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Zhao YN, Zhang X, Bai JJ, Jia HY, Chen ML, Wang JH. Inertial and Deterministic Lateral Displacement Integrated Microfluidic Chips for Epithelial-Mesenchymal Transition Analysis. Anal Chem 2024; 96:18187-18194. [PMID: 39484816 DOI: 10.1021/acs.analchem.4c04366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
With the aim of efficiently sorting rare circulating tumor cells (CTCs) from blood and minimizing damage to CTCs during isolation, we constructed an inertia-assisted single-cell focusing generator (I-SCF) and a water droplet deterministic lateral displacement cell sorting (D-DLD) microfluidic system (IDIC) based on different sizes, the device is initially sorted by a continuous fluid swing and Dean flow-assisted helical micromixers, then flows through a droplet shaped DLD region, enabling single-cell focused sequencing and precise separation, improving cell separation efficiency (>95%) and purity, while ensuring a high single cells survival rate of more than 98.6%. Subsequently, breast cancer cell lines were run through our chip, and then the downstream epithelial-mesenchymal transition (EMT) process induced by TGF-β was detected, and the levels of three proteins, EpCAM, PD-L1, and N-cadherin, were analyzed to establish the relationship between PD-L1 and the EMT process. Compared with other analytical techniques such as the filtration method, the enrichment method and immunoaffinity capture methods, this method not only ensures the separation efficiency and purity, but also ensures the cell activity, and avoids missing the different results caused by the heterogeneity of CTCs due to the isolation of high purity (84.01%). The device has a high throughput processing capacity (5 mL of diluted whole blood/∼2.8 h). By using the chip, we can more easily and conveniently predict tumor stage and carry out cancer prevention and treatment in advance, and it is expected to be further developed into a clinical liquid biopsy technology in the future.
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Affiliation(s)
- Ya-Nan Zhao
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Xuan Zhang
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Jun-Jie Bai
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Hao-Yu Jia
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Ming-Li Chen
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
| | - Jian-Hua Wang
- Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China
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Zhu Z, Zhang Y, Zhang W, Tang D, Zhang S, Wang L, Zou X, Ni Z, Zhang S, Lv Y, Xiang N. High-throughput enrichment of portal venous circulating tumor cells for highly sensitive diagnosis of CA19-9-negative pancreatic cancer patients using inertial microfluidics. Biosens Bioelectron 2024; 259:116411. [PMID: 38781696 DOI: 10.1016/j.bios.2024.116411] [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: 10/25/2023] [Revised: 05/09/2024] [Accepted: 05/19/2024] [Indexed: 05/25/2024]
Abstract
The carbohydrate antigen 19-9 (CA19-9) is commonly used as a representative biomarker for pancreatic cancer (PC); however, it lacks sensitivity and specificity for early-stage PC diagnosis. Furthermore, some patients with PC are negative for CA19-9 (<37 U/mL), which introduces additional limitations to their accurate diagnosis and treatment. Hence, improved methods to accurately detect PC stages in CA19-9-negative patients are warranted. In this study, tumor-proximal liquid biopsy and inertial microfluidics were coupled to enable high-throughput enrichment of portal venous circulating tumor cells (CTCs) and support the effective diagnosis of patients with early-stage PC. The proposed inertial microfluidic system was shown to provide size-based enrichment of CTCs using inertial focusing and Dean flow effects in slanted spiral channels. Notably, portal venous blood samples were found to have twice the yield of CTCs (21.4 cells per 5 mL) compared with peripheral blood (10.9 CTCs per 5 mL). A combination of peripheral and portal CTC data along with CA19-9 results showed to greatly improve the average accuracy of CA19-9-negative PC patients from 47.1% with regular CA19-9 tests up to 87.1%. Hence, portal venous CTC-based microfluidic biopsy can be used with high sensitivity and specificity for the diagnosis of early-stage PC, particularly in CA19-9-negative patients.
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Affiliation(s)
- Zhixian Zhu
- School of Mechanical Engineering and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, 211189, China
| | - Yixuan Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China; Nanjing University Institute of Pancreatology, China
| | - Wenjun Zhang
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Dezhi Tang
- School of Mechanical Engineering and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, 211189, China
| | - Song Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China; Nanjing University Institute of Pancreatology, China
| | - Lei Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China; Nanjing University Institute of Pancreatology, China
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China; Nanjing University Institute of Pancreatology, China
| | - Zhonghua Ni
- School of Mechanical Engineering and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, 211189, China.
| | - Shu Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China; Nanjing University Institute of Pancreatology, China.
| | - Ying Lv
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No.321 Zhongshan Road, Nanjing, 210008, Jiangsu, China; Nanjing University Institute of Pancreatology, China.
| | - Nan Xiang
- School of Mechanical Engineering and Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments, Southeast University, Nanjing, 211189, China.
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Xuan Y, Gao Q, Wang C, Cai D. Positive peritoneal lavage fluid cytology based on isolation by size of epithelial tumor cells indicates a high risk of peritoneal metastasis. PeerJ 2024; 12:e17602. [PMID: 38952968 PMCID: PMC11216200 DOI: 10.7717/peerj.17602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 05/30/2024] [Indexed: 07/03/2024] Open
Abstract
Background Peritoneal metastasis (PM) is the most prevalent type of metastasis in patients with gastric cancer (GC) and has an extremely poor prognosis. The detection of free cancer cells (FCCs) in the peritoneal cavity has been demonstrated to be one of the worst prognostic factors for GC. However, there is a lack of sensitive detection methods for FCCs in the peritoneal cavity. This study aimed to use a new peritoneal lavage fluid cytology examination to detect FCCs in patients with GC, and to explore its clinical significance on diagnosing of occult peritoneal metastasis (OPM) and prognosis. Methods Peritoneal lavage fluid from 50 patients with GC was obtained and processed via the isolation by size of epithelial tumor cells (ISET) method. Immunofluorescence and fluorescence in situ hybridization (FISH) were used to identify FCCs expressing chromosome 8 (CEP8), chromosome 17 (CEP17), and epithelial cell adhesion molecule (EpCAM). Results Using a combination of the ISET platform and immunofluorescence-FISH, the detection of FCCs was higher than that by light microscopy (24.0% vs. 2.0%). Samples were categorized into positive and negative groups, based on the expressions of CEP8, CEP17, and EpCAM. Statistically significant relationships were demonstrated between age (P = 0.029), sex (P = 0.002), lymphatic invasion (P = 0.001), pTNM stage (P = 0.001), and positivity for FCCs. After adjusting for covariates, patients with positive FCCs had lower progression-free survival than patients with negative FCCs. Conclusion The ISET platform highly enriched nucleated cells from peritoneal lavage fluid, and indicators comprising EpCAM, CEP8, and CEP17 confirmed the diagnosis of FCCs. As a potential detection method, it offers an opportunity for early intervention of OPM and an extension of patient survival.
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Affiliation(s)
- Ying Xuan
- Jiangnan University, Wuxi School of Medicine, Wuxi, China
- Affiliated Hospital of Jiangnan University, Department of Oncology, Wuxi, China
| | - Qizhong Gao
- Affiliated Hospital of Jiangnan University, Department of Oncology, Wuxi, China
| | - Chenhu Wang
- Affiliated Hospital of Jiangnan University, Department of Oncology, Wuxi, China
| | - Dongyan Cai
- Affiliated Hospital of Jiangnan University, Department of Oncology, Wuxi, China
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Jia Y, Zhang L, Xu J, Xiang L. Recent advances in cell membrane camouflaged nanotherapeutics for the treatment of bacterial infection. Biomed Mater 2024; 19:042006. [PMID: 38697197 DOI: 10.1088/1748-605x/ad46d4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 05/01/2024] [Indexed: 05/04/2024]
Abstract
Infectious diseases caused by bacterial infections are common in clinical practice. Cell membrane coating nanotechnology represents a pioneering approach for the delivery of therapeutic agents without being cleared by the immune system in the meantime. And the mechanism of infection treatment should be divided into two parts: suppression of pathogenic bacteria and suppression of excessive immune response. The membrane-coated nanoparticles exert anti-bacterial function by neutralizing exotoxins and endotoxins, and some other bacterial proteins. Inflammation, the second procedure of bacterial infection, can also be suppressed through targeting the inflamed site, neutralization of toxins, and the suppression of pro-inflammatory cytokines. And platelet membrane can affect the complement process to suppress inflammation. Membrane-coated nanoparticles treat bacterial infections through the combined action of membranes and nanoparticles, and diagnose by imaging, forming a theranostic system. Several strategies have been discovered to enhance the anti-bacterial/anti-inflammatory capability, such as synthesizing the material through electroporation, pretreating with the corresponding pathogen, membrane hybridization, or incorporating with genetic modification, lipid insertion, and click chemistry. Here we aim to provide a comprehensive overview of the current knowledge regarding the application of membrane-coated nanoparticles in preventing bacterial infections as well as addressing existing uncertainties and misconceptions.
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Affiliation(s)
- Yinan Jia
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Li Zhang
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Junhua Xu
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Lin Xiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Gaya A, Rohatgi N, Limaye S, Shreenivas A, Ajami R, Akolkar D, Datta V, Srinivasan A, Patil D. Liquid Biopsy for Detection of Pancreaticobiliary Cancers by Functional Enrichment and Immunofluorescent Profiling of Circulating Tumor Cells and Their Clusters. Cancers (Basel) 2024; 16:1400. [PMID: 38611078 PMCID: PMC11010988 DOI: 10.3390/cancers16071400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 03/27/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Circulating tumor cells (CTCs) have historically been used for prognostication in oncology. We evaluate the performance of liquid biopsy CTC assay as a diagnostic tool in suspected pancreaticobiliary cancers (PBC). The assay utilizes functional enrichment of CTCs followed by immunofluorescent profiling of organ-specific markers. The performance of the assay was first evaluated in a multicentric case-control study of blood samples from 360 participants, including 188 PBC cases (pre-biopsy samples) and 172 healthy individuals. A subsequent prospective observational study included pre-biopsy blood samples from 88 individuals with suspicion of PBC and no prior diagnosis of cancer. CTCs were harvested using a unique functional enrichment method and used for immunofluorescent profiling for CA19.9, Maspin, EpCAM, CK, and CD45, blinded to the tissue histopathological diagnosis. TruBlood® malignant or non-malignant predictions were compared with tissue diagnoses to establish sensitivity and specificity. The test had 95.9% overall sensitivity (95% CI: 86.0-99.5%) and 92.3% specificity (95% CI: 79.13% to 98.38%) to differentiate PBC (n = 49) from benign conditions (n = 39). The high accuracy of the CTC-based TruBlood test demonstrates its potential clinical application as a diagnostic tool to assist the effective detection of PBC when tissue sampling is unviable or inconclusive.
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Affiliation(s)
- Andrew Gaya
- Department of Clinical Oncology, Cromwell Hospital, London SW5 0TU, UK
| | - Nitesh Rohatgi
- Department of Medical Oncology, Fortis Memorial Research Institute, Gurugram 122002, HR, India
| | - Sewanti Limaye
- Department of Medical and Precision Oncology, Sir HN Reliance Foundation Hospital and Research Centre, Mumbai 400004, MH, India
| | - Aditya Shreenivas
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ramin Ajami
- Department of Oncology, The Royal Free Hospital, London NW3 2QG, UK
| | - Dadasaheb Akolkar
- Department of Research and Innovation, Datar Cancer Genetics, Nasik 422010, MH, India; (D.A.); (V.D.); (A.S.); (D.P.)
| | - Vineet Datta
- Department of Research and Innovation, Datar Cancer Genetics, Nasik 422010, MH, India; (D.A.); (V.D.); (A.S.); (D.P.)
| | - Ajay Srinivasan
- Department of Research and Innovation, Datar Cancer Genetics, Nasik 422010, MH, India; (D.A.); (V.D.); (A.S.); (D.P.)
| | - Darshana Patil
- Department of Research and Innovation, Datar Cancer Genetics, Nasik 422010, MH, India; (D.A.); (V.D.); (A.S.); (D.P.)
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Yakar M, Etiz D. Circulating tumor cells as prognostic marker in pancreatic cancer. World J Clin Oncol 2024; 15:165-168. [PMID: 38455127 PMCID: PMC10915936 DOI: 10.5306/wjco.v15.i2.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/16/2023] [Accepted: 01/09/2024] [Indexed: 02/20/2024] Open
Abstract
In this editorial we comment on the article by Zhang et al published in the recent issue of the World Journal of Clinical Oncology. Pancreatic cancer is the fourth most common cause of cancer-related mortality and has the lowest survival rate among all solid cancers. It causes 227000 deaths annually worldwide, and the 5-year survival rate is very low due to early metastasis, which is 4.6%. Cancer survival increases with better knowledge of risk factors and early and accurate diagnosis. Circulating tumor cells (CTCs) are tumor cells that intravasate from the primary tumor or metastasis foci into the peripheral blood circulation system spontaneously or during surgical operations. Detection of CTC in blood is promising for early diagnosis. In addition, studies have associated high CTC levels with a more advanced stage, and more intensive treatments should be considered in cases with high CTC. In tumors that are considered radiologically resectable, it may be of critical importance in detecting occult metastases and preventing unnecessary surgeries.
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Affiliation(s)
- Melek Yakar
- Department of Radiation Oncology, Osmangazi University, Eskişehir 26040, Turkey
| | - Durmuş Etiz
- Department of Radiation Oncology, Eskisehir Osmangazi University Faculty of Medicine, Eskişehir 26040, Turkey
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Ju M, Gao Z, Gu G, Huang H, Sun A, Zheng C, Li H, Zhang Y, Li K. Prognostic value of circulating tumor cells associated with white blood cells in solid cancer: a systematic review and meta-analysis of 1471 patients with solid tumors. BMC Cancer 2023; 23:1224. [PMID: 38087278 PMCID: PMC10717563 DOI: 10.1186/s12885-023-11711-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 12/04/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND The clinical relevance of circulating tumor cell-white blood cell (CTC-WBC) clusters in cancer prognosis is a subject of ongoing debate. This study aims to unravel their contentious predictive value for patient outcomes. METHODS We conducted a comprehensive literature search of PubMed, Embase, and Cochrane Library up to December 2022. Eligible studies that reported survival outcomes and examined the presence of CTC-WBC clusters in solid tumor patients were included. Hazard ratios (HR) were pooled to assess the association between CTC-WBC clusters and overall survival (OS), as well as progression-free survival (PFS)/disease-free survival (DFS)/metastasis-free survival (MFS)/recurrence-free survival (RFS). Subgroup analyses were performed based on sampling time, treatment method, detection method, detection system, and cancer type. RESULTS A total of 1471 patients from 10 studies were included in this meta-analysis. The presence of CTC-WBCs was assessed as a prognostic factor for overall survival and PFS/DFS/MFS/RFS. The pooled analysis demonstrated that the presence of CTC-WBC clusters was significantly associated with worse OS (HR = 2.44, 95% CI: 1.74-3.40, P < 0.001) and PFS/DFS/MFS/RFS (HR = 1.83, 95% CI: 1.49-2.24, P < 0.001). Subgroup analyses based on sampling time, treatment method, detection method, detection system, cancer type, and study type consistently supported these findings. Further analyses indicated that CTC-WBC clusters were associated with larger tumor size (OR = 2.65, 95% CI: 1.58-4.44, P < 0.001) and higher alpha-fetoprotein levels (OR = 2.52, 95% CI: 1.50-4.22, P < 0.001) in hepatocellular carcinoma. However, no significant association was found between CTC-WBC clusters and TNM stage, depth of tumor invasion, or lymph node metastasis in the overall analysis. CONCLUSIONS CTC-WBC clusters are negative predictors for OS and PFS/DFS/MFS/RFS in patients with solid tumors. Monitoring CTC-WBC levels may provide valuable information for predicting disease progression and guiding treatment decisions.
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Affiliation(s)
- Mingguang Ju
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Ziming Gao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Gaoxiang Gu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Haibo Huang
- VIP International Department, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Anqi Sun
- VIP International Department, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Chen Zheng
- Department of Anesthesiology, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - He Li
- Department of Ultrasound, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Yixiao Zhang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China
| | - Kai Li
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Heping District, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang City, 110001, China.
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Malkawi W, Lutfi A, Afghan MK, Shah LM, Costandy L, Ramirez AB, George TC, Toor F, Salem AK, Kasi PM. Circulating tumour cell enumeration, biomarker analyses, and kinetics in patients with colorectal cancer and other GI malignancies. Front Oncol 2023; 13:1305181. [PMID: 38044994 PMCID: PMC10693413 DOI: 10.3389/fonc.2023.1305181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 11/03/2023] [Indexed: 12/05/2023] Open
Abstract
Objective Most of the work in terms of liquid biopsies in patients with solid tumors is focused on circulating tumor DNA (ctDNA). Our aim was to evaluate the feasibility of using circulating tumor cells (CTCs) in peripheral blood samples from patients with advanced or metastatic gastrointestinal (GI) cancers. Methods In this prospective study, blood samples were collected from each patient in 2 AccuCyte® blood collection tubes and each tube underwent CTC analysis performed utilizing the RareCyte® platform. The results from both tubes were averaged and a total of 150 draws were done, with 281 unique reported results. The cadence of sampling was based on convenience sampling and piggybacked onto days of actual clinical follow-ups and treatment visits. The CTC results were correlated with patient- and tumor-related variables. Results Data from a total of 59 unique patients were included in this study. Patients had a median age of 58 years, with males representing 69% of the study population. More than 57% had received treatment prior to taking blood samples. The type of GI malignancy varied, with more than half the patients having colorectal cancer (CRC, 54%) followed by esophageal/gastric cancer (17%). The least common cancer was cholangiocarcinoma (9%). The greatest number of CTCs were found in patients with colorectal cancer (Mean: 15.8 per 7.5 ml; Median: 7.5 per 7.5 ml). In comparison, patients with pancreatic cancer (PC) had considerably fewer CTCs (Mean: 4.2 per 7.5 ml; Median: 3 per 7.5 ml). Additionally, we found that patients receiving treatment had significantly fewer CTCs than patients who were not receiving treatment (Median 2.7 versus 0.7). CTC numbers showed noteworthy disparities between patients with responding/stable disease in comparison to those with untreated/progressive disease (Median of 2.7 versus 0). When CTCs were present, biomarker analyses of the four markers human epidermal growth factor receptor 2 (HER2)/programmed death-ligand 1 (PD-L1)/Kiel 67 (Ki-67)/epidermal growth factor receptor (EGFR) was feasible. Single cell sequencing confirmed the tumor of origin. Conclusion Our study is one of the first prospective real-time studies evaluating CTCs in patients with GI malignancies. While ctDNA-based analyses are more common in clinical trials and practice, CTC analysis provides complementary information from a liquid biopsy perspective that is of value and worthy of continued research.
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Affiliation(s)
- Walla Malkawi
- Division of Pharmaceutics and Translational Therapeutics, University of Iowa, Iowa, IA, United States
| | - Areeb Lutfi
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Maaz Khan Afghan
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Lamisha Mashiyat Shah
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, United States
| | | | | | | | - Fatima Toor
- Experimental Therapeutics Program, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa, IA, United States
- Department of Electrical and Computer Engineering, University of Iowa, Iowa, IA, United States
| | - Aliasger K. Salem
- Division of Pharmaceutics and Translational Therapeutics, University of Iowa, Iowa, IA, United States
- Experimental Therapeutics Program, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa, IA, United States
| | - Pashtoon Murtaza Kasi
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, United States
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Chen J, Xie T, Yang J, Lin X, Huang L, Su S, Deng J. Feasibility study of expressing epcam + /vimentin + CTC in prostate cancer diagnosis. J Cancer Res Clin Oncol 2023; 149:8699-8709. [PMID: 37127827 DOI: 10.1007/s00432-023-04819-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
PURPOSE Prostate cancer (PCa) is one of the most common malignancies in men and one of the leading causes of cancer-related deaths; circulating tumor cells (CTC) are malignant cells that have broken off from original tumor or metastatic sites and extravasated into the blood vessels either naturally or maybe as a consequence of surgical procedures. This study aims to explore the feasibility of liquid biopsy technique to diagnose prostate cancer. METHOD We constructed an assay platform integrating magnetic separation and fluorescence in situ hybridization (FISH) to effectively capture prostate cancer CTCs and evaluate the distribution between healthy volunteers and prostate cancer patients, respectively. RESULTS There was a significant difference in the number of CTCs between the healthy population and prostate cancer patients (P < 0.001). The results of the study showed that the CTCs capture identification system has good sensitivity and specificity in identifying prostate cancer patients. CONCLUSION The CTCs test allows us to accurately identify patients who are at high risk for prostate cancer, allowing for early intervention and treating patients effectively.
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Affiliation(s)
- Junyong Chen
- Department of Urology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), 79 Kangning Rd., Zhuhai, 519000, China
| | - Tao Xie
- Department of Urology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), 79 Kangning Rd., Zhuhai, 519000, China
| | - Jing Yang
- Department of Pathology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, China
| | - Xuehua Lin
- Department of Urology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), 79 Kangning Rd., Zhuhai, 519000, China
| | - Long Huang
- Department of Urology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), 79 Kangning Rd., Zhuhai, 519000, China.
| | - Shiya Su
- Department of Urology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), 79 Kangning Rd., Zhuhai, 519000, China.
| | - Jian Deng
- Department of Urology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), 79 Kangning Rd., Zhuhai, 519000, China.
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Amaral MJ, Oliveira RC, Donato P, Tralhão JG. Pancreatic Cancer Biomarkers: Oncogenic Mutations, Tissue and Liquid Biopsies, and Radiomics-A Review. Dig Dis Sci 2023:10.1007/s10620-023-07904-6. [PMID: 36988759 DOI: 10.1007/s10620-023-07904-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 02/24/2023] [Indexed: 03/30/2023]
Abstract
Pancreatic cancer is one of the most fatal malignancies, as approximately 80% of patients are at advanced stages by the time of diagnosis. The main reason for the poor overall survival is late diagnosis that is partially due to the lack of tools for early-stage detection. In addition, there are several challenges in evaluating response to treatment and predicting prognosis. In this article, we do a review of the most common pancreatic cancer biomarkers with emphasis in new and promising approaches. Liquid biopsies seem to have important clinical applications in early detection, screening, prognosis, and longitudinal monitoring of on-treatment patients. Together with biomarkers in imaging, can represent valuable alternative non-invasive tools in order to achieve a more effective management of pancreatic cancer patients.
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Affiliation(s)
- Maria João Amaral
- General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
| | - Rui Caetano Oliveira
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Paulo Donato
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Radiology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - José Guilherme Tralhão
- General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Biophysics Institute, University of Coimbra, Coimbra, Portugal
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11
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David P, Mittelstädt A, Kouhestani D, Anthuber A, Kahlert C, Sohn K, Weber GF. Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease-From Early Cancer Detection to Individualized Cancer Treatment. Cancers (Basel) 2023; 15:cancers15071924. [PMID: 37046585 PMCID: PMC10093361 DOI: 10.3390/cancers15071924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.
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Affiliation(s)
- Paul David
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anke Mittelstädt
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Dina Kouhestani
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anna Anthuber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christoph Kahlert
- Department of Surgery, Carl Gustav Carus University Hospital, 01307 Dresden, Germany
| | - Kai Sohn
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, 70569 Stuttgart, Germany
| | - Georg F Weber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
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12
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Zhao B, Zhang L, Liu Z, Yuan D. The Protocol of Circulating Tumor Cell Detection. Methods Mol Biol 2023; 2695:1-8. [PMID: 37450108 DOI: 10.1007/978-1-0716-3346-5_1] [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] [Indexed: 07/18/2023]
Abstract
The detection of CTCs is related to the development of tumors and can be used in medical fields such as early diagnosis, postoperative evaluation, monitoring treatment, and predicting disease prognosis. This article focuses on the entire process of CTC detection, including negative enrichment isolation and immunofluorescence in situ hybridization detection.
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13
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Hasanzadeh Kafshgari M, Hayden O. Advances in analytical microfluidic workflows for differential cancer diagnosis. NANO SELECT 2023. [DOI: 10.1002/nano.202200158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Morteza Hasanzadeh Kafshgari
- Heinz‐Nixdorf‐Chair of Biomedical Electronics Campus Klinikum München rechts der Isar TranslaTUM Technical University of Munich Munich Germany
| | - Oliver Hayden
- Heinz‐Nixdorf‐Chair of Biomedical Electronics Campus Klinikum München rechts der Isar TranslaTUM Technical University of Munich Munich Germany
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14
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Watanabe F, Suzuki K, Noda H, Rikiyama T. Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer. World J Gastroenterol 2022; 28:6478-6496. [PMID: 36569270 PMCID: PMC9782840 DOI: 10.3748/wjg.v28.i46.6478] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/25/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.
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Affiliation(s)
- Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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15
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Epithelial to Mesenchymal Transition as Mechanism of Progression of Pancreatic Cancer: From Mice to Men. Cancers (Basel) 2022; 14:cancers14235797. [PMID: 36497278 PMCID: PMC9735867 DOI: 10.3390/cancers14235797] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022] Open
Abstract
Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis involves an intricate cascade of events comprising the pleiotropic process of epithelial to mesenchymal transition (EMT) facilitating cancer spread. The elucidation of this pivotal phenotypic change in cancer cell morphology, initially heretic, moved from basic studies dissecting the progression of pancreatic cancer in animal models to move towards human disease, although no clinical translation of the concept emerged yet. Despite this transition, a full-blown mesenchymal phenotype may not be accomplished; rather, the plasticity of the program and its dependency on heterotopic signals implies a series of fluctuating modifications of cancer cells encompassing mesenchymal and epithelial features. Despite the evidence supporting the activation of EMT and MET during cancer progression, our understanding of the relationship between tumor microenvironment and EMT is not yet mature for a clinical application. In this review, we attempt to resume the knowledge on EMT and pancreatic cancer, aiming to include the EMT among the hallmarks of cancer that could potentially modify our clinical thinking with the purpose of filling the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers, as well as their application for prognostic and predictive purposes.
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16
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The Number of Intraoperative Intestinal Venous Circulating Tumor Cells Is a Prognostic Factor for Colorectal Cancer Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:4162354. [PMID: 36193123 PMCID: PMC9525778 DOI: 10.1155/2022/4162354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/21/2022] [Accepted: 08/30/2022] [Indexed: 11/18/2022]
Abstract
Purpose To assess the association between intestinal venous blood (IVB) circulating tumor cells (CTCs) and clinicopathological parameters in stage I-III colorectal cancer (CRC) patients. Methods Participants were retrospectively retrieved, who were admitted to our hospital or took annual physical exams between December 1, 2015 and December 31, 2018. A negative enrichment-immunofluorescence in situ hybridization (NE-imFISH) technique was used to isolate and identify CTCs. Receiver operating characteristic (ROC) curves and Youden index values were used to determine the critical CTC cutoff value for the diagnosis of CRC. Kaplan-Meier and log-rank methods were used to conduct survival analyses, and multivariate Cox regression analyses were employed for multivariate corrections to comprehensively evaluate the value of CTCs in the diagnosis of CRC. Relationships between IVB CTCs, clinicopathological parameters, and prognosis were then analyzed based upon patient postoperative follow-up data. Results In total, we retrieved 282 patients including 48 healthy controls, 72 patients with benign colorectal tumors, and 162 CRC patients. CRC patients exhibited significantly higher numbers of CTCs relative to control patients or those with benign disease. CTC numbers in CRC patient peripheral blood (PB) and IVB were closely associated with tumor node metastasis (TNM) staging (P < 0.01), carbohydrate antigen-125 (CA-125) levels (P < 0.001), and KRAS (Kirsten rat sarcoma virus oncogene) mutation status (P < 0.001). The disease-free survival (DFS) of patients in the CTC-negative group was significantly longer than that of patients in the CTC-positive group (24.60 ± 13.31 months vs. 18.70 ± 10.19 months, P < 0.05), with the same being true with respect to their overall survival (OS) (30.60 ± 12.44 months vs. 35.25 ± 11.57 months, P < 0.05). A multivariate analysis revealed that the detection ≥2 CTCs/3.2 ml was independently associated with poorer DFS and OS. CTC counts were independently predictive of CRC patients TNM staging, CA-125, and KRAS mutation status in both univariate and multivariate Cox proportional hazards regression analyses. Conclusion CTCs are valuable biomarkers that can be monitored to predict CRC patient disease progression.
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17
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Chen L, Zhou W, Ye Z, Zhong X, Zhou J, Chen S, Liu W, Sun Y, Ren L, Tan X, Cui J, Zeng Z, He W, Ke Z. Predictive Value of Circulating Tumor Cells Based on Subtraction Enrichment for Recurrence Risk in Stage II Colorectal Cancer. ACS APPLIED MATERIALS & INTERFACES 2022; 14:35389-35399. [PMID: 35904812 DOI: 10.1021/acsami.2c08560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Current guidelines recommend adjuvant chemotherapy (ACT) for stage II colorectal cancer (CRC) patients by using clinical high risk factors, with which circulating tumor cells (CTCs) were not considered. Here, an assessment to detect CTCs based on subtraction enrichment mediated by magnetic beads conjugated with CD45, immunofluorescence staining of CK, and fluorescence in situ hybridization of CEP8 is established. Both CEP8- and CK-positive CTCs have the potential to improve the risk stratification of stage II CRC patients. Patients with preoperative CTCs of ≥4 had a significantly higher recurrence risk than those with preoperative CTCs of <4 in two external validation cohorts (P < 0.0001). In the subgroup with clinical high risk, when preoperative CTCs were <4, patients did not benefit from ACT (P = 0.5764); however, when preoperative CTCs were ≥4, patients received benefit from ACT (P = 0.0064). Additionally, regardless of clinical risk status and preoperative CTC levels, if postoperative CTC levels were ≥4 for more than three consecutive time points (monitoring time interval, 2-6 months), the recurrence rate was 100%. Our findings suggested that the subtraction enrichment of CTCs could provide a reliable method to stratify the recurrence risk and make therapeutic decisions after surgery in stage II CRC patients.
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Affiliation(s)
- Lili Chen
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Wenpeng Zhou
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Ziyin Ye
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Xiaoming Zhong
- School of Medicine, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Jianwen Zhou
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Shaohong Chen
- Department of Pathology, Guangzhou First People's Hospital, Guangzhou 510180, P. R. China
| | - Wei Liu
- School of Medicine, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Yu Sun
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Department of Dermatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P. R. China
| | - Lijuan Ren
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Xiaojun Tan
- Department of Pathology, Guangzhou Medical University Cancer Center, Guangzhou 510095, P. R. China
| | - Ji Cui
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, P. R. China
| | - Zhirong Zeng
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Weiling He
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, P. R. China
| | - Zunfu Ke
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
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18
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Luo K, Wang X, Zhang X, Liu Z, Huang S, Li R. The Value of Circulating Tumor Cells in the Prognosis and Treatment of Pancreatic Cancer. Front Oncol 2022; 12:933645. [PMID: 35860591 PMCID: PMC9293050 DOI: 10.3389/fonc.2022.933645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/31/2022] [Indexed: 12/21/2022] Open
Abstract
In the past few decades, tumor diagnosis and treatment theory have developed in a variety of directions. The number of people dying from pancreatic cancer increases while the mortality rate of other common tumors decreases. Traditional imaging methods show the boundaries of pancreatic tumor, but they are not sufficient to judge early micrometastasis. Although carcinoembryonic antigen (CEA) and carbohydrate antigen19-9 (CA19-9) have the obvious advantages of simplicity and minimal invasiveness, these biomarkers obviously lack sensitivity and specificity. Circulating tumor cells (CTCs) have attracted attention as a non-invasive, dynamic, and real-time liquid biopsy technique for analyzing tumor characteristics. With the continuous development of new CTCs enrichment technologies, substantial progress has been made in the basic research of CTCs clinical application prospects. In many metastatic cancers, CTCs have been studied as an independent prognostic factor. This article reviews the research progress of CTCs in the treatment and prognosis of pancreatic cancer.
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19
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Zhang Q, Xia F, Mo A, He W, Chen J, Zhang W, Chen W. Guiding Value of Circulating Tumor Cells for Preoperative Transcatheter Arterial Embolization in Solitary Large Hepatocellular Carcinoma: A Single-Center Retrospective Clinical Study. Front Oncol 2022; 12:839597. [PMID: 35664772 PMCID: PMC9159764 DOI: 10.3389/fonc.2022.839597] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/15/2022] [Indexed: 12/07/2022] Open
Abstract
Background Large hepatocellular carcinoma (LHCC) is highly malignant and prone to recurrence, leading to a poor long-term prognosis for patients. There is an urgent need for measures to intervene in postoperative recurrence. Preoperative Transcatheter Arterial Embolization (TACE) is an effective treatment. However, there is a lack of reliable preoperative indicators to guide the application of preoperative TACE. We, therefore, investigated whether the preoperative status of circulating tumor cells (CTCs) could be used to guide preoperative TACE for HCC treatment. Methods This study recruited 361 HCC patients and compared recurrence-free survival (RFS) and overall survival (OS) in patients treated with TACE prior to surgery and those not treated with TACE. Patients were divided into CTC-positive group and CTC-negative group according to CTC status, and the effect of preoperative TACE on RFS and OS was compared in each subgroup. Results In CTC-positive patients, preoperative TACE reduces early recurrence and improves long-term survival. However, HCC patients did not benefit from preoperative TACE for the overall population and CTC-negative patients. Conclusions Preoperative CTC testing is a reliable indicator of whether HCC patients received TACE preoperatively. CTC positivity was associated with early tumor recurrence, and preoperative TACE could reduce early recurrence and long-term prognosis in CTC-positive patients.
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Affiliation(s)
- Qiao Zhang
- Zhongshan People's Hospital, Guangdong Medical University, Zhongshan, China
| | - Feng Xia
- Department of Hepatic Surgery Center, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ali Mo
- Zhongshan People's Hospital, Guangdong Medical University, Zhongshan, China
| | - Weiming He
- Zhongshan People's Hospital, Guangdong Medical University, Zhongshan, China
| | - Jiazhen Chen
- Zhongshan People's Hospital, Guangdong Medical University, Zhongshan, China
| | - Weiqiao Zhang
- Zhongshan People's Hospital, Guangdong Medical University, Zhongshan, China
| | - Weiqiang Chen
- Zhongshan People's Hospital, Guangdong Medical University, Zhongshan, China
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Chen J, Wang H, Zhou L, Liu Z, Tan X. A combination of circulating tumor cells and CA199 improves the diagnosis of pancreatic cancer. J Clin Lab Anal 2022; 36:e24341. [PMID: 35334495 PMCID: PMC9102772 DOI: 10.1002/jcla.24341] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/29/2022] [Accepted: 02/27/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to the lack of effective screening tests. CA199, the standard biomarker for PDAC management, is not sufficiently reliable for early diagnosis. This prospective study aimed to evaluate whether circulating tumor cells (CTCs) could complement or perform better than CA199 in determining PDAC. METHODS A total of 168 blood samples were collected from 80 patients with PDAC, 32 patients with acute pancreatitis, 22 patients with benign pancreatic masses, and 34 healthy donors. CTCs were detected by a novel system combining negative enrichment with immunostaining and fluorescence in situ hybridization (NE-imFISH). Next, ROC curves and AUC analyses were conducted to assess diagnostic abilities of CA199, CTCs, and the combination of the two biomarkers in PDAC. RESULTS CTCs were stained as CD45-/DAPI+/CEP8 ≥3. With 2 CTCs/3.2 ml as the cut-off value, the sensitivity/specificity of the CTC number was 0.76/0.94, which was comparable to that of CA199 (0.78/0.83; Delong test p = 0.3360). Improved performance was achieved through a logistic regression model integrating CA199 and CTC number (AUCCTC+CA199 = 0.95, AUCCA199 = 0.80, AUCCTC number = 0.85; Delong test p vs . CA199 < 0.0001 and p vs . CTC number = 0.0002). CTC subtype was inferior to CTC number as a diagnostic marker (AUCCTC subtype = 0.73; Delong test p vs . CTC number < 0.0001). CONCLUSION The dual-marker panel consisting of CA199 and CTC number can significantly improve upon the diagnostic performance of CA199 alone, highlighting the promising clinical utilization as an effective strategy for PDAC surveillance.
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Affiliation(s)
- Junliang Chen
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Huaitao Wang
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Lei Zhou
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Zhihao Liu
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Xiaodong Tan
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
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21
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Optimal Strategy for Colorectal Cancer Patients' Diagnosis Based on Circulating Tumor Cells and Circulating Tumor Endothelial Cells by Subtraction Enrichment and Immunostaining-Fluorescence In Situ Hybridization Combining with CEA and CA19-9. JOURNAL OF ONCOLOGY 2022; 2021:1517488. [PMID: 34976053 PMCID: PMC8720022 DOI: 10.1155/2021/1517488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/15/2021] [Accepted: 12/10/2021] [Indexed: 02/08/2023]
Abstract
Background Cancerous embryo antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are commonly used in clinical practice to assist in diagnosing CRC. However, their sensitivity is very low. This study aims to investigate the clinical significance of circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) compared with CEA and CA19-9 in the auxiliary diagnosis of colorectal cancer (CRC) patients. Methods 115 pathologically confirmed CRC patients and 20 healthy controls were enrolled in this study. CTCs and CTECs were enriched and identified by subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH). A logistic regression was used to establish a model for the receiver-operating characteristic (ROC) curve analysis, and the diagnostic efficacy of CTCs, CTECs, CEA, CA19-9, and their combinations was analyzed. Results The CTC (P < 0.0001) and CTEC (P=0.0009) level was significantly higher in CRC patients than that in healthy controls. For CRC patients, CTC and CTEC level was significantly correlated with tumor stage and lymph node metastasis status, but not with sex, age, tumor location, and degree of differentiation. The positive rate of CTCs, CTECs, CEA, and CA19-9 in CRC patients was 87.8%, 39.1%, 28.7%, and 26.1%, respectively. To distinguish CRC patients from controls, the area under the curve (AUC) of CTC was 0.889, which was much higher than 0.695 of CTEC, 0.696 of CEA, and 0.695 of CA19-9. Establishing ROC curve by logistic regression algorithm, the highest AUC was 0.935, which combined CTCs with CTEC, CEA, and CA19-9. Conclusions CTCs combined with CTEC, CEA, and CA19-9 are useful to improve the diagnostic efficiency, which has high clinical significance in the diagnosis of colorectal cancer.
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22
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Zhang Y, Su H, Wang H, Xu C, Zhou S, Zhao J, Shen S, Xu G, Wang L, Zou X, Zhang S, Lv Y. Endoscopic Ultrasound-Guided Acquisition of Portal Venous Circulating Tumor Cells as a Potential Diagnostic and Prognostic Tool for Pancreatic Cancer. Cancer Manag Res 2021; 13:7649-7661. [PMID: 34675662 PMCID: PMC8502022 DOI: 10.2147/cmar.s330473] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/16/2021] [Indexed: 12/11/2022] Open
Abstract
Background Circulating tumor cells (CTCs) were a promising liquid biopsy for pancreatic cancer (PC) but circulate in low counts in peripheral blood. We evaluated the diagnostic and prognostic values of portal vein (PoV) CTCs in PC patients. Methods PoV was aspirated under EUS guidance from 40 patients with suspected pancreaticobiliary cancers. Epithelial–mesenchymal-transition-related subtypes of CTCs were identified via immunofluorescence using EpCAM and Twist antibodies. The diagnostic and prognostic performance of PoV CTCs was investigated by receiver-operating characteristic (AUC) curve and Kaplan–Meier survival analysis. Results In total, 40 patients including 31 with PC, 4 with non-pancreatic periampullary cancer and 5 with benign pancreatic diseases (BPD) were enrolled. CTCs were detected more in PoV compared with peripheral blood. PoV CTC numbers in BPD patients were lower than in PC patients. The number of PoV CTCs, especially mesenchymal-CTCs (M-CTCs), was positively correlated with the tumor burden, instead of epithelial-CTCs (E-CTCs). The combination of PoV CTC numbers and CA19-9 demonstrated better diagnostic efficiency (AUC value 0.987) than either alone in differentiating PC with BPD. Moreover, the diagnostic efficacy of PoV CTCs and M-CTCs were obviously better than that of E-CTCs and CA19-9 in distinguishing early and late stage PC. Lastly, high PoV CTC and M-CTC numbers were both associated with shorter overall survival. Conclusion Acquisition of the PoV samples in PC patients via EUS-guided procedures has been proved safe and feasible. PoV CTCs, especially M-CTCs, have great potentials in diagnosing and predicting the prognosis of PC, especially in combination with CA19-9.
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Affiliation(s)
- Yixuan Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Haochen Su
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People's Republic of China
| | - Haibo Wang
- Cyttelbio Corporation, Beijing, People's Republic of China
| | - Chenghu Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Siqi Zhou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated of Jiangsu University, Nanjing, People's Republic of China
| | - Jing Zhao
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Shanshan Shen
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Guifang Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Lei Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Shu Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Ying Lv
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
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23
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Negative enrichment of circulating tumor cells from unmanipulated whole blood with a 3D printed device. Sci Rep 2021; 11:20583. [PMID: 34663896 PMCID: PMC8523721 DOI: 10.1038/s41598-021-99951-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 09/23/2021] [Indexed: 01/07/2023] Open
Abstract
Reliable and routine isolation of circulating tumor cells (CTCs) from peripheral blood would allow effective monitoring of the disease and guide the development of personalized treatments. Negative enrichment of CTCs by depleting normal blood cells ensures against a biased selection of a subpopulation and allows the assay to be applied on different tumor types. Here, we report an additively manufactured microfluidic device that can negatively enrich viable CTCs from clinically-relevant volumes of unmanipulated whole blood samples. Our device depletes nucleated blood cells based on their surface antigens and the smaller anucleated cells based on their size. Enriched CTCs are made available off the device in suspension making our technique compatible with standard immunocytochemical, molecular and functional assays. Our device could achieve a ~ 2.34-log depletion by capturing > 99.5% of white blood cells from 10 mL of whole blood while recovering > 90% of spiked tumor cells. Furthermore, we demonstrated the capability of the device to isolate CTCs from blood samples collected from patients (n = 15) with prostate and pancreatic cancers in a pilot study. A universal CTC assay that can differentiate tumor cells from normal blood cells with the specificity of clinically established membrane antigens yet require no label has the potential to enable routine blood-based tumor biopsies at the point-of-care.
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24
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Deregulation of protein phosphatase 2A inhibitor SET is associated with malignant progression in breast cancer. Sci Rep 2021; 11:14238. [PMID: 34244560 PMCID: PMC8270961 DOI: 10.1038/s41598-021-93620-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/22/2021] [Indexed: 11/18/2022] Open
Abstract
To understand the mechanism underlying metastasis, identification of a mechanism-based and common biomarker for circulating tumour cells (CTCs) in heterogenous breast cancer is needed. SET, an endogenous inhibitor of protein phosphatase 2A, was overexpressed in all subtypes of invasive breast carcinoma tissues. Treatment with SET-targeted siRNAs reduced the motility of MCF-7 and MDA-MB-231 cells in transwell assay. SET knockdown reduced the number of mammospheres by 60–70% in MCF-7 and MDA-MB-231 cells, which was associated with the downregulation of OCT4 and SLUG. Hence, we analysed the presence of SET-expressing CTCs (SET-CTCs) in 24 breast cancer patients. CTCs were enriched using a size-based method and then immunocytochemically analysed using an anti-SET antibody. SET-CTCs were detected in 6/6 (100%) patients with recurrent breast cancer with a median value of 12 (12 cells/3 mL blood), and in 13/18 (72.2%) patients with stage I–III breast cancer with a median value of 2.5, while the median value of healthy controls was 0. Importantly, high numbers of SET-CTCs were correlated with lymph node metastasis in patients with stage I–III disease. Our results indicate that SET contributes to breast cancer progression and can act as a potential biomarker of CTCs for the detection of metastasis.
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25
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Wang S, Zheng Y, Yang F, Zhu L, Zhu XQ, Wang ZF, Wu XL, Zhou CH, Yan JY, Hu BY, Kong B, Fu DL, Bruns C, Zhao Y, Qin LX, Dong QZ. The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives. Signal Transduct Target Ther 2021; 6:249. [PMID: 34219130 PMCID: PMC8255319 DOI: 10.1038/s41392-021-00659-4] [Citation(s) in RCA: 170] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/27/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.
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Affiliation(s)
- Shun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Feng Yang
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Fudan University, Shanghai, China
| | - Le Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Xiao-Qiang Zhu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhe-Fang Wang
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Xiao-Lin Wu
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Cheng-Hui Zhou
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Jia-Yan Yan
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Bo Kong
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - De-Liang Fu
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Fudan University, Shanghai, China
| | - Christiane Bruns
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Yue Zhao
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany.
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
- Key laboratory of whole-period monitoring and precise intervention of digestive cancer, Shanghai Municipal Health Commission (SMHC), Shanghai, China.
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26
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Al-Shaheri FN, Alhamdani MSS, Bauer AS, Giese N, Büchler MW, Hackert T, Hoheisel JD. Blood biomarkers for differential diagnosis and early detection of pancreatic cancer. Cancer Treat Rev 2021; 96:102193. [PMID: 33865174 DOI: 10.1016/j.ctrv.2021.102193] [Citation(s) in RCA: 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.
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Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany.
| | - Mohamed S S Alhamdani
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Nathalia Giese
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Markus W Büchler
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
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27
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Hong Y, Si J, Zhang J, Xiong Y, Zhang J, Lin PP, Fang J, Yang Y, Lv C, Ma Y. Small Cell Size Circulating Aneuploid Cells as a Biomarker of Prognosis in Resectable Non-Small Cell Lung Cancer. Front Oncol 2021; 11:590952. [PMID: 33747909 PMCID: PMC7968455 DOI: 10.3389/fonc.2021.590952] [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: 08/05/2020] [Accepted: 01/15/2021] [Indexed: 01/10/2023] Open
Abstract
Objective The size distribution of circulating aneuploid cells (CACs) and its clinical significance were investigated in resectable non-small cell lung cancer (NSCLC). Patients and Methods A total of 50 patients with resectable NSCLC were enrolled in this study. Blood samples (50 pre-surgery and 35 post-surgery) were collected and used for the detection of CAC chromosome 8 heteroploidy through the subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) method. Results Less than 20% small cell size and more than 80% large cell size CACs were detected. Karyotypes, including triploid, tetraploid, and multiploid, had varying distributions. The triploid subtype accounted for the majority of small cell size CACs, whereas the multiploid subtype accounted for the majority of large cell size CACs. We found that total small cell size and triploid small cell size CACs, but not large cell size CACs, derived from pre-surgery samples, were associated with shorter disease-free survival. Moreover, total small cell size and triploid small cell size CACs were associated with higher TNM stage and recurrence. Nevertheless, the variation between pre- and post-surgery CACs was not related to survival among patients with resectable NSCLC. Conclusions Pre-surgery small cell size CACs, especially the triploid subtype, could be regarded as a potential prognostic biomarker for patients with resectable NSCLC.
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Affiliation(s)
- Yang Hong
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jiahui Si
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jie Zhang
- Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ying Xiong
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianzhi Zhang
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Peter Ping Lin
- Department of Oncology, Cytelligen, San Diego, CA, United States
| | - Jian Fang
- Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yue Yang
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Chao Lv
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yuanyuan Ma
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
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28
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Cheng H, Wang S, Luan W, Ye X, Dou S, Tang Z, Zhu H, Lin PP, Li Y, Cui H, Chang X. Combined detection and subclass characteristics analysis of CTCs and CTECs by SE-iFISH in ovarian cancer. Chin J Cancer Res 2021; 33:256-270. [PMID: 34158744 PMCID: PMC8181871 DOI: 10.21147/j.issn.1000-9604.2021.02.12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective Hematogenous metastasis is essential for the progression of ovarian cancer (OC), and circulating tumor cells (CTCs) are part of the metastatic cascade. However, the detection rate of CTC is low due to the use of less sensitive detection methods. Therefore, this study aimed to detect CTCs and circulating tumorigenic endothelial cells (CTECs) in patients with OC using subtraction enrichment and immunostaining and fluorescence in situ hybridization (SE-iFISH).
Methods We enrolled a total of 56 subjects, including 20 OC patients and 36 ovarian benign tumor patients. CTCs and CTECs were captured by subtraction enrichment (SE) and counted and classified according to immunofluorescence staining of tumor markers (TMs) carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) combined with fluorescence in situ hybridization (iFISH) of chromosome 8 (Chr8) aneuploidy. The diagnostic value and subtype characteristics of CTCs and CTECs were investigated.
Results The detection rate of CTCs by SE-iFISH was high. Compared with CA125 and HE4, Chr8 aneuploidy was the major identification feature of CTC. CTC counts in OC were statistically higher than those in benign groups. CTC and CTEC with ≥pentaploidy were detected in both groups, illustrating the poor diagnostic value of CTC or CTEC. Distributions of triploid and tetraploid CTC subtypes were significantly different, and combined detection of triploid and tetraploid CTCs showed the best diagnostic value. In contrast, the distribution of CTECs in the OC and benign groups had no statistically significant difference. Small CTCs accounted for over 1/3 of the total CTC count. We also found that small CTCs and CTECs primarily comprised triploid cells, while large CTCs and CTECs mainly comprised pentaploidy and beyond. Conclusions The application of SE-iFISH offered a more comprehensive understanding of heterogeneous CTCs and CTECs in OC. Analysis of subclass characteristics of the CTCs and CTECs according to Chr8 aneuploidy and cell size may broaden their potential clinical utility and deepen mechanistic studies in OC.
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Affiliation(s)
- Hongyan Cheng
- Department of Obstetrics and Gynecology.,Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Shang Wang
- Department of Obstetrics and Gynecology.,Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Wenqing Luan
- Department of Obstetrics and Gynecology.,Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Xue Ye
- Department of Obstetrics and Gynecology.,Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Sha Dou
- Department of Obstetrics and Gynecology
| | | | | | | | - Yi Li
- Department of Obstetrics and Gynecology
| | - Heng Cui
- Department of Obstetrics and Gynecology.,Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Xiaohong Chang
- Department of Obstetrics and Gynecology.,Center of Gynecologic Oncology, Peking University People's Hospital, Beijing 100044, China
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29
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GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12123774. [PMID: 33333841 PMCID: PMC7765300 DOI: 10.3390/cancers12123774] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.
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30
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Zhang WH, Wang WQ, Han X, Gao HL, Li TJ, Xu SS, Li S, Xu HX, Li H, Ye LY, Lin X, Wu CT, Long J, Yu XJ, Liu L. Advances on diagnostic biomarkers of pancreatic ductal adenocarcinoma: A systems biology perspective. Comput Struct Biotechnol J 2020; 18:3606-3614. [PMID: 33304458 PMCID: PMC7710502 DOI: 10.1016/j.csbj.2020.11.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/26/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial “network” to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.
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Affiliation(s)
- Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Han
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuai-Shuai Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Long-Yun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Lin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Long
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Pancreatic Cancer Institute, Shanghai, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, China
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31
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Pelle M, Das AAK, Madden LA, Paunov VN. Bioimprint Mediated Label-Free Isolation of Pancreatic Tumor Cells from a Healthy Peripheral Blood Cell Population. ADVANCED BIOSYSTEMS 2020; 4:e2000054. [PMID: 33016004 DOI: 10.1002/adbi.202000054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 09/22/2020] [Indexed: 11/11/2022]
Abstract
New techniques are required for earlier diagnosis and response to treatment of pancreatic cancer. Here, a label-free approach is reported in which circulating pancreatic tumor cells are isolated from healthy peripheral blood cells via cell bioimprinting technology. The method involves pre-fabrication of pancreatic cell layers and sequential casting of cell surfaces with a series of custom-made resins to produce negative cell imprints. The imprint is functionalized with a combination of polymers to engineer weak attraction to the cells which is further amplified by the increased area of contact with the matching cells. A flow-through bioimprint chip is designed and tested for selectivity toward two pancreatic tumor cell lines, ASPC-1 and Mia-PaCa-2. Healthy human peripheral blood mononuclear cells (PBMCs) are spiked with pancreatic tumor cells at various concentrations. Bioimprints are designed for preferential retention of the matching pancreatic tumor cells and with respect to PBMCs. Tumor bioimprints are capable of capturing and concentrating pancreatic tumor cells from a mixed cell population with increased retention observed with the number of seedings. ASPC-1 bioimprints preferentially retain both types of pancreatic tumor cells. This technology could be relevant for the collection and interrogation of liquid biopsies, early detection, and relapse monitoring of pancreatic cancer patients.
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Affiliation(s)
- Marie Pelle
- Department of Chemistry and Biochemistry, University of Hull, Hull, HU6 7RX, UK
| | - Anupam A K Das
- Department of Chemistry and Biochemistry, University of Hull, Hull, HU6 7RX, UK
| | - Leigh A Madden
- Department of Biomedical Sciences, University of Hull, Hull, HU6 7RX, UK
| | - Vesselin N Paunov
- Department of Chemistry and Biochemistry, University of Hull, Hull, HU6 7RX, UK
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32
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Li C, Wang J, Lu X, Ge H, Jin X, Guan Q, su Y, Pan R, Li P, Cai W, Zhu X. Hydrogen peroxide-response nanoprobe for CD44-targeted circulating tumor cell detection and H2O2 analysis. Biomaterials 2020; 255:120071. [DOI: 10.1016/j.biomaterials.2020.120071] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 04/14/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022]
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33
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Nagai M, Sho M, Akahori T, Nakagawa K, Nakamura K. Application of liquid biopsy for surgical management of pancreatic cancer. Ann Gastroenterol Surg 2020; 4:216-223. [PMID: 32490335 PMCID: PMC7240145 DOI: 10.1002/ags3.12317] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/19/2019] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Although drug development over the past decade has gradually improved the prognosis of PDAC, the prognosis remains extremely poor. The predominant determinant of a poor prognosis is that patients are already at the advanced stage when they are diagnosed. Therefore, it is essential to detect early-stage PDAC to ensure a good prognosis. However, in general, being asymptomatic at the early stage makes the detection of early-stage PDAC very difficult. Recently, much attention has been focused on the utility of a liquid biopsy as a biomarker. Theoretically, early-stage tumors can be detected even under asymptomatic conditions. A number of studies on liquid biopsies have been reported so far. Several biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCS), and exosomes, are used in liquid biopsies, with the potential to be applied to the clinical setting. Each biomarker is reported to have different utilities, such as the detection of early-stage disease, the differential diagnosis of PDAC from other types of pancreatic tumors, the prediction of the prognosis or risk of recurrence, and monitoring the treatment response. In this review, we focus on ctDNA, CTCS, and exosomes as representative liquid biopsy biomarkers and describe the specific functions of each biomarker in the treatment of PDAC. Furthermore, we discuss the application of liquid biopsies, especially for the surgical management of PDAC.
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Affiliation(s)
- Minako Nagai
- Department of Surgery Nara Medical University Kashihara Japan
| | - Masayuki Sho
- Department of Surgery Nara Medical University Kashihara Japan
| | | | - Kenji Nakagawa
- Department of Surgery Nara Medical University Kashihara Japan
| | - Kota Nakamura
- Department of Surgery Nara Medical University Kashihara Japan
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Wang Y, Yu X, Hartmann D, Zhou J. Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis. HPB (Oxford) 2020; 22:660-669. [PMID: 31786054 DOI: 10.1016/j.hpb.2019.11.003] [Citation(s) in RCA: 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.
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Affiliation(s)
- Yang Wang
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China
| | - Xiaojin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar der Technischen Universitat Munchen, Munchen, 81675, Germany
| | - Jiahua Zhou
- Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Nanjing, 210009, China; Department of Hepatobiliary Surgery Research Institute, Southeast University, Nanjing, 210009, China.
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Rivera-Báez L, Lohse I, Lin E, Raghavan S, Owen S, Harouaka R, Herman K, Mehta G, Lawrence TS, Morgan MA, Cuneo KC, Nagrath S. Expansion of Circulating Tumor Cells from Patients with Locally Advanced Pancreatic Cancer Enable Patient Derived Xenografts and Functional Studies for Personalized Medicine. Cancers (Basel) 2020; 12:cancers12041011. [PMID: 32326109 PMCID: PMC7225920 DOI: 10.3390/cancers12041011] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/03/2020] [Accepted: 04/14/2020] [Indexed: 12/22/2022] Open
Abstract
Improvement in pancreatic cancer treatment represents an urgent medical goal that has been hampered by the lack of predictive biomarkers. Circulating Tumor Cells (CTCs) may be able to overcome this issue by allowing the monitoring of therapeutic response and tumor aggressiveness through ex vivo expansion. The successful expansion of CTCs is challenging, due to their low numbers in blood and the high abundance of blood cells. Here, we explored the utility of pancreatic CTC cultures as a preclinical model for treatment response. CTCs were isolated from ten patients with locally advanced pancreatic cancer using the Labyrinth, a biomarker independent, size based, inertial microfluidic separation device. Three patient-derived CTC samples were successfully expanded in adherent and spheroid cultures. Molecular and functional characterization was performed on the expanded CTC lines. CTC lines exhibited KRAS mutations, consistent with pancreatic cancers. Additionally, we evaluated take rate and metastatic potential in vivo and examined the utility of CTC lines for cytotoxicity assays. Patient derived expanded CTCs successfully generated patient derived xenograft (PDX) models with a 100% take rate. Our results demonstrate that CTC cultures are possible and provide a valuable resource for translational pancreatic cancer research, while also providing meaningful insight into the development of distant metastasis, as well as treatment resistance.
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Affiliation(s)
- Lianette Rivera-Báez
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Ines Lohse
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
| | - Eric Lin
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Shreya Raghavan
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Sarah Owen
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Ramdane Harouaka
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Kirk Herman
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Geeta Mehta
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Theodore S. Lawrence
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Meredith A. Morgan
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Kyle C. Cuneo
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
- Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
- Correspondence: (K.C.C.); (S.N.)
| | - Sunitha Nagrath
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
- Correspondence: (K.C.C.); (S.N.)
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Zinc finger protein 367 promotes metastasis by inhibiting the Hippo pathway in breast cancer. Oncogene 2020; 39:2568-2582. [PMID: 31988454 DOI: 10.1038/s41388-020-1166-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/07/2020] [Accepted: 01/15/2020] [Indexed: 12/24/2022]
Abstract
Circulating tumor cells (CTC) disseminating is an important cause of distant metastasis. However, the mechanism involved in increasing the numbers of CTCs in breast cancer is unclear. Herein, Zinc finger protein 367 (ZNF367) was identified as a potential prometastatic gene in an integrative breast cancer datasets. ZNF367 was upregulated in breast cancer tissues and cell lines, and significantly correlated with poorer metastasis-free and overall survivals in patients. ZNF367 promoted tumor metastasis accompanied with increase of CTC numbers. Mechanistically, ZNF367 interacted with chromatin remodeling protein BRG1 and transcriptionally activated CIT and TP53BP2, leading to the inhibition of the Hippo pathway and activation of YAP1, which gave rise to the resistance of anoikis and increased CTCs in the blood circulation. More importantly, administration of a YAP1 inhibitor Verteporfin resensitized ZNF367-overexpressing breast cancer cells to anoikis and abrogated metastasis. Our findings addressed the importance of ZNF367 in breast cancer as a prognostic biomarker and offered a potential therapeutic strategy for the treatment of a subset of metastatic breast cancer with ZNF367 overexpression.
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Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers (Basel) 2019; 11:cancers11111659. [PMID: 31717773 PMCID: PMC6895979 DOI: 10.3390/cancers11111659] [Citation(s) in RCA: 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.
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Zhao P, Zhou W, Liu C, Zhang H, Cheng Z, Wu W, Liu K, Hu H, Zhong C, Zhang Y, Zhou D, Liu F, Dai Y, Wang J, Zou C. Establishment and Characterization of a CTC Cell Line from Peripheral Blood of Breast Cancer Patient. J Cancer 2019; 10:6095-6104. [PMID: 31762819 PMCID: PMC6856591 DOI: 10.7150/jca.33157] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 08/21/2019] [Indexed: 12/26/2022] Open
Abstract
Background: Circulating tumor cell (CTC)-based patient-derived cells are ideal models for investigating the molecular basis of cancer. However, the rarity and heterogeneity of CTCs as well as the difficulties of primary culture limit their practical application. Establishing efficient in vitro culture methods and functionally characterizing CTCs is essential for cancer studies. To this end, we developed an experimental protocol for the isolation, expansion, and identification of breast cancer CTCs. Methods: The CTC-3 cell line was established from peripheral blood cells of a breast cancer patient. A karyotype analysis was performed. The molecular profile was assessed by flow cytometry, quantitative real-time PCR, and western blot. The characteristics of tumors formed by CTC-3 cells were evaluated by cell growth and tumor sphere formation assays and in a mouse xenograft model. The tumors were analyzed by immunohistochemistry, immunofluorescence analysis, and hematoxylin and eosin staining. Results: The CTC-3 cell line showed more aggressive growth both in vitro and in vivo than the widely used MCF-7 breast cancer cell line. CTC-3 cells were also more resistant to chemotherapeutic agents, and gene profiling indicated higher expression levels of the epithelial-to-mesenchymal transition and stemness markers as compared to MCF-7 cells. Conclusions: CTC-3 cells are a better model for investigating the malignant behavior of breast cancer than existing cell lines.
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Affiliation(s)
- Pan Zhao
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Wenbin Zhou
- Department of breast and thyroid surgery, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Chang Liu
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China.,Central Laboratory, Dalian Municipal Central Hospital, Dalian 116033, China
| | - Huirong Zhang
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Zhiqiang Cheng
- Department of Pathology, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Weiqing Wu
- Department of Health Management, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Kaisheng Liu
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Hong Hu
- Department of breast and thyroid surgery, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Caineng Zhong
- Department of breast and thyroid surgery, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Yayuan Zhang
- Department of breast and thyroid surgery, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Dongxian Zhou
- Department of breast and thyroid surgery, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Feiyuan Liu
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Yong Dai
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Jianhong Wang
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Chang Zou
- Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen 518020, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
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Lee J, Park SS, Lee YK, Norton JA, Jeffrey SS. Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA. Mol Oncol 2019; 13:1623-1650. [PMID: 31243883 PMCID: PMC6670020 DOI: 10.1002/1878-0261.12537] [Citation(s) in RCA: 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.
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Affiliation(s)
- Jee‐Soo Lee
- Department of Laboratory MedicineHallym University Sacred Heart HospitalAnyangKorea
- Department of Laboratory MedicineSeoul National University College of MedicineSeoulKorea
| | - Sung Sup Park
- Department of Laboratory MedicineSeoul National University College of MedicineSeoulKorea
| | - Young Kyung Lee
- Department of Laboratory MedicineHallym University Sacred Heart HospitalAnyangKorea
- Department of Laboratory MedicineHallym University College of MedicineAnyangKorea
| | - Jeffrey A. Norton
- Department of SurgeryStanford University School of MedicineStanfordCAUSA
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Kobayashi T, Honda K. Trends in biomarker discoveries for the early detection and risk stratification of pancreatic cancer using omics studies. Expert Rev Mol Diagn 2019; 19:651-654. [PMID: 31298060 DOI: 10.1080/14737159.2019.1643718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Takashi Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine , Kobe , Hyogo , Japan
| | - Kazufumi Honda
- Department of Biomarkers for Early Detection of Cancer, National Cancer Center Research Institute , Tokyo , Japan
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Li Y, Tian X, Gao L, Jiang X, Fu R, Zhang T, Ren T, Hu P, Wu Y, Zhao P, Yang D. Clinical significance of circulating tumor cells and tumor markers in the diagnosis of lung cancer. Cancer Med 2019; 8:3782-3792. [PMID: 31132233 PMCID: PMC6639255 DOI: 10.1002/cam4.2286] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/12/2019] [Accepted: 05/13/2019] [Indexed: 01/05/2023] Open
Abstract
Background Lung cancer has the highest fatality rate of all cancer types. To improve patients’ survival and life quality, it is therefore very important to screen for and detect it at an early stage. Methods A negative enrichment–fluorescence in situ hybridization (NE‐FISH) approach was used to detect circulating tumor cells (CTCs) in lung cancer patients, and levels of lung cancer‐associated serum markers were also measured in the peripheral blood of these same patients. The correlation between CTCs, serum cancer markers (carcinoembryonic antigen [CEA], CA 125, CYFRA 21‐1, and SCC), and clinicopathological characteristics was then investigated. Moreover, the potential clinical use of the combination of CTCs and tumor markers for the diagnosis of lung cancer, especially at early stages, was also explored. Results CTC frequencies in lung cancer patients were significantly higher than in healthy control volunteers or patients with benign lung disease, and the area under the receiver operating characteristics curve for the control group was 0.846 (95% CI 0.796‐0.887, P < 0.001). The rate of CTC positivity in lung cancer patients was 68.29% when the CTC cutoff value was 2, and the sensitivity of this means of lung cancer detection rose to 82.93% by combining CTC‐based detection with measurements of serum tumor markers. Similarly, the diagnostic sensitivity of this approach in early‐stage lung cancer patients (I‐II) was improved from 63.93% to 78.69%. Detection of CTCs can thus assist with the identification of benign and malignant pulmonary nodules. Conclusions It is potentially helpful and effective to employ a combination of CTCs and serum tumor markers for the clinical diagnosis of lung cancer.
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Affiliation(s)
- Yang Li
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Xudong Tian
- Department of Thoracic Surgery, Liaocheng People's Hospital, Liaocheng, China
| | - Lei Gao
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Xiaohong Jiang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Rao Fu
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Tingting Zhang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Tianying Ren
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Ping Hu
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Yaping Wu
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Peige Zhao
- Department of Respiratory Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Dawei Yang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
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Han L, Li YJ, Zhang WD, Song PP, Li H, Li S. Clinical significance of tumor cells in the peripheral blood of patients with esophageal squamous cell carcinoma. Medicine (Baltimore) 2019; 98:e13921. [PMID: 30732126 PMCID: PMC6380864 DOI: 10.1097/md.0000000000013921] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Circulating tumor cells (CTCs) are suspected of predicting the prognosis of malignant tumor, but there are few relevant reports specific to esophageal squamous cell carcinoma (ESCC). This study investigated the clinical significance of CTCs in patients with ESCC.Sixty patients with ESCC were enrolled, from whom CTCs had been tested by our team previously. Peripheral blood samples were obtained from these patients before treatment; and CTCs were assayed by isolation by size of epithelial tumor cells (ISET). Associations between the presence of CTCs and patients' clinicopathological parameters and clinical outcomes were analyzed.CTCs were detected in 20 patients (33.3%), who experienced significantly shorter progression-free survival (PFS) than did the CTC-negative patients. Overall, PFS was negatively associated with the number of CTCs. Multivariate analyses showed that a CTC count >2 was a strong independent prognostic indicator of tumor recurrence (hazard ratio [HR] 5.63; 95% confidence interval [CI] 1.77-17.89; P = .003). In the subgroup of 50 patients who underwent R0 resection and postoperative adjuvant radiotherapy or chemotherapy, CTC was a strong, independent, and prognostic indicator of tumor recurrence (HR 10.70; 95% CI, 1.40-81.91; P = .022). The number of CTCs correlated with the T stage (r = 0.26, P = .043) but not with the N or M stage. For subgroups in stages II or I-IIIB or T3 or T3 + T4, the PFS of patients with CTCs > 1 or > 2 was significantly shorter than that of the patients with CTCs ≤ 1 or CTCs ≤ 2. In the stage III or T3 + T4 groups, the PFS of patients with CTCs > 0 was significantly shorter than that of patients with CTC = 0.This is the first study to report that the CTC detected by ISET is an independent and prognostic indicator of patients' outcome in ESCC. Consideration of CTCs may improve the accuracy of preoperative staging in ESCC.
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Affiliation(s)
- Lu Han
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences
- Department of Hepatobiliary Surgery, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University
| | - Yun-Jie Li
- Equipment Management Office, Jinan Central Hospital Affiliated to Shandong University
| | - Wei-Di Zhang
- Department of Thoracic Surgery, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University
| | - Ping-Ping Song
- Department of Thoracic Surgery, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University
| | - Hao Li
- Department of Interventional Radiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, P. R. China
| | - Sheng Li
- Department of Hepatobiliary Surgery, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University
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Rofi E, Vivaldi C, Del Re M, Arrigoni E, Crucitta S, Funel N, Fogli S, Vasile E, Musettini G, Fornaro L, Falcone A, Danesi R. The emerging role of liquid biopsy in diagnosis, prognosis and treatment monitoring of pancreatic cancer. Pharmacogenomics 2018; 20:49-68. [PMID: 30520336 DOI: 10.2217/pgs-2018-0149] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Circulating tumor DNA, circulating tumor cells and tumor-related exosomes may offer new opportunities to provide insights into the biological and clinical characteristics of a neoplastic disease. They represent alternative routes for diagnostic and prognostic purposes, and for predicting and longitudinally monitoring response to treatment and disease progression. Hence, circulating biomarkers represent promising noninvasive tools in the scenario of pancreatic cancer, where neither molecular nor clinical predictors of treatment benefit have been identified yet. This review aims to provide an overview of the current status of circulating biomarker research in pancreatic cancer, and discusses their potential clinical utility to facilitate clinical decision-making.
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Affiliation(s)
- Eleonora Rofi
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Elena Arrigoni
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Stefania Crucitta
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Niccola Funel
- Department of Translational Research & The New Technologies in Medicine & Surgery, University of Pisa, Pisa, Italy
| | - Stefano Fogli
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Gianna Musettini
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Alfredo Falcone
- Unit of Medical Oncology, Department of Translational Research & New Technologies in Medicine, University of Pisa, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology & Pharmacogenetics, Department of Clinical & Experimental Medicine, University of Pisa, Italy
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Zhang J, Shi H, Jiang T, Liu Z, Lin PP, Chen N. Circulating tumor cells with karyotyping as a novel biomarker for diagnosis and treatment of nasopharyngeal carcinoma. BMC Cancer 2018; 18:1133. [PMID: 30454007 PMCID: PMC6245898 DOI: 10.1186/s12885-018-5034-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 11/01/2018] [Indexed: 02/05/2023] Open
Abstract
Background Circulating tumor cells (CTCs) have been considered great clinical significance in various cancers. However, it remains unknown that how is the role of CTCs in patients with nasopharyngeal carcinoma (NPC). We investigated the value of CTCs enumeration and karyotyping in NPC. Methods In the present study, we applied integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) automatic testing system to detect and characterize CTCs of NPC patients. Enumeration and aneuploidy of chromosome 8 in CTCs were examined in various stages of patients with NPC. The changes of CTCs number and karyotyping post to chemotherapy were investigated in NPC. Results CTCs were detected by SE-iFISH in 46 out of 50 pre-treatment NPC patients, and performed a positive rate of 92.0%. No significant association was found between disease staging and CTCs detection rate. CTCs number constantly increased with TNM stage rising (from stage II to stage IV) no matter in newly diagnosed patients without distant metastasis (M0) and relapsed or distant metastatic patients. The number of CTCs decreased after treatment in patients with partial response (PR), while increased in patients with progressive disease or stable disease (PD/SD). More interestingly, CTCs karyotyping indicated that aneuploidy of chromosome 8 in CTCs was dramatically related to chemotherapeutic efficacy in NPC. Positive correlation was found between CTCs count and plasma EBV DNA level of NPC patients. Conclusions CTCs could be detected in various stages of NPC patients using SE-iFISH. CTCs number could indicate the severity degree of disease in NPC. Dynamically monitoring the variations in CTCs number may predict chemotherapy efficacy during treatment. CTCs karyotyping is related to the sensibility of chemotherapy and drug resistance, and karyotyping of CTCs might predict therapeutic efficacy and evaluate chemo-resistance in NPC. CTCs could be used as a monitoring indicator in the fields of treatment, diagnosis and follow-up of NPC.
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Affiliation(s)
- Jing Zhang
- Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 37 GuoXueXiang, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Huashan Shi
- Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 37 GuoXueXiang, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Tingting Jiang
- Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 37 GuoXueXiang, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Zhe Liu
- Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 37 GuoXueXiang, Wuhou District, Chengdu, 610041, Sichuan, China
| | | | - Nianyong Chen
- Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 37 GuoXueXiang, Wuhou District, Chengdu, 610041, Sichuan, China.
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Samandari M, Julia MG, Rice A, Chronopoulos A, Del Rio Hernandez AE. Liquid biopsies for management of pancreatic cancer. Transl Res 2018; 201:98-127. [PMID: 30118658 DOI: 10.1016/j.trsl.2018.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/17/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
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Affiliation(s)
- Mohamadmahdi Samandari
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - María Gil Julia
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Antonios Chronopoulos
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Armando E Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
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Improvement of sensitive and specific detection of circulating tumor cells using negative enrichment and immunostaining-FISH. Clin Chim Acta 2018; 485:95-102. [DOI: 10.1016/j.cca.2018.06.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 06/21/2018] [Accepted: 06/21/2018] [Indexed: 02/07/2023]
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Neves M, Azevedo R, Lima L, Oliveira MI, Peixoto A, Ferreira D, Soares J, Fernandes E, Gaiteiro C, Palmeira C, Cotton S, Mereiter S, Campos D, Afonso LP, Ribeiro R, Fraga A, Tavares A, Mansinho H, Monteiro E, Videira PA, Freitas PP, Reis CA, Santos LL, Dieguez L, Ferreira JA. Exploring sialyl-Tn expression in microfluidic-isolated circulating tumour cells: A novel biomarker and an analytical tool for precision oncology applications. N Biotechnol 2018; 49:77-87. [PMID: 30273682 DOI: 10.1016/j.nbt.2018.09.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 09/14/2018] [Accepted: 09/25/2018] [Indexed: 12/17/2022]
Abstract
Circulating tumour cells (CTCs) originating from a primary tumour, lymph nodes and distant metastases hold great potential for liquid biopsies by providing a molecular fingerprint for disease dissemination and its temporal evolution through the course of disease management. CTC enumeration, classically defined on the basis of surface expression of Epithelial Cell Adhesion Molecule (EpCAM) and absence of the pan-leukocyte marker CD45, has been shown to correlate with clinical outcome. However, existing approaches introduce bias into the subsets of captured CTCs, which may exclude biologically and clinically relevant subpopulations. Here we explore the overexpression of the membrane protein O-glycan sialyl-Tn (STn) antigen in advanced bladder and colorectal tumours, but not in blood cells, to propose a novel CTC isolation technology. Using a size-based microfluidic device, we show that the majority (>90%) of CTCs isolated from the blood of patients with metastatic bladder and colorectal cancers express the STn antigen, supporting a link with metastasis. STn+ CTC counts were significantly higher than EpCAM-based detection in colorectal cancer, providing a more efficient cell-surface biomarker for CTC isolation. Exploring this concept, we constructed a glycan affinity-based microfluidic device for selective isolation of STn+ CTCs and propose an enzyme-based strategy for the recovery of viable cancer cells for downstream investigations. Finally, clinically relevant cancer biomarkers (transcripts and mutations) in bladder and colorectal tumours, were identified in cells isolated by microfluidics, confirming their malignant origin and highlighting the potential of this technology in the context of precision oncology.
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Affiliation(s)
- Manuel Neves
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; International Iberian Nanotechnology Laboratory (INL), Braga, Portugal
| | - Rita Azevedo
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal
| | - Luís Lima
- Portuguese Institute of Oncology, Porto, Portugal; Glycobiology in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal
| | - Marta I Oliveira
- International Iberian Nanotechnology Laboratory (INL), Braga, Portugal
| | - Andreia Peixoto
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal; INEB-Institute for Biomedical Engineering of Porto, Portugal
| | | | - Janine Soares
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal
| | - Elisabete Fernandes
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal; INEB-Institute for Biomedical Engineering of Porto, Portugal
| | - Cristiana Gaiteiro
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal
| | | | - Sofia Cotton
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal
| | - Stefan Mereiter
- Glycobiology in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal
| | - Diana Campos
- Glycobiology in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal
| | | | - Ricardo Ribeiro
- Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal; INEB-Institute for Biomedical Engineering of Porto, Portugal
| | - Avelino Fraga
- Hospital Centre- Hospital of Santo António of Porto, Portugal
| | - Ana Tavares
- Portuguese Institute of Oncology, Porto, Portugal
| | - Hélder Mansinho
- Hemato-Oncology Clinic, Hospital Garcia de Orta, EPE, Almada, Portugal; Gupo de Investigação do Cancro Digestivo-GICD, Portugal
| | | | - Paula A Videira
- Glycoimmunology Group, UCIBIO, Departamento Ciências da Vida, Faculdade de Ciência e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal
| | - Paulo P Freitas
- International Iberian Nanotechnology Laboratory (INL), Braga, Portugal; INESC - Microsistemas e Nanotecnologias, Lisboa, Lisbon, Portugal
| | - Celso A Reis
- Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; Glycobiology in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal; Faculty of Medicine, University of Porto, Portugal
| | - Lúcio Lara Santos
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; UFP: School of Health Sciences, Fernando Pessoa University of Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), Porto, Portugal
| | - Lorena Dieguez
- International Iberian Nanotechnology Laboratory (INL), Braga, Portugal
| | - José Alexandre Ferreira
- Portuguese Institute of Oncology, Porto, Portugal; Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal; International Iberian Nanotechnology Laboratory (INL), Braga, Portugal; Glycobiology in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal; Instituto de Investigação e Inovação em Saúde (I3S), University of Porto, Portugal.
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Kunovsky L, Tesarikova P, Kala Z, Kroupa R, Kysela P, Dolina J, Trna J. The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterol Hepatol 2018; 2018:5389820. [PMID: 30186820 PMCID: PMC6112218 DOI: 10.1155/2018/5389820] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/27/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies with increasing incidence. The poor prognosis is due to the aggressive nature of the tumor, late detection, and the resistance to chemotherapy and radiotherapy. A radical surgery procedure is the only treatment that has been shown to improve the 5-year survival rate to 20-25%. However, the majority of patients (80-85%) are diagnosed with locally advanced or metastatic disease and just 15-20% patients are diagnosed in an early stage allowing them to undergo the potentially curative surgical resection. The early detection of PDAC without the use of invasive methods is challenging and discovery of a cost-effective biomarker with high specificity and sensitivity could significantly improve the treatment and survival in these patients. In this review, we summarize current and newly examined biomarkers in early PDAC detection.
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Affiliation(s)
- Lumir Kunovsky
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Pavla Tesarikova
- Department of Internal Medicine, Hospital Boskovice, Czech Republic
| | - Zdenek Kala
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Radek Kroupa
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Petr Kysela
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Jiri Dolina
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Jan Trna
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
- Department of Internal Medicine, Hospital Boskovice, Czech Republic
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Liu X, Zhang Z, Zhang B, Zheng Y, Zheng C, Liu B, Zheng S, Dong K, Dong R. Circulating tumor cells detection in neuroblastoma patients by EpCAM-independent enrichment and immunostaining-fluorescence in situ hybridization. EBioMedicine 2018; 35:244-250. [PMID: 30104180 PMCID: PMC6154868 DOI: 10.1016/j.ebiom.2018.08.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 08/01/2018] [Accepted: 08/01/2018] [Indexed: 12/17/2022] Open
Abstract
Detecting circulating tumor cells (CTCs) has proven valuable for evaluating the prognosis of cancer patients and for studying the mechanisms of treatment resistance. Owing to the lack of universal and specific tumor markers for neuroblastoma (NB), in this prospective study, we adopted an EpCAM-independent method to detect CTCs in the peripheral blood of NB patients. We used an EpCAM-independent assay to delete leukocytes and to enrich the CTCs. CTCs were identified by immunostaining of CD45, DAPI and DNA fluorescence in situ hybridization (FISH) of the centromere of chromosome 8 probe (CEP8). Cells that were DAPI+/CD45-/CEP8 ≥ 3 were considered CTCs. We collected peripheral blood from 28 NB patients as well as clinical and follow-up data. The number of CTCs among the different risk groups were significantly different (p = .0208, Kruskal–Wallis test). Patients with metastasis had more CTCs than those without metastasis (p < .0001, Mann–Whitney test). Patients with ≥3 CTCs per 4 ml of peripheral blood had an increased likelihood of having metastasis (sensitivity, 88.89%; specificity, 78.59%), and patients with ≥10 CTCs per 4 ml of peripheral blood had poorer overall survival. The EpCAM-independent assay along with immunostaining-FISH (i-FISH) described here can detect CTCs in patients with NB at a high sensitivity and may have clinical value for prognosis evaluation and diagnosing metastasis when imaging data are ambiguous.
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Affiliation(s)
- Xiangqi Liu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Zhenzhen Zhang
- Biotecan Medical Diagnostics Co., Ltd, Zhangjiang Center for Translational Medicine, Shanghai, China
| | - Binbin Zhang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Yijie Zheng
- Medical Scientific Liaison Asian Pacific, Abbott Diagnostics Division, Abbott Laboratories, Shanghai, China
| | - Chao Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Baihui Liu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Kuiran Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China.
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China.
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Su Z, Zhao J, Ke S, Zhang J, Liu X, Wang Y, Sun Q, Pan Q. Clinical significance of circulating tumor cells via combined whole exome sequencing in early stage cancer screening: A case report. Exp Ther Med 2018; 16:2527-2533. [PMID: 30186486 PMCID: PMC6122440 DOI: 10.3892/etm.2018.6507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 06/27/2018] [Indexed: 01/06/2023] Open
Abstract
A newly-developed platform, integrating subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH), was applied to analyze the clinical significance of circulating tumor cells (CTCs) for early screening of cancer in healthy people. The present case report describes one healthy individual who accepted a CTC peripheral blood test, and 8 CTCs/7.5 ml blood were detected. However, various conventional cancer biomarkers were all negative, including cervical cytological inspection, alpha-fetoprotein, cancer antigen (CA)-125, CA19-9, carcinoembryonic antigen (CEA), CA15-3 and human papilloma virus. To explore the origin of the CTCs, whole exome sequencing was used to analyze the CTC variation spectrum. A total of 42 mutations were associated with cancer according to analysis in COSMIC (http://cancer.sanger.ac.uk/cosmic). The results revealed a high risk of tumor in the colorectum, stomach and breast (13, 12 and 6 variations matched, respectively). In this individual, an intestinal polyp was discovered and removed by colonoscopy. The intestinal polyp was identified to be a hyperplastic polyp by pathological diagnosis. No lesions were discovered in the stomach and breast. No CTCs were detected in this patient's blood at 1 and 6 months after removal of the lesions. This case indicates that CTC detection by SE-iFISH has potential in early stage cancer screening, and the mutation spectrum of CTC assists the tracking of its sources.
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Affiliation(s)
- Zijian Su
- Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Jiangman Zhao
- Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 200120, P.R. China
| | - Shaoying Ke
- Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Jian Zhang
- Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Xiaoyu Liu
- Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Yu Wang
- Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 200120, P.R. China
| | - Qihong Sun
- Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 200120, P.R. China
| | - Qunxiong Pan
- Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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