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Yang J, Li ZX, Song MJ, Han SJ, Yang AJ, Zhang ZP, Sui CS, Qiao JL, Huang WH, He JQ. Prognostic value and therapeutic efficacy of interstitial circulating tumor cells in patients with advanced gastric cancer. World J Clin Oncol 2025; 16:101762. [DOI: 10.5306/wjco.v16.i5.101762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 03/08/2025] [Accepted: 04/08/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND The high mortality rate and recurrence/metastasis remain major challenges in the clinical management of gastric cancer (GC) patients. To optimize treatment stratification and management, there is an urgent need for efficient and non-invasive biomarkers. A meta-analysis on the prognostic role of circulating tumor cells (CTCs) in GC revealed a strong association between CTCs and patient prognosis. Among CTC subtypes, Interstitial CTCs (I-CTCs) exhibited the strongest invasiveness. This study innovatively investigated the expression profile of I-CTCs in advanced GC patients to evaluate their clinical utility.
AIM To evaluate the clinical utility of I-CTCs as a non-invasive prognostic biomarker in advanced GC. To investigate the correlation between I-CTC count thresholds and chemotherapy efficacy in advanced GC patients. To establish the potential of preoperative I-CTC profiling for optimizing treatment stratification and postoperative surveillance.
METHODS This study retrospectively analyzed 59 patients with advanced GC treated at the General Surgery Clinical Medical Center of Gansu Provincial Hospital between October 2019 and October 2020. The expression levels of I-CTCs were measured, and patient survival was monitored. The receiver operating characteristic curve was plotted to determine the optimal cut-off value for I-CTCs expression levels. Based on this cut-off value, 59 GC patients were grouped into positive and negative groups. The differences in clinicopathological characteristics between the two groups were analyzed. Patient survival was follow-up and recorded until October 2022. Plotting survival curves and performing univariate and multifactorial analyses of patient prognostic factors. The Kaplan-Meier method and Cox regression model were used, respectively.
RESULTS A total of 59 patients were included in this study, and receiver operating characteristic curve analysis showed that the best cut-off value for I-CTCs was 5, with an area under the curve of 0.8356 (95%CI: 0.7122-0.9590). The I-CTC count of ≥ 5 defines the positive group, while counts < 5 are classified as the negative group. Positive I-CTCs correlated with the degree of tumor differentiation and disease progression (P < 0.05). 16 of 59 patients received neoadjuvant chemotherapy. There were divided into progressive disease and disease control groups based on response to neoadjuvant chemotherapy. Patients in the I-CTCs-negative group had longer overall survival and disease-free survival than those in the positive group (P < 0.05). Multifactorial analysis revealed that I-CTCs positivity (HR = 13.323, 95%CI: 1.675-105.962, P = 0.014) was an independent risk factor for survival in patients with advanced GC.
CONCLUSION In patients with advanced GC, an I-CTC count of ≥ 5 is associated with both poor prognosis and reduced chemotherapy efficacy. I-CTCs may serve as a valuable preoperative biomarker for predicting the prognosis of advanced GC.
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Affiliation(s)
- Jing Yang
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, Guangdong Province, China
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
| | - Zu-Xi Li
- Department of Peripheral Vascular Intervention, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou 730060, Gansu Province, China
| | - Mei-Juan Song
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Shang-Jun Han
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Ai-Jia Yang
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Ze-Ping Zhang
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Chang-Sheng Sui
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Ji-Lin Qiao
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Wen-Hua Huang
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, Guangdong Province, China
| | - Jun-Qiang He
- Department of General Surgery, Xinhui People’s Hospital of Southern Medical University, Jiangmen 529000, Guangdong Province, China
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Waldron RT, Wang R, Shishido SN, Lugea A, Ibrahim AG, Mason J, Ayres M, Parker SJ, Van Eyk JE, Lo SK, Kuhn P, Pandol SJ. Selective removal of proteins and microvesicles ex vivo from blood of pancreatic cancer patients using bioengineered adsorption filters. Cancer Lett 2025; 614:217546. [PMID: 39952600 PMCID: PMC12010918 DOI: 10.1016/j.canlet.2025.217546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/24/2025] [Accepted: 02/09/2025] [Indexed: 02/17/2025]
Abstract
Metastatic pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with limited efficacious therapeutic options. Recent investigations have provided proof of concept that circulating tumor cells (CTCs) are reduced by purification of PDAC patient blood samples through ExThera Seraph100™ adsorption filters. Whether additional tumorigenic factors are also removed remains inadequately studied. Here, matched whole blood and purified blood samples from seven PDAC patients were analyzed for microparticle and soluble protein content. For microparticle analysis, patient samples were stratified by abundance. Filters markedly reduced ∼200-nm particles when in high abundance. Exosomes, or vesicles ranging from ∼50 to 150-nm were not significantly affected by the purification process. Proteomic analysis of plasma from the whole and purified blood revealed only a limited number of differentially expressed proteins. The complement C1Q proteins were reduced by the purification process, likely due to their heparin binding affinity. In contrast, there was an elevation in cytoplasmic proteins after purification, which may be due to cell destruction. Taken together, this study shows the selective removal of a subfraction of larger (>200 nm) microvesicles and C1Q during blood purification by the Seraph100™. The clinical significance of these findings requires further study.
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Affiliation(s)
- Richard T Waldron
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
| | - Ruoxiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Stephanie N Shishido
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Aurelia Lugea
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Ahmed G Ibrahim
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Jeremy Mason
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA; Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Matthew Ayres
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Sarah J Parker
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Jennifer E Van Eyk
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Simon K Lo
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Peter Kuhn
- Convergent Science Institute for Cancer, Michelson Center, University of Southern California, Los Angeles, CA, 90089, USA; Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA; Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA; Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, 90089, USA
| | - Stephen J Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
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Duhamel L, Schwarz L. Surgical techniques and tumor dissemination: a critical review of the CETUPANC trial on the superior mesenteric artery vs. no-touch approaches. Hepatobiliary Surg Nutr 2025; 14:267-270. [PMID: 40342770 PMCID: PMC12057520 DOI: 10.21037/hbsn-2024-714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/20/2025] [Indexed: 05/11/2025]
Affiliation(s)
- Lola Duhamel
- Department of Digestive Surgery, Rouen University Hospital, Rouen, France
| | - Lilian Schwarz
- Department of Digestive Surgery, Rouen University Hospital, Rouen, France
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Yasui K, Saito T, Ueda S, Shinohara K, Fukami Y, Sano T, Nakanishi H. Sequential Changes in Circulating Tumor Cells in the Peripheral Blood of Pancreatic Cancer Patients with Preoperative Chemotherapy Using a New Immunocytology-Based, Light Microscopic CTC Detection Platform. Diagnostics (Basel) 2025; 15:752. [PMID: 40150094 PMCID: PMC11941569 DOI: 10.3390/diagnostics15060752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/26/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Circulating tumor cells (CTCs) have recently been developed as biomarkers. Several studies have reported on the clinical use of CTCs to assess drug resistance in various cancers. However, sequential and multiple CTC measurements during chemotherapy are relatively rare. We recently reported a transient increase in CTCs early after chemotherapy by sequentially detecting CTCs in a human pancreatic cancer xenograft model in nude mice. Method: In the present study, using a newly developed immunocytology and glass slide-based convenient CTC detection platform, we examined CTC numbers sequentially before, during, and after chemotherapy in the peripheral blood of 14 pancreatic cancer patients, pathological stage (pStage) I-IV, who underwent surgery with preoperative chemotherapy and GS (Gem/S-1) and GnP (Gem/nab-PTX). Results: Among patients with strongly or weakly elevated CTC counts (3-44/5 mL of blood) following GS treatment, four out of six pancreatic cancer patients were judged to have a partial response (PR), and two out of six were deemed to have stable disease (SD) as a clinical response based on the CT image. In contrast, in patients with GnP therapy, three out of four patients showed no CTC response, and these three patients were judged to have progressive disease (PD), while the remaining one patient was judged to have SD in terms of their clinical response. Conclusion: These results suggest that sequential CTC monitoring during preoperative chemotherapy in pancreatic cancer patients can be a helpful liquid biopsy diagnostic tool as a therapeutic marker to predict tumor chemosensitivity and chemoresistance in clinical settings. Further large-scale clinical studies are required to confirm and clarify this hypothesis.
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Affiliation(s)
- Kohei Yasui
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
| | - Takuya Saito
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
| | - Sho Ueda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
| | - Kentaro Shinohara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
| | - Yasuyuki Fukami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
| | - Tsuyoshi Sano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
| | - Hayao Nakanishi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Aichi Medical University, Nagoya 480-1195, Japan; (K.Y.); (S.U.); (K.S.); (Y.F.); (T.S.); (H.N.)
- Laboratory of Clinical Pathology, Okazaki City Hospital, Okazaki 444-0002, Japan
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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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Balaraman AK, Moglad E, Afzal M, Babu MA, Goyal K, Roopashree R, Kaur I, Kumar S, Kumar MR, Chauhan AS, Hemalatha S, Gupta G, Ali H. Liquid biopsies and exosomal ncRNA: Transforming pancreatic cancer diagnostics and therapeutics. Clin Chim Acta 2025; 567:120105. [PMID: 39706249 DOI: 10.1016/j.cca.2024.120105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
Pancreatic cancer is a highly fatal malignancy due to poor early detection rate and resistance to conventional therapies. This review examines the potential for liquid biopsy as a transformative technology to identify diagnostic and therapeutic targets in pancreatic cancer. Specifically, we explore emerging biomarkers such as exosomal non-coding RNAs (ncRNAs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Tumor-derived exosomes contain nucleic acid and protein that reflect the unique molecular landscape of the malignancy and can serve as an alternative diagnostic approach vs traditional biomarkers like CA19-9. Herein we highlight exosomal miRNAs, lncRNAs, and other ncRNAs alongside ctDNA and CTC-based strategies, evaluating their combined ability to improve early detection, disease monitoring and treatment response. Furthermore, the therapeutic implications of ncRNAs such as lncRNA UCA1 and miR-3960 in chemoresistance and progression are also discussed via suppression of EZH2 and PTEN/AKT pathways. Emerging therapeutic strategies that target the immune response, epithelial-mesenchymal transition (EMT) and drug resistance are explored. This review demonstrates a paradigm shift in pancreatic cancer management toward personalized, less invasive and more effective approaches.
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Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya, Selangor 63000, Malaysia
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - M Arockia Babu
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Irwanjot Kaur
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Sachin Kumar
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - MRavi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Ashish Singh Chauhan
- Uttaranchal Institute of Pharmaceutical Sciences, Division of Research and Innovation, Uttaranchal University, India
| | - S Hemalatha
- Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India.
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Götze J, Meißner K, Pereira-Veiga T, Belloum Y, Schneegans S, Kropidlowski J, Gorgulho J, Busch A, Honselmann KC, Schönrock M, Putscher A, Peine S, Nitschke C, Simon R, Spindler V, Izbicki JR, Hackert T, Bokemeyer C, Pantel K, Uzunoglu FG, Sinn M, Wikman H. Identification and characterization of tumor and stromal derived liquid biopsy analytes in pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res 2025; 44:14. [PMID: 39815324 PMCID: PMC11737273 DOI: 10.1186/s13046-024-03262-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 12/19/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND The lack of predictive biomarkers contributes notably to the poor outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer-associated fibroblasts (CAFs) are the key components of the prominent PDAC stroma. Data on clinical relevance of CAFs entering the bloodstream, known as circulating CAFs (cCAFs) are scarce. Here, we developed a combined liquid biopsy assay to detect cCAFs and circulating tumor cells (CTCs) in metastatic PDAC (mPDAC) and other metastatic gastrointestinal malignancies (mGI). In addition, we evaluated plasma hyaluronan (HA) levels as a complementary surrogate biomarker of the stromal extent in patients with PDAC. METHODS A sequential liquid biopsy assay based on a two step-enrichment, combining marker dependent and independent cell enrichment, was established for cCAF and CTC detection and validated in mPDAC and mGI patients. The enriched cells were identified by multiplex immunofluorescence. HA measurement was performed by ELISA on blood samples from healthy blood donors (HD), localized and late-stage PDAC patients. RESULTS cCAFs (≥ 1cCAFs/7.5 mL blood) were detected in 95.4% of mPDAC and in 78.2% of mGI patients, with significantly higher numbers in mPDAC compared to mGI patients (mean number 22.7 vs. 11.0; P = 0.0318). mPDAC patients with ≥ 15 cCAFs/7.5 mL blood had a significant shorter median overall survival (mOS 3.2 months (95% confidence interval (CI) 0.801-5.855) vs. 14.2 months (95% CI 6.055-22.332); P = 0.013), whereby CTC levels were not associated with mOS. In mGI neither cCAFs nor CTCs had a significant impact on OS. HA plasma levels in mPDAC patients were significantly higher compared to HD (mean 123.0 ng/mL vs. 74.45 ng/mL, P = 0.015). High HA in localized and late-stage PDAC were associated with a significantly shorter mOS (mOSlocalized PDAC: 12.6 months vs. 23.5 months (P = 0.008); mOSmPDAC: 1.8 months vs. 5.3 months (P = 0.004)). CONCLUSIONS Our liquid biopsy assay provides robust detection of cCAFs in mPDAC and mGI patients. The measurement of both circulatory stromal parameters, cCAFs and HA, adds valuable clinical information as they are associated with an unfavorable outcome in PDAC. These results highlight that stromal characteristics unique to PDAC could be leveraged to fill the current gap in discovering predictive biomarkers.
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Affiliation(s)
- Julian Götze
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany.
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany.
| | - Kira Meißner
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Thais Pereira-Veiga
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Yassine Belloum
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Svenja Schneegans
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Jolanthe Kropidlowski
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Joao Gorgulho
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Alina Busch
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Kim Christin Honselmann
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Martin Schönrock
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Arne Putscher
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Sven Peine
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Mildred Scheel Cancer Career Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Volker Spindler
- Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob Robert Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Faik Güntaç Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marianne Sinn
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany.
| | - Harriet Wikman
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany.
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8
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Cox M, Vitello DJ, Chawla A. The Current Role of Circulating Tumor DNA in the Management of Pancreatic Cancer. J Gastrointest Cancer 2025; 56:44. [PMID: 39808248 DOI: 10.1007/s12029-024-01129-0] [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] [Accepted: 10/23/2024] [Indexed: 01/16/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer-related death by 2030. Early identification is rare, with a 5-year overall survival (OS) of less than 10%. Advances in the understanding of PDAC tumor biology are needed to improve these outcomes. Circulating tumor DNA (ctDNA) represents a promising novel biomarker in the identification and management of PDAC. Drawn from peripheral blood and analyzed using a variety of techniques, the detection of ctDNA in PDAC has been associated with shorter OS, minimal residual disease presence, and shorter recurrence-free survival. The use of ctDNA has also been examined as an indicator of therapeutic resistance, susceptibility to targeted therapy, and therapeutic response. While promising, ctDNA analysis is limited by its low rates of detection in some settings and lack of predictive ability in others. Many studies examining the utility of ctDNA for the management of PDAC have been relatively small retrospective cohort studies. The current findings will need to be validated by incorporation of ctDNA analysis into cancer registries and larger prospective studies. Given the current, rapid evolution in the field, it is possible that with time, ctDNA will be more routinely incorporated into the clinical management of PDAC.
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Affiliation(s)
- Madison Cox
- Division of Surgical Oncology, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Northwestern Medicine Cancer Centers, Northwestern Medicine Regional Medical Group, Winfield, IL, USA
| | - Dominic J Vitello
- Division of Surgical Oncology, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Northwestern Quality Improvement, Research and Education in Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Akhil Chawla
- Division of Surgical Oncology, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
- Northwestern Medicine Cancer Centers, Northwestern Medicine Regional Medical Group, Winfield, IL, USA.
- Northwestern Quality Improvement, Research and Education in Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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9
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Ma L, Guo H, Zhao Y, Liu Z, Wang C, Bu J, Sun T, Wei J. Liquid biopsy in cancer current: status, challenges and future prospects. Signal Transduct Target Ther 2024; 9:336. [PMID: 39617822 PMCID: PMC11609310 DOI: 10.1038/s41392-024-02021-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/10/2024] [Accepted: 10/14/2024] [Indexed: 12/06/2024] Open
Abstract
Cancer has a high mortality rate across the globe, and tissue biopsy remains the gold standard for tumor diagnosis due to its high level of laboratory standardization, good consistency of results, relatively stable samples, and high accuracy of results. However, there are still many limitations and drawbacks in the application of tissue biopsy in tumor. The emergence of liquid biopsy provides new ideas for early diagnosis and prognosis of tumor. Compared with tissue biopsy, liquid biopsy has many advantages in the diagnosis and treatment of various types of cancer, including non-invasive, quickly and so on. Currently, the application of liquid biopsy in tumor detection has received widely attention. It is now undergoing rapid progress, and it holds significant potential for future applications. Around now, liquid biopsies encompass several components such as circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. In addition, advances in the identification of liquid biopsy indicators have significantly enhanced the possibility of utilizing liquid biopsies in clinical settings. In this review, we will discuss the application, advantages and challenges of liquid biopsy in some common tumors from the perspective of diverse systems of tumors, and look forward to its future development prospects in the field of cancer diagnosis and treatment.
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Affiliation(s)
- Liwei Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China.
| | - Huiling Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Yunxiang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhibo Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Chenran Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China
| | - Jiahao Bu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ting Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Clinical Laboratory of Henan province, Zhengzhou, Henan, China.
| | - Jianwei Wei
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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10
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Pirrello A, Killingsworth M, Spring K, Rasko JE, Yeo D. Cancer-associated macrophage-like cells as a prognostic biomarker in solid tumors. THE JOURNAL OF LIQUID BIOPSY 2024; 6:100275. [PMID: 40027315 PMCID: PMC11863711 DOI: 10.1016/j.jlb.2024.100275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/30/2024] [Accepted: 11/13/2024] [Indexed: 03/05/2025]
Abstract
Cancer-associated macrophage-like cells (CAMLs) are myeloid-lineage cells associated with cancer-derived material that are detectable in the blood. In addition to circulating tumor cells, CAMLs are a promising liquid biopsy biomarker which may assist with prognostication for patient stratification and monitoring response to chemotherapy and radiotherapy in solid tumors. CAMLs have been detected in blood samples from patients with various tumors including lung, pancreas, breast, oesophageal, and colorectal cancers, and to date have not been detected in healthy individuals. However, the optimal method of detection, their origin, function in the circulation, and ultimate utility have not been fully elucidated. This review provides an overview of CAML-related studies and explores their future potential to guide clinical decision-making.
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Affiliation(s)
- Anthony Pirrello
- Li Ka Shing Cell and Gene Therapy Program, The University of Sydney, Camperdown, 2050, NSW, Australia
- Precision Oncology Laboratory, Centenary Institute, Camperdown, 2050, NSW, Australia
| | - Murray Killingsworth
- Department of Anatomical Pathology, NSW Health Pathology, Liverpool, 2170, NSW, Australia
| | - Kevin Spring
- Medical Oncology Group, Liverpool Clinical School, Western Sydney University and Ingham Institute for Applied Medical Research, Liverpool, 2170, NSW, Australia
| | - John E.J. Rasko
- Li Ka Shing Cell and Gene Therapy Program, The University of Sydney, Camperdown, 2050, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, 2050, NSW, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, 2050, NSW, Australia
| | - Dannel Yeo
- Li Ka Shing Cell and Gene Therapy Program, The University of Sydney, Camperdown, 2050, NSW, Australia
- Precision Oncology Laboratory, Centenary Institute, Camperdown, 2050, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, 2050, NSW, Australia
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11
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Coupland SE, Sonntag SR, Heimann H, Grisanti S. [The concept of the liquid biopsy in the treatment of malignant eye tumours]. DIE OPHTHALMOLOGIE 2024; 121:946-953. [PMID: 39516408 DOI: 10.1007/s00347-024-02132-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/05/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024]
Abstract
The liquid biopsy is a cutting-edge technique that involves analysing non-solid biological tissues, primarily blood but also ocular fluids, for the presence of cancer cells or fragments of tumour DNA. Unlike traditional biopsies, liquid biopsies are usually minimally invasive and can be performed more frequently, enabling continuous monitoring of disease progression and treatment efficacy. This article (and the associated series of articles) outlines the key developments in liquid biopsy, which include the analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTC) and exosomal RNA and protein biomarkers. Techniques, such as digital droplet PCR and next-generation sequencing (NGS) have made it possible to detect even very low levels of ctDNA, which is crucial for early cancer detection and monitoring minimal residual disease. The detection of rare CTCs is enhanced by techniques, such as microfluidic devices and immunomagnetic separation. Multiomic approaches, whereby exosomal RNA, protein and ctDNA analyses are combined, help to create a more comprehensive picture of tumour biology, including insights into tumour heterogeneity, potentially leading to better diagnostic and prognostic tools and helping to predict treatment response and resistance. The challenges of liquid biopsy application, which will be described in the following article, include (a) standardization, (b) cost and accessibility, (c) validation and clinical utility. However, the liquid biopsy represents a promising frontier in the application of precision ocular oncology, with ongoing research likely to expand its applications and improve its effectiveness in the coming years.
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Affiliation(s)
- Sarah E Coupland
- Liverpool Ocular Oncology Research Group, Department of Eye and Vision Science, University of Liverpool, 3rd Floor, William Henry Duncan Building, 6 West Derby Street, L7 8TX, Liverpool, Großbritannien.
- Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool, Großbritannien.
| | - Svenja R Sonntag
- Department of Ophthalmology, University Medical Center Schleswig-Holstein, Luebeck, Deutschland
| | - Heinrich Heimann
- Liverpool Ocular Oncology Research Group, Department of Eye and Vision Science, University of Liverpool, 3rd Floor, William Henry Duncan Building, 6 West Derby Street, L7 8TX, Liverpool, Großbritannien
- Liverpool Ocular Oncology Centre, Liverpool University Hospitals Foundation Trust, Liverpool, Großbritannien
| | - Salvatore Grisanti
- Department of Ophthalmology, University Medical Center Schleswig-Holstein, Luebeck, Deutschland
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12
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Ahmed TM, Kawamoto S, Lopez-Ramirez F, Yasrab M, Hruban RH, Fishman EK, Chu LC. Early detection of pancreatic cancer in the era of precision medicine. Abdom Radiol (NY) 2024; 49:3559-3573. [PMID: 38761272 DOI: 10.1007/s00261-024-04358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/23/2024] [Accepted: 04/23/2024] [Indexed: 05/20/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality and it is often diagnosed at advanced stages due to non-specific clinical presentation. Disease detection at localized disease stage followed by surgical resection remains the only potentially curative treatment. In this era of precision medicine, a multifaceted approach to early detection of PDAC includes targeted screening in high-risk populations, serum biomarkers and "liquid biopsies", and artificial intelligence augmented tumor detection from radiologic examinations. In this review, we will review these emerging techniques in the early detection of PDAC.
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Affiliation(s)
- Taha M Ahmed
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Satomi Kawamoto
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Felipe Lopez-Ramirez
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Mohammad Yasrab
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elliot K Fishman
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Linda C Chu
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA.
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13
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Shrestha P, Kao S, Cheung VK, Cooper WA, van Zandwijk N, Rasko JEJ, Yeo D. Circulating tumor cells: advancing personalized therapy in small cell lung cancer patients. Mol Oncol 2024. [PMID: 38956984 DOI: 10.1002/1878-0261.13696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/27/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024] Open
Abstract
Small cell lung cancer (SCLC) is a highly aggressive cancer with a dismal 5-year survival of < 7%, despite the addition of immunotherapy to first-line chemotherapy. Specific tumor biomarkers, such as delta-like ligand 3 (DLL3) and schlafen11 (SLFN11), may enable the selection of more efficacious, novel immunomodulating targeted treatments like bispecific T-cell engaging monoclonal antibodies (tarlatamab) and chemotherapy with PARP inhibitors. However, obtaining a tissue biopsy sample can be challenging in SCLC. Circulating tumor cells (CTCs) have the potential to provide molecular insights into a patient's cancer through a "simple" blood test. CTCs have been studied for their prognostic ability in SCLC; however, their value in guiding treatment decisions is yet to be elucidated. This review explores novel and promising targeted therapies in SCLC, summarizes current knowledge of CTCs in SCLC, and discusses how CTCs can be utilized for precision medicine.
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Affiliation(s)
- Prajwol Shrestha
- Li Ka Shing Cell and Gene Therapy Program, Faculty of Medicine and Health, University of Sydney, Camperdown, Australia
- Precision Oncology Program, Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, Australia
- Medical Oncology, Calvary Mater Newcastle, Waratah, Australia
| | - Steven Kao
- Faculty of Medicine and Health, University of Sydney, Australia
- Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia
| | - Veronica K Cheung
- Faculty of Medicine and Health, University of Sydney, Australia
- Department of Tissue Pathology and Diagnostic Oncology, NSW Health Pathology, Royal Prince Alfred Hospital, Camperdown, Australia
| | - Wendy A Cooper
- Faculty of Medicine and Health, University of Sydney, Australia
- Department of Tissue Pathology and Diagnostic Oncology, NSW Health Pathology, Royal Prince Alfred Hospital, Camperdown, Australia
- School of Medicine, University of Western Sydney, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, University of Sydney, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
- Concord Repatriation General Hospital, Sydney Local Health District, Concord, Australia
| | - John E J Rasko
- Li Ka Shing Cell and Gene Therapy Program, Faculty of Medicine and Health, University of Sydney, Camperdown, Australia
- Precision Oncology Program, Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
| | - Dannel Yeo
- Li Ka Shing Cell and Gene Therapy Program, Faculty of Medicine and Health, University of Sydney, Camperdown, Australia
- Precision Oncology Program, Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia
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14
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Chu X, Zhong X, Zang S, Wang M, Li P, Ma Y, Tian X, Yang Y, Wang C, Yang Y. Stem cell-like circulating tumor cells identified by Pep@MNP and their clinical significance in pancreatic cancer metastasis. Front Oncol 2024; 14:1327280. [PMID: 38983932 PMCID: PMC11231205 DOI: 10.3389/fonc.2024.1327280] [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: 10/26/2023] [Accepted: 06/10/2024] [Indexed: 07/11/2024] Open
Abstract
Objective The circulating tumor cells (CTCs) could be captured by the peptide functionalized magnetic nanoparticles (Pep@MNP) detection system in pancreatic ductal adenocarcinoma (PDAC). CTCs and the CXCR4 expression were detected to explore their clinical significance. The CXCR4+ CTCs, this is highly metastatic-prone stem cell-like subsets of CTCs (HM-CTCs), were found to be associated with the early recurrence and metastasis of PDAC. Methods CTCs were captured by Pep@MNP. CTCs were identified via immunofluorescence with CD45, cytokeratin antibodies, and the CXCR4 positive CTCs were assigned to be HM-CTCs. Results The over-expression of CXCR4 could promote the migration of pancreatic cancer cell in vitro and in vivo. In peripheral blood (PB), CTCs were detected positive in 79.0% of all patients (49/62, 9 (0-71)/2mL), among which 63.3% patients (31/49, 3 (0-23)/2mL) were HM-CTCs positive. In portal vein blood (PVB), CTCs were positive in 77.5% of patients (31/40, 10 (0-40)/2mL), and 67.7% of which (21/31, 4 (0-15)/2mL) were HM-CTCs positive CTCs enumeration could be used as diagnostic biomarker of pancreatic cancer (AUC = 0.862), and the combination of CTCs positive and CA19-9 increase shows improved diagnostic accuracy (AUC = 0.963). in addition, PVB HM-CTCs were more accurate to predict the early recurrence and liver metastasis than PB HM-CTCs (AUC 0.825 vs. 0.787 and 0.827 vs. 0.809, respectively). Conclusions The CTCs identified by Pep@MNP detection system could be used as diagnostic and prognostic biomarkers of PDAC patients. We identified and defined the CXCR4 over-expressed CTC subpopulation as highly metastatic-prone CTCs, which was proved to identify patients who were prone to suffering from early recurrence and metastasis.
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Affiliation(s)
- Xiangyu Chu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Xiejian Zhong
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Shouge Zang
- Department of General Surgery, Fuyang People's Hospital of Anhui Medical University, Fuyang, China
| | - Mengting Wang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Ping Li
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Yongsu Ma
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Xiaodong Tian
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Yanlian Yang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Chen Wang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Yinmo Yang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
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15
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Ke H, Kao S, van Zandwijk N, Rasko JEJ, Yeo D. Circulating tumor cell detection may offer earlier diagnosis in patients suspected of asbestos-related lung cancer. Lung Cancer 2024; 192:107829. [PMID: 38810528 DOI: 10.1016/j.lungcan.2024.107829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 05/21/2024] [Indexed: 05/31/2024]
Abstract
Asbestos-Related Lung Cancer (ARLC) presents ongoing diagnostic challenges despite improved imaging technologies. The long latency period, coupled with limited access to occupational and environmental data along with the confounding effects of smoking and other carcinogens adds complexity to the diagnostic process. Compounding these challenges is the absence of a specific histopathologic or mutational signature of ARLC. A correlation between PD-L1 expression and response to immune checkpoint inhibition has not yet been proven. Thus, new biomarkers are needed to allow accurate diagnoses of ARLC, to enable prognostication and to offer personalized treatments. Liquid biopsies, encompassing circulating DNA and circulating tumor cells (CTCs), have gained attention as novel diagnostic methods in lung cancer to screen high-risk populations including those exposed to asbestos. CTCs can be enumerated and molecularly profiled to provide predictive and prognostic information. CTC studies have not been undertaken in populations at risk of ARLC to date. The potential of CTCs to provide real-time molecular insight into ARLC biology may significantly improve the diagnosis and management of ARLC patients.
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Affiliation(s)
- Helen Ke
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, 2050 NSW, Australia; Precision Oncology Laboratory, Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, 2050 NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050 NSW, Australia; Medical Oncology, Chris O'Brien Lifehouse, NSW 2050 Camperdown, Australia
| | - Steven Kao
- Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050 NSW, Australia; Medical Oncology, Chris O'Brien Lifehouse, NSW 2050 Camperdown, Australia; Asbestos Diseases Research Institute, NSW 2139 Concord, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050 NSW, Australia; Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, 2050 NSW, Australia
| | - John E J Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, 2050 NSW, Australia; Precision Oncology Laboratory, Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, 2050 NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050 NSW, Australia; Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, 2050 NSW, Australia.
| | - Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, 2050 NSW, Australia; Precision Oncology Laboratory, Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, 2050 NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050 NSW, Australia; Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, 2050 NSW, Australia.
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16
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Sok CP, Polireddy K, Kooby DA. Molecular pathology and protein markers for pancreatic cancer: relevance in staging, in adjuvant therapy, in determination of minimal residual disease, and follow-up. Hepatobiliary Surg Nutr 2024; 13:56-70. [PMID: 38322203 PMCID: PMC10839718 DOI: 10.21037/hbsn-22-628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/10/2023] [Indexed: 02/08/2024]
Abstract
The diagnosis and monitoring of disease through the detection of circulating protein biomarkers is a growing field in the practice of oncology. The search for more effective protein biomarkers to aid in the diagnosis and treatment of patients with pancreatic ductal adenocarcinoma (PDAC) remains a valuable area of study, given the aggressive and often occult nature of this malignancy. Liquid biopsies are attractive, as they offer a minimally invasive and cost-effective approach when compared to traditional biopsy methods and imaging modalities used for diagnosis and surveillance. Carbohydrate antigen (CA) 19-9 is currently the most commonly used serum protein biomarker for the diagnosis and monitoring of patients with PDAC, but due to its sensitivity and specificity, its utility remains limited. In this review, we examine how circulating protein biomarkers are used in the diagnosis, prognostication, and surveillance of PDAC. We also highlight protein biomarkers that are currently under investigation that have the potential to enhance our ability to detect early-stage malignancies, predict response to therapy, and monitor for recurrence, but these markers require larger prospective validation studies before they can be widely implemented. Continued efforts to identify and validate novel biomarkers will be crucial for improving the management and outcomes of patients with this challenging disease.
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Affiliation(s)
- Caitlin P. Sok
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Karunesh Polireddy
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
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17
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Sagot M, Bou E, Bourrier D, Cerf A, Aubert H, Vieu C. Bio-Impedance Spectroscopy of Retained Cells Using a Micro-Perforated Sensing Membrane Filtrating Whole Blood Samples under High Flowrate. BIOSENSORS 2023; 13:996. [PMID: 38131756 PMCID: PMC10741909 DOI: 10.3390/bios13120996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/09/2023] [Accepted: 11/17/2023] [Indexed: 12/23/2023]
Abstract
Blood filtration using micro-fabricated devices is an interdisciplinary topic of research and innovation driven by clinical applications in cytapheresis, cardiovascular disease monitoring, or liquid biopsy. In this paper, we demonstrate that a micro-perforated membrane can be equipped with sensing microelectrodes for detecting, in situ and in real-time, the capture of cellular material during ex vivo filtration of whole blood under high flow rates. This work describes the fabrication process of the sift and detection microdevice. We demonstrate that reliable electrical signals can be measured in whole blood samples flowing inside a fluidic system at typical flow rates, as large as 11.5 mL/min, hence allowing for large-volume sample processing. The in situ monitoring of the electrical impedance of the microelectrodes is shown to characterize the accumulation of living circulating cells retained by the filtrating membrane, opening interesting applications for monitoring blood filtration processes.
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Affiliation(s)
- Matthieu Sagot
- LAAS-CNRS, Université de Toulouse, CNRS, INSA, INPT, 31400 Toulouse, France
- SmartCatch, 1 Place Pierre Potier, 31100 Toulouse, France
| | - Elise Bou
- SmartCatch, 1 Place Pierre Potier, 31100 Toulouse, France
| | - David Bourrier
- LAAS-CNRS, Université de Toulouse, CNRS, INSA, INPT, 31400 Toulouse, France
| | - Aline Cerf
- SmartCatch, 1 Place Pierre Potier, 31100 Toulouse, France
| | - Hervé Aubert
- LAAS-CNRS, Université de Toulouse, CNRS, INSA, INPT, 31400 Toulouse, France
| | - Christophe Vieu
- LAAS-CNRS, Université de Toulouse, CNRS, INSA, INPT, 31400 Toulouse, France
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18
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Ito Y, Kobuchi S, Kawakita A, Tosaka K, Matsunaga Y, Yoshioka S, Jonan S, Amagase K, Hashimoto K, Kanda M, Saito T, Nakanishi H. Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer. Cancers (Basel) 2023; 15:5482. [PMID: 38001741 PMCID: PMC10670901 DOI: 10.3390/cancers15225482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1-2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1-2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings.
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Affiliation(s)
- Yukako Ito
- Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (S.K.); (A.K.); (K.T.); (Y.M.); (S.Y.)
| | - Shinji Kobuchi
- Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (S.K.); (A.K.); (K.T.); (Y.M.); (S.Y.)
| | - Amiri Kawakita
- Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (S.K.); (A.K.); (K.T.); (Y.M.); (S.Y.)
| | - Kazuki Tosaka
- Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (S.K.); (A.K.); (K.T.); (Y.M.); (S.Y.)
| | - Yume Matsunaga
- Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (S.K.); (A.K.); (K.T.); (Y.M.); (S.Y.)
| | - Shoma Yoshioka
- Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (S.K.); (A.K.); (K.T.); (Y.M.); (S.Y.)
| | - Shizuka Jonan
- Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga 603-8577, Japan; (S.J.); (K.A.)
| | - Kikuko Amagase
- Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga 603-8577, Japan; (S.J.); (K.A.)
| | - Katsunori Hashimoto
- Department of Medical Technology, Faculty of Medical Sciences, Shubun University, Ichinomiya City 491-0938, Japan;
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
| | - Takuya Saito
- Department of Gastroenterological Surgery, Aichi Medical University, Nagakute City 480-1195, Japan; (T.S.); (H.N.)
| | - Hayao Nakanishi
- Department of Gastroenterological Surgery, Aichi Medical University, Nagakute City 480-1195, Japan; (T.S.); (H.N.)
- Laboratory of Pathology, Okazaki City Hospital, Okazaki 444-0002, Japan
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19
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Wang K, Wang X, Pan Q, Zhao B. Liquid biopsy techniques and pancreatic cancer: diagnosis, monitoring, and evaluation. Mol Cancer 2023; 22:167. [PMID: 37803304 PMCID: PMC10557192 DOI: 10.1186/s12943-023-01870-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/25/2023] [Indexed: 10/08/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most common malignancies. Surgical resection is a potential curative approach for PC, but most patients are unsuitable for operations when at the time of diagnosis. Even with surgery, some patients may still experience tumour metastasis during the operation or shortly after surgery, as precise prognosis evaluation is not always possible. If patients miss the opportunity for surgery and resort to chemotherapy, they may face the challenging issue of chemotherapy resistance. In recent years, liquid biopsy has shown promising prospects in disease diagnosis, treatment monitoring, and prognosis assessment. As a noninvasive detection method, liquid biopsy offers advantages over traditional diagnostic procedures, such as tissue biopsy, in terms of both cost-effectiveness and convenience. The information provided by liquid biopsy helps clinical practitioners understand the molecular mechanisms underlying tumour occurrence and development, enabling the formulation of more precise and personalized treatment decisions for each patient. This review introduces molecular biomarkers and detection methods in liquid biopsy for PC, including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), noncoding RNAs (ncRNAs), and extracellular vesicles (EVs) or exosomes. Additionally, we summarize the applications of liquid biopsy in the early diagnosis, treatment response, resistance assessment, and prognostic evaluation of PC.
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Affiliation(s)
- Kangchun Wang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Xin Wang
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Bei Zhao
- Department of Ultrasound, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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Yaghoubi Naei V, Bordhan P, Mirakhorli F, Khorrami M, Shrestha J, Nazari H, Kulasinghe A, Ebrahimi Warkiani M. Advances in novel strategies for isolation, characterization, and analysis of CTCs and ctDNA. Ther Adv Med Oncol 2023; 15:17588359231192401. [PMID: 37692363 PMCID: PMC10486235 DOI: 10.1177/17588359231192401] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 07/19/2023] [Indexed: 09/12/2023] Open
Abstract
Over the past decade, the detection and analysis of liquid biopsy biomarkers such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have advanced significantly. They have received recognition for their clinical usefulness in detecting cancer at an early stage, monitoring disease, and evaluating treatment response. The emergence of liquid biopsy has been a helpful development, as it offers a minimally invasive, rapid, real-time monitoring, and possible alternative to traditional tissue biopsies. In resource-limited settings, the ideal platform for liquid biopsy should not only extract more CTCs or ctDNA from a minimal sample volume but also accurately represent the molecular heterogeneity of the patient's disease. This review covers novel strategies and advancements in CTC and ctDNA-based liquid biopsy platforms, including microfluidic applications and comprehensive analysis of molecular complexity. We discuss these systems' operational principles and performance efficiencies, as well as future opportunities and challenges for their implementation in clinical settings. In addition, we emphasize the importance of integrated platforms that incorporate machine learning and artificial intelligence in accurate liquid biopsy detection systems, which can greatly improve cancer management and enable precision diagnostics.
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Affiliation(s)
- Vahid Yaghoubi Naei
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
- Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Pritam Bordhan
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
- Faculty of Science, Institute for Biomedical Materials & Devices, University of Technology Sydney, Australia
| | - Fatemeh Mirakhorli
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Motahare Khorrami
- Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jesus Shrestha
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Hojjatollah Nazari
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Arutha Kulasinghe
- Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, 1, Broadway, Ultimo New South Wales 2007, Australia
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21
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Wang Q, Šabanović B, Awada A, Reina C, Aicher A, Tang J, Heeschen C. Single-cell omics: a new perspective for early detection of pancreatic cancer? Eur J Cancer 2023; 190:112940. [PMID: 37413845 DOI: 10.1016/j.ejca.2023.112940] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 06/04/2023] [Indexed: 07/08/2023]
Abstract
Pancreatic cancer is one of the most lethal cancers, mostly due to late diagnosis and limited treatment options. Early detection of pancreatic cancer in high-risk populations bears the potential to greatly improve outcomes, but current screening approaches remain of limited value despite recent technological advances. This review explores the possible advantages of liquid biopsies for this application, particularly focusing on circulating tumour cells (CTCs) and their subsequent single-cell omics analysis. Originating from both primary and metastatic tumour sites, CTCs provide important information for diagnosis, prognosis and tailoring of treatment strategies. Notably, CTCs have even been detected in the blood of subjects with pancreatic precursor lesions, suggesting their suitability as a non-invasive tool for the early detection of malignant transformation in the pancreas. As intact cells, CTCs offer comprehensive genomic, transcriptomic, epigenetic and proteomic information that can be explored using rapidly developing techniques for analysing individual cells at the molecular level. Studying CTCs during serial sampling and at single-cell resolution will help to dissect tumour heterogeneity for individual patients and among different patients, providing new insights into cancer evolution during disease progression and in response to treatment. Using CTCs for non-invasive tracking of cancer features, including stemness, metastatic potential and expression of immune targets, provides important and readily accessible molecular insights. Finally, the emerging technology of ex vivo culturing of CTCs could create new opportunities to study the functionality of individual cancers at any stage and develop personalised and more effective treatment approaches for this lethal disease.
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Affiliation(s)
- Qi Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Berina Šabanović
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Azhar Awada
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy; Molecular Biotechnology Center, University of Turin (UniTO), Turin, Italy
| | - Chiara Reina
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Jiajia Tang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; South Chongqing Road 227, Shanghai, China.
| | - Christopher Heeschen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy; South Chongqing Road 227, Shanghai, China.
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22
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Ko SW, Yoon SB. Clinical implications and perspectives of portal venous circulating tumor cells in pancreatic cancer. World J Gastrointest Oncol 2023; 15:632-643. [PMID: 37123055 PMCID: PMC10134213 DOI: 10.4251/wjgo.v15.i4.632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/10/2023] [Accepted: 03/15/2023] [Indexed: 04/12/2023] Open
Abstract
Despite recent improvements in the diagnosis and treatment of pancreatic cancer (PC), clinical outcomes remain dismal. Moreover, there are no effective prognostic or predictive biomarkers or options beyond carbohydrate antigen 19-9 for personalized and precise treatment. Circulating tumor cells (CTCs), as a member of the liquid biopsy family, could be a promising biomarker; however, the rarity of CTCs in peripheral venous blood limits their clinical use. Because the first venous drainage of PC is portal circulation, the portal vein can be a more suitable location for the detection of CTCs. Endoscopic ultrasound-guided portal venous sampling of CTCs is both feasible and safe. Several studies have suggested that the detection rate and number of CTCs may be higher in the portal blood than in the peripheral blood. CTC counts in the portal blood are highly associated with hepatic metastasis, recurrence after surgery, and survival. The phenotypic and genotypic properties measured in the captured portal CTCs can help us to understand tumor heterogeneity and predict the prognosis of PC. Small sample sizes and heterogeneous CTC detection methods limit the studies to date. Therefore, a large number of prospective studies are needed to corroborate portal CTCs as a valid biomarker in PC.
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Affiliation(s)
- Sung Woo Ko
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Seung Bae Yoon
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, Seoul 03312, South Korea
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23
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Kung H, Yu J. Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study. MedComm (Beijing) 2023; 4:e216. [PMID: 36814688 PMCID: PMC9939368 DOI: 10.1002/mco2.216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 02/21/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5-year survival rate. Contributing to the poor prognosis of PDAC is the lack of early detection, a complex network of signaling pathways and molecular mechanisms, a dense and desmoplastic stroma, and an immunosuppressive tumor microenvironment. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. However, certain aspects of NAT against PDAC, including the optimal regimen, the use of radiotherapy, and the selection of patients that would benefit from NAT, have yet to be fully elucidated. This review describes the major signaling pathways and molecular mechanisms involved in PDAC initiation and progression in addition to the immunosuppressive tumor microenvironment of PDAC. We then review current guidelines, ongoing research, and future research directions on the use of NAT based on randomized clinical trials and other studies. Finally, the current use of and research regarding targeted therapy for PDAC are examined. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm.
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Affiliation(s)
- Heng‐Chung Kung
- Krieger School of Arts and SciencesJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Jun Yu
- Departments of Medicine and OncologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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24
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Yeo D, Kao S, Gupta R, Wahlroos S, Bastian A, Strauss H, Klemm V, Shrestha P, Ramirez AB, Costandy L, Huston R, Gardner BS, Grimison P, Clark JR, Rasko JEJ. Accurate isolation and detection of circulating tumor cells using enrichment-free multiparametric high resolution imaging. Front Oncol 2023; 13:1141228. [PMID: 37051527 PMCID: PMC10083432 DOI: 10.3389/fonc.2023.1141228] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 03/06/2023] [Indexed: 03/29/2023] Open
Abstract
IntroductionThe reliable and accurate detection of rare circulating tumor cells (CTCs) from cancer patient blood samples promises advantages in both research and clinical applications. Numerous CTC detection methods have been explored that rely on either the physical properties of CTCs such as density, size, charge, and/or their antigen expression profiles. Multiple factors can influence CTC recovery including blood processing method and time to processing. This study aimed to examine the accuracy and sensitivity of an enrichment-free method of isolating leukocytes (AccuCyte® system) followed by immunofluorescence staining and high-resolution imaging (CyteFinder® instrument) to detect CTCs.MethodHealthy human blood samples, spiked with cancer cells from cancer cell lines, as well as blood samples obtained from 4 subjects diagnosed with cancer (2 pancreatic, 1 thyroid, and 1 small cell lung) were processed using the AccuCyte-CyteFinder system to assess recovery rate, accuracy, and reliability over a range of processing times.ResultsThe AccuCyte-CyteFinder system was highly accurate (95.0%) at identifying cancer cells in spiked-in samples (in 7.5 mL of blood), even at low spiked-in numbers of 5 cells with high sensitivity (90%). The AccuCyte-CyteFinder recovery rate (90.9%) was significantly higher compared to recovery rates obtained by density gradient centrifugation (20.0%) and red blood cell lysis (52.0%). Reliable and comparable recovery was observed in spiked-in samples and in clinical blood samples processed up to 72 hours post-collection. Reviewer analysis of images from spiked-in and clinical samples resulted in high concordance (R-squared value of 0.998 and 0.984 respectively).DiscussionThe AccuCyte-CyteFinder system is as an accurate, sensitive, and clinically practical method to detect and enumerate cancer cells. This system addresses some of the practical logistical challenges in incorporating CTCs as part of routine clinical care. This could facilitate the clinical use of CTCs in guiding precision, personalized medicine.
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Affiliation(s)
- Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia
- Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Steven Kao
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Medical Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia
| | - Ruta Gupta
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Department of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Camperdown, NSW, Australia
- NSW Health Pathology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia
| | - Sara Wahlroos
- Medical Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia
| | - Althea Bastian
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia
- Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Heidi Strauss
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia
- Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Vera Klemm
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia
- Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Prajwol Shrestha
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- Medical Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia
| | | | | | | | | | - Peter Grimison
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Medical Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia
| | - Jonathan R. Clark
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Department of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Camperdown, NSW, Australia
- Royal Prince Alfred Institute of Academic Surgery, Sydney Local Health District, Camperdown, NSW, Australia
| | - John E. J. Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia
- Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- *Correspondence: John E. J. Rasko,
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25
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Baliss M, Patel D, Madi MY, Bazarbashi AN. EUS-Guided Vascular Interventions. J Clin Med 2023; 12:jcm12062165. [PMID: 36983165 PMCID: PMC10052848 DOI: 10.3390/jcm12062165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/14/2023] Open
Abstract
Endoscopic ultrasound (EUS) has numerous advanced applications as a diagnostic and therapeutic modality in contemporary medicine. Through intraluminal placement, EUS offers a real-time Doppler-guided endoscopic visualization and access to intra-abdominal vasculature, which were previously inaccessible using historical methods. We aim to provide a comprehensive review of key studies on both current and future EUS-guided vascular applications. This review details EUS-based vascular diagnostic techniques of portal pressure measurements in the prognostication of liver disease and portal venous sampling for obtaining circulating tumor cells in the diagnosis of cancer. From an interventional perspective, we describe effective EUS-guided treatments via coiling and cyanoacrylate injections of gastric varices and visceral artery pseudoaneurysms. Specific attention is given to clinical studies on efficacy and procedural techniques described by investigators for each EUS-based application. We explore novel and future emerging EUS-based interventions, such as liver tumor ablation and intrahepatic portosystemic shunt placement.
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Affiliation(s)
- Michelle Baliss
- Division of Gastroenterology, Saint Louis University Hospital, St. Louis, MO 63104, USA
| | - Devan Patel
- Division of Gastroenterology, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Mahmoud Y. Madi
- Division of Gastroenterology, Saint Louis University Hospital, St. Louis, MO 63104, USA
| | - Ahmad Najdat Bazarbashi
- Division of Gastroenterology, Washington University in St. Louis, St. Louis, MO 63130, USA
- Correspondence:
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26
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de Geus SWL, Sachs TE. A Paradigm Shifts: Neoadjuvant Therapy for Clearly Resectable Pancreatic Cancer. Ann Surg Oncol 2023; 30:3427-3436. [PMID: 36869916 DOI: 10.1245/s10434-023-13281-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 02/12/2023] [Indexed: 03/05/2023]
Abstract
Over the past decade, neoadjuvant therapy has become the standard of care for patients with borderline resectable and locally advanced pancreatic cancer. The surgical community remains divided regarding the value of neoadjuvant therapy for patients who present with clearly resectable disease. Thus far, randomized controlled trials comparing neoadjuvant therapy with conventional upfront surgical strategies for patients with clearly resectable pancreatic cancer have been plagued by poor accrual, and are often underpowered. Nonetheless, meta-analyses of the results of these trials suggest that neoadjuvant therapy can be offered as an acceptable standard of care for patients with clearly resectable pancreatic cancer. Previous trials used neoadjuvant gemcitabine, but more recent studies have demonstrated superior survival for patients who were able to tolerate neoadjuvant FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin). The increased utilization of FOLFIRINOX may be shifting the treatment paradigm in favor of neoadjuvant therapy among patients with clearly resectable disease. Randomized controlled trials assessing the value of neoadjuvant FOLFIRINOX in clearly resectable pancreatic cancer, which are expected to provide more conclusive recommendations, are still ongoing. This review outlines the rationale, considerations, and current level of evidence for the use of neoadjuvant therapy in patients with clearly resectable pancreatic cancer.
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Affiliation(s)
- Susanna W L de Geus
- Department of Surgical Oncology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Teviah E Sachs
- Department of Surgical Oncology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
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27
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Couto-Cunha A, Jerónimo C, Henrique R. Circulating Tumor Cells as Biomarkers for Renal Cell Carcinoma: Ready for Prime Time? Cancers (Basel) 2022; 15:cancers15010287. [PMID: 36612281 PMCID: PMC9818240 DOI: 10.3390/cancers15010287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Renal cell carcinoma (RCC) is among the 15 most common cancers worldwide, with rising incidence. In most cases, this is a silent disease until it reaches advance stages, demanding new effective biomarkers in all domains, from detection to post-therapy monitoring. Circulating tumor cells (CTC) have the potential to provide minimally invasive information to guide assessment of the disease's aggressiveness and therapeutic strategy, representing a special pool of neoplastic cells which bear metastatic potential. In some tumor models, CTCs' enumeration has been associated with prognosis, but there is a largely unexplored potential for clinical applicability encompassing screening, diagnosis, early detection of metastases, prognosis, response to therapy and monitoring. Nonetheless, lack of standardization and high cost hinder the translation into clinical practice. Thus, new methods for collection and analysis (genomic, proteomic, transcriptomic, epigenomic and metabolomic) are needed to ascertain the role of CTC as a RCC biomarker. Herein, we provide a critical overview of the most recently published data on the role and clinical potential of CTCs in RCC, addressing their biology and the molecular characterization of this remarkable set of tumor cells. Furthermore, we highlight the existing and emerging techniques for CTC enrichment and detection, exploring clinical applications in RCC. Notwithstanding the notable progress in recent years, the use of CTCs in a routine clinical scenario of RCC patients requires further research and technological development, enabling multimodal analysis to take advantage of the wealth of information they provide.
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Affiliation(s)
- Anabela Couto-Cunha
- Integrated Master in Medicine, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Carmen Jerónimo
- Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Department of Pathology & Cancer Biology & Epigenetics Group—Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Centre Raquel Seruca (P.CCC Raquel Seruca), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Rui Henrique
- Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Department of Pathology & Cancer Biology & Epigenetics Group—Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Centre Raquel Seruca (P.CCC Raquel Seruca), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
- Correspondence: or
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Nitschke C, Markmann B, Konczalla L, Kropidlowski J, Pereira-Veiga T, Scognamiglio P, Schönrock M, Sinn M, Tölle M, Izbicki J, Pantel K, Uzunoglu FG, Wikman H. Circulating Cancer Associated Macrophage-like Cells as a Potential New Prognostic Marker in Pancreatic Ductal Adenocarcinoma. Biomedicines 2022; 10:biomedicines10112955. [PMID: 36428523 PMCID: PMC9687633 DOI: 10.3390/biomedicines10112955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/07/2022] [Accepted: 11/12/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Circulating Cancer Associated Macrophage-like cells (CAMLs) have been described as novel liquid biopsy analytes and unfavorable prognostic markers in some tumor entities, with scarce data for Pancreatic Ductal Adenocarcinomas (PDAC). METHODS Baseline and follow-up blood was drawn from resected curative (n = 36) and palliative (n = 19) PDAC patients. A microfluidic size-based cell enrichment approach (ParsortixTM) was used for CAML detection, followed by immunofluorescence staining using pan-keratin, CD14, and CD45 antibodies to differentiate between CAMLs, circulating tumor cells (CTCs), and leukocytes. RESULTS CAMLs were detectable at baseline in 36.1% of resected patients and 47.4% of palliative PDAC patients. CAML detection was tumor stage independent. Follow-up data indicated that detection of CAMLs (in 45.5% of curative patients) was an independent prognostic factor for shorter recurrence-free survival (RFS) (HR: 4.3, p = 0.023). Furthermore, a combined analysis with CTCs showed the detectability of at least one of these cell populations in 68.2% of resected patients at follow-up. The combined detection of CAMLs and CTCs was also significantly associated with short RFS (HR: 8.7, p = 0.003). CONCLUSIONS This pilot study shows that detection of CAMLs in PDAC patients can provide prognostic information, either alone or even more pronounced in combination with CTCs, which indicates the power of liquid biopsy marker analyses.
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Affiliation(s)
- Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
- Mildred Scheel Cancer Career Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Benedikt Markmann
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Leonie Konczalla
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
- Mildred Scheel Cancer Career Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jolanthe Kropidlowski
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Thais Pereira-Veiga
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Pasquale Scognamiglio
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Martin Schönrock
- II Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marianne Sinn
- II Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marie Tölle
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jakob Izbicki
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Faik G. Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Harriet Wikman
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
- Correspondence: ; Tel.: +49-40-7510-51913
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Cheng H, Yang J, Fu X, Mao L, Chu X, Lu C, Li G, Qiu Y, He W. Folate receptor-positive circulating tumor cells predict survival and recurrence patterns in patients undergoing resection for pancreatic cancer. Front Oncol 2022; 12:1012609. [PMID: 36313690 PMCID: PMC9606765 DOI: 10.3389/fonc.2022.1012609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/26/2022] [Indexed: 12/03/2022] Open
Abstract
Objective To evaluate the prognostic impact of folate receptor (FR)-positive circulating tumor cells (FR+ CTCs) for patients with pancreatic cancer (PC). Background Risk stratification before surgery for PC patients remains challenging as there are no reliable prognostic markers currently. FR+ CTCs, detected by ligand-targeted polymerase chain reaction (LT-PCR), have shown excellent diagnostic value for PC in our previous study and prognostic value in a variety of cancer types. Methods Peripheral blood samples from 44 consecutive patients diagnosed with PC were analyzed for FR+ CTCs. 25 patients underwent tumor resection and were assigned to the surgical group. 19 patients failed to undergo radical resection because of local advance or distant metastasis and were assigned to the non-surgical group. The impact of CTCs on relapse and survival were explored. Results For the prognostic stratification, the optimal cut-off value of CTCs analyzed by receiver operating characteristic (ROC) curve was 14.49 folate units (FU)/3 ml. High CTC levels (> 14.49 FU/3 ml) were detected in 52.0% (13/25) of the patients in the surgical group and 63.2% (12/19) in the non-surgical group. In the surgical group, median disease-free survival (DFS) for patients with high CTC levels versus low CTC levels (< 14.49 FU/3 ml) was 8.0 versus 26.0 months (P = 0.008). In multivariable analysis, CTCs were an independent risk factor for DFS (HR: 4.589, P = 0.012). Concerning the recurrence patterns, patients with high CTC levels showed a significantly frequent rate of distant and early recurrence (P = 0.017 and P = 0.011). CTC levels remained an independent predictor for both distant (OR: 8.375, P = 0.014) and early recurrence (OR: 8.412, P = 0.013) confirmed by multivariable logistic regression. However, CTCs did not predict survival in the non-surgical group (P = 0.220). Conclusion FR+ CTCs in resected PC patients could predict impaired survival and recurrence patterns after surgery. Preoperative CTC levels detected by LT-PCR may help guide treatment strategies and further studies in a larger cohort are warranted.
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Affiliation(s)
- Hao Cheng
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Yang
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xu Fu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Mao
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xuehui Chu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chenglin Lu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Gang Li
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yudong Qiu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Yudong Qiu, ; Wei He,
| | - Wei He
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Yudong Qiu, ; Wei He,
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Characterization of RARRES1 Expression on Circulating Tumor Cells as Unfavorable Prognostic Marker in Resected Pancreatic Ductal Adenocarcinoma Patients. Cancers (Basel) 2022; 14:cancers14184405. [PMID: 36139565 PMCID: PMC9497091 DOI: 10.3390/cancers14184405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/04/2022] [Accepted: 09/01/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Our explorative study used a microfluidic-based approach for circulating tumor cell (CTC) detection in 55 pancreatic ductal adenocarcinoma (PDAC) patients before treatment initiation (baseline) and during follow-up (FUP). For the first time, we assessed the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs. CTCs were detected in 25.5% of patients at baseline, while the detection rate during FUP was higher (45.5%). Especially high CTC counts during FUP in resected patients were associated with early tumor relapse (p = 0.02). Combining CTC detection and RARRES1 protein expression showed that RARRES1-positive patients with high CTCs counts after curative operation during FUP had a worse prognosis (p = 0.001). In conclusion, RARRES1 is a new marker of interest for further research investigations on subtypes of CTCs in PDAC. Abstract Background: In pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse. Methods: The stable isotope labeling of amino acids in cell culture (SILAC)—approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker. Results: SILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001). Conclusions: CTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation.
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Tonini V, Zanni M. Early diagnosis of pancreatic cancer: What strategies to avoid a foretold catastrophe. World J Gastroenterol 2022; 28:4235-4248. [PMID: 36159004 PMCID: PMC9453775 DOI: 10.3748/wjg.v28.i31.4235] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/18/2022] [Accepted: 07/24/2022] [Indexed: 02/06/2023] Open
Abstract
While great strides in improving survival rates have been made for most cancers in recent years, pancreatic ductal adenocarcinoma (PDAC) remains one of the solid tumors with the worst prognosis. PDAC mortality often overlaps with incidence. Surgical resection is the only potentially curative treatment, but it can be performed in a very limited number of cases. In order to improve the prognosis of PDAC, there are ideally two possible ways: the discovery of new strategies or drugs that will make it possible to treat the tumor more successfully or an earlier diagnosis that will allow patients to be operated on at a less advanced stage. The aim of this review was to summarize all the possible strategies available today for the early diagnosis of PDAC and the paths that research needs to take to make this goal ever closer. All the most recent studies on risk factors and screening modalities, new laboratory tests including liquid biopsy, new imaging methods and possible applications of artificial intelligence and machine learning were reviewed and commented on. Unfortunately, in 2022 the results for this type of cancer still remain discouraging, while a catastrophic increase in cases is expected in the coming years. The article was also written with the aim of highlighting the urgency of devoting more attention and resources to this pathology in order to reach a solution that seems more and more unreachable every day.
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Affiliation(s)
- Valeria Tonini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Manuel Zanni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
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Götze J, Nitschke C, Uzunoglu FG, Pantel K, Sinn M, Wikman H. Tumor-Stroma Interaction in PDAC as a New Approach for Liquid Biopsy and its Potential Clinical Implications. Front Cell Dev Biol 2022; 10:918795. [PMID: 35712663 PMCID: PMC9197075 DOI: 10.3389/fcell.2022.918795] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/05/2022] [Indexed: 12/29/2022] Open
Abstract
The extremely poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) has remained unchanged for decades. As a hallmark of PDAC histology, the distinct desmoplastic response in the tumor microenvironment is considered a key factor exerting pro- and antitumor effects. Increasing emphasis has been placed on cancer-associated fibroblasts (CAFs), whose heterogeneity and functional diversity is reflected in the numerous subtypes. The myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs) and antigen presenting CAFs (apCAFs) are functionally divergent CAF subtypes with tumor promoting as well as repressing effects. Precise knowledge of the underlying interactions is the basis for a variety of treatment approaches, which are subsumed under the term antistromal therapy. Clinical implementation is still pending due to the lack of benefit-as well as paradoxical preclinical findings. While the prominent significance of CAFs in the immediate environment of the tumor is becoming clear, less is known about the circulating (c)CAFs. cCAFs are of particular interest as they seem not only to be potential new liquid biopsy biomarkers but also to support the survival of circulating tumor cells (CTC) in the bloodstream. In PDAC, CTCs correlate with an unfavorable outcome and can also be employed to monitor treatment response, but the current clinical relevance is limited. In this review, we discuss CTCs, cCAFs, secretomes that include EVs or fragments of collagen turnover as liquid biopsy biomarkers, and clinical approaches to target tumor stroma in PDAC.
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Affiliation(s)
- Julian Götze
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, Hamburg, Germany.,Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Faik G Uzunoglu
- 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
| | - Marianne Sinn
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, Hamburg, Germany
| | - Harriet Wikman
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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