedicineQU Health, Qatar UniversityQatarQatar
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10
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Shishido SN, Lin E, Nissen N, Courcoubetis G, Suresh D, Mason J, Osipov A, Hendifar AE, Lewis M, Gaddam S, Pandol S, Kuhn P, Lo SK. Cancer-related cells and oncosomes in the liquid biopsy of pancreatic cancer patients undergoing surgery. NPJ Precis Oncol 2024; 8:36. [PMID: 38360856 PMCID: PMC10869814 DOI: 10.1038/s41698-024-00521-0] [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: 07/27/2023] [Accepted: 01/15/2024] [Indexed: 02/17/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10% due to its late diagnosis, rapid metastasis, and chemotherapeutic resistance. For a small proportion (10-20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival but the effect of surgery on disease dissemination is unknown. The primary objective of this study was to characterize cellular and acellular blood-based analytes in portal and peripheral blood before pancreatic manipulation, during tumor dissection and immediately after surgical resection to determine the effects of the surgery. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate heterogeneous circulating rare cell population in the blood. Blood from both sites taken before surgical manipulation of the pancreas had significantly greater incidence of total rare cellular and acellular analytes than normal donor samples. Post-surgery portal and peripheral blood had significantly greater incidence of specific cellular and acellular subtypes compared to the matched pre- and during-surgery samples. Our results reveal that in patients with PDAC liquid biopsy analytes are increased in both the portal and peripheral blood; portal blood contains a higher frequency of analytes than in the peripheral blood; total analytes in the portal and peripheral blood samples were significantly associated with the tumor volume and pathological T stage; and the surgical procedure increased the blood levels of circulating cellular and acellular analytes, but not Epi.CTCs or Mes.CTCs. This study demonstrates liquid biopsy's utility in monitoring patients with PDAC with surgically resectable disease.
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Affiliation(s)
- Stephanie N Shishido
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Emmeline Lin
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Nicholas Nissen
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - George Courcoubetis
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Divya Suresh
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Jeremy Mason
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
- Institute of Urology, Catherine & Joseph Aresty Department 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
| | - Arsen Osipov
- IM Hematology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Andrew E Hendifar
- IM Hematology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Michael Lewis
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
- Greater Los Angeles Veterans Affairs System, Los Angeles, CA, 90073, USA
- Clark Atlanta University, Center for Cancer Research and Therapeutic Development, Atlanta, GA, 30314, USA
| | - Srinivas Gaddam
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Stephen Pandol
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Peter Kuhn
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA.
- Institute of Urology, Catherine & Joseph Aresty Department 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.
- Department of Biomedical Engineering, Viterbi School of Engineering, 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 Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
| | - Simon K Lo
- Pancreatic and Biliary Diseases Program, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA.
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11
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Gostomczyk K, Marsool MDM, Tayyab H, Pandey A, Borowczak J, Macome F, Chacon J, Dave T, Maniewski M, Szylberg Ł. Targeting circulating tumor cells to prevent metastases. Hum Cell 2024; 37:101-120. [PMID: 37874534 PMCID: PMC10764589 DOI: 10.1007/s13577-023-00992-6] [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: 09/11/2023] [Accepted: 10/03/2023] [Indexed: 10/25/2023]
Abstract
Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor, enter the bloodstream or body fluids, and spread to other body parts, leading to metastasis. Their presence and characteristics have been linked to cancer progression and poor prognosis in different types of cancer. Analyzing CTCs can offer valuable information about tumors' genetic and molecular diversity, which is crucial for personalized therapy. Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), play a significant role in generating and disseminating CTCs. Certain proteins, such as EpCAM, vimentin, CD44, and TGM2, are vital in regulating EMT and MET and could be potential targets for therapies to prevent metastasis and serve as detection markers. Several devices, methods, and protocols have been developed for detecting CTCs with various applications. CTCs interact with different components of the tumor microenvironment. The interactions between CTCs and tumor-associated macrophages promote local inflammation and allow the cancer cells to evade the immune system, facilitating their attachment and invasion of distant metastatic sites. Consequently, targeting and eliminating CTCs hold promise in preventing metastasis and improving patient outcomes. Various approaches are being explored to reduce the volume of CTCs. By investigating and discussing targeted therapies, new insights can be gained into their potential effectiveness in inhibiting the spread of CTCs and thereby reducing metastasis. The development of such treatments offers great potential for enhancing patient outcomes and halting disease progression.
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Affiliation(s)
- Karol Gostomczyk
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland.
- University Hospital No. 2 Im. Dr Jan Biziel, Ujejskiego 75, 85-168, Bydgoszcz, Poland.
| | | | | | | | - Jędrzej Borowczak
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland
| | - Facundo Macome
- Universidad del Norte Santo Tomás de Aquino, San Miquel de Tucuman, Argentina
| | - Jose Chacon
- American University of Integrative Sciences, Cole Bay, Saint Martin, Barbados
| | - Tirth Dave
- Bukovinian State Medical University, Chernivtsi, Ukraine
| | - Mateusz Maniewski
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland
| | - Łukasz Szylberg
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland
- Department of Tumor Pathology and Pathomorphology, Oncology Centre, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
- Chair of Pathology, Dr Jan Biziel Memorial University Hospital No. 2, Bydgoszcz, Poland
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12
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Islam MS, Gopalan V, Lam AK, Shiddiky MJA. Current advances in detecting genetic and epigenetic biomarkers of colorectal cancer. Biosens Bioelectron 2023; 239:115611. [PMID: 37619478 DOI: 10.1016/j.bios.2023.115611] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023]
Abstract
Colorectal carcinoma (CRC) is the third most common cancer in terms of diagnosis and the second in terms of mortality. Recent studies have shown that various proteins, extracellular vesicles (i.e., exosomes), specific genetic variants, gene transcripts, cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and altered epigenetic patterns, can be used to detect, and assess the prognosis of CRC. Over the last decade, a plethora of conventional methodologies (e.g., polymerase chain reaction [PCR], direct sequencing, enzyme-linked immunosorbent assay [ELISA], microarray, in situ hybridization) as well as advanced analytical methodologies (e.g., microfluidics, electrochemical biosensors, surface-enhanced Raman spectroscopy [SERS]) have been developed for analyzing genetic and epigenetic biomarkers using both optical and non-optical tools. Despite these methodologies, no gold standard detection method has yet been implemented that can analyze CRC with high specificity and sensitivity in an inexpensive, simple, and time-efficient manner. Moreover, until now, no study has critically reviewed the advantages and limitations of these methodologies. Here, an overview of the most used genetic and epigenetic biomarkers for CRC and their detection methods are discussed. Furthermore, a summary of the major biological, technical, and clinical challenges and advantages/limitations of existing techniques is also presented.
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Affiliation(s)
- Md Sajedul Islam
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia.
| | - Alfred K Lam
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia; Pathology Queensland, Gold Coast University Hospital, Southport, QLD, 4215, Australia
| | - Muhammad J A Shiddiky
- Rural Health Research Institute, Charles Sturt University, Orange, NSW, 2800, Australia.
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13
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Chen K, Wang Z. A Micropillar Array Based Microfluidic Device for Rare Cell Detection and Single-Cell Proteomics. Methods Protoc 2023; 6:80. [PMID: 37736963 PMCID: PMC10514859 DOI: 10.3390/mps6050080] [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: 08/02/2023] [Revised: 08/25/2023] [Accepted: 08/31/2023] [Indexed: 09/23/2023] Open
Abstract
Advancements in single-cell-related technologies have opened new possibilities for analyzing rare cells, such as circulating tumor cells (CTCs) and rare immune cells. Among these techniques, single-cell proteomics, particularly single-cell mass spectrometric analysis (scMS), has gained significant attention due to its ability to directly measure transcripts without the need for specific reagents. However, the success of single-cell proteomics relies heavily on efficient sample preparation, as protein loss in low-concentration samples can profoundly impact the analysis. To address this challenge, an effective handling system for rare cells is essential for single-cell proteomic analysis. Herein, we propose a microfluidics-based method that offers highly efficient isolation, detection, and collection of rare cells (e.g., CTCs). The detailed fabrication process of the micropillar array-based microfluidic device is presented, along with its application for CTC isolation, identification, and collection for subsequent proteomic analysis.
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Affiliation(s)
- Kangfu Chen
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA;
- Chan Zuckerberg Biohub Chicago, Chicago, IL 60607, USA
| | - Zongjie Wang
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA;
- Chan Zuckerberg Biohub Chicago, Chicago, IL 60607, USA
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14
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Yeh PY, Chen JY, Shen MY, Che TF, Lim SC, Wang J, Tsai WS, Frank CW, Huang CJ, Chang YC. Liposome-tethered supported lipid bilayer platform for capture and release of heterogeneous populations of circulating tumor cells. J Mater Chem B 2023; 11:8159-8169. [PMID: 37313622 DOI: 10.1039/d3tb00547j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Because of scarcity, vulnerability, and heterogeneity in the population of circulating tumor cells (CTCs), the CTC isolation system relying on immunoaffinity interaction exhibits inconsistent efficiencies for all types of cancers and even CTCs with different phenotypes in individuals. Moreover, releasing viable CTCs from an isolation system is of importance for molecular analysis and drug screening in precision medicine, which remains a challenge for current systems. In this work, a new CTC isolation microfluidic platform was developed and contains a coating of the antibody-conjugated liposome-tethered-supported lipid bilayer in a developed chaotic-mixing microfluidic system, referred to as the "LIPO-SLB" platform. The biocompatible, soft, laterally fluidic, and antifouling properties of the LIPO-SLB platform offer high CTC capture efficiency, viability, and selectivity. We successfully demonstrated the capability of the LIPO-SLB platform to recapitulate different cancer cell lines with different antigen expression levels. In addition, the captured CTCs in the LIPO-SLB platform can be detached by air foam to destabilize the physically assembled bilayer structures due to a large water/air interfacial area and strong surface tension. More importantly, the LIPO-SLB platform was constructed and used for the verification of clinical samples from 161 patients with different primary cancer types. The mean values of both single CTCs and CTC clusters correlated well with the cancer stages. Moreover, a considerable number of CTCs were isolated from patients' blood samples in the early/localized stages. The clinical validation demonstrated the enormous potential of the universal LIPO-SLB platform as a tool for prognostic and predictive purposes in precision medicine.
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Affiliation(s)
- Po-Ying Yeh
- Genomics Research Center, Academia Sinica, 128, Sec 2, Academic Rd., Nankang, Taipei 115, Taiwan.
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Jia-Yang Chen
- Genomics Research Center, Academia Sinica, 128, Sec 2, Academic Rd., Nankang, Taipei 115, Taiwan.
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Mo-Yuan Shen
- Genomics Research Center, Academia Sinica, 128, Sec 2, Academic Rd., Nankang, Taipei 115, Taiwan.
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Ting-Fang Che
- Genomics Research Center, Academia Sinica, 128, Sec 2, Academic Rd., Nankang, Taipei 115, Taiwan.
| | - Syer Choon Lim
- Genomics Research Center, Academia Sinica, 128, Sec 2, Academic Rd., Nankang, Taipei 115, Taiwan.
| | - Jocelyn Wang
- The College, The University of Chicago, Chicago, IL 60637, USA
| | - Wen-Sy Tsai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University, Linkou, Taoyuan, Taiwan
| | - Curtis W Frank
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Chun-Jen Huang
- Department of Chemical & Materials Engineering, and NCU-Covestro Research Center, National Central University, Jhong-Li, Taoyuan 320, Taiwan.
- R&D Center for Membrane Technology, Chung Yuan Christian University, 200 Chung Pei Rd., Chung-Li City 32023, Taiwan
| | - Ying-Chih Chang
- Genomics Research Center, Academia Sinica, 128, Sec 2, Academic Rd., Nankang, Taipei 115, Taiwan.
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
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15
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Mishra S, Kumarasamy M. Microfluidics engineering towards personalized oncology-a review. IN VITRO MODELS 2023; 2:69-81. [PMID: 39871996 PMCID: PMC11756504 DOI: 10.1007/s44164-023-00054-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 01/29/2025]
Abstract
Identifying and monitoring the presence of cancer metastasis and highlighting inter-and intratumoral heterogeneity is a central tenet of targeted precision oncology medicine (POM). This process of relocation of cancer cells is often referred to as the missing link between a tumor and metastasis. In recent years, microfluidic technologies have been developed to isolate a plethora of different biomarkers, such as circulating tumor cells (CTCs), tumor-derived vesicles (exosomes), or cell/free nucleic acids and proteins directly from patients' blood samples. With the advent of microfluidic developments, minimally invasive and quantitative assessment of different tumors is becoming a reality. This short review article will touch briefly on how microfluidics at early-stage achievements can be combined or developed with the active vs passive microfluidic technologies, depending on whether they utilize external fields and forces (active) or just microchannel geometry and inherent fluid forces (passive) from the market to precision oncology research and our future prospectives in terms of the emergence of ultralow cost and rapid prototyping of microfluidics in precision oncology.
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Affiliation(s)
- Sushmita Mishra
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur (NIPERHajipur) Export Promotion Industrial Park (EPIP), Industrial Area, Vaishali, 844102 Bihar India
| | - Murali Kumarasamy
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur (NIPERHajipur) Export Promotion Industrial Park (EPIP), Industrial Area, Vaishali, 844102 Bihar India
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16
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Pedrosa VA, Chen K, George TJ, Fan ZH. Gold Nanoparticle-Based Microfluidic Chips for Capture and Detection of Circulating Tumor Cells. BIOSENSORS 2023; 13:706. [PMID: 37504105 PMCID: PMC10377447 DOI: 10.3390/bios13070706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/24/2023] [Accepted: 07/01/2023] [Indexed: 07/29/2023]
Abstract
Liquid biopsy has progressed to its current use to diagnose and monitor cancer. Despite the recent advances in investigating cancer detection and diagnosis strategies, there is still a room for improvements in capturing CTCs. We developed an efficient CTC detection system by integrating gold nanoparticles with a microfluidic platform, which can achieve CTC capture within 120 min. Here, we report our development of a simple and effective way to isolate CTCs using antibodies attached on gold nanoparticles to the surface of a lateral filter array (LFA) microdevice. Our method was optimized using three pancreatic tumor cell lines, enabling the capture with high efficiency (90% ± 3.2%). The platform was further demonstrated for isolating CTCs from patients with metastatic pancreatic cancer. Our method and platform enables the production of functionalized, patterned surfaces that interact with tumor cells, enhancing the selective capture of CTCs for biological assays.
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Affiliation(s)
- Valber A Pedrosa
- Institute of Bioscience of Botucatu, Sao Paulo State University-Unesp, Botucatu 18603-560, Brazil
| | - Kangfu Chen
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, P.O. Box 116250, Gainesville, FL 32611, USA
| | - Thomas J George
- Department of Medicine, University of Florida, P.O. Box 100278, Gainesville, FL 32610, USA
| | - Z Hugh Fan
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, P.O. Box 116250, Gainesville, FL 32611, USA
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, P.O. Box 116131, Gainesville, FL 32611, USA
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17
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Wang Q, Šabanović B, Awada A, Reina C, Aicher A, Tang J, Heeschen C. Single-cell omics: a new perspective for early detection of pancreatic cancer? Eur J Cancer 2023; 190:112940. [PMID: 37413845 DOI: 10.1016/j.ejca.2023.112940] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 06/04/2023] [Indexed: 07/08/2023]
Abstract
Pancreatic cancer is one of the most lethal cancers, mostly due to late diagnosis and limited treatment options. Early detection of pancreatic cancer in high-risk populations bears the potential to greatly improve outcomes, but current screening approaches remain of limited value despite recent technological advances. This review explores the possible advantages of liquid biopsies for this application, particularly focusing on circulating tumour cells (CTCs) and their subsequent single-cell omics analysis. Originating from both primary and metastatic tumour sites, CTCs provide important information for diagnosis, prognosis and tailoring of treatment strategies. Notably, CTCs have even been detected in the blood of subjects with pancreatic precursor lesions, suggesting their suitability as a non-invasive tool for the early detection of malignant transformation in the pancreas. As intact cells, CTCs offer comprehensive genomic, transcriptomic, epigenetic and proteomic information that can be explored using rapidly developing techniques for analysing individual cells at the molecular level. Studying CTCs during serial sampling and at single-cell resolution will help to dissect tumour heterogeneity for individual patients and among different patients, providing new insights into cancer evolution during disease progression and in response to treatment. Using CTCs for non-invasive tracking of cancer features, including stemness, metastatic potential and expression of immune targets, provides important and readily accessible molecular insights. Finally, the emerging technology of ex vivo culturing of CTCs could create new opportunities to study the functionality of individual cancers at any stage and develop personalised and more effective treatment approaches for this lethal disease.
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Affiliation(s)
- Qi Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Berina Šabanović
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Azhar Awada
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy; Molecular Biotechnology Center, University of Turin (UniTO), Turin, Italy
| | - Chiara Reina
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Jiajia Tang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; South Chongqing Road 227, Shanghai, China.
| | - Christopher Heeschen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy; South Chongqing Road 227, Shanghai, China.
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18
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Smejkal J, Aubrecht P, Semerádtová A, Štofik M, Liegertová M, Malý J. Immunocapturing rare cells from blood: A simple and robust microsystem approach. Biosens Bioelectron 2023; 227:115155. [PMID: 36821992 DOI: 10.1016/j.bios.2023.115155] [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: 12/13/2022] [Revised: 02/06/2023] [Accepted: 02/14/2023] [Indexed: 02/21/2023]
Abstract
Cell immunocapture microsystems are a fast-emerging field with several potential medical diagnostic applications. Isolation and quantification of circulating rare cells (CRCs) show great importance in the early stages of disease diagnostics and prognostics. Here, we present a simple and robust stop-flow microsystem (fabricated by a combination of glass microblasting and 3D printing) based on a planar antibody-coated surface that is effective in the immunocapture of the model as well as naturally occurring rare cells. A chip with a planar immunocapture channel working in the so-called stop-flow dynamic regime was designed to enable monitoring the efficiency of the cell capture by fluorescence microscopy. Up to 90% immunocapture efficiency of MCF-7 cells spiked into whole blood on CD326 antibody-coated planar surfaces was achieved. We discuss the role of the planar surface modifications, the influence of the set stop-flow dynamic conditions, and medium complexity on the efficiency of cell immunocapture. The presented results could be further employed in the design of microsystems for cell-size-independent isolation and identification of rare cells from blood.
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Affiliation(s)
- Jiří Smejkal
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí nad Labem, 400 96, Ústí nad Labem, Czech Republic.
| | - Petr Aubrecht
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí nad Labem, 400 96, Ústí nad Labem, Czech Republic
| | - Alena Semerádtová
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí nad Labem, 400 96, Ústí nad Labem, Czech Republic
| | - Marcel Štofik
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí nad Labem, 400 96, Ústí nad Labem, Czech Republic
| | - Michaela Liegertová
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí nad Labem, 400 96, Ústí nad Labem, Czech Republic
| | - Jan Malý
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí nad Labem, 400 96, Ústí nad Labem, Czech Republic
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19
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Mohamed BM, Ward MP, Bates M, Spillane CD, Kelly T, Martin C, Gallagher M, Heffernan S, Norris L, Kennedy J, Saadeh FA, Gleeson N, Brooks DA, Brooks RD, Selemidis S, O'Toole S, O'Leary JJ. Ex vivo expansion of circulating tumour cells (CTCs). Sci Rep 2023; 13:3704. [PMID: 36879003 PMCID: PMC9988863 DOI: 10.1038/s41598-023-30733-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Circulating tumour cells (CTCs) are a critical intermediate step in the process of cancer metastasis. The reliability of CTC isolation/purification has limited both the potential to report on metastatic progression and the development of CTCs as targets for therapeutic intervention. Here we report a new methodology, which optimises the culture conditions for CTCs using primary cancer cells as a model system. We exploited the known biology that CTCs thrive in hypoxic conditions, with their survival and proliferation being reliant on the activation of hypoxia-inducible factor 1 alpha (HIF-1α). We isolated epithelial-like and quasi-mesenchymal CTC phenotypes from the blood of a cancer patient and successfully cultured these cells for more than 8 weeks. The presence of CTC clusters was required to establish and maintain long-term cultures. This novel methodology for the long-term culture of CTCs will aid in the development of downstream applications, including CTC theranostics.
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Affiliation(s)
- Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland. .,Trinity St James's Cancer Institute, Dublin 8, Ireland. .,Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland.
| | - Mark P Ward
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Mark Bates
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Cathy D Spillane
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Tanya Kelly
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Cara Martin
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Michael Gallagher
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Sheena Heffernan
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Lucy Norris
- Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John Kennedy
- HOPE Directorate, St. James's Hospital, Dublin 8, Ireland
| | - Feras Abu Saadeh
- Division of Gynaecological Oncology, St. James's Hospital, Dublin 8, Ireland
| | - Noreen Gleeson
- Division of Gynaecological Oncology, St. James's Hospital, Dublin 8, Ireland
| | - Doug A Brooks
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland.,Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia
| | - Robert D Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland.,Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland.,Trinity St James's Cancer Institute, Dublin 8, Ireland
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20
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Lv S, Zheng D, Chen Z, Jia B, Zhang P, Yan J, Jiang W, Zhao X, Xu JJ. Near-Infrared Light-Responsive Size-Selective Lateral Flow Chip for Single-Cell Manipulation of Circulating Tumor Cells. Anal Chem 2023; 95:1201-1209. [PMID: 36541430 DOI: 10.1021/acs.analchem.2c03947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Accurately obtaining information on the heterogeneity of CTCs at the single-cell level is a very challenging task that may facilitate cancer pathogenesis research and personalized therapy. However, commonly used multicellular population capture and release assays tend to lose effective information on heterogeneity and cannot accurately assess molecular-level studies and drug resistance assessment of CTCs in different stages of tumor metastasis. Herein, we designed a near-infrared (NIR) light-responsive microfluidic chip for biocompatible single-cell manipulation and study the heterogeneity of CTCs by a combination of the lateral flow microarray (LFM) chip and photothermal response system. First, immunomagnetic labeling and a gradient magnetic field were combined to distribute CTCs in different regions of the chip according to the content of surface markers. Subsequently, the LFM chip achieves high single-cell capture efficiency and purity (even as low as 5 CTCs per milliliter of blood) under the influence of lateral fluid and magnetic fields. Due to the rapid dissolution of the gelatin capture structure at 37 °C and the photothermal properties of gold nanorods, the captured single CTC cell can be recovered in large quantities at physiological temperature or released individually at a specific point by NIR. The multifunctional NIR-responsive LFM chip demonstrates excellent performance in capture and site release of CTCs with high viability, which provides a robust and versatile means for CTCs heterogeneity study at the single-cell level.
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Affiliation(s)
- Songwei Lv
- State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.,School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Dong Zheng
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou 213003, China
| | - Zhaoxian Chen
- College of Engineering and Applied Sciences, Nanjing University, Nanjing 210023, China
| | - Bin Jia
- School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Peng Zhang
- School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Jiaxuan Yan
- School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Wanlan Jiang
- Department of Rheumatology and Immunology, The First People's Hospital of Changzhou (The Third Affiliated Hospital of Soochow University), Changzhou 213003, China
| | - Xiubo Zhao
- School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Jing-Juan Xu
- State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
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21
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Xiao J, Pohlmann PR, Schlegel R, Agarwal S. State of the Art in the Propagation of Circulating Tumor Cells. CURRENT CANCER RESEARCH 2023:247-274. [DOI: 10.1007/978-3-031-22903-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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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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23
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Liu J, Enloe C, Li-Oakey KD, Oakey J. Optimizing Immunofunctionalization and Cell Capture on Micromolded Hydrogels via Controlled Oxygen-Inhibited Photopolymerization. ACS APPLIED BIO MATERIALS 2022; 5:5004-5013. [PMID: 36174120 DOI: 10.1021/acsabm.2c00776] [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: 11/29/2022]
Abstract
With circulating tumor cells (CTCs) playing a critical role in cancer metastasis, the quantitation and characterization of CTCs promise to provide precise diagnostic and prognostic information in service of personalized therapies. However, as CTCs are extremely rare, high yield, high purity strategies are required to target and isolate CTCs from patient samples. Recently, we demonstrated the selective capture of CTCs upon antibody-functionalized polyethylene glycol diacrylate (PEGDA) hydrogels photopolymerized within polydimethylsiloxane (PDMS) microfluidic molds. Isolated CTC purity was subsequently enriched by selectively releasing desired cells from photodegradable hydrogel capture surfaces. However, the fabrication of these acrylate-based hydrogels by photopolymerization is subject to oxygen inhibition, which dramatically affects the physical and chemical properties of hydrogel interfaces formed in proximity to PDMS boundaries. To evaluate how antibody conjugation density and cell capture is impacted by fabrication parameters affected by oxygen inhibition, PEGDA hydrogel features were polymerized within PDMS micromolds under different UV exposure conditions and linker (acrylate-PEG-biotin) concentrations. Predictions of acrylate conversion throughout the hydrogel feature were performed using a 1D reaction-diffusion model that describes oxygen-inhibited photopolymerization. The functional consequences of photopolymerization parameters and solution stoichiometry on CTC capture were experimentally quantified and evaluated. Results show that hydrogel surfaces polymerized under shorter exposure times and with higher linker concentrations display superior functionalization and higher CTC capture efficiency. Conversely, highly cross-linked hydrogel surfaces polymerized under longer exposure times are insensitive to functionalization and display poor capture, regardless of linker concentration. By highlighting the importance of oxygen-inhibited photopolymerization, these findings provide guidelines to design micromolded hydrogels with controlled ligand expression. In addition to enhancing the selective cell capture capacity of immunofunctional hydrogels, the ability to quantifiably design hydrogel interfaces described here will improve the sensitivity of hydrogel biosensors, provide a platform to finely screen cell-matrix interactions, and generally enhance the fidelity of micromolded hydrogel features.
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Affiliation(s)
- Jing Liu
- Department of Chemical Engineering, University of Wyoming, Laramie, Wyoming 82071, United States
| | - Cassidy Enloe
- Department of Chemical Engineering, University of Wyoming, Laramie, Wyoming 82071, United States
| | - Katie D Li-Oakey
- Department of Chemical Engineering, University of Wyoming, Laramie, Wyoming 82071, United States
| | - John Oakey
- Department of Chemical Engineering, University of Wyoming, Laramie, Wyoming 82071, United States
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24
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Advances in the Biology, Detection Techniques, and Clinical Applications of Circulating Tumor Cells. JOURNAL OF ONCOLOGY 2022; 2022:7149686. [PMID: 36090904 PMCID: PMC9462976 DOI: 10.1155/2022/7149686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/12/2022] [Accepted: 08/02/2022] [Indexed: 12/01/2022]
Abstract
Circulating tumor cells (CTCs) play a crucial role in tumor recurrence and metastasis, and their early detection has shown remarkable benefits in clinical theranostics. However, CTCs are extremely rare, thus detecting them in the blood is very challenging. New CTC detection techniques are continuously being developed, enabling deeper analysis of CTC biology and potential clinical application. This article reviews current CTC detection techniques and their clinical application. CTCs have provided, and will continue to provide, important insights into the process of metastasis, which could lead to development of new therapies for different cancers.
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25
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Lv J, Li S, Zhen X, Li D, Zhang N, Liu X, Han J, Bing T, Shangguan D. Characterization and Identification of Aptamers against CD49c for the Detection, Capture, and Release of Cancer Cells. ACS APPLIED BIO MATERIALS 2022; 5:3461-3468. [PMID: 35792891 DOI: 10.1021/acsabm.2c00389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
As a kind of recognition molecule, aptamers can be inserted into some regulatory sequences for the smart response of their targets. However, the molecular engineering might lead to the change of the binding affinity. Here, we present a stable aptamer ZAJ-2c and an environmentally sensitive aptamer ZAJ-2d optimized from an original cell-binding aptamer ZAJ-2, and the molecular target was further identified as CD49c on the cell membrane. ZAJ-2c was characterized with high binding ability independent of the presence of divalent cations at a temperature range from 4 to 37 °C, showing promise for measuring the expression of CD49c on cancer cells. Moreover, ZAJ-2d had a nanomolar binding affinity in the binding buffer at 4 °C, the same as ZAJ-2c, but lost the binding ability in a PBS buffer supplemented with 5 mM EDTA at 37 °C. This aptamer variant proved to selectively capture and release the CD49c positive cells by simply adjusting the temperatures and divalent cations. This set of aptamers might provide a toolbox for monitoring and operating of a wide range of cancer cells with CD49c expression on the surface, which will be helpful for the studying the heterogeneity of rare cells.
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Affiliation(s)
- Jing Lv
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,College of New Energy and Materials, China University of Petroleum (Beijing), Beijing 102249, China
| | - Shengnan Li
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,College of New Energy and Materials, China University of Petroleum (Beijing), Beijing 102249, China
| | - Xiaoxiao Zhen
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,College of New Energy and Materials, China University of Petroleum (Beijing), Beijing 102249, China
| | - Dandan Li
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,College of New Energy and Materials, China University of Petroleum (Beijing), Beijing 102249, China
| | - Nan Zhang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Xiangjun Liu
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Juanjuan Han
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Tao Bing
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Dihua Shangguan
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.,School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310013, China.,University of Chinese Academy of Sciences, Beijing 100049, China
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26
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Senhaji N, Squalli Houssaini A, Lamrabet S, Louati S, Bennis S. Molecular and Circulating Biomarkers in Patients with Glioblastoma. Int J Mol Sci 2022; 23:7474. [PMID: 35806478 PMCID: PMC9267689 DOI: 10.3390/ijms23137474] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/28/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023] Open
Abstract
Glioblastoma is the most aggressive malignant tumor of the central nervous system with a low survival rate. The difficulty of obtaining this tumor material represents a major limitation, making the real-time monitoring of tumor progression difficult, especially in the events of recurrence or resistance to treatment. The identification of characteristic biomarkers is indispensable for an accurate diagnosis, the rigorous follow-up of patients, and the development of new personalized treatments. Liquid biopsy, as a minimally invasive procedure, holds promise in this regard. The purpose of this paper is to summarize the current literature regarding the identification of molecular and circulating glioblastoma biomarkers and the importance of their integration as a valuable tool to improve patient care.
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Affiliation(s)
- Nadia Senhaji
- Department of Biology, Faculty of Sciences, Moulay Ismail University, Meknes 50000, Morocco
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
| | - Asmae Squalli Houssaini
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
| | - Salma Lamrabet
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
| | - Sara Louati
- Medical Biotechnology Laboratory, Faculty of Medicine and Pharmacy of Rabat, Mohammed Vth University, Rabat 10000, Morocco;
| | - Sanae Bennis
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
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27
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Wang C, Xu Y, Li S, Zhou Y, Qian Q, Liu Y, Mi X. Designer tetrahedral DNA framework-based microfluidic technology for multivalent capture and release of circulating tumor cells. Mater Today Bio 2022; 16:100346. [PMID: 35833198 PMCID: PMC9272028 DOI: 10.1016/j.mtbio.2022.100346] [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: 05/07/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) have been recognized as a general biomarker for the early detection, diagnosis and therapy monitoring of cancer. Due to their extreme rarity in peripheral blood, the isolation and analysis of CTCs with high efficiency, high purity and high viability remains a tremendous technological challenge. Herein, we combined tetrahedral DNA framework (TDFs), herringbone channel (HB) chip, together with aptamer-triggered hybridization chain reaction (apt-HCR) to develop an efficient microfluidic system (T-μFS) for capture and release of simulated CTCs. The capture efficiency of MCF-7 cells was from 83.3% to 94.2% when the cell numbers ranged from 10 to 103 using our T-μFS in the whole blood. The release efficiency of the MCF-7 cells was 96.2% and the MCF-7 cell viability after release was 94.6% using our T-μFS in PBS buffer. Reculture and RT-qPCR studies showed that there was almost no damage by the capture and release treatment for the MCF-7 cells viability. These results revealed that our T-μFS could be developed as an integrated and automatic technical platform with great performance for multivalent capture and release of CTCs and have a wide application prospect for tumor liquid biopsy.
Three-dimensional amine modified tetrahedral DNA frameworks (TDFs) as rigid scaffolds were anchored on the aldehyde modified substrate of HB-chip, which provided the better spatial orientation compared with single-stranded DNA. Aptamer partially hybridized to an initiator was employed to trigger HCR reaction, and HCR produced modified long products with multi-branched arms for multivalent binding on TDFs to improve the capture efficiency of CTCs. This is the first time that only employed DNA nanostructures in a microfluidic device system to capture CTCs, and all DNA nanostructures could be efficiently removed by enzymes without harming cells.
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28
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Varillas JI, Chen K, Dopico P, Zhang J, George TJ, Fan ZH. Comparison of sample preparation methods for rare cell isolation in microfluidic devices. CAN J CHEM 2022; 100:512-519. [PMID: 36338875 PMCID: PMC9635407 DOI: 10.1139/cjc-2021-0229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2024]
Abstract
The analysis of circulating tumor cells (CTCs) is important for cancer diagnosis and prognosis. Microfluidics has been employed for CTC analysis due to its scaling advantages and high performance. However, pre-analytical methods for CTC sample preparation are often combined with microfluidic platforms because a large sample volume is required to detect extremely rare CTCs. Among pre-analytical methods, Ficoll-Paque™, OncoQuick™, and RosetteSep™ are commonly used to separate cells of interest. To compare their performance, we spiked L3.6pl pancreatic cancer cells into healthy blood samples and then employed each technique to prepare blood samples, followed by using a microfluidic platform to capture and detect L3.6pl cells. We found these three methods have similar performance, though the slight edge of RosetteSep™ over Ficoll-Paque™ is statistically significant. We also studied the effects of the tumor cell concentrations on the performance of the frequently used Ficoll-Paque™ method. Furthermore, we examined the repeatability and variability of each pre-analytical technique and the microfluidics-enabled detection. This study will provide researchers and clinicians with comparative data that can influence the choice of sample preparation method, help estimate CTC loss in each pre-analytical method, and correlate the results of clinical studies that employ different techniques.
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Affiliation(s)
- Jose I Varillas
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, P.O. Box 116131, Gainesville, FL 32611, USA
| | - Kangfu Chen
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, P.O. Box 116250, Gainesville, FL 32611, USA
| | - Pablo Dopico
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, P.O. Box 116250, Gainesville, FL 32611, USA
| | - Jinling Zhang
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, P.O. Box 116250, Gainesville, FL 32611, USA
| | - Thomas J George
- Department of Medicine, University of Florida, P.O. Box 100278, Gainesville, FL 32610, USA
| | - Z Hugh Fan
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, P.O. Box 116250, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, P.O. Box 116131, Gainesville, FL 32611, USA; Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611, USA
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29
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Regmi S, Poudel C, Adhikari R, Luo KQ. Applications of Microfluidics and Organ-on-a-Chip in Cancer Research. BIOSENSORS 2022; 12:bios12070459. [PMID: 35884262 PMCID: PMC9313151 DOI: 10.3390/bios12070459] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 06/11/2022] [Accepted: 06/17/2022] [Indexed: 12/27/2022]
Abstract
Taking the life of nearly 10 million people annually, cancer has become one of the major causes of mortality worldwide and a hot topic for researchers to find innovative approaches to demystify the disease and drug development. Having its root lying in microelectronics, microfluidics seems to hold great potential to explore our limited knowledge in the field of oncology. It offers numerous advantages such as a low sample volume, minimal cost, parallelization, and portability and has been advanced in the field of molecular biology and chemical synthesis. The platform has been proved to be valuable in cancer research, especially for diagnostics and prognosis purposes and has been successfully employed in recent years. Organ-on-a-chip, a biomimetic microfluidic platform, simulating the complexity of a human organ, has emerged as a breakthrough in cancer research as it provides a dynamic platform to simulate tumor growth and progression in a chip. This paper aims at giving an overview of microfluidics and organ-on-a-chip technology incorporating their historical development, physics of fluid flow and application in oncology. The current applications of microfluidics and organ-on-a-chip in the field of cancer research have been copiously discussed integrating the major application areas such as the isolation of CTCs, studying the cancer cell phenotype as well as metastasis, replicating TME in organ-on-a-chip and drug development. This technology’s significance and limitations are also addressed, giving readers a comprehensive picture of the ability of the microfluidic platform to advance the field of oncology.
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Affiliation(s)
- Sagar Regmi
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Department of Physics, Kathmandu University, Dhulikhel 45200, Nepal;
- Research Centre for Applied Science and Technology (RECAST), Tribhuvan University, Kathmandu 44600, Nepal;
- Nepal Academy of Science and Technology (NAST), Khumaltar, Lalitpur 44700, Nepal
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Chetan Poudel
- Department of Physics, Kathmandu University, Dhulikhel 45200, Nepal;
| | - Rameshwar Adhikari
- Research Centre for Applied Science and Technology (RECAST), Tribhuvan University, Kathmandu 44600, Nepal;
| | - Kathy Qian Luo
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau, China
- Correspondence:
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30
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Chien HW, Wu JC, Chang YC, Tsai WB. Polycarboxybetaine-Based Hydrogels for the Capture and Release of Circulating Tumor Cells. Gels 2022; 8:gels8070391. [PMID: 35877476 PMCID: PMC9317810 DOI: 10.3390/gels8070391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/17/2022] [Accepted: 06/19/2022] [Indexed: 02/04/2023] Open
Abstract
Circulating tumor cells (CTCs) are indicators for the detection, diagnosis, and monitoring of cancers and offer biological information for the development of personalized medicine. Techniques for the specific capture and non-destructive release of CTCs from millions of blood cells remain highly desirable. Here, we present a CTC capture-and-release system using a disulfide-containing poly(carboxybetaine methacrylate) (pCB) hydrogel. The non-fouling characteristic of pCB prevents unwanted, nonspecific cell binding, while the carboxyl functionality of pCB is used for the conjugation of anti-epithelial cell adhesion molecule (anti-EpCAM) antibodies for the capture of CTCs. The results demonstrated that the anti-EpCAM-conjugated pCB hydrogel captured HCT116 cells from blood, and the capture ratio reached 45%. Furthermore, the captured HCT116 cells were released within 30 min from the dissolution of the pCB hydrogel by adding cysteine, which breaks the disulfide bonds of the crosslinkers. The cells released were viable and able to grow. Our system has potential in the development of a device for CTC diagnosis.
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Affiliation(s)
- Hsiu-Wen Chien
- Department of Chemical and Material Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 807, Taiwan;
| | - Jen-Chia Wu
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;
| | - Ying-Chih Chang
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
- Correspondence: or (Y.-C.C.); (W.-B.T.); Tel./Fax: +886-2-27871277 (Y.-C.C.); +886-2-33663996 (W.-B.T.)
| | - Wei-Bor Tsai
- Department of Chemical Engineering, National Taiwan University, Taipei 106, Taiwan
- Correspondence: or (Y.-C.C.); (W.-B.T.); Tel./Fax: +886-2-27871277 (Y.-C.C.); +886-2-33663996 (W.-B.T.)
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Li C, He W, Wang N, Xi Z, Deng R, Liu X, Kang R, Xie L, Liu X. Application of Microfluidics in Detection of Circulating Tumor Cells. Front Bioeng Biotechnol 2022; 10:907232. [PMID: 35646880 PMCID: PMC9133555 DOI: 10.3389/fbioe.2022.907232] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/11/2022] [Indexed: 12/22/2022] Open
Abstract
Tumor metastasis is one of the main causes of cancer incidence and death worldwide. In the process of tumor metastasis, the isolation and analysis of circulating tumor cells (CTCs) plays a crucial role in the early diagnosis and prognosis of cancer patients. Due to the rarity and inherent heterogeneity of CTCs, there is an urgent need for reliable CTCs separation and detection methods in order to obtain valuable information on tumor metastasis and progression from CTCs. Microfluidic technology is increasingly used in various studies of CTCs separation, identification and characterization because of its unique advantages, such as low cost, simple operation, less reagent consumption, miniaturization of the system, rapid detection and accurate control. This paper reviews the research progress of microfluidic technology in CTCs separation and detection in recent years, as well as the potential clinical application of CTCs, looks forward to the application prospect of microfluidic technology in the treatment of tumor metastasis, and briefly discusses the development prospect of microfluidic biosensor.
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Affiliation(s)
- Can Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei He
- Department of Clinical Medical Engineering, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Nan Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhipeng Xi
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Rongrong Deng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiyu Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ran Kang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Orthopedics, Nanjing Lishui Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Lin Xie
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing, China
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Cell Lines of Circulating Tumor Cells: What Is Known and What Needs to Be Resolved. J Pers Med 2022; 12:jpm12050666. [PMID: 35629089 PMCID: PMC9148030 DOI: 10.3390/jpm12050666] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/13/2022] [Accepted: 04/15/2022] [Indexed: 12/03/2022] Open
Abstract
The importance of circulating tumor cells (CTC) is well recognized. However, the biological characteristics of CTC in the bloodstream have not yet been examined in detail, due to the limited number of CTC cell lines currently available. Thirty-nine CTC cell lines were reported by 2021. For successful cell culturing, these CTC cell lines were reviewed. Previous studies on short-term cultures of CTC also analyzed approaches for establishing the long-term culture of CTC. Negative selection, hypoxic conditions, three-dimensional conditions, and careful management are preferable for the long-term culture of CTC. However, the establishment of CTC cell lines is dependent on the specific characteristics of each cell type. Therefore, a method to establish CTC cell lines has not yet been developed. Further efforts are needed to resolve this issue.
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Bhat MP, Thendral V, Uthappa UT, Lee KH, Kigga M, Altalhi T, Kurkuri MD, Kant K. Recent Advances in Microfluidic Platform for Physical and Immunological Detection and Capture of Circulating Tumor Cells. BIOSENSORS 2022; 12:220. [PMID: 35448280 PMCID: PMC9025399 DOI: 10.3390/bios12040220] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 05/05/2023]
Abstract
CTCs (circulating tumor cells) are well-known for their use in clinical trials for tumor diagnosis. Capturing and isolating these CTCs from whole blood samples has enormous benefits in cancer diagnosis and treatment. In general, various approaches are being used to separate malignant cells, including immunomagnets, macroscale filters, centrifuges, dielectrophoresis, and immunological approaches. These procedures, on the other hand, are time-consuming and necessitate multiple high-level operational protocols. In addition, considering their low efficiency and throughput, the processes of capturing and isolating CTCs face tremendous challenges. Meanwhile, recent advances in microfluidic devices promise unprecedented advantages for capturing and isolating CTCs with greater efficiency, sensitivity, selectivity and accuracy. In this regard, this review article focuses primarily on the various fabrication methodologies involved in microfluidic devices and techniques specifically used to capture and isolate CTCs using various physical and biological methods as well as their conceptual ideas, advantages and disadvantages.
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Affiliation(s)
- Mahesh Padmalaya Bhat
- Centre for Research in Functional Materials (CRFM), Jain Global Campus, Jain University, Bengaluru 562112, Karnataka, India; (M.P.B.); (V.T.); (M.K.)
- Agricultural Automation Research Center, Chonnam National University, Gwangju 61186, Korea;
| | - Venkatachalam Thendral
- Centre for Research in Functional Materials (CRFM), Jain Global Campus, Jain University, Bengaluru 562112, Karnataka, India; (M.P.B.); (V.T.); (M.K.)
| | | | - Kyeong-Hwan Lee
- Agricultural Automation Research Center, Chonnam National University, Gwangju 61186, Korea;
- Department of Convergence Biosystems Engineering, Chonnam National University, Gwangju 61186, Korea
| | - Madhuprasad Kigga
- Centre for Research in Functional Materials (CRFM), Jain Global Campus, Jain University, Bengaluru 562112, Karnataka, India; (M.P.B.); (V.T.); (M.K.)
| | - Tariq Altalhi
- Department of Chemistry, Faculty of Science, Taif University, Taif 21944, Saudi Arabia;
| | - Mahaveer D. Kurkuri
- Centre for Research in Functional Materials (CRFM), Jain Global Campus, Jain University, Bengaluru 562112, Karnataka, India; (M.P.B.); (V.T.); (M.K.)
| | - Krishna Kant
- Departamento de Química Física, Campus Universitario, CINBIO Universidade de Vigo, 36310 Vigo, Spain
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Dotse E, Lim KH, Wang M, Wijanarko KJ, Chow KT. An Immunological Perspective of Circulating Tumor Cells as Diagnostic Biomarkers and Therapeutic Targets. Life (Basel) 2022; 12:323. [PMID: 35207611 PMCID: PMC8878951 DOI: 10.3390/life12020323] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 11/19/2022] Open
Abstract
Immune modulation is a hallmark of cancer. Cancer-immune interaction shapes the course of disease progression at every step of tumorigenesis, including metastasis, of which circulating tumor cells (CTCs) are regarded as an indicator. These CTCs are a heterogeneous population of tumor cells that have disseminated from the tumor into circulation. They have been increasingly studied in recent years due to their importance in diagnosis, prognosis, and monitoring of treatment response. Ample evidence demonstrates that CTCs interact with immune cells in circulation, where they must evade immune surveillance or modulate immune response. The interaction between CTCs and the immune system is emerging as a critical point by which CTCs facilitate metastatic progression. Understanding the complex crosstalk between the two may provide a basis for devising new diagnostic and treatment strategies. In this review, we will discuss the current understanding of CTCs and the complex immune-CTC interactions. We also present novel options in clinical interventions, targeting the immune-CTC interfaces, and provide some suggestions on future research directions.
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Affiliation(s)
- Eunice Dotse
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
| | - King H. Lim
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
| | - Meijun Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
| | - Kevin Julio Wijanarko
- Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia;
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia
| | - Kwan T. Chow
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
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Rapid and efficient capturing of circulating tumor cells from breast cancer Patient's whole blood via the antibody functionalized microfluidic (AFM) chip. Biosens Bioelectron 2022; 201:113965. [PMID: 35016111 DOI: 10.1016/j.bios.2022.113965] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/29/2021] [Accepted: 01/03/2022] [Indexed: 12/20/2022]
Abstract
Accurate enumeration of circulating tumor cells (CTCs) in cancer patient's blood functions as a form of "liquid biopsy", which is pivotal for cancer screening, prognosis, and diagnosis. Herein, we demonstrate a novel antibody functionalized microfluidic (AFM) chip that rapidly and accurately qualifies CTCs from breast cancer patient's whole blood. The AFM chip consists of three buffering zones, and four main capturing zones filled with equilateral triangular pillars and periodically distributed obstacles. We validate the AFM chip with three Epithelial cell adhesion molecule (EpCAM) positive cancer cell lines, including breast (MCF-7), prostate (PC3), and lung cancer cell lines (A549), achieving capture efficiencies of 99.5%, 98.5%, and 96.72%, respectively, at a flow rate of 0.6 mL/hour. We further confirm the efficacy of the AFM chip with five advanced breast cancer patients' whole blood to capture EpCAM+/CK19+/CD45-/DAPI + CTCs. Interestingly, high number of CTCs were identified from each patient's 1 mL whole blood (595-2270), The AFM chip is highly efficient at rapidly capturing CTCs from cancer patients' whole blood without requiring extra equipment, which is critically beneficial for clinical application.
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Chícharo A, Caetano DM, Cardoso S, Freitas P. Evolution in Automatized Detection of Cells: Advances in Magnetic Microcytometers for Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1379:413-444. [DOI: 10.1007/978-3-031-04039-9_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Liu X, Ma L, Yan W, Aazmi A, Fang M, Xu X, Kang H, Xu X. A review of recent progress toward the efficient separation of circulating tumor cells via micro‐/nanostructured microfluidic chips. VIEW 2022. [DOI: 10.1002/viw.20210013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Xiaoshi Liu
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
| | - Liang Ma
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
- State Key Laboratory of Fluid Power and Mechatronic Systems Zhejiang University Hangzhou P. R. China
- School of Mechanical Engineering Zhejiang University Hangzhou P. R. China
| | - Wenyuan Yan
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
| | - Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems Zhejiang University Hangzhou P. R. China
- School of Mechanical Engineering Zhejiang University Hangzhou P. R. China
| | - Minghe Fang
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
| | - Xiuzhen Xu
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
| | - Hanyue Kang
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
| | - Xiaobin Xu
- Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Laboratory of D&A for Metal‐Functional Materials School of Materials Science and Engineering Institute for Advanced Study Tongji University Shanghai P. R. China
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Yadav A, Kumar A, Siddiqui MH. Detection of circulating tumour cells in colorectal cancer: Emerging techniques and clinical implications. World J Clin Oncol 2021; 12:1169-1181. [PMID: 35070736 PMCID: PMC8716996 DOI: 10.5306/wjco.v12.i12.1169] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/15/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Despite several advances in oncological management of colorectal cancer, morbidity and mortality are still high and devastating. The diagnostic evaluation by endoscopy is cumbersome, which is uncomfortable to many. Because of the intra- and inter-tumour heterogeneity and changing tumour dynamics, which is continuous in nature, the diagnostic biopsy and assessment of the pathological sample are difficult and also not adequate. Late manifestation of the disease and delayed diagnosis may lead to relapse or metastases. One of the keys to improving the outcome is early detection of cancer, ease of technology to detect with uniformity, and its therapeutic implications, which are yet to come. "Liquid biopsy" is currently the most recent area of interest in oncology, which may provide important tools regarding the characterization of the primary tumour and its metastasis as cancer cells shed into the bloodstream even at the early stages of the disease. By using this approach, clinicians may be able to find out information about the tumour at a given time. Any of the following three types of sampling of biological material can be used in the "liquid biopsy". These are circulating tumour cells (CTCs), circulating tumour DNA, and exosomes. The most commonly studied amongst the three is CTCs. CTCs with their different applications and prognostic value has been found useful in colorectal cancer detection and therapeutics. In this review, we will discuss various markers for CTCs, the core tools/techniques for detection, and also important findings of clinical studies in colorectal cancer and its clinical implications.
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Affiliation(s)
- Alka Yadav
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Gou Y, Chen Z, Sun C, Wang P, You Z, Yalikun Y, Tanaka Y, Ren D. Specific capture and intact release of breast cancer cells using a twin-layer vein-shaped microchip with a self-assembled surface. NANOSCALE 2021; 13:17765-17774. [PMID: 34558589 DOI: 10.1039/d1nr04018a] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Breast cancer is the most fatal disease among female cancers yet its detection still relies on needle biopsy. The unique physical and immune characteristics of breast cancer cells different from blood cells make them suitable to be employed as excellent biomarkers in liquid biopsy, through which breast cancer cells are collected from peripheral blood for further cancer diagnosis, medical treatment monitoring, and drug screening. Although the separation and enrichment of breast cancer cells from peripheral blood have been studied for years, there are still two problems to be solved in these methods: the low efficiency of on-chip immunologic capture in the flow state and the influence of the conjugated antibodies for the following analyses during cell release. In this paper, a vein-shaped microchip with self-assembled surface was developed for the specific and robust capture (91.2%) of breast cancer cells in the flow state. A protein-recovery process was proposed, in which trypsin served as a mild release reagent, releasing 92% of cells with high viability (96%), normal adherent proliferation, and complete proteins on the cell membrane, avoiding disturbance of the conjugated chemical molecules in the following clinical study. The excellent performance demonstrated in isolating free breast cancer cells from real peripheral blood sample, originating from the orthotopic 4T1 breast cancer metastatic models, suggest the microchip could be utilized as a multiple circulating tumor cell capture and release platform that could allow providing more reliable information in liquid biopsies.
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Affiliation(s)
- Yixing Gou
- State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, Tianjin, 300072, China
- State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, 100084, China.
| | - Zhuyuan Chen
- Department of Basic Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Changku Sun
- State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, Tianjin, 300072, China
| | - Peng Wang
- State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, Tianjin, 300072, China
| | - Zheng You
- State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, 100084, China.
| | - Yaxiaer Yalikun
- Center for Biosystems Dynamics Research (BDR), RIKEN, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
- Division of Materials Science, Nara Institute of Science and Technology, 8916-5 Takayamacho, Ikoma, Nara 630-0192, Japan
| | - Yo Tanaka
- Center for Biosystems Dynamics Research (BDR), RIKEN, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Dahai Ren
- State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, 100084, China.
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Chen X, Ding H, Zhang D, Zhao K, Gao J, Lin B, Huang C, Song Y, Zhao G, Ma Y, Wu L, Yang C. Reversible Immunoaffinity Interface Enables Dynamic Manipulation of Trapping Force for Accumulated Capture and Efficient Release of Circulating Rare Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2102070. [PMID: 34473422 PMCID: PMC8529431 DOI: 10.1002/advs.202102070] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/19/2021] [Indexed: 05/04/2023]
Abstract
Controllable assembly and disassembly of recognition interface are vital for bioanalysis. Herein, a strategy of dynamic manipulation of trapping force by engineering a dynamic and reversible immunoaffinity microinterface (DynarFace) in a herringbone chip (DynarFace-Chip) for liquid biopsy is proposed. The DynarFace is assembled by magnetically attracting immunomagnetic beads (IMBs) on chip substrate, with merits of convenient operation and reversible assembly. The DynarFace allows accumulating attachment of IMBs on circulating rare cell (CRC) surfaces during hydrodynamically enhanced interface collision, where accumulatively enhanced magnetic trapping force improves capture efficiency toward CRCs with medium expression of biomarkers from blood samples by 134.81% compared with traditional non-dynamic interfaces. Moreover, magnet withdrawing-induced disappearance of trapping force affords DynarFace disassembly and CRC release with high efficiency (>98%) and high viability (≈98%), compatible with downstream in vitro culture and gene analysis of CRCs. This DynarFace strategy opens a new avenue to accumulated capture and reversible release of CRCs, holding great potential for liquid biopsy-based precision medicine.
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Affiliation(s)
- Xiaofeng Chen
- The MOE Key Laboratory of Spectrochemical Analysis & InstrumentationThe Key Laboratory of Chemical Biology of Fujian ProvinceState Key Laboratory of Physical Chemistry of Solid SurfacesCollaborative Innovation Center of Chemistry for Energy MaterialsDepartment of Chemical BiologyCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen361005China
| | - Hongming Ding
- Center for Soft Condensed Matter Physics and Interdisciplinary ResearchSchool of Physical Science and TechnologySoochow UniversitySuzhou215021China
| | - Dongdong Zhang
- The MOE Key Laboratory of Spectrochemical Analysis & InstrumentationThe Key Laboratory of Chemical Biology of Fujian ProvinceState Key Laboratory of Physical Chemistry of Solid SurfacesCollaborative Innovation Center of Chemistry for Energy MaterialsDepartment of Chemical BiologyCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen361005China
| | - Kaifeng Zhao
- The MOE Key Laboratory of Spectrochemical Analysis & InstrumentationThe Key Laboratory of Chemical Biology of Fujian ProvinceState Key Laboratory of Physical Chemistry of Solid SurfacesCollaborative Innovation Center of Chemistry for Energy MaterialsDepartment of Chemical BiologyCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen361005China
| | - Jiafeng Gao
- Institute of Molecular MedicineState Key Laboratory of Oncogenes and Related GenesRenji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
| | - Bingqian Lin
- The MOE Key Laboratory of Spectrochemical Analysis & InstrumentationThe Key Laboratory of Chemical Biology of Fujian ProvinceState Key Laboratory of Physical Chemistry of Solid SurfacesCollaborative Innovation Center of Chemistry for Energy MaterialsDepartment of Chemical BiologyCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen361005China
| | - Chen Huang
- Institute of Molecular MedicineState Key Laboratory of Oncogenes and Related GenesRenji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
| | - Yanling Song
- The MOE Key Laboratory of Spectrochemical Analysis & InstrumentationThe Key Laboratory of Chemical Biology of Fujian ProvinceState Key Laboratory of Physical Chemistry of Solid SurfacesCollaborative Innovation Center of Chemistry for Energy MaterialsDepartment of Chemical BiologyCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen361005China
| | - Gang Zhao
- Institute of Molecular MedicineState Key Laboratory of Oncogenes and Related GenesRenji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
| | - Yuqiang Ma
- National Laboratory of Solid State Microstructures and Department of PhysicsCollaborative Innovation Center of Advanced MicrostructuresNanjing UniversityNanjing210046China
| | - Lingling Wu
- Institute of Molecular MedicineState Key Laboratory of Oncogenes and Related GenesRenji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
| | - Chaoyong Yang
- The MOE Key Laboratory of Spectrochemical Analysis & InstrumentationThe Key Laboratory of Chemical Biology of Fujian ProvinceState Key Laboratory of Physical Chemistry of Solid SurfacesCollaborative Innovation Center of Chemistry for Energy MaterialsDepartment of Chemical BiologyCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen361005China
- Institute of Molecular MedicineState Key Laboratory of Oncogenes and Related GenesRenji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
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Circulating Tumor Cells from Enumeration to Analysis: Current Challenges and Future Opportunities. Cancers (Basel) 2021; 13:cancers13112723. [PMID: 34072844 PMCID: PMC8198976 DOI: 10.3390/cancers13112723] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/25/2021] [Indexed: 01/19/2023] Open
Abstract
Simple Summary With estimated numbers of 1–10 per mL of blood, circulating tumor cells (CTCs) are extremely rare compared to white (a few million) or red (billions) blood cells. Given their critical role in metastasis, CTCs have enormous potential as a biomarker for cancer diagnosis, prognosis, and monitoring of treatment response. There are now efforts to characterize CTCs more precisely through molecular and functional analysis, expanding the CTC effort from one of diagnosis and prognosis to now include the use of CTCs to specifically target cancers and discover therapeutic solutions, establishing CTCs as critical in precision medicine. This article summarizes current knowledge about CTC isolation technologies and discusses the translational benefits of different types of downstream analysis approaches, including single-CTC analysis, ex vivo expansion of CTCs, and characterization of CTC-associated cells. Abstract Circulating tumor cells (CTCs) have been recognized as a major contributor to distant metastasis. Their unique role as metastatic seeds renders them a potential marker in the circulation for early cancer diagnosis and prognosis as well as monitoring of therapeutic response. In the past decade, researchers mainly focused on the development of isolation techniques for improving the recovery rate and purity of CTCs. These developed techniques have significantly increased the detection sensitivity and enumeration accuracy of CTCs. Currently, significant efforts have been made toward comprehensive molecular characterization, ex vivo expansion of CTCs, and understanding the interactions between CTCs and their associated cells (e.g., immune cells and stromal cells) in the circulation. In this review, we briefly summarize existing CTC isolation technologies and specifically focus on advances in downstream analysis of CTCs and their potential applications in precision medicine. We also discuss the current challenges and future opportunities in their clinical utilization.
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Carmona-Ule N, González-Conde M, Abuín C, Cueva JF, Palacios P, López-López R, Costa C, Dávila-Ibáñez AB. Short-Term Ex Vivo Culture of CTCs from Advance Breast Cancer Patients: Clinical Implications. Cancers (Basel) 2021; 13:cancers13112668. [PMID: 34071445 PMCID: PMC8198105 DOI: 10.3390/cancers13112668] [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: 04/15/2021] [Revised: 05/14/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Circulating tumor cells (CTCs) are responsible for metastasis, they represent tumor biology and have also predictive value for therapy monitoring and prognosis of metastatic breast cancer patients. In the blood, CTCs are found in low frequency and a small percentage of them survive. Therefore, achieving their expansion in vitro will allow performing characterization and functional analysis. In this work, we used growth factors and Nanoemulsions to support CTCs culture. We have seen that the CTCs subpopulation capable of ex vivo expanding presented mesenchymal and stem characteristics and loss of epithelial markers. Besides, CTC culture predicted progression-free survival. Abstract Background: Circulating tumor cells (CTC) have relevance as prognostic markers in breast cancer. However, the functional properties of CTCs or their molecular characterization have not been well-studied. Experimental models indicate that only a few cells can survive in the circulation and eventually metastasize. Thus, it is essential to identify these surviving cells capable of forming such metastases. Methods: We isolated viable CTCs from 50 peripheral blood samples obtained from 35 patients with advanced metastatic breast cancer using RosetteSepTM for ex vivo culture. The CTCs were seeded and monitored on plates under low adherence conditions and with media supplemented with growth factors and Nanoemulsions. Phenotypic analysis was performed by immunofluorescence and gene expression analysis using RT-PCR and CTCs counting by the Cellsearch® system. Results: We found that in 75% of samples the CTC cultures lasted more than 23 days, predicting a shorter Progression-Free Survival in these patients, independently of having ≥5 CTC by Cellsearch®. We also observed that CTCs before and after culture showed a different gene expression profile. Conclusions: the cultivability of CTCs is a predictive factor. Furthermore, the subset of cells capable of growing ex vivo show stem or mesenchymal features and may represent the CTC population with metastatic potential in vivo.
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Affiliation(s)
- Nuria Carmona-Ule
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (N.C.-U.); (M.G.-C.); (C.A.); (R.L.-L.)
| | - Miriam González-Conde
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (N.C.-U.); (M.G.-C.); (C.A.); (R.L.-L.)
- CIBERONC, Centro de Investigación Biomédica en Red Cáncer, 28029 Madrid, Spain; (J.F.C.); (P.P.)
| | - Carmen Abuín
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (N.C.-U.); (M.G.-C.); (C.A.); (R.L.-L.)
| | - Juan F. Cueva
- CIBERONC, Centro de Investigación Biomédica en Red Cáncer, 28029 Madrid, Spain; (J.F.C.); (P.P.)
- Translational Medical Oncology Group (Oncomet), Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Patricia Palacios
- CIBERONC, Centro de Investigación Biomédica en Red Cáncer, 28029 Madrid, Spain; (J.F.C.); (P.P.)
- Translational Medical Oncology Group (Oncomet), Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Rafael López-López
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (N.C.-U.); (M.G.-C.); (C.A.); (R.L.-L.)
- CIBERONC, Centro de Investigación Biomédica en Red Cáncer, 28029 Madrid, Spain; (J.F.C.); (P.P.)
- Translational Medical Oncology Group (Oncomet), Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Clotilde Costa
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (N.C.-U.); (M.G.-C.); (C.A.); (R.L.-L.)
- CIBERONC, Centro de Investigación Biomédica en Red Cáncer, 28029 Madrid, Spain; (J.F.C.); (P.P.)
- Correspondence: (C.C.); (A.B.D.-I.); Tel.: +34-981-955-602 (C.C.)
| | - Ana Belén Dávila-Ibáñez
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (N.C.-U.); (M.G.-C.); (C.A.); (R.L.-L.)
- Correspondence: (C.C.); (A.B.D.-I.); Tel.: +34-981-955-602 (C.C.)
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Mahhengam N, Fahem Ghetran Khazaali A, Aravindhan S, Olegovna Zekiy A, Melnikova L, Siahmansouri H. Applications of Microfluidic Devices in the Diagnosis and Treatment of Cancer: A Review Study. Crit Rev Anal Chem 2021; 52:1863-1877. [PMID: 34024197 DOI: 10.1080/10408347.2021.1922870] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Many cancer-related deaths are reported annually due to a lack of appropriate diagnosis and treatment strategies. Microfluidic technology, as new creativity has a great impact on automation and miniaturization via handling a small volume of materials and samples (in microliter to femtoliter range) to set up the system. Microfluidic devices not only detect various cancer-diagnostic factors from biological fluids but also can produce proper nanoparticles for drug delivery. With the contribution of microfluidics; multiple treatments for cancer such as chemotherapy, radiation therapy, and gene delivery can be implemented and studied. Hence, Microfluidics can be worth for the cancer field because of its high Throughput, high sensitivity, less material use, and low expense. In this review study, we intend to look at positive microfluidics prospects, features, benefits, and clinical applications.
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Affiliation(s)
- Negah Mahhengam
- Faculty of General Medicine, Belarusian State Medical University, Minsk, Belarus
| | | | - Surendar Aravindhan
- Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Lyubov Melnikova
- Business Analysis Department, Financial University under the Government of the Russian Federation, Moscow, Russian Federation
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Analysis of Temperature-Jump Boundary Conditions on Heat Transfer for Heterogeneous Microfluidic Immunosensors. SENSORS 2021; 21:s21103502. [PMID: 34069780 PMCID: PMC8157299 DOI: 10.3390/s21103502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/13/2021] [Accepted: 01/28/2021] [Indexed: 12/20/2022]
Abstract
The objective of the current study is to analyze numerically the effect of the temperature-jump boundary condition on heterogeneous microfluidic immunosensors under electrothermal force. A three-dimensional simulation using the finite element method on the binding reaction kinetics of C-reactive protein (CRP) was performed. The kinetic reaction rate was calculated with coupled Laplace, Navier−Stokes, energy, and mass diffusion equations. Two types of reaction surfaces were studied: one in the form of a disc surrounded by two electrodes and the other in the form of a circular ring, one electrode is located inside the ring and the other outside. The numerical results reveal that the performance of a microfluidic biosensor is enhanced by using the second design of the sensing area (circular ring) coupled with the electrothermal force. The improvement factor under the applied ac field 15 Vrms was about 1.2 for the first geometry and 3.6 for the second geometry. Furthermore, the effect of temperature jump on heat transfer rise and response time was studied. The effect of two crucial parameters, viz. Knudsen number (Kn) and thermal accommodation coefficient (σT) with and without electrothermal effect, were analyzed for the two configurations.
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Enhancement of Heterogeneous Microfluidic Immunosensors Using New Sensing Area Shape with Electrothermal Effect. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11104566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In heterogeneous microfluidic immunosensors, the diffusion boundary layer produced on the sensing area represents a critical factor that limits the biosensor performance. A three-dimensional simulation using the finite element method on the binding reaction kinetics of C-reactive protein (CRP) has been performed. We present a new microfluidic biosensor based on a novel reaction-surface design without and with electrothermal force. Two reaction surface configurations were studied. The kinetic reaction rate was calculated with coupled Navier−Stokes, mass diffusion, energy, and Laplace equations. The numerical results reveal that the characteristics of a microfluidic biosensor are more enhanced by using the circular ring design of the sensing area coupled with the electrothermal force. The rate of initial slope related to the association phase is multiplied by a factor 2 when the voltage is increased from 10 to 15 V. The results prove to be valuable in designing new microfluidic biosensors.
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Liu Y, Zhao W, Cheng R, Harris BN, Murrow JR, Hodgson J, Egan M, Bankey A, Nikolinakos PG, Laver T, Meichner K, Mao L. Fundamentals of integrated ferrohydrodynamic cell separation in circulating tumor cell isolation. LAB ON A CHIP 2021; 21:1706-1723. [PMID: 33720269 PMCID: PMC8102387 DOI: 10.1039/d1lc00119a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Methods to separate circulating tumor cells (CTCs) from blood samples were intensively researched in order to understand the metastatic process and develop corresponding clinical assays. However current methods faced challenges that stemmed from CTCs' heterogeneity in their biological markers and physical morphologies. To this end, we developed integrated ferrohydrodynamic cell separation (iFCS), a scheme that separated CTCs independent of their surface antigen expression and physical characteristics. iFCS integrated both diamagnetophoresis of CTCs and magnetophoresis of blood cells together via a magnetic liquid medium, ferrofluid, whose magnetization could be tuned by adjusting its magnetic volume concentration. In this paper, we presented the fundamental theory of iFCS and its specific application in CTC separation. Governing equations of iFCS were developed to guide its optimization process. Three critical parameters that affected iFCS's cell separation performance were determined and validated theoretically and experimentally. These parameters included the sample flow rate, the volumetric concentration of magnetic materials in the ferrofluid, and the gradient of the magnetic flux density. We determined these optimized parameters in an iFCS device that led to a high recovery CTC separation in both spiked and clinical samples.
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Affiliation(s)
- Yang Liu
- Department of Chemistry, The University of Georgia, Athens, GA 30602, USA
| | - Wujun Zhao
- Department of Chemistry, The University of Georgia, Athens, GA 30602, USA
| | - Rui Cheng
- School of Electrical and Computer Engineering, College of Engineering, The University of Georgia, Athens, GA 30602, USA.
| | - Bryana N Harris
- Department of Chemical Engineering, Auburn University, Auburn, AL 36830, USA
| | - Jonathan R Murrow
- Department of Medicine, Augusta University - The University of Georgia Medical Partnership, Athens, GA 30602, USA
| | - Jamie Hodgson
- University Cancer & Blood Center, LLC, Athens, GA 30607, USA
| | - Mary Egan
- University Cancer & Blood Center, LLC, Athens, GA 30607, USA
| | | | | | - Travis Laver
- Small Animal Medicine and Surgery, Veterinary Teaching Hospital, The University of Georgia, Athens, GA 30602, USA
| | - Kristina Meichner
- Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA
| | - Leidong Mao
- School of Electrical and Computer Engineering, College of Engineering, The University of Georgia, Athens, GA 30602, USA.
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Smit DJ, Pantel K, Jücker M. Circulating tumor cells as a promising target for individualized drug susceptibility tests in cancer therapy. Biochem Pharmacol 2021; 188:114589. [PMID: 33932470 DOI: 10.1016/j.bcp.2021.114589] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023]
Abstract
Circulating tumor cells (CTCs) play a crucial role in metastasis and became an emerging topic in today's cancer research. In addition, the analysis of CTCs in liquid biopsies will be a valuable tool for prognosis prediction and real time therapy monitoring. The characterization of CTCs may open up a new field of treatment strategy to prevent metastasis or maintain a stable disease. In 2013, the first cell cultures of CTCs have been established in vitro. Additionally, functional studies have been successfully performed over the last years. Meanwhile, more than 300 short-term CTC cultures and 42 long-term CTC cultures from a variety of tumor entities have been described. More than 45 inhibitors have already been tested for their efficacy to target CTCs in several studies in vitro as well as in xenograft mouse models in vivo. Here, we summarize the currently available data of these inhibition experiments and their effects in targeting CTCs. The results suggest that CTCs may be useful for individualized drug susceptibility testing.
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Affiliation(s)
- Daniel J Smit
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
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Fasanya HO, Dopico PJ, Yeager Z, Fan ZH, Siemann DW. Using a combination of gangliosides and cell surface vimentin as surface biomarkers for isolating osteosarcoma cells in microfluidic devices. J Bone Oncol 2021; 28:100357. [PMID: 33912384 PMCID: PMC8065304 DOI: 10.1016/j.jbo.2021.100357] [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: 01/23/2021] [Revised: 02/18/2021] [Accepted: 03/01/2021] [Indexed: 12/28/2022] Open
Abstract
Background Osteosarcoma (OS) is the most common primary bone tumor and the third leading cause of pediatric cancer deaths. Liquid biopsies are an alternative to current diagnostic imaging modalities that can be used to monitor treatment efficacy and the development of metastases. This study addresses the use of novel biomarkers to detect circulating osteosarcoma cells. Procedures Flow cytometry was used to evaluate the relative expression of epithelial cell adhesion molecule (EpCAM), ganglioside 2 and 3 (GD2/3), and cell surface vimentin (CSV) on a panel of OS cell lines. A microfluidic device was used to affirm the efficacy of GD2/3 and CSV to capture CTCs. Once captured, CTCs on the device are enumerated and the capture efficiency for each marker is measured. Patient samples were captured using the LFAM chip. Results We report the evaluation of GD2, GD3, and CSV as markers for OS cell capture in cell lines and in patient samples. The results of our capture studies correlate with our flow cytometry data and have shown a low capture efficiency of OS cells using EpCAM antibodies, while showing a moderate capture efficiency of OS cells using the GD2, GD3, and CSV antibodies independently. The combination of biomarkers demonstrate a high capture efficiency of approximately 80%. This is further supported by the detection of 1-1.5 CTCs per mL of blood using GD2 + CSV in OS patient samples. Conclusions The combination of GD2 + CSV significantly increased the capture efficacy of OS cells. The detection of CTCs through routine blood sampling may be used clinically for earlier detection of metastases and monitoring the therapeutic effect of treatments in metastatic osteosarcomas.
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Key Words
- CK, Cytokeratin
- CSV, Cell Surface Vimentin
- CTC, Circulating Tumor Cell
- Circulating tumor cells
- DAPI, 4′,6-diamidino-2-phenylindole
- EpCAM, Epithelial Cell Adhesion Molecule
- GD2, Ganglioside 2
- GD3, Ganglioside 3
- Ganglioside GD2
- Ganglioside GD3
- IHC, Immunohistochemistry
- OS, Osteosarcoma
- Osteosarcoma
- PET, Positron Emission Tomography
- Vimentin
- mL, Milliliter
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Affiliation(s)
- Henrietta O. Fasanya
- Department of Radiation Oncology, University of Florida, Gainesville, FL, USA
- College of Medicine MD-PhD Program, University of Florida, Gainesville, FL, USA
- Corresponding authors at: Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL, USA (Z.H. Fan) Department of Radiation Oncology, University of Florida, Gainesville, FL, USA (H.O. Fasanya).
| | - Pablo J. Dopico
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL, USA
| | - Zachary Yeager
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL, USA
| | - Z. Hugh Fan
- J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL, USA
- Corresponding authors at: Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL, USA (Z.H. Fan) Department of Radiation Oncology, University of Florida, Gainesville, FL, USA (H.O. Fasanya).
| | - Dietmar W. Siemann
- Department of Radiation Oncology, University of Florida, Gainesville, FL, USA
- Corresponding authors at: Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL, USA (Z.H. Fan) Department of Radiation Oncology, University of Florida, Gainesville, FL, USA (H.O. Fasanya).
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Wang Z, Sargent EH, Kelley SO. Ultrasensitive Detection and Depletion of Rare Leukemic B Cells in T Cell Populations via Immunomagnetic Cell Ranking. Anal Chem 2021; 93:2327-2335. [PMID: 33432815 DOI: 10.1021/acs.analchem.0c04202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Rare CD19+ leukemic B cells present in purified T cell populations can cause disease relapse and even the failure of CD19-targeting CAR-T therapy as these rare cells have the ability to self-mask their surface CD19 and escape from the recognition of T cells. It is therefore critical to efficiently detect and robustly deplete rare leukemic B cells in samples of therapeutic T cells. Here, we present a novel microfluidic approach to address the challenges specific to quality control of therapeutic T cells - CAR-QC. CAR-QC utilizes immunomagnetic labeling with a highly selective microfluidic device to rank and isolate rare leukemic B cells in T cell populations. CAR-QC offers ultrasensitive detection of leukemic B cells at single-cell resolution and robust depletion efficiency up to 99.985%. We demonstrate that CAR-QC outperforms flow cytometry and magnetic-activated cell sorting for detecting or purifying spiked samples. In addition, we prove that the improved performance of CAR-QC helps to avoid the occurrence and possibly relapse of rare leukemic B cells in vitro.
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Affiliation(s)
- Zongjie Wang
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto M5S 3G4, Canada.,Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9, Canada
| | - Edward H Sargent
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto M5S 3G4, Canada
| | - Shana O Kelley
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9, Canada.,Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto M5S 3M2, Canada.,Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto M5S 1A8, Canada.,Department of Chemistry, Faculty of Arts and Science, University of Toronto, Toronto M5S 3H6, Canada
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Park Y, Jun HR, Choi HW, Hwang DW, Lee JH, Song KB, Lee W, Kwon J, Ha SH, Jun E, Kim SC. Circulating tumour cells as an indicator of early and systemic recurrence after surgical resection in pancreatic ductal adenocarcinoma. Sci Rep 2021; 11:1644. [PMID: 33462311 PMCID: PMC7814057 DOI: 10.1038/s41598-020-80383-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Early recurrence in pancreatic ductal adenocarcinoma (PDAC) is a decisive factor in determining a patient's prognosis. We determined in our current study whether circulating tumour cells (CTCs) exist in the blood of PDAC patients and can be used as a predictor of recurrence patterns (i.e. time and site) after surgical resection. Between December 2017 and November 2018, the mononuclear cell layer was obtained from the peripheral blood of 36 patients diagnosed with PDAC. CTCs were then isolated using the CD-PRIME™ platform and detected via immunostaining. The patient records were analyzed to correlate these data with survival and recurrence patterns. Twelve patients were CTC-positive (33.3%) and showed a significantly frequent rate of systemic recurrence (distant metastases and peritoneal dissemination) (p = 0.025). On multi-variable logistic regression analysis, CTC positivity was an independent risk factor for early recurrence (p = 0.027) and for systemic recurrence (p = 0.033). In summary, the presence or absence of CTC in the blood of the patients with PDAC could help predict the recurrence pattern after surgery. PDAC patients with CTC positivity at tumour diagnosis should therefore undergo a comprehensive strategy for systemic therapy and active monitoring to detect possible early recurrence.
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Affiliation(s)
- Yejong Park
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Ryeong Jun
- Biomedical Engineering Research Center, Asan Medical Center, Seoul, Republic of Korea
| | - Hwi Wan Choi
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaewoo Kwon
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Su Hyeon Ha
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eunsung Jun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea. .,Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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