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Mahdian SMA, Mahmoudi-Aznaveh A, Mousavi SM, Larijani B, Azizi Z, Javar HA. Plasma treatment can efficiently increase the attachment of pancreatic circulatory tumor cells to the surface. Discov Oncol 2025; 16:222. [PMID: 39982607 PMCID: PMC11845332 DOI: 10.1007/s12672-025-01988-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 02/17/2025] [Indexed: 02/22/2025] Open
Abstract
Pancreatic cancer ranks as the fourth most common cause of cancer-related fatalities globally, with a notably low 5-year relative survival rate. We need to immediately develop fast, dependable, and noninvasive diagnostic techniques that can accurately identify pancreatic cancer at an early stage. The research project created a straightforward but effective method for detecting and increasing the amount of tumor cells that could bind to polystyrene (PS) well plates. To significantly improve the adhesion of the pancreatic cancer cell line PANC-1 on PS well plates, a 5-min exposure to high-power oxygen plasma was implemented. This treatment caused a significant increase in surface energy and roughness. Surface characterization was assessed by utilizing an atomic force microscope and X-ray photoelectron spectroscopy. Water contact angle measurement is used to assess the level of wettability present on the treated surface. To determine how well the circulatory tumor cells (CTCs) model adheres to a plasma-treated surface (PTS), appropriate amounts of mCherry-labeled PANC-1 cells are mixed into a sample of blood cells to mimic clinical conditions. After applying plasma treatment, the experiment achieved a 96% success rate in binding at 2 h, specifically for the PANC-1 cell type. Moreover, the platform demonstrated a considerable ability to attach to cancerous cells compared to non-cancerous cells found in blood. To summarize, this study has shown that non-thermal plasma treatment could be a novel and efficient method for the better adhesion of pancreatic cancer cells, with the benefits of being cost-effective and quick. It is necessary for additional research to be conducted to confirm the clinical efficacy of the method.
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Affiliation(s)
- Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Mahmoudi-Aznaveh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mojtaba Mousavi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hamid Akbari Javar
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Stosic K, Senar OA, Tarfouss J, Bouchart C, Navez J, Van Laethem JL, Arsenijevic T. A Comprehensive Review of the Potential Role of Liquid Biopsy as a Diagnostic, Prognostic, and Predictive Biomarker in Pancreatic Ductal Adenocarcinoma. Cells 2023; 13:3. [PMID: 38201207 PMCID: PMC10778087 DOI: 10.3390/cells13010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity, as well as the lack of distinct symptoms in the early phases, it is very often diagnosed at an advanced stage, resulting in poor prognosis. Traditional tissue biopsies remain the gold standard for making a diagnosis, but have an obvious disadvantage in their inapplicability for frequent sampling. Blood-based biopsies represent a non-invasive method which potentially offers easy and repeated sampling, leading to the early detection and real-time monitoring of the disease and hopefully an accurate prognosis. Given the urgent need for a reliable biomarker that can estimate a patient's condition and response to an assigned treatment, blood-based biopsies are emerging as a potential new tool for improving patients' survival and surveillance. In this article, we discuss the current advances and challenges in using liquid biopsies for pancreatic cancer, focusing on circulating tumour DNA (ctDNA), extracellular vesicles (EVs), and circulating tumour cells (CTCs), and compare the performance and reliability of different biomarkers and combinations of biomarkers.
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Affiliation(s)
- Kosta Stosic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Oier Azurmendi Senar
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Jawad Tarfouss
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Christelle Bouchart
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Radiation Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Julie Navez
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Hepato-Biliary-Pancreatic Surgery, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Jean-Luc Van Laethem
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
| | - Tatjana Arsenijevic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
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Lee HS, Jung EH, Shin H, Park CS, Park SB, Jung DE, Leem G, Kim SJ, Jo JH, Chung MJ, Park JY, Bang S, Park SW, Song SY. Phenotypic characteristics of circulating tumor cells and predictive impact for efficacy of chemotherapy in patients with pancreatic cancer: a prospective study. Front Oncol 2023; 13:1206565. [PMID: 37736542 PMCID: PMC10509470 DOI: 10.3389/fonc.2023.1206565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/14/2023] [Indexed: 09/23/2023] Open
Abstract
Objective Early chemoresistance and tumor mass progression are associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) have been studied as potential predictors of treatment response and prognosis in PDAC; however, this approach has yet to be applied in clinical practice. The aim of our study was to investigate the phenotypic characteristics of CTCs and determine their predictive value for PDAC progression. Methods We prospectively enrolled 40 patients who were pathologically diagnosed with PDAC and collected blood samples at diagnosis, 2 months after diagnosis, and during disease progression or recurrence. We used a microfabricated filter-based enrichment system to retrieve and analyze CTCs, which were classified using immunofluorescence staining (CD45, EpCAM, and vimentin). Results Our study included 20 women and 20 men (median age, 66 years). Overall, 45% of the patients (18/40) had disseminated disease, and 77.5% (31/40) received chemotherapy. Multivariate analysis revealed that the total CTC count and carbohydrate antigen 19-9 level at 2 months after diagnosis were associated with disease progression (P<0.05). Linear mixed model analysis revealed that the total CTC count and vimentin-positive CTCs were significantly correlated with treatment response during chemotherapy (P=0.024 and 0.017, respectively). Kaplan-Meier analysis showed that total CTC positivity at 2 months was significantly associated with poor progression-free survival (P=0.038). Conclusion Our study's findings suggest that CTCs can serve as predictive biomarkers of clinical outcomes in patients with PDAC receiving palliative chemotherapy. In particular, the total CTC count and vimentin-positive CTCs showed changes associated with the chemotherapy response.
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Affiliation(s)
- Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Hye Jung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyejung Shin
- Biostatistics Collaboration Unit, Medical Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chan Su Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Been Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dawoon E. Jung
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Galam Leem
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Jung Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Hyun Jo
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Peller MT, Das KK. Blood-Based Biomarkers in the Diagnosis and Risk Stratification of Pancreatic Cysts. Gastrointest Endosc Clin N Am 2023; 33:559-581. [PMID: 37245936 DOI: 10.1016/j.giec.2023.03.009] [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: 05/30/2023]
Abstract
The use of blood-based biomarkers for the assessment of pancreatic cystic lesions is a rapidly growing field with incredible potential. CA 19-9 remains the only blood-based marker in common use, while many novel biomarkers are in early stages of development and validation. We highlight current work in the fields of proteomics, metabolomics, cell-free DNA/circulating tumor DNA, extracellular vesicles, and microRNA among others, as well as barriers to development and future directions in the work of blood-based biomarkers for pancreatic cystic lesions.
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Affiliation(s)
- Matthew T Peller
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8124, Saint Louis, MO 63110, USA
| | - Koushik K Das
- Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8124, Saint Louis, MO 63110, USA.
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Javed AA, Floortje van Oosten A, Habib JR, Hasanain A, Kinny-Köster B, Gemenetzis G, Groot VP, Ding D, Cameron JL, Lafaro KJ, Burns WR, Burkhart RA, Yu J, He J, Wolfgang CL. A Delay in Adjuvant Therapy Is Associated With Worse Prognosis Only in Patients With Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma. Ann Surg 2023; 277:866-872. [PMID: 36111839 DOI: 10.1097/sla.0000000000005710] [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: 11/26/2022]
Abstract
OBJECTIVES The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in the initiation of adjuvant therapy. BACKGROUND Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. Although systemic therapies improve survival in resected patients, factors such as a delay in the initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS A retrospective study was performed on PDAC patients enrolled in the prospective CircuLating tUmor cellS in pancreaTic cancER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (isolation by size of epithelial tumor cells; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify 2 CTC types: epithelial CTCs (eCTCs), expressing pancytokeratin, and transitional CTCs (trCTCs), expressing both pancytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in the receipt of adjuvant therapy was defined as the initiation of therapy ≥8 weeks after surgical resection. Clinicopathologic features, CTCs characteristics, and outcomes were analyzed. RESULTS Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, the presence of trCTCs ( P =0.002) and the absence of adjuvant therapy ( P =0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs 17.9 mo, P =0.004) or no administration of adjuvant chemotherapy (3.4 vs NR, P =0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy ( P =0.293). CONCLUSIONS Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in the initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.
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Affiliation(s)
- Ammar A Javed
- Department of Surgery, New York University Langone Hospital, New York City, NY
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Anne Floortje van Oosten
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht University, The Netherlands
| | - Joseph R Habib
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alina Hasanain
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Benedict Kinny-Köster
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Georgios Gemenetzis
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vincent P Groot
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ding Ding
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Manhasset, NY
| | - John L Cameron
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kelly J Lafaro
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - William R Burns
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Richard A Burkhart
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jun Yu
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jin He
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
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Watanabe F, Suzuki K, Noda H, Rikiyama T. Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer. World J Gastroenterol 2022; 28:6478-6496. [PMID: 36569270 PMCID: PMC9782840 DOI: 10.3748/wjg.v28.i46.6478] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/25/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.
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Affiliation(s)
- Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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Epithelial to Mesenchymal Transition as Mechanism of Progression of Pancreatic Cancer: From Mice to Men. Cancers (Basel) 2022; 14:cancers14235797. [PMID: 36497278 PMCID: PMC9735867 DOI: 10.3390/cancers14235797] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022] Open
Abstract
Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis involves an intricate cascade of events comprising the pleiotropic process of epithelial to mesenchymal transition (EMT) facilitating cancer spread. The elucidation of this pivotal phenotypic change in cancer cell morphology, initially heretic, moved from basic studies dissecting the progression of pancreatic cancer in animal models to move towards human disease, although no clinical translation of the concept emerged yet. Despite this transition, a full-blown mesenchymal phenotype may not be accomplished; rather, the plasticity of the program and its dependency on heterotopic signals implies a series of fluctuating modifications of cancer cells encompassing mesenchymal and epithelial features. Despite the evidence supporting the activation of EMT and MET during cancer progression, our understanding of the relationship between tumor microenvironment and EMT is not yet mature for a clinical application. In this review, we attempt to resume the knowledge on EMT and pancreatic cancer, aiming to include the EMT among the hallmarks of cancer that could potentially modify our clinical thinking with the purpose of filling the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers, as well as their application for prognostic and predictive purposes.
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Zhu J, Tan Z, Zhang J, An M, Khaykin VM, Cuneo KC, Parikh ND, Lubman DM. Sequential Method for Analysis of CTCs and Exosomes from the Same Sample of Patient Blood. ACS OMEGA 2022; 7:37581-37588. [PMID: 36312392 PMCID: PMC9609053 DOI: 10.1021/acsomega.2c04428] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/29/2022] [Indexed: 06/16/2023]
Abstract
Circulating tumor cells (CTCs) and exosomes, both released from the primary tumor into peripheral blood, are a promising source of cancer biomarkers. They are detectable in the blood and carry a large diversity of biological molecules, which can be used for the diagnosis and monitoring of minimally invasive cancers. However, due to their intrinsic differences in counts, size, and molecular contents, studies have focused on only one type of vesicle. Herein, we have developed an integrated system to sequentially isolate CTCs and exosomes from a single patient blood sample for further profiling and analysis. The CTCs are isolated using a commercial filtration method and then the remaining blood is processed using multiple cycles of ultracentrifugation to isolate the exosomes. The method uses two available technologies where the eluent from CTC isolation is usually discarded and interfaces them, so that the eluent can be interfaced to exosome isolation methods. The CTCs are identified based on fluorescence staining of their surface markers, while the exosomes are analyzed using transmission electron microscopy, nanosight tracking analysis, and mass spec proteomic analysis. This analysis showed CTCs detected by their surface markers for metastatic hepatocellular carcinoma (HCC), while essentially none were detected for cirrhosis. The exosome analysis resulted in the identification of ∼500-1000 exosome proteins per sample confirmed by detection of exosome surface markers CD9, CD63, CD81, and TSG101 in addition to proteins related to cancer progression. Proteins enriched in HCC exosomes were shown to be involved in the immune response, metastasis, and proliferation.
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Affiliation(s)
- Jianhui Zhu
- Department
of Surgery, The University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Zhijing Tan
- Department
of Surgery, The University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Jie Zhang
- Department
of Surgery, The University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Mingrui An
- Department
of Surgery, The University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Valerie M. Khaykin
- Division
of Gastroenterology and Hepatology, University
of Michigan Medical Center, Ann
Arbor, Michigan 48109, United States
| | - Kyle C. Cuneo
- Department
of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Neehar D. Parikh
- Division
of Gastroenterology and Hepatology, University
of Michigan Medical Center, Ann
Arbor, Michigan 48109, United States
| | - David M. Lubman
- Department
of Surgery, The University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
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ALCAM: A Novel Surface Marker on EpCAMlow Circulating Tumor Cells. Biomedicines 2022; 10:biomedicines10081983. [PMID: 36009530 PMCID: PMC9405826 DOI: 10.3390/biomedicines10081983] [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: 06/25/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Current strategies in circulating tumor cell (CTC) isolation in pancreatic cancer heavily rely on the EpCAM and cytokeratin cell status. EpCAM is generally not considered a good marker given its transitory change during Epithelial to Mesenchymal Transition (EMT) or reverse EMT. There is a need to identify other surface markers to capture the complete repertoire of PDAC CTCs. The primary objective of the study is to characterize alternate surface biomarkers to EpCAM on CTCs that express low or negligible levels of surface EpCAM in pancreatic cancer patients. Methods: Flow cytometry and surface mass spectrometry were used to identify proteins expressed on the surface of PDAC CTCs in culture. CTCs were grown under conditions of attachment and in co-culture with naïve neutrophils. Putative biomarkers were then validated in GEMMs and patient samples. Results: Surface proteomic profiling of CTCs identified several novel protein biomarkers. ALCAM was identified as a novel robust marker in GEMM models and in patient samples. Conclusions: We identified several novel surface biomarkers on CTCs expressed under differing conditions of culture. ALCAM was validated and identified as a novel alternate surface marker on EpCAMlow CTCs.
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10
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Luo K, Wang X, Zhang X, Liu Z, Huang S, Li R. The Value of Circulating Tumor Cells in the Prognosis and Treatment of Pancreatic Cancer. Front Oncol 2022; 12:933645. [PMID: 35860591 PMCID: PMC9293050 DOI: 10.3389/fonc.2022.933645] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/31/2022] [Indexed: 12/21/2022] Open
Abstract
In the past few decades, tumor diagnosis and treatment theory have developed in a variety of directions. The number of people dying from pancreatic cancer increases while the mortality rate of other common tumors decreases. Traditional imaging methods show the boundaries of pancreatic tumor, but they are not sufficient to judge early micrometastasis. Although carcinoembryonic antigen (CEA) and carbohydrate antigen19-9 (CA19-9) have the obvious advantages of simplicity and minimal invasiveness, these biomarkers obviously lack sensitivity and specificity. Circulating tumor cells (CTCs) have attracted attention as a non-invasive, dynamic, and real-time liquid biopsy technique for analyzing tumor characteristics. With the continuous development of new CTCs enrichment technologies, substantial progress has been made in the basic research of CTCs clinical application prospects. In many metastatic cancers, CTCs have been studied as an independent prognostic factor. This article reviews the research progress of CTCs in the treatment and prognosis of pancreatic cancer.
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11
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Chapin WJ, Till JE, Hwang WT, Eads JR, Karasic TB, O'Dwyer PJ, Schneider CJ, Teitelbaum UR, Romeo J, Black TA, Christensen TE, Redlinger Tabery C, Anderson A, Slade M, LaRiviere M, Yee SS, Reiss KA, O'Hara MH, Carpenter EL. Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma. JCO Precis Oncol 2022; 6:e2200060. [PMID: 35939771 PMCID: PMC9384952 DOI: 10.1200/po.22.00060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/24/2022] [Accepted: 06/15/2022] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.
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Affiliation(s)
- William J. Chapin
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jacob E. Till
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA
| | - Jennifer R. Eads
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Thomas B. Karasic
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Peter J. O'Dwyer
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Charles J. Schneider
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Ursina R. Teitelbaum
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Janae Romeo
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Taylor A. Black
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Theresa E. Christensen
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Colleen Redlinger Tabery
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | | | | | - Michael LaRiviere
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Stephanie S. Yee
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kim A. Reiss
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Mark H. O'Hara
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Erica L. Carpenter
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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12
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Chen J, Wang H, Zhou L, Liu Z, Tan X. A combination of circulating tumor cells and CA199 improves the diagnosis of pancreatic cancer. J Clin Lab Anal 2022; 36:e24341. [PMID: 35334495 PMCID: PMC9102772 DOI: 10.1002/jcla.24341] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/29/2022] [Accepted: 02/27/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to the lack of effective screening tests. CA199, the standard biomarker for PDAC management, is not sufficiently reliable for early diagnosis. This prospective study aimed to evaluate whether circulating tumor cells (CTCs) could complement or perform better than CA199 in determining PDAC. METHODS A total of 168 blood samples were collected from 80 patients with PDAC, 32 patients with acute pancreatitis, 22 patients with benign pancreatic masses, and 34 healthy donors. CTCs were detected by a novel system combining negative enrichment with immunostaining and fluorescence in situ hybridization (NE-imFISH). Next, ROC curves and AUC analyses were conducted to assess diagnostic abilities of CA199, CTCs, and the combination of the two biomarkers in PDAC. RESULTS CTCs were stained as CD45-/DAPI+/CEP8 ≥3. With 2 CTCs/3.2 ml as the cut-off value, the sensitivity/specificity of the CTC number was 0.76/0.94, which was comparable to that of CA199 (0.78/0.83; Delong test p = 0.3360). Improved performance was achieved through a logistic regression model integrating CA199 and CTC number (AUCCTC+CA199 = 0.95, AUCCA199 = 0.80, AUCCTC number = 0.85; Delong test p vs . CA199 < 0.0001 and p vs . CTC number = 0.0002). CTC subtype was inferior to CTC number as a diagnostic marker (AUCCTC subtype = 0.73; Delong test p vs . CTC number < 0.0001). CONCLUSION The dual-marker panel consisting of CA199 and CTC number can significantly improve upon the diagnostic performance of CA199 alone, highlighting the promising clinical utilization as an effective strategy for PDAC surveillance.
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Affiliation(s)
- Junliang Chen
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Huaitao Wang
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Lei Zhou
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Zhihao Liu
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Xiaodong Tan
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
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13
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Exploring the Clinical Utility of Pancreatic Cancer Circulating Tumor Cells. Int J Mol Sci 2022; 23:ijms23031671. [PMID: 35163592 PMCID: PMC8836025 DOI: 10.3390/ijms23031671] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type, characterized by a dismal prognosis due to late diagnosis, frequent metastases, and limited therapeutic response to standard chemotherapy. Circulating tumor cells (CTCs) are a rare subset of tumor cells found in the blood of cancer patients. CTCs has the potential utility for screening, early and definitive diagnosis, prognostic and predictive assessment, and offers the potential for personalized management. However, a gold-standard CTC detection and enrichment method remains elusive, hindering comprehensive comparisons between studies. In this review, we summarize data regarding the utility of CTCs at different stages of PDAC from early to metastatic disease and discuss the molecular profiling and culture of CTCs. The characterization of CTCs brings us closer to defining the specific CTC subpopulation responsible for metastasis with the potential to uncover new therapies and more effective management options for PDAC.
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14
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Wang X, Hu L, Yang X, Chen F, Xu H, Yu H, Song Z, Fei J, Zhong Z. Clinical prognostic value of circulating tumor cells in the treatment of pancreatic cancer with gemcitabine chemotherapy. Exp Ther Med 2021; 22:1140. [PMID: 34504586 PMCID: PMC8394002 DOI: 10.3892/etm.2021.10574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 07/06/2021] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant tumor type with a high early metastasis rate and no obvious symptoms. Gemcitabine is a first-line chemotherapeutic drug for PC. Since there is no distinct method to determine the efficacy of chemotherapy with gemcitabine in patients with PC, the purpose of the present study was to determine whether positivity for circulating tumor cells (CTCs) in patients with advanced PC is associated with response to gemcitabine chemotherapy and to explore whether CTCs may be used as a predictor of prognosis of patients with advanced PC undergoing chemotherapy. First, immunomagnetic microspheres (magnetic beads; MIL) were prepared to detect CTCs. The patients' clinical characteristics and survival data, as well as efficacy and adverse effects of chemotherapy, were prospectively obtained and their association with CTCs was analyzed. The results indicated that CTC-positive patients with advanced PC had a higher probability of developing resistance to gemcitabine chemotherapy than CTC-negative patients. Survival in the CTC-negative group was significantly higher than in the CTC-positive group (χ2=14.58, P<0.001). CTC-positive patients with advanced PC also had shorter progression-free survival (PFS) after chemotherapy with gemcitabine (P=0.01). In conclusion, CTC-positive patients with PC are more likely to develop gemcitabine resistance, have poor PFS and low incidence of thrombocytopenia. CTCs are expected to become a prognostic indicator for chemotherapy response in patients with PC.
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Affiliation(s)
- Xiaoguang Wang
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Lingyu Hu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Xiaodan Yang
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Fei Chen
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Haokai Xu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Haitao Yu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Zhengwei Song
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Jianguo Fei
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Zhengxiang Zhong
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
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15
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Zhu P, Liu HY, Liu FC, Gu FM, Yuan SX, Huang J, Pan ZY, Wang WJ. Circulating Tumor Cells Expressing Krüppel-Like Factor 8 and Vimentin as Predictors of Poor Prognosis in Pancreatic Cancer Patients. Cancer Control 2021; 28:10732748211027163. [PMID: 34378430 PMCID: PMC8361509 DOI: 10.1177/10732748211027163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) with an epithelial-mesenchymal transition phenotype in peripheral blood may be a useful marker of carcinomas with poor prognosis. The aim of this study was to determine the prognostic significance of CTCs expressing Krüppel-like factor 8 (KLF8) and vimentin in pancreatic cancer (PC). METHODS CTCs were isolated by immunomagnetic separation from the peripheral blood of 40 PC patients before undergoing surgical resection. Immunocytochemistry was performed to identify KLF8+ and vimentin+ CTCs. The associations between CTCs and time to recurrence (TTR), clinicopathologic factors, and survival were assessed. Univariate and multivariate analyzes were performed to identify risk factors. RESULTS Patients with CTCs (n = 30) had a higher relapse rate compared to those without (n = 10) (70.0% vs 20.0%; P < 0.01). The proportion of KLF8+/vimentin+ CTCs to total CTCs was inversely related to TTR (r = -0.646; P < 0.01); TTR was reduced in patients with > 50% of CTCs identified as KLF8+/vimentin+ (P < 0.01). Independent risk factors for recurrence were perineural invasion and > 50% KLF8+/vimentin+ CTCs (both P < 0.05). CONCLUSION Poor prognosis can be predicted in PC patients when > 50% of CTCs are positive for KLF8 and vimentin.
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Affiliation(s)
- Peng Zhu
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hui-Ying Liu
- Department of Biotherapy, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fu-Chen Liu
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fang-Ming Gu
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Sheng-Xian Yuan
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jian Huang
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Ze-Ya Pan
- Department of Hepatic Surgery (III), Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wei-Jun Wang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
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16
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Al-Shaheri FN, Alhamdani MSS, Bauer AS, Giese N, Büchler MW, Hackert T, Hoheisel JD. Blood biomarkers for differential diagnosis and early detection of pancreatic cancer. Cancer Treat Rev 2021; 96:102193. [PMID: 33865174 DOI: 10.1016/j.ctrv.2021.102193] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is currently the most lethal tumor entity and case numbers are rising. It will soon be the second most frequent cause of cancer-related death in the Western world. Mortality is close to incidence and patient survival after diagnosis stands at about five months. Blood-based diagnostics could be one crucial factor for improving this dismal situation and is at a stage that could make this possible. Here, we are reviewing the current state of affairs with its problems and promises, looking at various molecule types. Reported results are evaluated in the overall context. Also, we are proposing steps toward clinical utility that should advance the development toward clinical application by improving biomarker quality but also by defining distinct clinical objectives and the respective diagnostic accuracies required to achieve them. Many of the discussed points and conclusions are highly relevant to other solid tumors, too.
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Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany.
| | - Mohamed S S Alhamdani
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Nathalia Giese
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Markus W Büchler
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
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17
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Ding P, Wang Z, Wu Z, Zhu W, Liu L, Sun N, Pei R. Aptamer-based nanostructured interfaces for the detection and release of circulating tumor cells. J Mater Chem B 2021; 8:3408-3422. [PMID: 32022083 DOI: 10.1039/c9tb02457c] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Analysis of circulating tumor cells (CTCs) can provide significant clinical information for tumors, which has proven to be helpful for cancer diagnosis, prognosis monitoring, treatment efficacy, and personalized therapy. However, CTCs are an extremely rare cell population, which challenges the isolation of CTCs from patient blood. Over the last few decades, many strategies for CTC detection have been developed based on the physical and biological properties of CTCs. Among them, nanostructured interfaces have been widely applied as CTC detection platforms to overcome the current limitations associated with CTC capture. Furthermore, aptamers have attracted significant attention in the detection of CTCs due to their advantages, including good affinity, low cost, easy modification, excellent stability, and low immunogenicity. In addition, effective and nondestructive release of CTCs can be achieved by aptamer-mediated methods that are used under mild conditions. Herein, we review some progress in the detection and release of CTCs through aptamer-functionalized nanostructured interfaces.
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Affiliation(s)
- Pi Ding
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
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18
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Preoperative CTC-Detection by CellSearch ® Is Associated with Early Distant Metastasis and Impaired Survival in Resected Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13030485. [PMID: 33513877 PMCID: PMC7865868 DOI: 10.3390/cancers13030485] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/23/2022] Open
Abstract
In patients with presumed pancreatic ductal adenocarcinoma (PDAC), biomarkers that may open for personalised, risk-adapted treatment are lacking. The study analysed the impact of CTCs-presence on the patterns of recurrence and survival in 98 patients resected for PDAC with 5-10 years of follow-up. Preoperative samples were analysed by the CellSearch® system for EpCAM+/DAPI+/CK+/CD45-CTCs. CTCs were detected in 7 of the 98 patients. CTCs predicted a significantly shorter median disease-free survival (DFS) of 3.3 vs. 9.2 months and a median cancer specific survival (CSS)of 6.3 vs. 18.5 months. Relapse status was confirmed by imaging for 87 patients. Of these, 58 patients developed distant metastases (DM) and 29 developed isolated local recurrence (ILR) as the first sign of cancer relapse. All patients with CTCs experienced DM. pN-status and histological grade >2 were other independent risk factors for DM, but only CTCs predicted significantly shorter cancer-specific, disease-free and post-recurrence survival. Preoperative parameters did not affect clinical outcome. We conclude that CTC presence in resected PDAC patients predicted early distant metastasis and impaired survival. Preoperative CTCs alone or in combination with histopathological factors may guide initial treatment decisions in patients with resectable PDAC in the future.
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19
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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] [Key Words] [MESH Headings] [Grants] [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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MESH Headings
- Aged
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Pancreatic Ductal/blood
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Humans
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Neoplastic Cells, Circulating/pathology
- Prognosis
- Survival Rate
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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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20
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Pang TCY, Po JW, Becker TM, Goldstein D, Pirola RC, Wilson JS, Apte MV. Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications. Pancreatology 2021; 21:103-114. [PMID: 33309014 DOI: 10.1016/j.pan.2020.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. METHODS A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. RESULTS The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood. CONCLUSIONS CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.
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Affiliation(s)
- Tony C Y Pang
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Joseph W Po
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Therese M Becker
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia
| | - David Goldstein
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Romano C Pirola
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia.
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21
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Konno N, Suzuki R, Takagi T, Sugimoto M, Asama H, Sato Y, Irie H, Hikichi T, Ohira H. Clinical utility of a newly developed microfluidic device for detecting circulating tumor cells in the blood of patients with pancreatico-biliary malignancies. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:115-124. [PMID: 33090657 DOI: 10.1002/jhbp.850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The development of an optimal screening method is required to improve the prognosis of pancreatico-biliary (PB) cancers. A recently developed microfluidic device achieved a high diagnostic yield by detecting circulating tumor cells (CTCs) in the blood of cancer patients. We conducted this study to investigate the clinical utility of measuring CTCs in peripheral venous blood to diagnose PB cancer. METHODS Sixty-three subjects were enrolled in this study (29 with pancreatic cancer [PC], 19 with biliary cancer [BC] and 16 non-tumor controls). Using a microfluidic chip device and image analyzer, circulating blood cells were selected based on their size and immunocytochemistry staining pattern. The primary endpoint was the diagnostic accuracy of CTCs with regard to distinguishing between PB cancer patients and controls. We divided all cases into the training set (n = 32) and validation set (n = 31). The diagnostic accuracy of CTCs, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) were analyzed. RESULTS In both the training set and validation set, CTCs showed the highest diagnostic accuracy (training set: CTCs 90.6%, CA19-9 90.6%, CEA 65.6%, validation set: CTCs 87.5%, CA19-9 78.1%, CEA 81.2). Regarding non-metastatic PC (cStage I-III, n = 11), CTCs also had the highest diagnostic accuracy among the three markers tested (CTCs: 84.6%, CA19-9:80.7%, CEA 73.0%). CONCLUSIONS A newly developed microfluidic device could diagnose PB cancers by detecting CTCs. This trial was registered with the UMIN Clinical Trials Registry, no. UMIN000029808.
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Affiliation(s)
- Naoki Konno
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Rei Suzuki
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tadayuki Takagi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mitsuru Sugimoto
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroyuki Asama
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuki Sato
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroki Irie
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Takuto Hikichi
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12123774. [PMID: 33333841 PMCID: PMC7765300 DOI: 10.3390/cancers12123774] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.
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23
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Park K, Lew D, Chapman C, Wachsman A, Bloom M, Bancila L, Perry R, Wang Q, Jamil L, Pandol S, Lo S. Feasibility and safety study of 22-gauge endoscopic ultrasound (EUS) needles for portal vein sampling in a swine model. Endosc Int Open 2020; 8:E1717-E1724. [PMID: 33140030 PMCID: PMC7581479 DOI: 10.1055/a-1264-7206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/20/2020] [Indexed: 11/09/2022] Open
Abstract
Background and study aims Endoscopic ultrasound (EUS) has been used for portal vein sampling in patients with pancreaticobiliary cancers for enumerating circulating tumor cells but is not yet a standard procedure. Further evaluation is needed to refine the methodology. Therefore, we evaluated the feasibility and safety of 19-gauge (19G) versus a 22-gauge (22 G) EUS fine-needle aspiration needles for portal vein sampling in a swine model. Methods Celiotomy was performed on two farm pigs. Portal vein sampling occurred transhepatically. We compared 19 G and 22 G needles coated interiorly with saline, heparin or ethylenediaminetetraacetic acid (EDTA). Small- (10 mL) and large- (25 mL) volume blood collections were evaluated. Two different collection methods were tested: direct-to-vial and suction syringe. A bleeding risk trial for saline-coated 19 G and 22 G needles was performed by puncturing the portal vein 20 times. Persistent bleeding after 3 minutes was considered significant. Results All small-volume collection trials were successful except for 22 G saline-coated needles with direct-to-vial method. All large-volume collection trials were successful when using suction syringe; direct-to-vial method for both 19 G and 22 G needles were unsuccessful. Collection times were shorter for 19 G vs. 22 G needles for both small and large-volume collections ( P < 0.05). Collection times for saline-coated 22 G needles were longer compared to heparin/EDTA-coated ( P < 0.05). Bleeding occurred in 10 % punctures with 19 G needles compared to 0 % with 22 G needles. Conclusion The results of this animal study demonstrate the feasibility and the safety of using 22 G needles for portal vein sampling and can form the basis for a pilot study in patients.
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Affiliation(s)
- Kenneth Park
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Daniel Lew
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Christopher Chapman
- University of Chicago Medical Center, Center for Endoscopic Research and Therapeutics, Chicago, Illinois, United States
| | - Ashley Wachsman
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Matthew Bloom
- Cedars-Sinai Medical Center – Surgery, Los Angeles, California, United States
| | - Liiana Bancila
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Rachel Perry
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Qiang Wang
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Laith Jamil
- William Beaumont Hospital – Royal Oak, Gastroenterology and Hepatology, Royal Oak, Michigan, United States
| | - Stephen Pandol
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
| | - Simon Lo
- Cedars-Sinai Medical Center, Division of Digestive Diseases, Los Angeles, California
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24
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Ahrens TD, Bang-Christensen SR, Jørgensen AM, Løppke C, Spliid CB, Sand NT, Clausen TM, Salanti A, Agerbæk MØ. The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis. Front Cell Dev Biol 2020; 8:749. [PMID: 32984308 PMCID: PMC7479181 DOI: 10.3389/fcell.2020.00749] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/17/2020] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.
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Affiliation(s)
- Theresa D. Ahrens
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sara R. Bang-Christensen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
| | | | - Caroline Løppke
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Charlotte B. Spliid
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Nicolai T. Sand
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas M. Clausen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ali Salanti
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mette Ø. Agerbæk
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
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25
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Hasanain A, Blanco BA, Yu J, Wolfgang CL. The importance of circulating and disseminated tumor cells in pancreatic cancer. Surg Open Sci 2020; 1:49-55. [PMID: 32754693 PMCID: PMC7391911 DOI: 10.1016/j.sopen.2019.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/24/2019] [Accepted: 08/30/2019] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer is a lethal disease in a large part due to the systemic nature at the time of diagnosis. In those patients who undergo a potentially curative resection of pancreatic cancer, the overwhelming majority will have systemic relapse. Circulating tumor cells are an important mediator of the development of metastases. Circulating tumor cells have been identified in patients with clinically localized resectable pancreatic cancer and exist as several phenotypes. Mesenchymal and stem cell-like phenotypes of circulating tumor cells predict early recurrence and worse survival. This review focuses on the current understanding of circulating tumor cells in pancreatic cancer and how this information can be used in developing more effective therapy in the future.
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Affiliation(s)
- Alina Hasanain
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| | | | - Jun Yu
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| | - Christopher L Wolfgang
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
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26
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Okazaki M, Yamaguchi T, Tajima H, Fushida S, Ohta T. Platelet adherence to cancer cells promotes escape from innate immune surveillance in cancer metastasis. Int J Oncol 2020; 57:980-988. [PMID: 32945350 DOI: 10.3892/ijo.2020.5102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 07/07/2020] [Indexed: 11/05/2022] Open
Abstract
The impacts of post‑operative abdominal infectious complications increase hematogenous distant metastasis and result in poor long‑term survival after curative resection. Even if curative resection can be performed, the presence of circulating tumor cells is affected. The liver, the most common site of metastases, is an important organ in innate immune surveillance. However, the molecular mechanisms of distant hematogenous metastasis are not yet fully known. Platelets are crucial components in the tumor microenvironment that function to promote tumor progression and metastasis. The purpose of this study was to identify the effect of platelets on escape from innate immune surveillance in post‑operative abdominal infectious complications. Platelet adherence was assessed by co‑culturing human pancreatic cancer cells including transforming growth factor (TGF‑β)‑treated BxPC‑3. CD44 isoform, transcription factors and epithelial‑mesenchymal transition markers were examined using western blotting. We also assessed whether cancer cells surrounded by activated platelets could escape from innate immune surveillance, using infectious and non‑infectious mouse models injected intraperitoneally with LPS. Platelets were found to preferentially adhere to mesenchymal cells rather than epithelial cells. BxPC‑3 epithelial cells showed upregulation of CD44‑variant and epithelial splicing regulatory protein 1 (ESRP‑1) expression. However, Panc‑1 mesenchymal cells and TGF‑β‑treated BxPC‑3 cells showed upregulation of CD44‑standard and zinc finger E‑box‑binding homeobox 1 (ZEB‑1) expression and a reduction in ESRP‑1. In the non‑infectious model, cancer cells were not found in the liver. In the infectious model, although epithelial cells without platelet adhesion were in an apoptotic state, mesenchymal cells showed many viable cancer cells surrounded by activated platelets. Cancer cells were suggested to have phenotypic plasticity through the switching of CD44 isoforms. Mesenchymal cells, which express CD44‑standard, could escape from immune surveillance by becoming surrounded by adhered activated platelets. Therefore, it may be necessary to administer antiplatelet agents to prevent distant hematogenous metastasis when post‑operative abdominal infectious complications occur.
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Affiliation(s)
- Mitsuyoshi Okazaki
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
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27
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Hugenschmidt H, Labori KJ, Brunborg C, Verbeke CS, Seeberg LT, Schirmer CB, Renolen A, Borgen EF, Naume B, Wiedswang G. Circulating Tumor Cells are an Independent Predictor of Shorter Survival in Patients Undergoing Resection for Pancreatic and Periampullary Adenocarcinoma. Ann Surg 2020; 271:549-558. [PMID: 30216219 DOI: 10.1097/sla.0000000000003035] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE We evaluated the prognostic impact of circulating tumor cells (CTCs) for patients with presumed resectable pancreatic and periampullary cancers. SUMMARY OF BACKGROUND DATA Initial treatment decisions for this group are currently taken without a reliable prognostic marker. The CellSearch system allows standardized CTC-testing and has shown excellent specificity and prognostic value in other applications. METHODS Preoperative blood samples from 242 patients between September 2009 and December 2014 were analyzed. One hundred seventy-nine patients underwent tumor resection, of whom 30 with stage-I tumors and duodenal cancer were assigned to the low-risk group, and the others to the high-risk group. Further 33 had advanced disease, 30 benign histology. Observation ended in December 2016. Cancer-specific survival (CSS) and disease-free survival (DFS) were calculated by log-rank and Cox regression. RESULTS CTCs (CTC-positive; ≥1 CTC/7.5 mL) were detected in 6.8% (10/147) of the high-risk patients and 6.2% (2/33) with advanced disease. No CTCs (CTC-negative) were detected in the low-risk patients or benign disease. In high-risk patients, median CSS for CTC-positive versus CTC-negative was 8.1 versus 20.0 months (P < 0.0001), and DFS 4.0 versus 10.5 months (P < 0.001). Median CSS in advanced disease was 7.7 months. Univariate hazard ratio (HR) of CTC-positivity was 3.4 (P < 0.001). In multivariable analysis, CTC-status remained independent (HR: 2.4, P = 0.009) when corrected for histological type (HR: 2.7, P = 0.030), nodal status (HR: 1.7, P = 0.016), and vascular infiltration (HR: 1.7, P = 0.001). CONCLUSION Patients testing CTC-positive preoperatively showed a detrimental outcome despite successful tumor resections. Although the low CTC-rate seems a limiting factor, results indicate high specificity. Thus, preoperative analysis of CTCs by this test may guide treatment decisions and warrants further testing in clinical trials.
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Affiliation(s)
- Harald Hugenschmidt
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Transplantation Surgery, Division of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway
| | - Knut Jørgen Labori
- Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway
| | - Cathrine Brunborg
- Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway
| | - Caroline Sophie Verbeke
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Lars Thomas Seeberg
- Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway.,Department of Gastrointestinal Surgery, Vestfold Hospital Trust, Tønsberg, Norway
| | | | - Anne Renolen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | | | - Bjørn Naume
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Gro Wiedswang
- Department of GI-Surgery, Division of Surgery and Oncology, Oslo University Hospital, Oslo, Norway
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Wang Y, Yu X, Hartmann D, Zhou J. Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis. HPB (Oxford) 2020; 22:660-669. [PMID: 31786054 DOI: 10.1016/j.hpb.2019.11.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/28/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND It has been shown that circulating tumor cells in peripheral blood can be used to predict survival in patients with breast, prostate and other epithelial tumors. In the present study, we performed a meta-analysis to evaluate the prognostic role of circulating tumor cells (CTCs) in patients with pancreatic cancer. METHODS A systematic literature search of the databases was conducted from the inception to Jul 20, 2019. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated under a fixed or random effect model. RESULTS A total of 19 studies with 1320 confirmed individuals were included. Our meta-analysis showed that patients in the CTC-positive group had a significantly shorter overall survival (OS) (RR = 0.47, 95%CI = 0.33-0.61, P < 0.001) and progression-free survival (PFS) (P = 0.003) than CTC-negative patients. Moreover, subgroup analysis by ethnicity indicated that CTC-positive patients had a significantly shorter OS in both Asian and Western populations. Further subgroup analysis by detection methods, treatments, and Tumor Node Metastasis (TNM) stages also indicated that CTC-positive patients were associated with significant decreases in both OS and PFS in most subgroups. CONCLUSION Our meta-analysis indicates that CTC-positive patients have a worse OS and PFS than CTC-negative patients, which suggests that CTCs may act as predictive biomarkers for pancreatic cancer patients before treatment.
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Affiliation(s)
- Yang Wang
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China
| | - Xiaojin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar der Technischen Universitat Munchen, Munchen, 81675, Germany
| | - Jiahua Zhou
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China.
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29
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Yu Q, Yao Y, Zhu X, Gao Y, Chen Y, Wang R, Xu P, Wei X, Jiang L. In Vivo Flow Cytometric Evaluation of Circulating Metastatic Pancreatic Tumor Cells after High-Intensity Focused Ultrasound Therapy. Cytometry A 2020; 97:900-908. [PMID: 32307867 PMCID: PMC7540359 DOI: 10.1002/cyto.a.24014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/14/2020] [Accepted: 03/09/2020] [Indexed: 12/15/2022]
Abstract
We examined our hypothesis that high-intensity focused ultrasound (HIFU) treatment of pancreatic ductal adenocarcinoma (PDAC) in nude mice models may lead to an increased occurrence of hematogenous metastasis. The human PDAC cell line BxPC-3 transfected with mCherry was implanted into nude mice to establish orthotopic and subcutaneous xenograft (OX and SX) tumor models. Mice were exposed to HIFU when tumor sizes reached approximately 200-300 mm3 . The OX and SX tumor models were monitored continuously for tumor growth characteristics and hematogenous metastasis using in vivo flow cytometric (IVFC) detection of circulating tumor cells (CTCs) from the pancreas. We chose an appropriate mouse model to further examine whether or not HIFU increases the potential risk of hematogenous metastasis, using IVFC detection. Our results showed that the CTC number was greater in the OX model than in the SX model. The CTC number in the OX model increased gradually over time, whereas the CTC number in the SX model remained low. Therefore, the OX model was better for studying tumor metastasis by IVFC detection. We found significantly decreased CTC numbers and tumor volume after HIFU ablation. Our results showed the applicability of the PDAC OX tumor model for studying the occurrence of tumor metastasis due to the generation of CTCs. HIFU ablation substantially restricted PDAC hematogenous metastasis and provided effective tumor control locally. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals Inc., on behalf of International Society for Advancement of Cytometry.
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Affiliation(s)
- Qian Yu
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
| | - Yijing Yao
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
| | - Xi Zhu
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China
| | - Yihui Gao
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
| | - Yini Chen
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
| | - Rui Wang
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
| | - Pingping Xu
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
| | - Xunbin Wei
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.,Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, 100083, People's Republic of China
| | - Lixin Jiang
- Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People's Republic of China.,Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People's Republic of China
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30
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Wu J, Raba K, Guglielmi R, Behrens B, Van Dalum G, Flügen G, Koch A, Patel S, Knoefel WT, Stoecklein NH, Neves RPL. Magnetic-Based Enrichment of Rare Cells from High Concentrated Blood Samples. Cancers (Basel) 2020; 12:E933. [PMID: 32290064 PMCID: PMC7225976 DOI: 10.3390/cancers12040933] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/30/2020] [Accepted: 04/08/2020] [Indexed: 12/12/2022] Open
Abstract
Here, we tested two magnetic-bead based systems for the enrichment and detection of rare tumor cells in concentrated blood products. For that, the defined numbers of cells from three pancreatic cancer cell lines were spiked in 108 peripheral blood mononuclear cells (PBMNCs) concentrated in 1 mL, mimicking diagnostic leukapheresis (DLA) samples, and samples were processed for circulating tumor cells (CTC) enrichment with the IsoFlux or the KingFisher systems, using different types of magnetic beads from the respective technology providers. Beads were conjugated with different anti-EpCAM and MUC-1 antibodies. Recovered cells were enumerated and documented by fluorescent microscopy. For the IsoFlux system, best performance was obtained with IsoFlux CTC enrichment kit, but these beads compromised the subsequent immunofluorescence staining. For the KingFisher system, best recoveries were obtained using Dynabeads Biotin Binder beads. These beads also allowed one to capture CTCs with different antibodies and the subsequent immunofluorescence staining. KingFisher instrument allowed a single and streamlined protocol for the enrichment and staining of CTCs that further prevented cell loss at the enrichment/staining interface. Both IsoFlux and KingFisher systems allowed the enrichment of cell line cells from the mimicked-DLA samples. However, in this particular experimental setting, the recovery rates obtained with the KingFisher system were globally higher, the system was more cost-effective, and it allowed higher throughput.
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Affiliation(s)
- Junhao Wu
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Katharina Raba
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Rosa Guglielmi
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Bianca Behrens
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Guus Van Dalum
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Georg Flügen
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Andreas Koch
- Thermo Fisher Scientific, Postfach 200152, Frankfurter Str. 129B, 64293 Darmstadt, Germany;
| | - Suraj Patel
- Thermo Fisher Scientific, 3 Fountain Drive, Inchinnan, Renfrew PA4 9RF, UK;
| | - Wolfram T. Knoefel
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Nikolas H. Stoecklein
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
| | - Rui P. L. Neves
- Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; (J.W.); (R.G.); (B.B.); (G.V.D.); (G.F.); (W.T.K.)
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Circulating tumor cell as the functional aspect of liquid biopsy to understand the metastatic cascade in solid cancer. Mol Aspects Med 2020; 72:100816. [PMID: 31377345 DOI: 10.1016/j.mam.2019.07.008] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/26/2019] [Accepted: 07/31/2019] [Indexed: 12/19/2022]
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Yang C, Xia BR, Jin WL, Lou G. Circulating tumor cells in precision oncology: clinical applications in liquid biopsy and 3D organoid model. Cancer Cell Int 2019; 19:341. [PMID: 31866766 PMCID: PMC6918690 DOI: 10.1186/s12935-019-1067-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022] Open
Abstract
Circulating tumor cells (CTCs) are a rare subset of cells found in the blood of patients with solid tumors, which function as a seed for metastases. Cancer cells metastasize through the bloodstream either as single migratory CTCs or as multicellular groupings-CTC clusters. The CTCs preserve primary tumor heterogeneity and mimic tumor properties, and may be considered as clinical biomarker, preclinical model, and therapeutic target. The potential clinical application of CTCs is being a component of liquid biopsy. CTCs are also good candidates for generating preclinical models, especially 3D organoid cultures, which could be applied in drug screening, disease modeling, genome editing, tumor immunity, and organoid biobanks. In this review, we summarize current knowledge on the value and promise of evolving CTC technologies and highlight cutting-edge research on CTCs in liquid biopsy, tumor metastasis, and organoid preclinical models. The study of CTCs offers broad pathways to develop new biomarkers for tumor patient diagnosis, prognosis, and response to therapy, as well as translational models accelerating oncologic drug development.
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Affiliation(s)
- Chang Yang
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
| | - Bai-Rong Xia
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
| | - Wei-Lin Jin
- 2Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, 200240 People's Republic of China.,3National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai, 200240 People's Republic of China
| | - Ge Lou
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
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Abstract
PURPOSE OF REVIEW Although liquid biopsies hold significant promise in the management of patients with cancer, peripheral blood analyses remain dependent on the degree of tumor burden with prohibitively low yields until the cancer is widely metastatic. Multiple lines of evidence support a dynamic, spatiotemporal localization of circulating tumor cells (CTCs) supporting specific targeting of vascular compartments, such as the portal vein. This review discusses the literature evaluating the possibility of portal venous blood as a new, potentially higher yield liquid biopsy and the current devices and techniques for endoscopic ultrasound (EUS)-guided portal venous sampling for CTC detection. RECENT FINDINGS Two recent studies in pancreatic cancer have demonstrated that portal venous blood can be safely sampled via EUS and consistently yields significantly higher CTC counts compared with matched peripheral blood. EUS-acquired samples can be used for molecular testing, clinical prognostication, and drug sensitivity analyses. Portal venous CTCs are identified in higher quantity relative to peripheral blood and can be safely obtained via EUS. Further studies are required to demonstrate the clinical utility of EUS-guided portal venous tumor material enrichment and analysis; however, obtaining EUS-guided "liquid biopsies" appears to merit significant consideration for procedural adoption.
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Affiliation(s)
- Christopher G Chapman
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine and Biological Sciences, 5700 S Maryland Ave. MC 8043, Chicago, IL, 60637, USA
| | - Irving Waxman
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine and Biological Sciences, 5700 S Maryland Ave. MC 8043, Chicago, IL, 60637, USA.
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Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers (Basel) 2019; 11:cancers11111659. [PMID: 31717773 PMCID: PMC6895979 DOI: 10.3390/cancers11111659] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. In the last twenty years (1999-2019), 140 articles have contained the key words "Circulating tumor cells, pancreatic cancer, prognosis and diagnosis." Articles were evaluated for the use of CTCs as prognostic markers and their correlation to survival in pancreatic ductal adenocarcinoma (PDAC). In the final selected 17 articles, the CTC detection rate varied greatly between different enrichment methodologies and ranged from 11% to 92%; the majority of studies used the antigen-dependent CellSearch© system for CTC detection. Fifteen of the reviewed studies showed a correlation between CTC presence and a worse overall survival. The heterogeneity of CTC-detection methods and the lack of uniform results hinder a comparison of the evaluated studies. However, CTCs can be detected in pancreatic cancer and harbor a hope to serve as an early detection tool. Larger studies are needed to corroborate CTCs as valid biomarkers in pancreatic cancer.
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Gall TMH, Belete S, Khanderia E, Frampton AE, Jiao LR. Circulating Tumor Cells and Cell-Free DNA in Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:71-81. [PMID: 30558725 DOI: 10.1016/j.ajpath.2018.03.020] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 03/06/2018] [Accepted: 03/26/2018] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer is detected late in the disease process and has an extremely poor prognosis. A blood-based biomarker that can enable early detection of disease, monitor response to treatment, and potentially allow for personalized treatment would be of great benefit. This review analyzes the literature regarding two potential biomarkers, circulating tumor cells (CTCs) and cell-free DNA (cfDNA), with regard to pancreatic ductal adenocarcinoma. The origin of CTCs and the methods of detection are discussed and a decade of research examining CTCs in pancreatic cancer is summarized, including both levels of CTCs and analyzing their molecular characteristics and how they may affect survival in both advanced and early disease and allow for treatment monitoring. The origin of cfDNA is discussed, and the literature over the past 15 years is summarized. This includes analyzing cfDNA for genetic mutations and methylation abnormalities, which have the potential to be used for the detection and prognosis of pancreatic ductal adenocarcinoma. However, the research certainly remains in the experimental stage, warranting future large trials in these areas.
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Affiliation(s)
- Tamara M H Gall
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom.
| | - Samuel Belete
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| | - Esha Khanderia
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| | - Adam E Frampton
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| | - Long R Jiao
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
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Kamyabi N, Bernard V, Maitra A. Liquid biopsies in pancreatic cancer. Expert Rev Anticancer Ther 2019; 19:869-878. [PMID: 31533487 PMCID: PMC6824837 DOI: 10.1080/14737140.2019.1670063] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 09/16/2019] [Indexed: 02/07/2023]
Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a disease of high lethality. Invasive tissue biopsies of primary or metastatic lesions remain the gold standard for diagnosis, but repeated sampling is infeasible. Noninvasive liquid biopsies offer new opportunities for early diagnosis for high-risk cohorts, and for the longitudinal analysis of tumor evolution and progression in patients on therapy. Liquid biopsies can capture tumor-associated components, such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs), each of which provides genomic and molecular information about the underlying PDAC that can potentially inform clinical decisions. Areas covered: Here, we reviewed current knowledge and recent technological advances regarding liquid biopsy in PDAC and mention the pitfalls and benefits in each methodology. We also discuss clinical correlative studies for diagnosis and prognosis in PDAC. Expert opinion:In pancreatic cancer where tissue samples are limited and repeated tissue biopsies are mostly invasive and infeasible, liquid biopsies opened a new window for tumor diagnosis, molecular stratification, and treatment monitoring. While none of the isolation and analysis methods have gained widespread clinical acceptance, it is imperative that the advantages and limitations of each platform for isolation and analysis of tumor associated components are taken into consideration.
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Affiliation(s)
- Nabiollah Kamyabi
- Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, Texas, 77030
| | - Vincent Bernard
- Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, Texas, 77030
| | - Anirban Maitra
- Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, Texas, 77030
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Lee J, Park SS, Lee YK, Norton JA, Jeffrey SS. Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA. Mol Oncol 2019; 13:1623-1650. [PMID: 31243883 PMCID: PMC6670020 DOI: 10.1002/1878-0261.12537] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 06/07/2019] [Accepted: 06/25/2019] [Indexed: 12/22/2022] Open
Abstract
Reliable biomarkers are required to evaluate and manage pancreatic ductal adenocarcinoma. Circulating tumor cells and circulating tumor DNA are shed into blood and can be relatively easily obtained from minimally invasive liquid biopsies for serial assays and characterization, thereby providing a unique potential for early diagnosis, forecasting disease prognosis, and monitoring of therapeutic response. In this review, we provide an overview of current technologies used to detect circulating tumor cells and circulating tumor DNA and describe recent advances regarding the multiple clinical applications of liquid biopsy in pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Jee‐Soo Lee
- Department of Laboratory MedicineHallym University Sacred Heart HospitalAnyangKorea
- Department of Laboratory MedicineSeoul National University College of MedicineSeoulKorea
| | - Sung Sup Park
- Department of Laboratory MedicineSeoul National University College of MedicineSeoulKorea
| | - Young Kyung Lee
- Department of Laboratory MedicineHallym University Sacred Heart HospitalAnyangKorea
- Department of Laboratory MedicineHallym University College of MedicineAnyangKorea
| | - Jeffrey A. Norton
- Department of SurgeryStanford University School of MedicineStanfordCAUSA
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Zhao XH, Wang ZR, Chen CL, Di L, Bi ZF, Li ZH, Liu YM. Molecular detection of epithelial-mesenchymal transition markers in circulating tumor cells from pancreatic cancer patients: Potential role in clinical practice. World J Gastroenterol 2019; 25:138-150. [PMID: 30643364 PMCID: PMC6328963 DOI: 10.3748/wjg.v25.i1.138] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) patients.
METHODS We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule (EpCAM) (E-CTC), the mesenchymal cell markers vimentin and twist (M-CTC), or both (E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.
RESULTS CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage (P < 0.01) and distant metastasis (P < 0.01). Additionally, lymphocyte counts and NLR in patients without CTCs were significantly different from those in patients testing positive for each CTC subpopulation (P < 0.01).
CONCLUSION Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.
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Affiliation(s)
- Xiao-Hui Zhao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zai-Rui Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Chang-Long Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Ling Di
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zhuo-Fei Bi
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zhi-Hua Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Yi-Min Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
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Rofi E, Vivaldi C, Del Re M, Arrigoni E, Crucitta S, Funel N, Fogli S, Vasile E, Musettini G, Fornaro L, Falcone A, Danesi R. The emerging role of liquid biopsy in diagnosis, prognosis and treatment monitoring of pancreatic cancer. Pharmacogenomics 2019; 20:49-68. [PMID: 30520336 DOI: 10.2217/pgs-2018-0149] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/05/2018] [Indexed: 12/11/2022] Open
Abstract
Circulating tumor DNA, circulating tumor cells and tumor-related exosomes may offer new opportunities to provide insights into the biological and clinical characteristics of a neoplastic disease. They represent alternative routes for diagnostic and prognostic purposes, and for predicting and longitudinally monitoring response to treatment and disease progression. Hence, circulating biomarkers represent promising noninvasive tools in the scenario of pancreatic cancer, where neither molecular nor clinical predictors of treatment benefit have been identified yet. This review aims to provide an overview of the current status of circulating biomarker research in pancreatic cancer, and discusses their potential clinical utility to facilitate clinical decision-making.
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Affiliation(s)
- Eleonora Rofi
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Elena Arrigoni
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Stefania Crucitta
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Niccola Funel
- Department of Translational Research & The New Technologies in Medicine & Surgery, University of Pisa, Pisa, Italy
| | - Stefano Fogli
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Gianna Musettini
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Alfredo Falcone
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
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Zeinali M, Murlidhar V, Fouladdel S, Shao S, Zhao L, Cameron H, Bankhead A, Shi J, Cuneo KC, Sahai V, Azizi E, Wicha MS, Hafner M, Simeone DM, Nagrath S. Profiling Heterogeneous Circulating Tumor Cells (CTC) Populations in Pancreatic Cancer Using a Serial Microfluidic CTC Carpet Chip. ADVANCED BIOSYSTEMS 2018; 2. [DOI: 10.1002/adbi.201800228] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Indexed: 01/24/2023]
Abstract
AbstractAlthough isolation of circulating tumor cells (CTCs) from pancreatic adenocarcinoma patients is feasible, investigating their clinical utility has proven less successful than other cancers due to the limitations of epithelial cellular adhesion molecule (EpCAM)‐only based CTC assays. An integrated technology‐ and biology‐based approach using a microfluidic “Carpet Chip” is presented to study the biological relevance of heterogeneous CTC populations. Both epithelial CTCs (EpCs) and epithelial‐to‐mesenchymal transition (EMT)‐like CTCs (EMTCs) are isolated simultaneously from the whole blood of pancreatic cancer (PaCa) patients (n = 35) by separately targeting two surface markers: EpCAM and CD133. Recovery of cancer cell lines spiked into whole blood is ≥97% with >76% purity. Thirty‐four patients had ≥5 EpCs mL−1 and 35 patients had ≥15 EMTCs mL−1. Overall, significantly higher numbers of EMTCs than EpCs are recovered, reflecting the aggressive nature of PaCa. Furthermore, higher numbers of EMTCs are observed in patients with lymph node involvement compared to patients without. Gene expression profiling of CTCs from 17 patients reveals that CXCR1 is significantly upregulated in EpCs, while known stem cell markers POU5F1/Oct‐4 and MYC are upregulated in EMTCs. In conclusion, successful isolation and genomic profiling of heterogeneous CTC populations are demonstrated, revealing genetic signatures relevant to patient outcomes.
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Affiliation(s)
- Mina Zeinali
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Institute for Medical Technology of Heidelberg University & University of Applied Sciences Mannheim Mannheim 68163 Germany
| | - Vasudha Murlidhar
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
| | - Shamileh Fouladdel
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Shimeng Shao
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
| | - Lili Zhao
- Biostatistics Department University of Michigan Ann Arbor MI 48109 USA
| | - Heather Cameron
- Department of Surgery and Molecular and Integrative Physiology University of Michigan 1500 E. Medical Center Drive, 2210B Taubman Center Ann Arbor MI 48109 USA
| | - Armand Bankhead
- Biostatistics Department University of Michigan Ann Arbor MI 48109 USA
- Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI 48109 USA
| | - Jiaqi Shi
- Department of Pathology University of Michigan Ann Arbor MI 48109 USA
| | - Kyle C. Cuneo
- Department of Radiation Oncology University of Michigan Ann Arbor MI 48109 USA
| | - Vaibhav Sahai
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Ebrahim Azizi
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Max S. Wicha
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Mathias Hafner
- Institute for Medical Technology of Heidelberg University & University of Applied Sciences Mannheim Mannheim 68163 Germany
| | - Diane M. Simeone
- Department of Surgery and Molecular and Integrative Physiology University of Michigan 1500 E. Medical Center Drive, 2210B Taubman Center Ann Arbor MI 48109 USA
| | - Sunitha Nagrath
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
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Samandari M, Julia MG, Rice A, Chronopoulos A, Del Rio Hernandez AE. Liquid biopsies for management of pancreatic cancer. Transl Res 2018; 201:98-127. [PMID: 30118658 DOI: 10.1016/j.trsl.2018.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/17/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
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Affiliation(s)
- Mohamadmahdi Samandari
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - María Gil Julia
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Antonios Chronopoulos
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Armando E Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
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Chakraborty S. Electrokinetics with blood. Electrophoresis 2018; 40:180-189. [DOI: 10.1002/elps.201800353] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 11/08/2022]
Affiliation(s)
- Suman Chakraborty
- Department of Mechanical Engineering; Indian Institute of Technology Kharagpur; Kharagpur India
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Ou H, Huang Y, Xiang L, Chen Z, Fang Y, Lin Y, Cui Z, Yu S, Li X, Yang D. Circulating Tumor Cell Phenotype Indicates Poor Survival and Recurrence After Surgery for Hepatocellular Carcinoma. Dig Dis Sci 2018; 63:2373-2380. [PMID: 29926241 DOI: 10.1007/s10620-018-5124-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 05/11/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Circulating tumors cells (CTCs) may be a promising prognostic marker for patients with malignant tumors. However, there are few reports regarding its value for hepatocellular carcinoma (HCC) patients. AIMS To investigate CTCs with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for HCC patients. METHODS Peripheral blood samples were obtained from 165 HCC patients before radical surgery. CTCs were isolated via the CanPatrol CTC enrichment technique and classified using epithelial-mesenchymal transition (EMT) markers. The relationship of CTC phenotype with clinicopathological factors and HCC recurrence in patients was analyzed. RESULTS CTC-positive status (count ≥ 2/5 mL) was found in 70.9% of the 165 HCC patients. Increased CTC number was more common in patients with higher AFP levels, multiple tumors, advanced TNM and BCLC staging, and presence of embolus or microembolus (P < 0.05). CTCs heterogeneity was noted using EMT markers. Mesenchymal CTCs were significantly correlated with high AFP levels, multiple tumors, advanced TNM and BCLC stage, presence of embolus or microembolus, and earlier recurrence (P < 0.05). The presence of mesenchymal CTCs predicted the shortest relapse-free survival, followed by mixed phenotypic CTCs, and then epithelial CTCs (P < 0.001). CONCLUSION CTC phenotype may serve as a prognostic indicator for HCC patients. CTCs assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.
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Affiliation(s)
- Huohui Ou
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yu Huang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Leyang Xiang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Zhanjun Chen
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yinghao Fang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yixiong Lin
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Zhonglin Cui
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Sheng Yu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Xianghong Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Dinghua Yang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
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DiPardo BJ, Winograd P, Court CM, Tomlinson JS. Pancreatic cancer circulating tumor cells: applications for personalized oncology. Expert Rev Mol Diagn 2018; 18:809-820. [PMID: 30099926 DOI: 10.1080/14737159.2018.1511429] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Pancreatic cancer (PC) is a highly lethal disease, in part because of early metastasis, late diagnosis, and limited treatment options. Circulating tumor cells (CTCs) are cancer cells that have achieved the metastatic step of intravasation, and are thus a unique source of biomarkers with potential applications in the staging, prognostication, and treatment of PC. Areas covered: This review describes the use of CTCs in PC, including isolation methods, the significance of CTC enumeration, and studies examining phenotypic and molecular characteristics of CTCs. We also speculate on future directions for PC CTC research such as single-cell analysis and CTC culture. Expert commentary: CTCs represent a potential unique serial source of cancer tissue via a convenient and minimally invasive blood draw. Recent development of isolation methods that allow for the release of viable CTCs with unaltered molecular characteristics has set the stage for single-cell analysis and ex vivo culture. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC.
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Affiliation(s)
- Benjamin J DiPardo
- a Department of Surgery , University of California Los Angeles , Los Angeles , CA , USA.,b Department of Surgery , Greater Los Angeles Veterans Health Administration , Los Angeles , CA , USA
| | - Paul Winograd
- a Department of Surgery , University of California Los Angeles , Los Angeles , CA , USA.,b Department of Surgery , Greater Los Angeles Veterans Health Administration , Los Angeles , CA , USA
| | - Colin M Court
- a Department of Surgery , University of California Los Angeles , Los Angeles , CA , USA.,b Department of Surgery , Greater Los Angeles Veterans Health Administration , Los Angeles , CA , USA
| | - James S Tomlinson
- a Department of Surgery , University of California Los Angeles , Los Angeles , CA , USA.,b Department of Surgery , Greater Los Angeles Veterans Health Administration , Los Angeles , CA , USA
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Abstract
Metastasis contributes to poor prognosis in many types of cancer and is the leading cause of cancer-related deaths. Tumor cells metastasize to distant sites via the circulatory and lymphatic systems. In this review, we discuss the potential of circulating tumor cells for diagnosis and describe the experimental therapeutics that aim to target these disseminating cancer cells. We discuss the advantages and limitations of such strategies and how they may lead to the development of the next generation of antimetastasis treatments.
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Affiliation(s)
- Eric Lin
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
- University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Thong Cao
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, USA
| | - Sunitha Nagrath
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
- University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Michael R. King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, USA
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Lou E, Vogel RI, Teoh D, Hoostal S, Grad A, Gerber M, Monu M, Lukaszewski T, Deshpande J, Linden MA, Geller MA. Assessment of Circulating Tumor Cells as a Predictive Biomarker of Histology in Women With Suspected Ovarian Cancer. Lab Med 2018; 49:134-139. [PMID: 29361118 DOI: 10.1093/labmed/lmx084] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background The clinical assessment of circulating tumor cells (CTCs) as a blood-based biomarker is FDA-approved for use in breast, colorectal, and prostate cancers. The objective of this prospective clinical study was to determine whether pretreatment CTCs are a useful diagnostic biomarker in women with complex pelvic masses. Methods Whole blood was collected from 49 women with newly diagnosed pelvic masses. The presence of CTCs was compared between women with and without ovarian cancer histopathologic diagnosis after surgery using a Chi-squared test. Results CTCs were absent in those with benign disease (0/14), present in 17% (5/29) of patients with a histologic diagnosis of ovarian carcinoma, and present in 80% (4/5) of patients with ovarian metastases from other cancers (P = 0.001). All 5 women with ovarian cancer who had CTCs present presented stage III or IV of the disease (P = 0.13). Conclusions CTCs were more prevalent in patients with metastases to the ovary than in primary ovarian carcinomas.
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Affiliation(s)
- Emil Lou
- Department of Medicine, Division of Hematology, Oncology and Transplantation, Minneapolis, Minnesota
| | - Rachel I Vogel
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
| | - Deanna Teoh
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
| | - Spencer Hoostal
- Department of Medicine, Division of Hematology, Oncology and Transplantation, Minneapolis, Minnesota
| | - Aaron Grad
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
| | - Matthew Gerber
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
| | - Minnu Monu
- Department of Medicine, Division of Hematology, Oncology and Transplantation, Minneapolis, Minnesota
| | - Tomasz Lukaszewski
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
| | - Jaai Deshpande
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
| | - Michael A Linden
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Melissa A Geller
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minneapolis, Minnesota
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48
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Ko J, Bhagwat N, Black T, Yee SS, Na YJ, Fisher S, Kim J, Carpenter EL, Stanger BZ, Issadore D. miRNA Profiling of Magnetic Nanopore-Isolated Extracellular Vesicles for the Diagnosis of Pancreatic Cancer. Cancer Res 2018; 78:3688-3697. [PMID: 29735554 DOI: 10.1158/0008-5472.can-17-3703] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/08/2018] [Accepted: 05/04/2018] [Indexed: 11/16/2022]
Abstract
Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with precancerous lesions in a training set of n = 27 mice and a user-blinded validation set of n = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.Significance: These findings present a panel of extracellular vesicle miRNA blood-based biomarkers that can detect pancreatic cancer at a precancerous stage in a transgenic mouse model. Cancer Res; 78(13); 3688-97. ©2018 AACR.
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Affiliation(s)
- Jina Ko
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Neha Bhagwat
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Taylor Black
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephanie S Yee
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Young-Ji Na
- Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Stephen Fisher
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Junhyong Kim
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Erica L Carpenter
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David Issadore
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania. .,Department of Electrical and Systems Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
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Effenberger KE, Schroeder C, Hanssen A, Wolter S, Eulenburg C, Tachezy M, Gebauer F, Izbicki JR, Pantel K, Bockhorn M. Improved Risk Stratification by Circulating Tumor Cell Counts in Pancreatic Cancer. Clin Cancer Res 2018; 24:2844-2850. [PMID: 29559560 DOI: 10.1158/1078-0432.ccr-18-0120] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/26/2018] [Accepted: 03/16/2018] [Indexed: 12/11/2022]
Affiliation(s)
| | - Cornelia Schroeder
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Annkathrin Hanssen
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Wolter
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Eulenburg
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Tachezy
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Gebauer
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jacob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Maximilian Bockhorn
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Jan YJ, Chen JF, Zhu Y, Lu YT, Chen SH, Chung H, Smalley M, Huang YW, Dong J, Chen LC, Yu HH, Tomlinson JS, Hou S, Agopian VG, Posadas EM, Tseng HR. NanoVelcro rare-cell assays for detection and characterization of circulating tumor cells. Adv Drug Deliv Rev 2018; 125:78-93. [PMID: 29551650 PMCID: PMC5993593 DOI: 10.1016/j.addr.2018.03.006] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 03/08/2018] [Accepted: 03/13/2018] [Indexed: 12/12/2022]
Abstract
Circulating tumor cells (CTCs) are cancer cells shredded from either a primary tumor or a metastatic site and circulate in the blood as the potential cellular origin of metastasis. By detecting and analyzing CTCs, we will be able to noninvasively monitor disease progression in individual cancer patients and obtain insightful information for assessing disease status, thus realizing the concept of "tumor liquid biopsy". However, it is technically challenging to identify CTCs in patient blood samples because of the extremely low abundance of CTCs among a large number of hematologic cells. In order to address this challenge, our research team at UCLA pioneered a unique concept of "NanoVelcro" cell-affinity substrates, in which CTC capture agent-coated nanostructured substrates were utilized to immobilize CTCs with remarkable efficiency. Four generations of NanoVelcro CTC assays have been developed over the past decade for a variety of clinical utilities. The 1st-gen NanoVelcro Chips, composed of a silicon nanowire substrate (SiNS) and an overlaid microfluidic chaotic mixer, were created for CTC enumeration. The 2nd-gen NanoVelcro Chips (i.e., NanoVelcro-LMD), based on polymer nanosubstrates, were developed for single-CTC isolation in conjunction with the use of the laser microdissection (LMD) technique. By grafting thermoresponsive polymer brushes onto SiNS, the 3rd-gen Thermoresponsive NanoVelcro Chips have demonstrated the capture and release of CTCs at 37 and 4 °C respectively, thereby allowing for rapid CTC purification while maintaining cell viability and molecular integrity. Fabricated with boronic acid-grafted conducting polymer-based nanomaterial on chip surface, the 4th-gen NanoVelcro Chips (Sweet chip) were able to purify CTCs with well-preserved RNA transcripts, which could be used for downstream analysis of several cancer specific RNA biomarkers. In this review article, we will summarize the development of the four generations of NanoVelcro CTC assays, and the clinical applications of each generation of devices.
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Affiliation(s)
- Yu Jen Jan
- Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jie-Fu Chen
- Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yi-Tsung Lu
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Szu Hao Chen
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Howard Chung
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Matthew Smalley
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA; CytoLumina Technologies Corp., Los Angeles, CA, USA
| | - Yen-Wen Huang
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA; CytoLumina Technologies Corp., Los Angeles, CA, USA
| | - Jiantong Dong
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Li-Ching Chen
- Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan
| | - Hsiao-Hua Yu
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan
| | - James S Tomlinson
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA; Center for Pancreatic Disease, University of California, Los Angeles, Los Angeles, CA, USA; Department of Surgery, Greater Los Angeles Veteran's Affairs Administration, Los Angeles, CA, USA
| | - Shuang Hou
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Vatche G Agopian
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA; Liver Transplantation and Hepatobiliary Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Edwin M Posadas
- Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA.
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