|
1
|
Chauhan A, Boora GS, Maitra A, Gupta R, Bakshi J, Ghoshal S, Pal A. PADI4 expression in baseline circulating tumour cells acts as a prognostic biomarker in oral squamous cell carcinoma. THE JOURNAL OF LIQUID BIOPSY 2025; 7:100289. [PMID: 40027234 PMCID: PMC11863982 DOI: 10.1016/j.jlb.2025.100289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/20/2024] [Accepted: 01/15/2025] [Indexed: 03/05/2025]
Abstract
Oral Squamous Cell Carcinoma (OSCC), one of the most prevalent cancers in developing countries. It is associated with poor prognosis due to relapse in a significant number of patients. Circulating tumour cells (CTCs) are precursors for metastasis and thought to be key players in early relapse in various cancers including OSCC. Though CTC enumeration has been associated with disease outcome, in-depth molecular analysis of CTCs remained minimal as the techniques for CTC isolation and analysis are challenging. While exploring gene expression in CTCs, we performed whole transcriptome analysis of paired primary tumour and CTCs isolated from Oral Squamous Cell Carcinoma (OSCC) patients. Various genes were found to be differentially expressed in CTCs. We found PADI4 gene was significantly upregulated in CTCs. PADI4 gene encodes for an enzyme that converts arginine to citrulline. PADI4 expression in primary tumours was previously observed to be associated with metastasis. Here, we are reporting PADI4 expression for the first time in CTCs and its association with relapse. Interestingly in our data, PADI4 expression was more seen in CTCs with EMT (epithelial to mesenchymal transition)-phenotype than with CTCs only epithelial-phenotype. In conclusion, this is the first study presenting the potential prognostic utility of PADI4 expression in CTCs isolated from OSCC patients.
Collapse
Affiliation(s)
- Anshika Chauhan
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Geeta S. Boora
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arindam Maitra
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | - Rijuneeta Gupta
- Department of ENT, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaimanti Bakshi
- Department of ENT, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sushmita Ghoshal
- Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arnab Pal
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
2
|
Reduzzi C, Nicolo' E, Singhal S, Venetis K, Ortega-Franco A, de Miguel-Perez D, Dipasquale A, Gouda MA, Saldanha EF, Kasi PM, Jantus-Lewintre E, Fusco N, Malapelle U, Gandara DR, Rolfo C, Serrano MJ, Cristofanilli M. Unveiling the impact of circulating tumor cells: Two decades of discovery and clinical advancements in solid tumors. Crit Rev Oncol Hematol 2024; 203:104483. [PMID: 39159706 DOI: 10.1016/j.critrevonc.2024.104483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
Circulating tumor cells (CTCs) enumeration and molecular profiling hold promise in revolutionizing the management of solid tumors. Their understanding has evolved significantly over the past two decades, encompassing pivotal biological discoveries and clinical studies across various malignancies. While for some tumor types, such as breast, prostate, and colorectal cancer, CTCs are ready to enter clinical practice, for others, additional research is required. CTCs serve as versatile biomarkers, offering insights into tumor biology, metastatic progression, and treatment response. This review summarizes the latest advancements in CTC research and highlights future directions of investigation. Special attention is given to concurrent evaluations of CTCs and other circulating biomarkers, particularly circulating tumor DNA. Multi-analyte assessment holds the potential to unlock the full clinical capabilities of liquid biopsy. In conclusion, CTCs represent a transformative biomarker in precision oncology, offering extraordinary opportunities to translate scientific discoveries into tangible improvements in patient care.
Collapse
Affiliation(s)
- Carolina Reduzzi
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA.
| | - Eleonora Nicolo'
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA.
| | - Surbhi Singhal
- Division of Hematology and Oncology, Department of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA
| | - Konstantinos Venetis
- Division of Pathology, IEO European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Ana Ortega-Franco
- Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
| | - Diego de Miguel-Perez
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Angelo Dipasquale
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Mohamed A Gouda
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Erick F Saldanha
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, ON, Canada
| | - Pashtoon M Kasi
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA
| | - Eloisa Jantus-Lewintre
- Department of Biotechnology, Universitat Politècnica de València, Unidad Mixta TRIAL (Fundación para la Investigación del Hospital General Universitario de Valencia y Centro de Investigación Príncipe Felipe) and CIBERONC, Valencia, Spain
| | - Nicola Fusco
- Division of Pathology, IEO European Institute of Oncology IRCCS, Milan 20141, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20121, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Napoli 80131, Italy
| | - David R Gandara
- Division of Hematology and Oncology, Department of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA
| | - Christian Rolfo
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Maria Jose Serrano
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid biopsy and Cancer Interception group, PTS Granada, Avenida de la Ilustración 114, Granada 18016, Spain; Pathological Anatomy Unit, Molecular Pathology Laboratory,Virgen de las Nieves. University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain
| | - Massimo Cristofanilli
- Department of Medicine, Weill Cornell Medicine, Englander Institute for Precision Medicine, New York Presbyterian Hospital, New York, NY 10021, USA
| |
Collapse
|
|
3
|
Li Z, Qin C, Zhao B, Li T, Zhao Y, Zhang X, Wang W. Circulating tumor cells in pancreatic cancer: more than liquid biopsy. Ther Adv Med Oncol 2024; 16:17588359241284935. [PMID: 39421679 PMCID: PMC11483845 DOI: 10.1177/17588359241284935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that slough off the primary lesions and extravasate into the bloodstream. By forming CTC clusters and interacting with other circulating cells (platelets, NK cells, macrophage, etc.), CTCs are able to survive in the circulatory system of tumor patients and colonize to metastatic organs. In recent years, the potential of CTCs in diagnosis, prognostic assessment, and individualized therapy of various types of tumors has been gradually explored, while advances in biotechnology have made it possible to extract CTCs from patient blood samples. These biological features of CTCs provide us with new insights into cancer vulnerabilities. With the advent of new immunotherapies and personalized medicines, disrupting the heterotypical interaction between CTCs and circulatory cells as well as direct CTCs targeting hold great promise. Pancreatic cancer (PC) is one of the most malignant cancers, in part because of early metastasis, difficult diagnosis, and limited treatment options. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC. In this review, we summed up the progress made in understanding biological characteristics and exceptional technological advances of CTCs and provided insight into exploiting these developments to design future clinical tools for improving the diagnosis and treatment of PC.
Collapse
Affiliation(s)
- Zeru Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cheng Qin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bangbo Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianyu Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yutong Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyu Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weibin Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Wangfujing Street Dongcheng District Beijing China, Beijing 100730, China
| |
Collapse
|
|
4
|
Rodriguez-Tirado C, Sosa MS. How much do we know about the metastatic process? Clin Exp Metastasis 2024; 41:275-299. [PMID: 38520475 PMCID: PMC11374507 DOI: 10.1007/s10585-023-10248-0] [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] [Received: 08/13/2023] [Accepted: 11/17/2023] [Indexed: 03/25/2024]
Abstract
Cancer cells can leave their primary sites and travel through the circulation to distant sites, where they lodge as disseminated cancer cells (DCCs), even during the early and asymptomatic stages of tumor progression. In experimental models and clinical samples, DCCs can be detected in a non-proliferative state, defined as cellular dormancy. This state can persist for extended periods until DCCs reawaken, usually in response to niche-derived reactivation signals. Therefore, their clinical detection in sites like lymph nodes and bone marrow is linked to poor survival. Current cancer therapy designs are based on the biology of the primary tumor and do not target the biology of the dormant DCC population and thus fail to eradicate the initial or subsequent waves of metastasis. In this brief review, we discuss the current methods for detecting DCCs and highlight new strategies that aim to target DCCs that constitute minimal residual disease to reduce or prevent metastasis formation. Furthermore, we present current evidence on the relevance of DCCs derived from early stages of tumor progression in metastatic disease and describe the animal models available for their study. We also discuss our current understanding of the dissemination mechanisms utilized by genetically less- and more-advanced cancer cells, which include the functional analysis of intermediate or hybrid states of epithelial-mesenchymal transition (EMT). Finally, we raise some intriguing questions regarding the clinical impact of studying the crosstalk between evolutionary waves of DCCs and the initiation of metastatic disease.
Collapse
Affiliation(s)
- Carolina Rodriguez-Tirado
- Department of Microbiology and Immunology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Department of Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Cancer Dormancy and Tumor Microenvironment Institute/Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
| | - Maria Soledad Sosa
- Department of Microbiology and Immunology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Department of Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Cancer Dormancy and Tumor Microenvironment Institute/Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
| |
Collapse
|
|
5
|
Chauhan A, Pal A, Sachdeva M, Boora GS, Parsana M, Bakshi J, Verma RK, Srinivasan R, Chatterjee D, Maitra A, Ghoshal S. A FACS-based novel isolation technique identifies heterogeneous CTCs in oral squamous cell carcinoma. Front Oncol 2024; 14:1269211. [PMID: 38469233 PMCID: PMC10925612 DOI: 10.3389/fonc.2024.1269211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 02/02/2024] [Indexed: 03/13/2024] Open
Abstract
Purpose Isolating circulating tumour cells (CTCs) from the blood is challenging due to their low abundance and heterogeneity. Limitations of conventional CTC detection methods highlight the need for improved strategies to detect and isolate CTCs. Currently, the Food and Drug Administration (FDA)-approved CellSearch™ and other RUO techniques are not available in India. Therefore, we wanted to develop a flexible CTC detection/isolation technique that addresses the limitation(s) of currently available techniques and is suitable for various downstream applications. Methods We developed a novel, efficient, user-friendly CTC isolation strategy combining density gradient centrifugation and immuno-magnetic hematogenous cell depletion with fluorescence-activated cell sorting (FACS)-based positive selection using multiple CTC-specific cell-surface markers. For FACS, a stringent gating strategy was optimised to exclude debris and doublets by side scatter/forward scatter (SSC/FSC) discriminator, remove dead cells by 4',6-diamidino-2-phenylindole (DAPI) staining, and eliminate non-specific fluorescence using a "dump" channel. APC-labelled anti-CD45mAB was used to gate remaining hematogenous cells, while multiple epithelial markers (EpCAM, EGFR, and Pan-Cytokeratin) and an epithelial-mesenchymal transition (EMT) marker (Vimentin) labelled with fluorescein isothiocyanate (FITC) were used to sort cancer cells. The technique was initially developed by spiking Cal 27 cancer cells into the blood of healthy donors and then validated in 95 biopsy-proven oral squamous cell carcinoma (OSCC) patients. CTCs isolated from patients were reconfirmed by Giemsa staining, immuno-staining, and whole transcriptome amplification (WTA), followed by qRT-PCR. In vitro culture and RNA sequencing (RNA-Seq) were also performed to confirm their suitability for various downstream applications. Results The mean detection efficiency for the Cal 27 tongue cancer cells spiked in the whole blood of healthy donors was 32.82% ± 12.71%. While ~75% of our patients (71/95) had detectable CTCs, the CTC positivity was independent of the TNM staging. The isolated potential cancer cells from OSCC patients were heterogeneous in size. They expressed different CTC-specific markers in various combinations as identified by qRT-PCR after WTA in different patients. Isolated CTCs were also found to be suitable for downstream applications like short-term CTC culture and RNA-Seq. Conclusion We developed a sensitive, specific, flexible, and affordable CTC detection/isolation technique, which is scalable to larger patient cohorts, provides a snapshot of CTC heterogeneity, isolates live CTCs ready for downstream molecular analysis, and, most importantly, is suitable for developing countries.
Collapse
Affiliation(s)
- Anshika Chauhan
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arnab Pal
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Meenakshi Sachdeva
- Department of Regenerative Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Geeta S. Boora
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Monil Parsana
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaimanti Bakshi
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Roshan Kumar Verma
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology and Gynecological Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Debajyoti Chatterjee
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arindam Maitra
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | - Sushmita Ghoshal
- Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
6
|
Ramírez-Maldonado E, López Gordo S, Major Branco RP, Pavel MC, Estalella L, Llàcer-Millán E, Guerrero MA, López-Gordo E, Memba R, Jorba R. Clinical Application of Liquid Biopsy in Pancreatic Cancer: A Narrative Review. Int J Mol Sci 2024; 25:1640. [PMID: 38338919 PMCID: PMC10855073 DOI: 10.3390/ijms25031640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/21/2024] [Accepted: 01/24/2024] [Indexed: 02/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma contributes significantly to global cancer-related deaths, featuring only a 10% survival rate over five years. The quest for novel tumor markers is critical to facilitate early diagnosis and tailor treatment strategies for this disease, which is key to improving patient outcomes. In pancreatic ductal adenocarcinoma, these markers have been demonstrated to play a crucial role in early identification, continuous monitoring, and prediction of its prognosis and have led to better patient outcomes. Nowadays, biopsy specimens serve to ascertain diagnosis and determine tumor type. However, liquid biopsies present distinct advantages over conventional biopsy techniques. They offer a noninvasive, easily administered procedure, delivering insights into the tumor's status and facilitating real-time monitoring. Liquid biopsies encompass a variety of elements, such as circulating tumor cells, circulating tumor DNA, extracellular vesicles, microRNAs, circulating RNA, tumor platelets, and tumor endothelial cells. This review aims to provide an overview of the clinical applications of liquid biopsy as a technique in the management of pancreatic cancer.
Collapse
Affiliation(s)
- Elena Ramírez-Maldonado
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| | - Sandra López Gordo
- General Surgery Department, Maresme Health Consortium, 08304 Mataro, Spain;
| | | | - Mihai-Calin Pavel
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| | - Laia Estalella
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| | - Erik Llàcer-Millán
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| | - María Alejandra Guerrero
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| | | | - Robert Memba
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| | - Rosa Jorba
- HBP Unit, General Surgery Department, Joan XXIII University Hospital, 43005 Tarragona, Spain; (M.-C.P.); (L.E.); (M.A.G.); (R.M.); (R.J.)
- Medicine and Surgery Department, Rovira i Virgili University, 43204 Reus, Spain
| |
Collapse
|
|
7
|
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.
Collapse
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.
| |
Collapse
|
|
8
|
Qi C, Xiong XZ. Value of peripheral blood circulating tumor cell detection in the diagnosis of thoracic diseases and the prediction of severity. Clin Exp Med 2023; 23:2331-2339. [PMID: 36929453 PMCID: PMC10543157 DOI: 10.1007/s10238-023-01022-3] [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: 01/18/2023] [Accepted: 02/05/2023] [Indexed: 03/18/2023]
Abstract
Circulating tumor cell (CTC) detection, as a noninvasive liquid biopsy method, has been used in the diagnosis, prognostic indication, and monitoring of a variety of cancers. In this study, we aimed to investigate whether CTC detection could be used in the early diagnosis and prediction of severity of thoracic diseases. We enrolled 168 thoracic disease patients, all of whom underwent pathological biopsy. Carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) measurement was also performed in 146 patients. There were 131 cases of malignant thoracic diseases and 37 cases of benign lesions. We detected CTCs in a 5 ml peripheral blood sample with the CTCBiopsy® system and analyzed the value of CTC count for predicting disease severity. Of 131 patients with a diagnosis of thoracic malignancy, CTCs were found in blood samples from 122 patients. However, only 2 out of 37 patients with benign thoracic disease had no detectable CTCs. There was no significant correlation between CTC count and benign and malignant lesions (P = 0.986). However, among 131 patients who had been diagnosed with malignant lesions, 33 had lymph node metastasis or distant metastasis. The presence of CTCs was significantly correlated with metastasis (P = 0.016 OR = 1.14). The area under the receiver operating characteristic (ROC) curve was 0.625 (95% confidence interval (CI), 0.519 to 0.730 P = 0.032). In addition, with stage IA1 as the cutoff, all patients were further divided into an early-stage group and a late-stage group. CTC count was significantly correlated with disease progression (P = 0.031 OR = 1.11), with an area under the curve (AUC) of 0.599 (95% CI, 0.506-0.692 P = 0.47). The sensitivity and specificity of CTC detection for the diagnosis of disease stage were 72.3% and 45.5%, respectively. In addition, the cutoff of 2.5 CTCs was the same when predicting disease metastasis and staging. Furthermore, the combination of CTC count, demographic characteristics and tumor markers had better predictive significance for disease staging. CTC count can effectively indicate the stages and metastasis of thoracic diseases, but it cannot differentiate benign and malignant diseases.
Collapse
Affiliation(s)
- Chang Qi
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Xian-Zhi Xiong
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.
| |
Collapse
|
|
9
|
Raufi AG, May MS, Hadfield MJ, Seyhan AA, El-Deiry WS. Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer. Int J Mol Sci 2023; 24:4238. [PMID: 36835649 PMCID: PMC9958987 DOI: 10.3390/ijms24044238] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 12/23/2022] [Accepted: 12/29/2022] [Indexed: 02/23/2023] Open
Abstract
Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.
Collapse
Affiliation(s)
- Alexander G. Raufi
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
| | - Michael S. May
- Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Matthew J. Hadfield
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
| | - Attila A. Seyhan
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Wafik S. El-Deiry
- Division of Hematology/Oncology, Department of Medicine, Lifespan Health System, Providence, RI 02903, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
- Joint Program in Cancer Biology, Brown University, Providence, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| |
Collapse
|
|
10
|
Comparative application of microfluidic systems in circulating tumor cells and extracellular vesicles isolation; a review. Biomed Microdevices 2022; 25:4. [PMID: 36574057 DOI: 10.1007/s10544-022-00644-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 12/28/2022]
Abstract
Cancer is a prevalent cause of mortality globally, where early diagnosis leads to a reduced death rate. Many researchers' common strategies are based on personalized diagnostic methods with rapid response and high accuracy. This technology was developed by applying liquid biopsy instead of tissue biopsies in the case of tumor cell analysis that facilitates point-of-care testing for cancer diagnosis and treatment. In recent years, significant progress in microfluidic technology led to the successful isolation, analysis, and monitoring of cancer biomarkers in body liquid biopsy with merits like high sensitivity and flexibility, low sample usage, cost effective, and the ability of automation. The most critical and informative markers in body liquid refer to circulating tumor cells (CTCs) and extracellular vesicles derived from tumors (EVs) that carry various biomarkers in their structure (DNAs, proteins, and RNAs) as compared to ctDNA. The released ctDNA has a low half-life and decreased sensitivity due to large amounts of nucleic acid in serum. This review intends to highlight different cancer screening tests with a particular focus on the details regarding the only FDA-approved and awaiting technologies for FDA clearance to isolate CTCs and EVs based on microfluidics systems.
Collapse
|
|
11
|
EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms. Int J Mol Sci 2022; 23:ijms232113645. [PMID: 36362433 PMCID: PMC9657865 DOI: 10.3390/ijms232113645] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples.
Collapse
|
|
12
|
Exploring the Clinical Utility of Pancreatic Cancer Circulating Tumor Cells. Int J Mol Sci 2022; 23:ijms23031671. [PMID: 35163592 PMCID: PMC8836025 DOI: 10.3390/ijms23031671] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type, characterized by a dismal prognosis due to late diagnosis, frequent metastases, and limited therapeutic response to standard chemotherapy. Circulating tumor cells (CTCs) are a rare subset of tumor cells found in the blood of cancer patients. CTCs has the potential utility for screening, early and definitive diagnosis, prognostic and predictive assessment, and offers the potential for personalized management. However, a gold-standard CTC detection and enrichment method remains elusive, hindering comprehensive comparisons between studies. In this review, we summarize data regarding the utility of CTCs at different stages of PDAC from early to metastatic disease and discuss the molecular profiling and culture of CTCs. The characterization of CTCs brings us closer to defining the specific CTC subpopulation responsible for metastasis with the potential to uncover new therapies and more effective management options for PDAC.
Collapse
|
|
13
|
Circulating Tumor Cells Enumeration from the Portal Vein for Risk Stratification in Early Pancreatic Cancer Patients. Cancers (Basel) 2021; 13:cancers13246153. [PMID: 34944773 PMCID: PMC8699156 DOI: 10.3390/cancers13246153] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 01/12/2023] Open
Abstract
Simple Summary Effective biomarkers are needed to enable personalized medicine for pancreatic cancer patients. This study analyzes the prognostic value, in early pancreatic cancer, of circulating tumor cells and clusters from the central venous catheter and portal blood. Circulating tumor cells were isolated using an immunomagnetic selection and were detected by microscopy using immunocytochemistry staining. In conclusion, the circulating tumor cell number in portal blood identifies a death risk in patients with early pancreatic cancer. Abstract Background. Effective biomarkers are needed to enable personalized medicine for pancreatic cancer patients. This study analyzes the prognostic value, in early pancreatic cancer, of single circulating tumor cell (CTC) and CTC clusters from the central venous catheter (CVC) and portal blood (PV). Methods. In total, 7 mL of PV and CVC blood from 35 patients with early pancreatic cancer were analyzed. CTC were isolated using a positive immunomagnetic selection. The detection and identification of CTC were performed by immunocytochemistry (ICC) and were analyzed by Epi-fluorescence and confocal microscopy. Results. CTC and the clusters were detected both in PV and CVC. In both samples, the CTC number per cluster was higher in patients with grade three or poorly differentiated tumors (G3) than in patients with well (G1) or moderately (G2) differentiated. Patients with fewer than 185 CTC in PV exhibited a longer OS than patients with more than 185 CTC (24.5 vs. 10.0 months; p = 0.018). Similarly, patients with fewer than 15 clusters in PV showed a longer OS than patients with more than 15 clusters (19 vs. 10 months; p = 0.004). These significant correlations were not observed in CVC analyses. Conclusions. CTC presence in PV could be an important prognostic factor to predict poor prognosis in early pancreatic cancer. In addition, the number of clustered-CTC correlate to a tumor negative differentiation degree and, therefore, could be used as a diagnostic biomarker for pancreatic cancer.
Collapse
|
|
14
|
Zhao X, Ma Y, Dong X, Zhang Z, Tian X, Zhao X, Yang Y. Molecular characterization of circulating tumor cells in pancreatic ductal adenocarcinoma: potential diagnostic and prognostic significance in clinical practice. Hepatobiliary Surg Nutr 2021; 10:796-810. [PMID: 35004946 DOI: 10.21037/hbsn-20-383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/07/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND The clinical value of heterogeneous sub-populations of circulating tumor cells (CTCs) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS Peripheral blood samples were obtained from 67 PDAC patients. CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition (EMT) or human equilibrative nucleoside transporter-1 (hENT-1). The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed. RESULTS EMT related CTCs could be isolated and identified from the 81% of patients (54/67), and both the total count (median: 5 vs. 17/mL, P<0.0001) and M-CTC percentage (median: 0.2 vs. 0.345, P=0.0244) of CTCs could differentiate local/regional with metastatic disease. Multivariate analysis showed that both AJCC stage (P=0.025) and M-CTC percentage (P=0.001) were independent prognostic indicators of recurrence free survival (RFS) in resected patients. Moreover, Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS (49.5 weeks vs. undefined, P=0.0288). No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues, and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS (P=0.016). Patients with low hENT-1 expression in CTCs had decreased RFS (32 weeks vs. undefined, P=0.0337). CONCLUSIONS CTCs could be the promising diagnostic biomarkers in PDAC patients, and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy. KEYWORDS Circulating tumor cells (CTCs); Pancreatic ductal adenocarcinoma (PDAC); Epithelial to mesenchymal transition (EMT); human equilibrative nucleoside transporter-1 (hENT-1).
Collapse
Affiliation(s)
- Xudong Zhao
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yongsu Ma
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Xiu Dong
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhengkui Zhang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Xiaodong Tian
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yinmo Yang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| |
Collapse
|
|
15
|
Heredia-Soto V, Rodríguez-Salas N, Feliu J. Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice? Cancers (Basel) 2021; 13:1986. [PMID: 33924143 PMCID: PMC8074327 DOI: 10.3390/cancers13081986] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.
Collapse
Affiliation(s)
- Victoria Heredia-Soto
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
| | - Nuria Rodríguez-Salas
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
| | - Jaime Feliu
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
| |
Collapse
|
|
16
|
Al-Shaheri FN, Alhamdani MSS, Bauer AS, Giese N, Büchler MW, Hackert T, Hoheisel JD. Blood biomarkers for differential diagnosis and early detection of pancreatic cancer. Cancer Treat Rev 2021; 96:102193. [PMID: 33865174 DOI: 10.1016/j.ctrv.2021.102193] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is currently the most lethal tumor entity and case numbers are rising. It will soon be the second most frequent cause of cancer-related death in the Western world. Mortality is close to incidence and patient survival after diagnosis stands at about five months. Blood-based diagnostics could be one crucial factor for improving this dismal situation and is at a stage that could make this possible. Here, we are reviewing the current state of affairs with its problems and promises, looking at various molecule types. Reported results are evaluated in the overall context. Also, we are proposing steps toward clinical utility that should advance the development toward clinical application by improving biomarker quality but also by defining distinct clinical objectives and the respective diagnostic accuracies required to achieve them. Many of the discussed points and conclusions are highly relevant to other solid tumors, too.
Collapse
Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany.
| | - Mohamed S S Alhamdani
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Nathalia Giese
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Markus W Büchler
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| |
Collapse
|
|
17
|
Wang PX, Xu Y, Sun YF, Cheng JW, Zhou KQ, Wu SY, Hu B, Zhang ZF, Guo W, Cao Y, Huang XW, Zhou J, Fan J, Yang XR. Detection of circulating tumour cells enables early recurrence prediction in hepatocellular carcinoma patients undergoing liver transplantation. Liver Int 2021; 41:562-573. [PMID: 33205544 DOI: 10.1111/liv.14734] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Liver transplantation (LTx) is one of the most effective treatments for hepatocellular carcinoma (HCC); however, tumour recurrence after LTx often leads to poor outcomes. This study investigated the value of circulating tumour cells (CTCs) as a predictor of recurrence following LTx in patients with HCC. METHODS This analysis included 193 patients with HCC who underwent LTx at our institute and accepted pre- and post-operative CTC detection; 38 were selected for serial CTC monitoring. The predictive value of CTCs for tumour recurrence in patients with HCC following LTx was evaluated. Single-cell whole genome sequencing was used to characterize CTCs. RESULTS Overall, the CTC burden decreased after LTx (P < .05). Post-operative CTC count ≥ 1 per 5 mL peripheral blood was identified as a potential biomarker for predicting tumour recurrence after LTx, especially in patients with no detectable CTCs prior to LTx and negative tumour serological biomarkers. The predictive value of post-operative CTC count ≥ 1 per 5 mL blood was retained in patients who did not meet the Milan criteria, University of California San Francisco (UCSF) criteria, or Fudan criteria (all P < .05). Furthermore, post-operative serial CTC detection may be useful in post-surgical surveillance for HCC recurrence. CONCLUSIONS CTCs may be a useful biomarker to evaluate recurrence risk following LTx in patients with HCC. Evaluation based on CTC detection may enhance the post-transplant management of HCC, and improve the therapeutic efficacy of LTx.
Collapse
Affiliation(s)
- Peng-Xiang Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Yang Xu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Yun-Fan Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Jian-Wen Cheng
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Kai-Qian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Sui-Yi Wu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Bo Hu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Ze-Fan Zhang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Ya Cao
- Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Central South University, Changsha, P. R. China
| | - Xiao-Wu Huang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China
| | - Xin-Rong Yang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| |
Collapse
|
|
18
|
Maatman TK, Zyromski NJ. In Brief. Curr Probl Surg 2021. [PMID: 32297552 DOI: 10.1016/j.cpsurg.2020.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
19
|
Song BG, Kwon W, Kim H, Lee EM, Han YM, Kim H, Byun Y, Lee KB, Lee KH, Lee KT, Lee JK, Jang JY, Park JK. Detection of Circulating Tumor Cells in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Evaluation as a Prognostic Marker. Front Oncol 2021; 10:616440. [PMID: 33680936 PMCID: PMC7930477 DOI: 10.3389/fonc.2020.616440] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/30/2020] [Indexed: 12/12/2022] Open
Abstract
Circulating tumor cells (CTCs) are useful biomarkers of many solid tumors, but are infrequently detected in early stage pancreatic ductal adenocarcinomas (PDACs). The first drainage of pancreatic venous blood flow come to portal vein and pass through the liver, and they finally go out for peripheral blood. We thought that comparing CTCs from portal vein and peripheral blood could enable us to understand the clinical meaning of CTCs from each different site in PDACs. Therefore, we aimed to determine 1) whether CTCs could be reliably identified in early stages (operable) of PDACs, 2) if there are any differences in the detected number of CTC in portal vein blood and peripheral blood, and 3) whether CTCs can be sensitive biomarkers for the prognosis of resectable PDAC patients. Newly diagnosed PDAC patients who underwent operation with curative intention between 2013 and 2015 were prospectively enrolled. Blood draws from portal and peripheral vein ran through the microfabricated porous filter, and anti-epithelial cell adhesion molecule (EpCAM) and anti-Plectin-1 antibodies were used for CTC identification. Baseline clinical characteristics, tumor characteristics, treatment, and clinical outcomes were assessed. The clinical stages of the 32 enrolled patients were as follows: IA/IB 1 (3.1%); IIA 9 (28.1%); IIB 17 (53.1%); III 5 (15.6%). Twenty-seven patients (84.4%) received R0 resection, while five patients (15.6%) received R1 resection. EpCAM+ CTCs were detected in 20 portal blood (62.5%) and 22 peripheral blood (68.8%). Plectin-1+ CTCs were identified in 14 portal blood (43.8%) and 16 peripheral blood (50%). Plectin-1-expressing CTCs were picked from CTC platform (microfabricated porous filter) and we could find out all KRAS mutation. Patients with detectable EpCAM+ CTC less than one in peripheral blood showed longer overall survival (OS) compared to patients with detectable CTCs more than one (35.5 months vs. 16.0 months). EpCAM and Plectin-1 successfully identified CTCs at the early stage of PDACs. Also, the number of CTCs could be a prognostic marker for survival in resectable PDACs.
Collapse
Affiliation(s)
- Byeong Geun Song
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Wooil Kwon
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyemin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Medical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eun Mi Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Young Min Han
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hongbeom Kim
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Yoonhyeong Byun
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyung Bun Lee
- Departments of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Kwang Hyuck Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Kyu Taek Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jong Kyun Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jin-Young Jang
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Joo Kyung Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| |
Collapse
|
|
20
|
Shah D, Lamarca A, Valle JW, McNamara MG. The Potential Role of Liquid Biopsies in Advancing the Understanding of Neuroendocrine Neoplasms. J Clin Med 2021; 10:jcm10030403. [PMID: 33494364 PMCID: PMC7865482 DOI: 10.3390/jcm10030403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/15/2021] [Accepted: 01/16/2021] [Indexed: 12/22/2022] Open
Abstract
Tumour tissue as a source for molecular profiling and for in vivo models has limitations (e.g., difficult access, limited availability, single time point, potential heterogeneity between primary and metastatic sites). Conversely, liquid biopsies provide an easily accessible approach, enabling timely and longitudinal interrogation of the tumour molecular makeup, with increased ability to capture spatial and temporal intra-tumour heterogeneity compared to tumour tissue. Blood-borne biomarker assays (e.g., circulating tumour cells (CTCs), circulating free/tumour DNA (cf/ctDNA)) pose unique opportunities for aiding in the molecular characterisation and phenotypic subtyping of neuroendocrine neoplasms and will be discussed in this article.
Collapse
Affiliation(s)
- Dinakshi Shah
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (D.S.); (A.L.)
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (D.S.); (A.L.)
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK;
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (D.S.); (A.L.)
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK;
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (D.S.); (A.L.)
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK;
- Correspondence:
| |
Collapse
|
|
21
|
Pang TCY, Po JW, Becker TM, Goldstein D, Pirola RC, Wilson JS, Apte MV. Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications. Pancreatology 2021; 21:103-114. [PMID: 33309014 DOI: 10.1016/j.pan.2020.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. METHODS A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. RESULTS The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood. CONCLUSIONS CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.
Collapse
Affiliation(s)
- Tony C Y Pang
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Joseph W Po
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Therese M Becker
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia
| | - David Goldstein
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Romano C Pirola
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia.
| |
Collapse
|
|
22
|
Tinganelli W, Durante M. Tumor Hypoxia and Circulating Tumor Cells. Int J Mol Sci 2020; 21:ijms21249592. [PMID: 33339353 PMCID: PMC7766826 DOI: 10.3390/ijms21249592] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Circulating tumor cells (CTCs) are a rare tumor cell subpopulation induced and selected by the tumor microenvironment's extreme conditions. Under hypoxia and starvation, these aggressive and invasive cells are able to invade the lymphatic and circulatory systems. Escaping from the primary tumor, CTCs enter into the bloodstream to form metastatic deposits or re-establish themselves in cancer's primary site. Although radiotherapy is widely used to cure solid malignancies, it can promote metastasis. Radiation can disrupt the primary tumor vasculature, increasing the dissemination of CTCs. Radiation also induces epithelial-mesenchymal transition (EMT) and eliminates suppressive signaling, causing the proliferation of existent, but previously dormant, disseminated tumor cells (DTCs). In this review, we collect the results and evidence underlying the molecular mechanisms of CTCs and DTCs and the effects of radiation and hypoxia in developing these cells.
Collapse
Affiliation(s)
- Walter Tinganelli
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, 64291 Darmstadt, Germany;
| | - Marco Durante
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, 64291 Darmstadt, Germany;
- Institut für Festkörperphysik, Technische Universität Darmstadt, 64291 Darmstadt, Germany
- Correspondence:
| |
Collapse
|
|
23
|
Frappart PO, Hofmann TG. Pancreatic Ductal Adenocarcinoma (PDAC) Organoids: The Shining Light at the End of the Tunnel for Drug Response Prediction and Personalized Medicine. Cancers (Basel) 2020; 12:E2750. [PMID: 32987786 PMCID: PMC7598647 DOI: 10.3390/cancers12102750] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for the development of early diagnostic and therapeutic tools. To this point, in the past 5 years, organoid technology has emerged as a revolution in the field of PDAC personalized medicine. Here, we are reviewing and discussing the current technical and scientific knowledge on PDAC organoids, their future perspectives, and how they can represent a game change in the fight against PDAC by improving both diagnosis and treatment options.
Collapse
Affiliation(s)
- Pierre-Olivier Frappart
- Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
| | | |
Collapse
|
|
24
|
Hasanain A, Blanco BA, Yu J, Wolfgang CL. The importance of circulating and disseminated tumor cells in pancreatic cancer. Surg Open Sci 2020; 1:49-55. [PMID: 32754693 PMCID: PMC7391911 DOI: 10.1016/j.sopen.2019.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/24/2019] [Accepted: 08/30/2019] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer is a lethal disease in a large part due to the systemic nature at the time of diagnosis. In those patients who undergo a potentially curative resection of pancreatic cancer, the overwhelming majority will have systemic relapse. Circulating tumor cells are an important mediator of the development of metastases. Circulating tumor cells have been identified in patients with clinically localized resectable pancreatic cancer and exist as several phenotypes. Mesenchymal and stem cell-like phenotypes of circulating tumor cells predict early recurrence and worse survival. This review focuses on the current understanding of circulating tumor cells in pancreatic cancer and how this information can be used in developing more effective therapy in the future.
Collapse
Affiliation(s)
- Alina Hasanain
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| | | | - Jun Yu
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| | - Christopher L Wolfgang
- Department of Surgery, Division of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21287.,The Johns Hopkins Pancreatic Cancer Precision Medicine Program
| |
Collapse
|
|
25
|
Lei Y, Sun N, Zhang G, Liu C, Lu Z, Huang J, Zhang C, Zang R, Che Y, Mao S, Fang L, Wang X, Zheng S, He J. Combined detection of aneuploid circulating tumor-derived endothelial cells and circulating tumor cells may improve diagnosis of early stage non-small-cell lung cancer. Clin Transl Med 2020; 10:e128. [PMID: 32659050 PMCID: PMC7418803 DOI: 10.1002/ctm2.128] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/26/2020] [Accepted: 06/28/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Many tumor-derived endothelial cells (TECs) are shed into the blood and turn into circulating TECs (CTECs). Rare circulating non-hematologic aneuploid cells contain CTCs and CTECs, which are biologically and functionally different from each other. CD31 is one of the most representative endothelial cell (EC) markers, yet CD31 alone is not sufficient to detect malignant CTECs due to the existence of abundant normal ECs in circulation. Aneuploidy of chromosome 8 (CEP8) is an important criterion for the identification of malignant cells. Combined in situ phenotypic and karyotypic characterization, which includes an examination of both protein expression and aneuploid chromosomes, has demonstrated its unique advantage for both effective distinguishing and comprehensive detection of CTCs and CTECs. METHODS A total of 98 subjects were recruited in the current study, including healthy donors and patients with benign disease and early-stage non-small-cell lung cancer (NSCLC). SE-iFISH was performed to quantitatively analyze diverse subtypes of aneuploid CD31+ CTECs and CD31- CTCs classified upon the ploidy of chromosome 8 and tumor marker expression in the specimens collected from the recruited subjects. RESULTS CD31- CTCs primarily consist of triploid CTCs with a small cell size (≤5 µm) and large hyperploid CTCs (≥ pentaploid), whereas CD31+ CTECs are mainly comprised of large hyperploid cells. Enumeration of the total numbers of both CTCs and CTECs might help identify malignant nodules with a high sensitivity, whereas quantification of tetraploid CTCs and CTECs specifically exhibited a high specificity for the identification of malignant nodules. CONCLUSIONS Combined detection of the specific subtypes of aneuploid CD31+ CTECs and CD31- CTCs may help to effectively identify malignant nodules with a higher sensitivity and specificity in early stage NSCLC patients.
Collapse
Affiliation(s)
- Yuanyuan Lei
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Nan Sun
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Guochao Zhang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Chengming Liu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Zhiliang Lu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Jianbing Huang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Chaoqi Zhang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Ruochuan Zang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Yun Che
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Shuangshuang Mao
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Lingling Fang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Xinfeng Wang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Sufei Zheng
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| | - Jie He
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical college, Beijing, China
| |
Collapse
|
|
26
|
Maatman TK, Zyromski NJ. Chronic Pancreatitis. Curr Probl Surg 2020; 58:100858. [PMID: 33663691 DOI: 10.1016/j.cpsurg.2020.100858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Thomas K Maatman
- Resident in General Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nicholas J Zyromski
- Professor of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA..
| |
Collapse
|
|
27
|
Stopa KB, Kusiak AA, Szopa MD, Ferdek PE, Jakubowska MA. Pancreatic Cancer and Its Microenvironment-Recent Advances and Current Controversies. Int J Mol Sci 2020; 21:E3218. [PMID: 32370075 PMCID: PMC7246785 DOI: 10.3390/ijms21093218] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) causes annually well over 400,000 deaths world-wide and remains one of the major unresolved health problems. This exocrine pancreatic cancer originates from the mutated epithelial cells: acinar and ductal cells. However, the epithelia-derived cancer component forms only a relatively small fraction of the tumor mass. The majority of the tumor consists of acellular fibrous stroma and diverse populations of the non-neoplastic cancer-associated cells. Importantly, the tumor microenvironment is maintained by dynamic cell-cell and cell-matrix interactions. In this article, we aim to review the most common drivers of PDAC. Then we summarize the current knowledge on PDAC microenvironment, particularly in relation to pancreatic cancer therapy. The focus is placed on the acellular stroma as well as cell populations that inhabit the matrix. We also describe the altered metabolism of PDAC and characterize cellular signaling in this cancer.
Collapse
Affiliation(s)
- Kinga B. Stopa
- Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7A, 30-387 Krakow, Poland;
| | - Agnieszka A. Kusiak
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland; (A.A.K.); (M.D.S.)
| | - Mateusz D. Szopa
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland; (A.A.K.); (M.D.S.)
| | - Pawel E. Ferdek
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland; (A.A.K.); (M.D.S.)
| | - Monika A. Jakubowska
- Malopolska Centre of Biotechnology, Jagiellonian University, ul. Gronostajowa 7A, 30-387 Krakow, Poland;
| |
Collapse
|
|
28
|
Wang Y, Yu X, Hartmann D, Zhou J. Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis. HPB (Oxford) 2020; 22:660-669. [PMID: 31786054 DOI: 10.1016/j.hpb.2019.11.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/28/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND It has been shown that circulating tumor cells in peripheral blood can be used to predict survival in patients with breast, prostate and other epithelial tumors. In the present study, we performed a meta-analysis to evaluate the prognostic role of circulating tumor cells (CTCs) in patients with pancreatic cancer. METHODS A systematic literature search of the databases was conducted from the inception to Jul 20, 2019. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated under a fixed or random effect model. RESULTS A total of 19 studies with 1320 confirmed individuals were included. Our meta-analysis showed that patients in the CTC-positive group had a significantly shorter overall survival (OS) (RR = 0.47, 95%CI = 0.33-0.61, P < 0.001) and progression-free survival (PFS) (P = 0.003) than CTC-negative patients. Moreover, subgroup analysis by ethnicity indicated that CTC-positive patients had a significantly shorter OS in both Asian and Western populations. Further subgroup analysis by detection methods, treatments, and Tumor Node Metastasis (TNM) stages also indicated that CTC-positive patients were associated with significant decreases in both OS and PFS in most subgroups. CONCLUSION Our meta-analysis indicates that CTC-positive patients have a worse OS and PFS than CTC-negative patients, which suggests that CTCs may act as predictive biomarkers for pancreatic cancer patients before treatment.
Collapse
Affiliation(s)
- Yang Wang
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China
| | - Xiaojin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar der Technischen Universitat Munchen, Munchen, 81675, Germany
| | - Jiahua Zhou
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China.
| |
Collapse
|
|
29
|
Davaran S, Sadeghinia M, Jamalpoor Z, Raeisdasteh Hokmabad V, Doosti-Telgerd M, Karimian A, Sadeghinia Z, Khalilifard J, Keramt A, Moradikhah F, Sadeghinia A. Multiple functions of microfluidic platforms: Characterization and applications in tissue engineering and diagnosis of cancer. Electrophoresis 2020; 41:1081-1094. [PMID: 32103511 DOI: 10.1002/elps.201900341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 02/16/2020] [Accepted: 02/19/2020] [Indexed: 12/13/2022]
Abstract
Microfluidic system, or lab-on-a-chip, has grown explosively. This system has been used in research for the first time and then entered in the clinical section. Due to economic reasons, this technique has been used for screening of laboratory and clinical indices. The microfluidic system solves some difficulties accompanied by clinical and biological applications. In this review, the interpretation and analysis of some recent developments in microfluidic systems in biomedical applications with more emphasis on tissue engineering and cancer will be discussed. Moreover, we try to discuss the features and functions of microfluidic systems.
Collapse
Affiliation(s)
- Soodabeh Davaran
- Department of Pharmaceutical Chemistry, Faculty of pharmacy, Tabriz University of Medical Science, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Sadeghinia
- School of Chemistry, University College of Science, University of Tehran, Tehran, Iran
| | - Zahra Jamalpoor
- Trauma Research Center, Aja University of Medical Science, Tehran, Iran
| | - Vahideh Raeisdasteh Hokmabad
- Drug Applied Research Center and Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Doosti-Telgerd
- Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ansar Karimian
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Zahra Sadeghinia
- Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Javad Khalilifard
- Hepatitis Research Center, Lorestan University of Medical Sciences, Kohorramabad, Iran
| | - Akram Keramt
- Department of Pharmaceutical Chemistry, Faculty of pharmacy, Tabriz University of Medical Science, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Farzad Moradikhah
- Department of Biomedical Engineering, Amirkabir, University of Technology, Tehran, Iran
| | - Ali Sadeghinia
- Department of Pharmaceutical Chemistry, Faculty of pharmacy, Tabriz University of Medical Science, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran.,Drug Applied Research Center and Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
30
|
Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers (Basel) 2019; 11:cancers11111659. [PMID: 31717773 PMCID: PMC6895979 DOI: 10.3390/cancers11111659] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. In the last twenty years (1999-2019), 140 articles have contained the key words "Circulating tumor cells, pancreatic cancer, prognosis and diagnosis." Articles were evaluated for the use of CTCs as prognostic markers and their correlation to survival in pancreatic ductal adenocarcinoma (PDAC). In the final selected 17 articles, the CTC detection rate varied greatly between different enrichment methodologies and ranged from 11% to 92%; the majority of studies used the antigen-dependent CellSearch© system for CTC detection. Fifteen of the reviewed studies showed a correlation between CTC presence and a worse overall survival. The heterogeneity of CTC-detection methods and the lack of uniform results hinder a comparison of the evaluated studies. However, CTCs can be detected in pancreatic cancer and harbor a hope to serve as an early detection tool. Larger studies are needed to corroborate CTCs as valid biomarkers in pancreatic cancer.
Collapse
|
|
31
|
Gall TMH, Belete S, Khanderia E, Frampton AE, Jiao LR. Circulating Tumor Cells and Cell-Free DNA in Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:71-81. [PMID: 30558725 DOI: 10.1016/j.ajpath.2018.03.020] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 03/06/2018] [Accepted: 03/26/2018] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer is detected late in the disease process and has an extremely poor prognosis. A blood-based biomarker that can enable early detection of disease, monitor response to treatment, and potentially allow for personalized treatment would be of great benefit. This review analyzes the literature regarding two potential biomarkers, circulating tumor cells (CTCs) and cell-free DNA (cfDNA), with regard to pancreatic ductal adenocarcinoma. The origin of CTCs and the methods of detection are discussed and a decade of research examining CTCs in pancreatic cancer is summarized, including both levels of CTCs and analyzing their molecular characteristics and how they may affect survival in both advanced and early disease and allow for treatment monitoring. The origin of cfDNA is discussed, and the literature over the past 15 years is summarized. This includes analyzing cfDNA for genetic mutations and methylation abnormalities, which have the potential to be used for the detection and prognosis of pancreatic ductal adenocarcinoma. However, the research certainly remains in the experimental stage, warranting future large trials in these areas.
Collapse
Affiliation(s)
- Tamara M H Gall
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom.
| | - Samuel Belete
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| | - Esha Khanderia
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| | - Adam E Frampton
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| | - Long R Jiao
- Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital Campus, London, United Kingdom
| |
Collapse
|
|
32
|
[Circulating tumor cells in pancreatic cancer : Results of morphological and molecular analyses and comparisons with the primary tumor]. DER PATHOLOGE 2019; 39:311-314. [PMID: 30483865 DOI: 10.1007/s00292-018-0550-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a disease with a poor prognosis. PDAC shows characteristic mutations within codon 12/13. Circulating tumor cells (CTC) detected in blood samples of patients with cancer are hypothesized as the means of systemic tumor spread. But less is known about morphological/molecular characteristics or the pathophysiological meaning of PDAC CTC. OBJECTIVES The aim of the study was a cytomorphological and genetic analysis of CTC from patients with PDAC followed by the correlation of the results with those of the corresponding tumor in the pancreas. MATERIAL AND METHODS Blood samples of 58 patients with PDAC and 10 "normal" control donors were processed through a size-based CTC isolation. KRAS-mutation analyses were performed for CTC and the primary tumor and the results were compared. Furthermore, their potential as a prognostic marker was evaluated. RESULTS In patients with different UICC stages CTC were detected, but not in normal control patients. There was a trend for a worse median overall survival (OS) for patients with >3 CTC/ml. Patients with a KRASG12V mutation showed a trend for a better median OS compared to those with other KRAS mutations (10 months) or even without KRAS mutation. Fifty-eight percent of the patients presented concordant KRAS mutations in the primary tumor and corresponding CTC, while 42% were discordant. The median OS for both groups was similar. CONCLUSIONS Detection and characterization of CTC (for example by KRAS mutation analysis) may be useful for prognosis. Furthermore, it expands our knowledge of tumor biology and may detect possible tumor heterogeneity regarding the mutation profile of some cancer types.
Collapse
|
|
33
|
Lee J, Park SS, Lee YK, Norton JA, Jeffrey SS. Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA. Mol Oncol 2019; 13:1623-1650. [PMID: 31243883 PMCID: PMC6670020 DOI: 10.1002/1878-0261.12537] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 06/07/2019] [Accepted: 06/25/2019] [Indexed: 12/22/2022] Open
Abstract
Reliable biomarkers are required to evaluate and manage pancreatic ductal adenocarcinoma. Circulating tumor cells and circulating tumor DNA are shed into blood and can be relatively easily obtained from minimally invasive liquid biopsies for serial assays and characterization, thereby providing a unique potential for early diagnosis, forecasting disease prognosis, and monitoring of therapeutic response. In this review, we provide an overview of current technologies used to detect circulating tumor cells and circulating tumor DNA and describe recent advances regarding the multiple clinical applications of liquid biopsy in pancreatic ductal adenocarcinoma.
Collapse
Affiliation(s)
- Jee‐Soo Lee
- Department of Laboratory MedicineHallym University Sacred Heart HospitalAnyangKorea
- Department of Laboratory MedicineSeoul National University College of MedicineSeoulKorea
| | - Sung Sup Park
- Department of Laboratory MedicineSeoul National University College of MedicineSeoulKorea
| | - Young Kyung Lee
- Department of Laboratory MedicineHallym University Sacred Heart HospitalAnyangKorea
- Department of Laboratory MedicineHallym University College of MedicineAnyangKorea
| | - Jeffrey A. Norton
- Department of SurgeryStanford University School of MedicineStanfordCAUSA
| | | |
Collapse
|
|
34
|
Lopresti A, Malergue F, Bertucci F, Liberatoscioli ML, Garnier S, DaCosta Q, Finetti P, Gilabert M, Raoul JL, Birnbaum D, Acquaviva C, Mamessier E. Sensitive and easy screening for circulating tumor cells by flow cytometry. JCI Insight 2019; 5:128180. [PMID: 31194699 DOI: 10.1172/jci.insight.128180] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Circulating Tumor Cells (CTCs) represent an easy, repeatable and representative access to information regarding solid tumors. However, their detection remains difficult because of their paucity, their short half-life, and the lack of reliable surface biomarkers. Flow cytometry (FC) is a fast, sensitive and affordable technique, ideal for rare cells detection. Adapted to CTCs detection (i.e. extremely rare cells), most FC-based techniques require a time-consuming pre-enrichment step, followed by a 2-hours staining procedure, impeding on the efficiency of CTCs detection. We overcame these caveats and reduced the procedure to less than one hour, with minimal manipulation. First, cells were simultaneously fixed, permeabilized, then stained. Second, using low-speed FC acquisition conditions and two discriminators (cell size and pan-cytokeratin expression), we suppressed the pre-enrichment step. Applied to blood from donors with or without known malignant diseases, this protocol ensures a high recovery of the cells of interest independently of their epithelial-mesenchymal plasticity and can predict which samples are derived from cancer donors. This proof-of-concept study lays the bases of a sensitive tool to detect CTCs from a small amount of blood upstream of in-depth analyses.
Collapse
Affiliation(s)
- Alexia Lopresti
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Fabrice Malergue
- Research, Beckman Coulter Life Sciences, Marseille, Marseille, France
| | - François Bertucci
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France.,Service d'Oncologie Médicale, Institut Paoli-Calmettes, Marseille, France
| | - Maria Lucia Liberatoscioli
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Severine Garnier
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Quentin DaCosta
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Pascal Finetti
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Marine Gilabert
- Service d'Oncologie Médicale, Institut Paoli-Calmettes, Marseille, France
| | - Jean Luc Raoul
- Service d'Oncologie Médicale, Institut Paoli-Calmettes, Marseille, France
| | - Daniel Birnbaum
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Claire Acquaviva
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| | - Emilie Mamessier
- Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France
| |
Collapse
|
|
35
|
Bankó P, Lee SY, Nagygyörgy V, Zrínyi M, Chae CH, Cho DH, Telekes A. Technologies for circulating tumor cell separation from whole blood. J Hematol Oncol 2019; 12:48. [PMID: 31088479 PMCID: PMC6518774 DOI: 10.1186/s13045-019-0735-4] [Citation(s) in RCA: 218] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 04/18/2019] [Indexed: 12/13/2022] Open
Abstract
The importance of early cancer diagnosis and improved cancer therapy has been clear for years and has initiated worldwide research towards new possibilities in the care strategy of patients with cancer using technological innovations. One of the key research fields involves the separation and detection of circulating tumor cells (CTC) because of their suggested important role in early cancer diagnosis and prognosis, namely, providing easy access by a liquid biopsy from blood to identify metastatic cells before clinically detectable metastasis occurs and to study the molecular and genetic profile of these metastatic cells. Provided the opportunity to further progress the development of technology for treating cancer, several CTC technologies have been proposed in recent years by various research groups and companies. Despite their potential role in cancer healthcare, CTC methods are currently mainly used for research purposes, and only a few methods have been accepted for clinical application because of the difficulties caused by CTC heterogeneity, CTC separation from the blood, and a lack of thorough clinical validation. Therefore, the standardization and clinical application of various developed CTC technologies remain important subsequent necessary steps. Because of their suggested future clinical benefits, we focus on describing technologies using whole blood samples without any pretreatment and discuss their advantages, use, and significance. Technologies using whole blood samples utilize size-based, immunoaffinity-based, and density-based methods or combinations of these methods as well as positive and negative enrichment during separation. Although current CTC technologies have not been truly implemented yet, they possess high potential as future clinical diagnostic techniques for the individualized therapy of patients with cancer. Thus, a detailed discussion of the clinical suitability of these new advanced technologies could help prepare clinicians for the future and can be a foundation for technologies that would be used to eliminate CTCs in vivo.
Collapse
Affiliation(s)
- Petra Bankó
- Department of Biochemical Engineering, Budapest University of Technology and Economics, Budapest, Hungary
| | - Sun Young Lee
- Department of Radiation Oncology, Chonbuk National University Hospital, Jeonju, Republic of Korea
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical, Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea
| | | | - Miklós Zrínyi
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Chang Hoon Chae
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Dong Hyu Cho
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical, Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea
- Department of Obstetrics and Gynecology, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - András Telekes
- Department of Oncology, St. Lazarus Hospital, Salgótarján, Hungary
| |
Collapse
|
|
36
|
|
|
37
|
Rostami P, Kashaninejad N, Moshksayan K, Saidi MS, Firoozabadi B, Nguyen NT. Novel approaches in cancer management with circulating tumor cell clusters. JOURNAL OF SCIENCE: ADVANCED MATERIALS AND DEVICES 2019; 4:1-18. [DOI: 10.1016/j.jsamd.2019.01.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
38
|
Thege FI, Gruber CN, Cardle II, Cong SH, Lannin TB, Kirby BJ. anti-EGFR capture mitigates EMT- and chemoresistance-associated heterogeneity in a resistance-profiling CTC platform. Anal Biochem 2019; 577:26-33. [PMID: 30790546 DOI: 10.1016/j.ab.2019.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 01/18/2019] [Accepted: 02/06/2019] [Indexed: 12/19/2022]
Abstract
Capture and analysis of circulating tumor cells (CTCs) holds promise for diagnosing and guiding treatment of pancreatic cancer. To accurately monitor disease progression, capture platforms must be robust to processes that increase the phenotypic heterogeneity of CTCs. Most CTC-analysis technologies rely on the recognition of epithelial-specific markers for capture and identification, in particular the epithelial cell-adhesion molecule (EpCAM) and cytokeratin. As the epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance are both associated with loss of epithelial markers and characteristics, the effect of these processes on the expression of commonly used CTC markers, specifically EpCAM, EGFR and cytokeratin, requires further exploration. To determine this effect, we developed an in vitro model of EMT and acquired gemcitabine resistance in human pancreatic cancer cell lines. Using this model, we show that EMT-induction and acquired chemoresistance decrease EpCAM expression and microfluidic anti-EpCAM capture performance. Furthermore, we find that EGFR capture is more robust to these processes. By measuring the expression of known mediators of chemoresistance in captured cells using automated imaging and image processing, we demonstrate the ability to resistance-profile cells on-chip. We expect that this approach will allow for the development of improved non-invasive biomarkers of pancreatic cancer progression.
Collapse
Affiliation(s)
| | | | | | | | | | - Brian J Kirby
- Cornell University, Ithaca, USA; Weill Cornell Medicine, New York, USA.
| |
Collapse
|
|
39
|
Samandari M, Julia MG, Rice A, Chronopoulos A, Del Rio Hernandez AE. Liquid biopsies for management of pancreatic cancer. Transl Res 2018; 201:98-127. [PMID: 30118658 DOI: 10.1016/j.trsl.2018.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/17/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
Collapse
Affiliation(s)
- Mohamadmahdi Samandari
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - María Gil Julia
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Antonios Chronopoulos
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Armando E Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
| |
Collapse
|
|
40
|
Circulating Tumor Cells for the Management of Renal Cell Carcinoma. Diagnostics (Basel) 2018; 8:diagnostics8030063. [PMID: 30177639 PMCID: PMC6164661 DOI: 10.3390/diagnostics8030063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 08/30/2018] [Accepted: 08/31/2018] [Indexed: 12/17/2022] Open
Abstract
Renal cell carcinoma is a highly malignant cancer that would benefit from non-invasive innovative markers providing early diagnosis and recurrence detection. Circulating tumor cells are a particularly promising marker of tumor invasion that could be used to improve the management of patients with RCC. However, the extensive genetic and immunophenotypic heterogeneity of cells from RCC and their trend to transition to the mesenchymal phenotype when they circulate in blood constitute a challenge for their sensitive and specific detection. This review analyzes published studies targeting CTC in patients with RCC, in the context of the biological, pathological, and molecular complexity of this particular cancer. Although further analytical and clinical studies are needed to pinpoint the most suitable approach for highly sensitive CTC detection in RCC patients, it is clear that this field can bring a relevant guide to clinicians and help to RCC patients. Furthermore, as described, a particular subtype of RCC-the ccRCC-can be used as a model to study the relationship between cytomorphological and genetic cellular markers of malignancy, an important issue for the study of CTC from any type of solid cancer.
Collapse
|
|
41
|
Mansilla C, Soria E, Ramírez N. The identification and isolation of CTCs: A biological Rubik's cube. Crit Rev Oncol Hematol 2018; 126:129-134. [PMID: 29759554 DOI: 10.1016/j.critrevonc.2018.03.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 02/22/2018] [Accepted: 03/29/2018] [Indexed: 12/17/2022] Open
Abstract
Liquid biopsy represents an alternative to conventional biopsies for the evaluation of tumors mainly due to its easy sampling. One of the main applications is the enumeration of Circulating Tumor Cells (CTCs) to evaluate tumor progression or response to treatment. The analysis of the functional characteristics of CTCs could give us much more information about their role in order to establish a more personalized treatment for the patients. The major issue that has to be solved is the isolation of the CTC population. Multiple protocols have been developed, however none of them has demonstrated to be the definitive one. In fact, a combination of these techniques has often been performed in order to obtain a purer and viable population of CTCs. In this review we have summarized for the first time the different combinatorial approaches used in the last years to optimize the isolation of CTCs and their limitations.
Collapse
Affiliation(s)
- Cristina Mansilla
- Oncohematology Research Group, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Elena Soria
- Oncohematology Research Group, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Natalia Ramírez
- Oncohematology Research Group, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain.
| |
Collapse
|
|
42
|
Wang Y, Chai N, Feng J, Linghu E. A prospective study of endoscopic ultrasonography features, cyst fluid carcinoembryonic antigen, and fluid cytology for the differentiation of small pancreatic cystic neoplasms. Endosc Ultrasound 2018; 7:335-342. [PMID: 28836521 PMCID: PMC6199906 DOI: 10.4103/eus.eus_40_17] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background and Objectives With improvements in imaging technologies, pancreatic cystic lesions (PCLs) have been increasingly identified in recent years. However, the imaging modalities used to differentiate the categories of pancreatic cysts remain limited, which may cause confusion when planning treatment. Due to progress in endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) technology, auxiliary diagnosis by the detection of cystic fluid has become a recent trend. Methods From March 2015 to April 2016, 120 patients with PCLs were enrolled in this study. According to the results of EUS, cyst fluid carcinoembryonic antigen (CEA) analysis, and cystic fluid cytology, the patients were divided into two groups: a nonmucinous and a mucinous group. Of those, 61 patients who had undergone surgical resection were included in the analysis. The clinical features, biochemical and tumor markers of cyst fluid as well as the cytological test results of the patients were compared with histopathology results. Results A cyst size of 4.0 cm was used as the boundary value; a cyst ≤4.0 cm was defined as a small PCL. 87 (72.5%) lesions were ≤4.0 cm, and 33 (27.5%) lesions were >4.0 cm. Regarding the analysis of CEA and carbohydrate antigens 19-9 (CA19-9), significant differences were found between the nonmucinous and mucinous groups (P < 0.05) according to nonparametric independent samples tests. The EUS, cystic fluid CEA, and cystic fluid cytology results were compared with the tissue pathology findings using McNemar's test (P < 0.05) and showed a sensitivity of 90% and a specificity of 84%. Conclusion A diagnostic combination of EUS, cyst fluid CEA, and cystic fluid cytology could be used to differentiate small pancreatic cystic neoplasms. Cystic fluid cytology analysis is helpful for planning treatment for pancreatic cystic tumors that pose a surgical risk.
Collapse
Affiliation(s)
- Ying Wang
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing; Department of Gastroenterology, The affiliated Fu Xing Hospital of Capital Medical University, Beijing, China
| | - Ningli Chai
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - Jia Feng
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - Enqiang Linghu
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
43
|
Awasthi NP, Kumari S, Neyaz A, Gupta S, Agarwal A, Singhal A, Husain N. EpCAM-based Flow Cytometric Detection of Circulating Tumor Cells in Gallbladder Carcinoma Cases. Asian Pac J Cancer Prev 2017; 18:3429-3437. [PMID: 29286615 PMCID: PMC5980906 DOI: 10.22034/apjcp.2017.18.12.3429] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose: Liquid biopsy has entered the arena of cancer diagnostics in the past decade and detection of circulating tumor cells (CTC) is one diagnostic component. CTCs in gallbladder cancer (GBC) have hitherto not been comprehensively analysed. Methods and Results: The current study focused on the diagnostic role of CTCs in 27 cases of treatment-naive GBC and 6 normal controls as well as 6 cases of cholecystitis. An EasySep kit featuring negative immunomagnetic bead separation and flow cytometric detection of EpCAM positive and CD45 negative cells revealed CTCs in 25 of the 27 cases. At a cut-off point of ≥1, the CTC count discriminated GBC from controls with a sensitivity, specificity and diagnostic accuracy of 92.6%, 91.7% and 92.3%, respectively. CTC levels in turn correlated significantly with clinico-pathological parameters of cases in terms of known prognostic indicators, with significant diagnostic potential at a cut-off point of >4, to discriminate disease stage I and II vs. III and IV GBC. With a cut-off of >3, the CTC count discriminated tumor stages I and II vs. III and IV and at >6 CTCs could discriminate metastatic vs. non metastatic GBCs with a sensitivity, specificity and diagnostic accuracy of 55. 6%, 100.0% and 85.2, respectively. A review of CTC in pancreatico-biliary malignancies is included. Conclusion: Detection and quantification of CTCs may serve as a non-invasive biomarker for GBC diagnosis in correlation with radiological studies.
Collapse
Affiliation(s)
- Namrata Punit Awasthi
- Department of Pathology,Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow-226010, India.
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Keane MG, Shah A, Pereira SP, Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy. F1000Res 2017; 6:1643. [PMID: 28944047 PMCID: PMC5585877 DOI: 10.12688/f1000research.11371.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/06/2017] [Indexed: 12/12/2022] Open
Abstract
The UK incidence of pancreatic ductal adenocarcinoma is 9 per 100,000 population, and biliary tract cancer occurs at a rate of 1–2 per 100,000. The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review.
Collapse
Affiliation(s)
| | - Amar Shah
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Stephen P Pereira
- UCL Institute for Liver and Digestive Health, Royal Free Campus, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
| |
Collapse
|
|
45
|
Wu T, Cheng B, Fu L. Clinical Applications of Circulating Tumor Cells in Pharmacotherapy: Challenges and Perspectives. Mol Pharmacol 2017; 92:232-239. [PMID: 28356334 DOI: 10.1124/mol.116.108142] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Accepted: 03/22/2017] [Indexed: 12/11/2022] Open
Abstract
Screening for circulating tumor cells (CTCs) has been identified as one approach to ultrasensitive liquid biopsy in real-time monitoring of cancer patients. The detection of CTCs in peripheral blood from cancer patients is promising as a diagnostic tool; however, the application of CTCs in therapeutic treatment still faces serious challenges with respect to specificity and sensitivity. Here, we review the significant roles of CTCs in metastasis and the strengths and weaknesses of the currently available methods for CTC detection and characterization. Moreover, we discuss the clinical application of CTCs as markers for patient prognosis, and we specifically focus on the application of CTCs as indicators in cancer pharmacotherapy. Characterization of the detected CTCs will provide new biologic perspectives and clinical applications for the treatment of cancer patients with metastasis.
Collapse
Affiliation(s)
- Tong Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute (T.W., L.F.); and Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China (T.W., B.C.)
| | - Bin Cheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute (T.W., L.F.); and Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China (T.W., B.C.)
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute (T.W., L.F.); and Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China (T.W., B.C.)
| |
Collapse
|
|
46
|
Abstract
OBJECTIVES Circulating epithelial cells (CECs) are identified in the blood of patients with intraductal papillary mucinous neoplasms (IPMNs) despite the absence of malignancy. We assessed the blood of patients undergoing resection for IPMN or other benign pancreatic lesions for CECs. METHODS Peripheral blood was collected from 26 patients prior to pancreatic resection and filtered by the ISET (Isolation by Size of Epithelial Tumor Cells) method. Circulating epithelial cells were identified with antibodies to cytokeratin and Pdx1 (pancreas and duodenal homeobox protein 1), a pancreas marker. RESULTS Nineteen patients underwent resection of an IPMN without associated malignancy. Eleven patients (58%) had cytokeratin-positive CECs. Circulating epithelial cells were significantly more likely to be found in patients with IPMNs with high-grade dysplasia (P = 0.04). In addition, 10 of the 11 patients with cytokeratin-positive CECs also had separate populations of cytokeratin-positive, Pdx1-positive CECs, suggesting a pancreatic source. Dual-staining CECs were more frequently found in patients with high-grade dysplasia (P = 0.04). Patients with IPMNs were significantly more likely to have pan-cytokeratin CECs in the blood compared with those without IPMNs (P = 0.01). CONCLUSIONS Circulating epithelial cells staining with potential pancreas-specific markers have been found in patients with IPMNs, even without malignancy. Circulating epithelial cells may help to differentiate patients with high-grade IPMN from lower grades of dysplasia and other pancreatic cysts.
Collapse
|
|
47
|
Mascalchi M, Maddau C, Sali L, Bertelli E, Salvianti F, Zuccherelli S, Matucci M, Borgheresi A, Raspanti C, Lanzetta M, Falchini M, Mazza E, Vella A, Luconi M, Pinzani P, Pazzagli M. Circulating tumor cells and microemboli can differentiate malignant and benign pulmonary lesions. J Cancer 2017; 8:2223-2230. [PMID: 28819424 PMCID: PMC5560139 DOI: 10.7150/jca.18418] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 02/26/2017] [Indexed: 01/02/2023] Open
Abstract
The presence of circulating tumor cells (CTC) or microemboli (CTM) in the peripheral blood can theoretically anticipate malignancy of solid lesions in a variety of organs. We aimed to preliminarily assess this capability in patients with pulmonary lesions of suspected malignant nature. We used a cell-size filtration method (ScreenCell) and cytomorphometric criteria to detect CTC/CTM in a 3 mL sample of peripheral blood that was taken just before diagnostic percutaneous CT-guided fine needle aspiration (FNA) or core biopsy of the suspicious lung lesion. At least one CTC/CTM was found in 47 of 67 (70%) patients with final diagnoses of lung malignancy and in none of 8 patients with benign pulmonary nodules. In particular they were detected in 38 (69%) of 55 primary lung cancers and in 9 (75%) of 12 lung metastases from extra-pulmonary cancers. Sensitivity of CTC/CTM presence for malignancy was 70.1% (95%CI: 56.9-83.1%), specificity 100%, positive predictive value 100% and negative predictive value 28.6% (95%CI: 11.9-45.3%). Remarkably, the presence of CTC/CTM anticipated the diagnosis of primary lung cancer in 3 of 5 patients with non-diagnostic or inconclusive results of FNA or core biopsy, whereas CTC/CTM were not observed in 1 patient with sarcoidosis and 1 with amarthocondroma. These results suggest that presently, due to the low sensitivity, the search of CTC/CTM cannot replace CT guided percutaneous FNA or core biopsy in the diagnostic work-up of patients with suspicious malignant lung lesions. However, the high specificity may as yet indicate a role in cases with non-diagnostic or inconclusive FNA or core biopsy results that warrants to be further investigated.
Collapse
Affiliation(s)
- Mario Mascalchi
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Cristina Maddau
- Oncological Prevention Laboratory, Institute for Cancer Research and Prevention (ISPO), Florence, Italy
| | - Lapo Sali
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Elena Bertelli
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Francesca Salvianti
- Clinical Biochemistry Unit, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Stefania Zuccherelli
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Marzia Matucci
- Oncological Prevention Laboratory, Institute for Cancer Research and Prevention (ISPO), Florence, Italy
| | - Alessandra Borgheresi
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Claudio Raspanti
- Interventional Radiology Unit, Careggi Hospital, Florence, Italy
| | - Monica Lanzetta
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Massimo Falchini
- Diagnostic and Interventional Radiology Units, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Ernesto Mazza
- Interventional Radiology Unit, Careggi Hospital, Florence, Italy
| | - Alessandra Vella
- Nuclear Medicine Unit, Le Scotte University Hospital, Siena, Italy
| | - Michaela Luconi
- Endocrinology Unit, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Pamela Pinzani
- Clinical Biochemistry Unit, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Mario Pazzagli
- Clinical Biochemistry Unit, "Mario Serio" Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| |
Collapse
|
|
48
|
Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations. Sci Rep 2017; 7:4510. [PMID: 28674438 PMCID: PMC5495768 DOI: 10.1038/s41598-017-04601-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 05/08/2017] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation. We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p < 0.001). Patients with >3 CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3–3 CTC/ml (P = 0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRASG12V mutation in their CTC (n = 14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P = 0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 “tumor-CTC-pairs” (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P = 0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology.
Collapse
|
|
49
|
Pang TCY, Xu Z, Pothula S, Becker T, Goldstein D, Pirola RC, Wilson JS, Apte MV. Circulating pancreatic stellate (stromal) cells in pancreatic cancer—a fertile area for novel research. Carcinogenesis 2017; 38:588-591. [PMID: 28379317 DOI: 10.1093/carcin/bgx030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
|
|
50
|
Rosenbaum MW, Cauley CE, Kulemann B, Liss AS, Castillo CFD, Warshaw AL, Lillemoe KD, Thayer SP, Pitman MB. Cytologic characteristics of circulating epithelioid cells in pancreatic disease. Cancer 2017; 125:332-340. [PMID: 28257167 PMCID: PMC5432380 DOI: 10.1002/cncy.21841] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 01/25/2017] [Accepted: 01/26/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. METHODS Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. RESULTS No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CONCLUSIONS CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332-340. © 2017 American Cancer Society.
Collapse
MESH Headings
- Adenocarcinoma/blood
- Adenocarcinoma/pathology
- Adenoma/blood
- Adenoma/pathology
- Ampulla of Vater/pathology
- Bile Duct Neoplasms/blood
- Bile Duct Neoplasms/pathology
- Carcinoma, Acinar Cell/blood
- Carcinoma, Acinar Cell/pathology
- Carcinoma, Pancreatic Ductal/blood
- Carcinoma, Pancreatic Ductal/pathology
- Case-Control Studies
- Cholangiocarcinoma/blood
- Cholangiocarcinoma/pathology
- Common Bile Duct Neoplasms/blood
- Common Bile Duct Neoplasms/pathology
- Cystadenoma, Serous/blood
- Cystadenoma, Serous/pathology
- Epidermal Cyst
- Humans
- Neoplasms, Cystic, Mucinous, and Serous/blood
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Neoplastic Cells, Circulating/pathology
- Neuroendocrine Tumors/blood
- Neuroendocrine Tumors/pathology
- Pancreatic Diseases/blood
- Pancreatic Diseases/pathology
- Pancreatic Neoplasms/blood
- Pancreatic Neoplasms/pathology
- Pancreatitis, Chronic/blood
- Pancreatitis, Chronic/pathology
- Prognosis
- Splenic Diseases
Collapse
Affiliation(s)
- Matthew W Rosenbaum
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Christy E Cauley
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Birte Kulemann
- Department of Surgery, University Hospital Freiburg, Freiburg, Germany
| | - Andrew S Liss
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Sarah P Thayer
- Division of Surgical Oncology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska
| | - Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| |
Collapse
|