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Izhar M, Ahmad Z, Moazzam M, Jader A. Targeted liquid biopsy for brain tumors. THE JOURNAL OF LIQUID BIOPSY 2024; 6:100170. [PMID: 40027302 PMCID: PMC11863980 DOI: 10.1016/j.jlb.2024.100170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 03/05/2025]
Abstract
Cerebrospinal fluid (CSF) is a promising source of molecular biomarkers in the detection and monitoring of brain malignancies. Unlike peripheral blood, where biomarker detection is hindered by the blood-brain barrier and the complex nature of biofluids, CSF offers a more direct and enriched source of tumor-derived markers, including circulating tumor DNA (ctDNA), microRNA (miRNA), proteins, and extracellular vesicles (EVs). These biomarkers, originating from brain tumor cells, are often more concentrated in CSF than in peripheral blood due to the proximity of CSF to the central nervous system (CNS). The presence of ctDNA in CSF is notably higher than in plasma, making CSF an advantageous medium for liquid biopsy in brain tumor patients. Traditional liquid biopsy approaches relying on peripheral venous blood samples often face challenges in detecting low concentrations of tumor-derived biomarkers. The direct contact of CSF with the CNS minimizes background noise, potentially enhancing the accuracy and sensitivity of diagnostic assays. Despite the barriers posed by the blood-brain barrier and other physiological factors that limit biomarker levels in the systemic circulation, CSF's unique position within the CNS allows for more effective biomarker collection. While peripheral blood remains the standard medium for liquid biopsy in oncology, the proximity of CSF to brain tumors suggests it may offer superior diagnostic capabilities. Emerging evidence from non-CNS malignancies indicates that collecting biofluids closer to the tumor site can significantly improve biomarker detection. Although this approach has been well-documented in other solid tumors, its application to CNS malignancies remains underexplored. This study hypothesizes that targeted blood sampling from CNS tumor-draining veins could similarly enhance biomarker detection, thereby increasing the sensitivity and efficacy of liquid biopsy techniques in diagnosing and monitoring brain malignancies.
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Affiliation(s)
- Muhammad Izhar
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94304, USA
| | - Ziyad Ahmad
- Department of Orthopedics, Medical Teaching Institute, Mardan Medical Complex, Mardan, Pakistan
| | | | - Arwa Jader
- Department of Neurosurgery, Kufa University, Kufa, Iraq
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Sun S, Yang Q, Jiang D, Zhang Y. Nanobiotechnology augmented cancer stem cell guided management of cancer: liquid-biopsy, imaging, and treatment. J Nanobiotechnology 2024; 22:176. [PMID: 38609981 PMCID: PMC11015566 DOI: 10.1186/s12951-024-02432-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent both a key driving force and therapeutic target of tumoral carcinogenesis, tumor evolution, progression, and recurrence. CSC-guided tumor diagnosis, treatment, and surveillance are strategically significant in improving cancer patients' overall survival. Due to the heterogeneity and plasticity of CSCs, high sensitivity, specificity, and outstanding targeting are demanded for CSC detection and targeting. Nanobiotechnologies, including biosensors, nano-probes, contrast enhancers, and drug delivery systems, share identical features required. Implementing these techniques may facilitate the overall performance of CSC detection and targeting. In this review, we focus on some of the most recent advances in how nanobiotechnologies leverage the characteristics of CSC to optimize cancer diagnosis and treatment in liquid biopsy, clinical imaging, and CSC-guided nano-treatment. Specifically, how nanobiotechnologies leverage the attributes of CSC to maximize the detection of circulating tumor DNA, circulating tumor cells, and exosomes, to improve positron emission computed tomography and magnetic resonance imaging, and to enhance the therapeutic effects of cytotoxic therapy, photodynamic therapy, immunotherapy therapy, and radioimmunotherapy are reviewed.
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Affiliation(s)
- Si Sun
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qiang Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dawei Jiang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China.
| | - Yuan Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Zhang Y, Liu WS, Zhang XY, Tong HX, Yang H, Liu WF, Fan J, Zhou J, Hu J. Low expression of exosomal miR-150 predicts poor prognosis in colorectal cancer patients after surgical resections. Carcinogenesis 2022; 43:930-940. [PMID: 35767307 DOI: 10.1093/carcin/bgac059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 01/13/2023] Open
Abstract
Liver metastasis is a leading indicator of poor prognosis in patients with colorectal cancer (CRC). Exosomal intercellular communication has been reported to play an important role in cancer invasion and metastasis. Here, we characterized exosomal miRNAs underlying liver metastasis in CRC patients (Cohort 1, n = 30) using miRNA arrays. Exosomal miR-150 was found to be downregulated in CRC patients with liver metastases compared to those without (P = 0.025, fold change [FC] = 2.01). These results were then validated using another independent cohort of CRC patients (Cohort 2, n = 64). Patients with low expression of exosomal miR-150 had significantly shorter overall survival (OS) time (33.3 months versus 43.3 months, P = 0.002). In addition, the low expression of exosomal miR-150 was significantly correlated with advanced tumor node metastasis staging (P = 0.013), higher CA199 level (P = 0.018), and the presence of liver metastasis (P = 0.048). Multivariate analysis showed that low expression of exosomal miR-150 (P = 0.035) and liver metastasis (P < 0.001) were independent prognostic factors for overall survival. In vivo and in vitro studies showed that the viability and invasion of CRC cells were both significantly suppressed by ExomiR-150. Target-prediction assessment and dual-luciferase reporter assay indicated that FTO (the fat mass and obesity-associated gene) was a direct target for miR-150. This study first demonstrated that exosomal miR-150 may be a potential prognostic factor and treatment target for CRC.
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Affiliation(s)
- Yong Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Shuai Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiang-Yu Zhang
- Liver Cancer Institution, Fudan University, Shanghai, China.,Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Han-Xing Tong
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hua Yang
- Department of General Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wei-Feng Liu
- Liver Cancer Institution, Fudan University, Shanghai, China.,Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jia Fan
- Liver Cancer Institution, Fudan University, Shanghai, China.,Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institution, Fudan University, Shanghai, China.,Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jie Hu
- Liver Cancer Institution, Fudan University, Shanghai, China.,Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
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Aramini B, Masciale V, Arienti C, Dominici M, Stella F, Martinelli G, Fabbri F. Cancer Stem Cells (CSCs), Circulating Tumor Cells (CTCs) and Their Interplay with Cancer Associated Fibroblasts (CAFs): A New World of Targets and Treatments. Cancers (Basel) 2022; 14:cancers14102408. [PMID: 35626011 PMCID: PMC9139858 DOI: 10.3390/cancers14102408] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The world of small molecules in solid tumors as cancer stem cells (CSCs), circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) continues to be under-debated, but not of minor interest in recent decades. One of the main problems in regard to cancer is the development of tumor recurrence, even in the early stages, in addition to drug resistance and, consequently, ineffective or an incomplete response against the tumor. The findings behind this resistance are probably justified by the presence of small molecules such as CSCs, CTCs and CAFs connected with the tumor microenvironment, which may influence the aggressiveness and the metastatic process. The mechanisms, connections, and molecular pathways behind them are still unknown. Our review would like to represent an important step forward to highlight the roles of these molecules and the possible connections among them. Abstract The importance of defining new molecules to fight cancer is of significant interest to the scientific community. In particular, it has been shown that cancer stem cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity; on the other side, circulating tumor cells (CTCs) seem to split away from the primary tumor and appear in the circulatory system as singular units or clusters. It is becoming more and more important to discover new biomarkers related to these populations of cells in combination to define the network among them and the tumor microenvironment. In particular, cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment with different functions, including matrix deposition and remodeling, extensive reciprocal signaling interactions with cancer cells and crosstalk with immunity. The settings of new markers and the definition of the molecular connections may present new avenues, not only for fighting cancer but also for the definition of more tailored therapies.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental, Diagnostic and Specialty Medicine—DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni—L. Pierantoni Hospital, 47121 Forlì, Italy;
- Correspondence:
| | - Valentina Masciale
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41122 Modena, Italy; (V.M.); (M.D.)
| | - Chiara Arienti
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (C.A.); (G.M.); (F.F.)
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41122 Modena, Italy; (V.M.); (M.D.)
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental, Diagnostic and Specialty Medicine—DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni—L. Pierantoni Hospital, 47121 Forlì, Italy;
| | - Giovanni Martinelli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (C.A.); (G.M.); (F.F.)
| | - Francesco Fabbri
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (C.A.); (G.M.); (F.F.)
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Yadav A, Kumar A, Siddiqui MH. Detection of circulating tumour cells in colorectal cancer: Emerging techniques and clinical implications. World J Clin Oncol 2021; 12:1169-1181. [PMID: 35070736 PMCID: PMC8716996 DOI: 10.5306/wjco.v12.i12.1169] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/15/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Despite several advances in oncological management of colorectal cancer, morbidity and mortality are still high and devastating. The diagnostic evaluation by endoscopy is cumbersome, which is uncomfortable to many. Because of the intra- and inter-tumour heterogeneity and changing tumour dynamics, which is continuous in nature, the diagnostic biopsy and assessment of the pathological sample are difficult and also not adequate. Late manifestation of the disease and delayed diagnosis may lead to relapse or metastases. One of the keys to improving the outcome is early detection of cancer, ease of technology to detect with uniformity, and its therapeutic implications, which are yet to come. "Liquid biopsy" is currently the most recent area of interest in oncology, which may provide important tools regarding the characterization of the primary tumour and its metastasis as cancer cells shed into the bloodstream even at the early stages of the disease. By using this approach, clinicians may be able to find out information about the tumour at a given time. Any of the following three types of sampling of biological material can be used in the "liquid biopsy". These are circulating tumour cells (CTCs), circulating tumour DNA, and exosomes. The most commonly studied amongst the three is CTCs. CTCs with their different applications and prognostic value has been found useful in colorectal cancer detection and therapeutics. In this review, we will discuss various markers for CTCs, the core tools/techniques for detection, and also important findings of clinical studies in colorectal cancer and its clinical implications.
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Affiliation(s)
- Alka Yadav
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Lin D, Shen L, Luo M, Zhang K, Li J, Yang Q, Zhu F, Zhou D, Zheng S, Chen Y, Zhou J. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther 2021; 6:404. [PMID: 34803167 PMCID: PMC8606574 DOI: 10.1038/s41392-021-00817-8] [Citation(s) in RCA: 444] [Impact Index Per Article: 111.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/06/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.
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Affiliation(s)
- Danfeng Lin
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lesang Shen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Luo
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Zhang
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinfan Li
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Yang
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangfang Zhu
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan Zhou
- Department of Surgery, Traditional Chinese Medical Hospital of Zhuji, Shaoxing, China
| | - Shu Zheng
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiding Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiaojiao Zhou
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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7
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Zhong Y, Ma T, Qiao T, Hu H, Li Z, Luo K, Wang Y, Tang Q, Wang G, Huang R, Wang X. Role of Phenotypes of Circulating Tumor Cells in the Diagnosis and Treatment of Colorectal Cancer. Cancer Manag Res 2021; 13:7077-7085. [PMID: 34531685 PMCID: PMC8439983 DOI: 10.2147/cmar.s316544] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate the relationship between circulating tumor cells (CTCs) and their subpopulations and colorectal cancer (CRC). To explore the application of CTCs' numbers and positive rates in the diagnosis and treatment of CRC, and to assess the effect of surgery on CTCs numbers and positivity. METHODS We identified CTCs using the CanPatrol technique after enrollment. Peripheral blood samples were collected from 74 CRC patients before anti-tumor treatment. CTCs can be divided into the following three phenotypes: epithelial CTCs (E-CTCs) (EpCAM+, Vimentin-), mesenchymal CTCs (M-CTCs) (EpCAM-, Vimentin+), and mixed CTCs (E/M-CTCs) (EpCAM+, Vimentin+). CTCs and the proportion of subtypes were statistically compared with clinicopathological characteristics. RESULTS The positive rate of M-CTCs was significantly higher in patients with tumor size ≥5 cm (85.7% vs 49.1%, P = 0.004) and carcinoembryonic antigen (CEA) >5 ng/mL (83.3% vs 51.0% p = 0.024). Moreover, the T stage (T1 0, T2 33.3%, T3 59.4%, T4 100%, p < 0.0005) and TNM stage (stage I 11.8%, stage II 79.2%, stage III 64.3%, stage IV 100%, p < 0.0005) were correlated with the positive rate of M-CTCs. We also found that the proportion of M-CTCs was correlated with the T stage (p < 0.0005) and TNM stage (p=0.0200), but not with the N stage (p=0.6889). In survival analysis, M-CTCs >1 were found associated with worse disease-free survival (p=0.007). After treatment, the number and proportion of CTCs and M-CTCs were significantly reduced. CONCLUSION The positive rate of M-CTCs was associated with tumor size, T stage, TNM stage, vascular invasion, and CEA. As the disease progressed, the proportion of M-CTCs gradually increased, and the survival performance was worse in patients with a high positive rate of M-CTCs.
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Affiliation(s)
- Yuchen Zhong
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
- Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310002, People’s Republic of China
| | - Tianyi Ma
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Tianyu Qiao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Hanqing Hu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Zhengliang Li
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Kangjia Luo
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Yuliuming Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Qingchao Tang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Guiyu Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
- Department of Colorectal Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310002, People’s Republic of China
| | - Rui Huang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150080, People’s Republic of China
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Cancer, Beijing, 100021, People’s Republic of China
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Gisina A, Novikova S, Kim Y, Sidorov D, Bykasov S, Volchenko N, Kaprin A, Zgoda V, Yarygin K, Lupatov A. CEACAM5 overexpression is a reliable characteristic of CD133-positive colorectal cancer stem cells. Cancer Biomark 2021; 32:85-98. [PMID: 34092615 DOI: 10.3233/cbm-203187] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND CD133 (prominin-1) is the most commonly used molecular marker of the cancer stem cells (CSCs) that maintain tumor progression and recurrence in colorectal cancer. However, the proteome of CSCs directly isolated from colorectal tumors based on CD133 expression has never been investigated. OBJECTIVE To reveal biomarkers of CD133-positive colorectal CSCs. METHODS Thirty colorectal tumor samples were collected from patients undergoing bowel resection. CD133-positive and CD133-negative cells were isolated by FACS. Comparative proteomic profiling was performed by LC-MS/MS analysis combined with label-free quantification. Verification of differentially expressed proteins was performed by flow cytometry or ELISA. CD133-knockout Caco-2 and HT-29 cell lines were generated using CRISPR-Cas9 gene editing. RESULTS LC-MS/MS analysis identified 29 proteins with at least 2.5-fold higher expression in CD133-positive cells versus CD133-negative cells. Flow cytometry confirmed CEACAM5 overexpression in CD133-positive cells in all clinical samples analyzed. S100A8, S100A9, and DEFA1 were differentially expressed in only a proportion of the samples. CD133 knockout in the colon cancer cell lines Caco-2 and HT-29 did not affect the median level of CEACAM5 expression, but led to higher variance of the percentage of CEACAM5-positive cells. CONCLUSIONS High CEACAM5 expression in colorectal cancer cells is firmly associated with the CD133-positive colorectal CSC phenotype, but it is unlikely that CD133 directly regulates CEACAM5 expression.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Svetlana Novikova
- Laboratory of Systems Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Yan Kim
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Dmitry Sidorov
- Department of Abdominal Surgery, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Stanislav Bykasov
- Department of Abdominal Surgery, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Nadezhda Volchenko
- Department of Oncomorphology, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Andrey Kaprin
- P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Victor Zgoda
- Laboratory of Systems Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Konstantin Yarygin
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Alexey Lupatov
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
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9
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Electrochemical Detection and Point-of-Care Testing for Circulating Tumor Cells: Current Techniques and Future Potentials. SENSORS 2020; 20:s20216073. [PMID: 33114569 PMCID: PMC7663783 DOI: 10.3390/s20216073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/18/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022]
Abstract
Circulating tumor cells (CTCs) are tumor cells that escaped from the primary tumor or the metastasis into the blood and they play a major role in the initiation of metastasis and tumor recurrence. Thus, it is widely accepted that CTC is the main target of liquid biopsy. In the past few decades, the separation of CTC based on the electrochemical method has attracted widespread attention due to its convenience, rapidness, low cost, high sensitivity, and no need for complex instruments and equipment. At present, CTC detection is not widely used in the clinic due to various reasons. Point-of-care CTC detection provides us with a possibility, which is sensitive, fast, cheap, and easy to operate. More importantly, the testing instrument is small and portable, and the testing does not require specialized laboratories and specialized clinical examiners. In this review, we summarized the latest developments in the electrochemical-based CTC detection and point-of-care CTC detection, and discussed the challenges and possible trends.
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10
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Vafaei S, Fattahi F, Ebrahimi M, Janani L, Shariftabrizi A, Madjd Z. Common molecular markers between circulating tumor cells and blood exosomes in colorectal cancer: a systematic and analytical review. Cancer Manag Res 2019; 11:8669-8698. [PMID: 31576171 PMCID: PMC6768129 DOI: 10.2147/cmar.s219699] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nearly half of patients with colorectal cancer (CRC), the third leading cause of cancer deaths worldwide, are diagnosed in the late stages of the disease. Appropriate treatment is not applied in a timely manner and nearly 90% of the patients who experience metastasis ultimately die. Timely detection of CRC can increase the five-year survival rate of patients. Existing histopathological and molecular classifications are insufficient for prediction of metastasis, which limits approaches to treatment. Detection of reliable cancer-related biomarkers can improve early diagnosis, prognosis, and treatment response prediction and recurrence risk. Circulating tumor cells (CTCs) and exosomes in peripheral blood can be used in a liquid biopsy to assess the status of a tumor. Exosomes are abundant and available in all fluids of the body, have a high half-life and are released by most cells. Tumor-derived exosomes are released from primary tumors or CTCs with selective cargo that represents the overall tumor. The current systematic review highlights new trends and approaches in the detection of CRC biomarkers to determine tumor signatures using CTC and exosomes. When these are combined, they could be used to guide molecular pathology and can revolutionize detection tools. Relevant observational studies published until July 24, 2019 which evaluated the expression of tumor markers in CTCs and exosomes were searched in PubMed, Scopus, Embase, and ISI Web of Science databases. The extracted biomarkers were analyzed using String and EnrichR tools.
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Affiliation(s)
- Somayeh Vafaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fahimeh Fattahi
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Leila Janani
- Department of Biostatistics, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Madjd
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
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11
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Xiao Y, Li Y, Yuan Y, Liu B, Pan S, Liu Q, Qi X, Zhou H, Dong W, Jia L. The potential of exosomes derived from colorectal cancer as a biomarker. Clin Chim Acta 2019; 490:186-193. [PMID: 30194933 DOI: 10.1016/j.cca.2018.09.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 08/28/2018] [Accepted: 09/03/2018] [Indexed: 12/11/2022]
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12
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Tsutsuyama M, Nakanishi H, Yoshimura M, Oshiro T, Kinoshita T, Komori K, Shimizu Y, Ichinosawa Y, Kinuta S, Wajima K, Sakakibara Y, Yatabe Y, Ito S, Kodera Y. Detection of circulating tumor cells in drainage venous blood from colorectal cancer patients using a new filtration and cytology-based automated platform. PLoS One 2019; 14:e0212221. [PMID: 30811434 PMCID: PMC6392262 DOI: 10.1371/journal.pone.0212221] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 01/29/2019] [Indexed: 12/30/2022] Open
Abstract
Numerous technologies exist to detect circulating tumor cells (CTCs), although reports on cytological detection of CTCs remain limited. We recently developed a cytology-based CTC detection device using glass slides and light microscopy. In this study, we automated this previously manual device to improve its efficiency and cost effectiveness for clinical applications. We conducted a pilot study using this device to compare CTCs in peripheral blood (PB) and draining venous blood (DVB) from patients with colorectal cancer (CRC). The cytology-based automated CTC detection platform consisted of a disposable filtration device with a three-dimensional (3D) metal filter and multichannel automated CTC enrichment device. This platform allowed rapid and gentle filtration of CTCs and their efficient transfer from the filter to glass slides for subsequent Papanicolaou (Pap) and immunocytochemical (ICC) staining. Cytological diagnosis of CTCs was performed by observing permanent glass slide specimens by light microscopy. The current pilot clinical study enrolled CRC patients (n = 26) with stage I–IV tumors, who underwent surgery. PB was collected before surgery, and DVB was obtained from the mesenteric vein immediately after resection. Based on the CTC morphology obtained from PB and DVB samples, we proposed the following cytological criteria for the diagnosis of CTCs: pan-cytokeratin-positive, atypical cells with malignant morphological features identified by Pap staining. The numbers of CTCs defined by these criteria were significantly higher in DVB than PB from CRC patients (p<0.01), and the number of CTCs in DVB was increased significantly with stage progression (p<0.05). These results suggest that DVB may be another potential source of CTCs other than PB for liquid biopsies including downstream analysis. This automated cytology-based CTC detection device therefore provides a unique and powerful tool to investigate the significance of CTCs in CRC patients in a clinical setting.
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Affiliation(s)
- Masayuki Tsutsuyama
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan
| | - Hayao Nakanishi
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
- Laboratory of Pathology and Clinical Research, Aichi Cancer Center Aichi Hospital, Okazaki, Aichi, Japan
- * E-mail: ,
| | - Mayumi Yoshimura
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | - Taihei Oshiro
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | - Takashi Kinoshita
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | - Koji Komori
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | | | | | | | | | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Chikusa-ku, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan
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13
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Shou X, Li Y, Hu W, Ye T, Wang G, Xu F, Sui M, Xu Y. Six-gene Assay as a new biomarker in the blood of patients with colorectal cancer: establishment and clinical validation. Mol Oncol 2019; 13:781-791. [PMID: 30556647 PMCID: PMC6441906 DOI: 10.1002/1878-0261.12427] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 11/28/2018] [Accepted: 11/28/2018] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the second most common cancer in men and the third most common cancer in women. Although long-term survival has improved over the past 30 years, at least 50% of patients with CRC will develop metastases after diagnosis. In this study, we examined whether quantifying the mRNA of six CRC-related genes in the blood could improve disease assessment through detection of circulating tumor cells (CTC), and thereby improve progression prediction in relapsed CRC patients. Cell spiking assay and RT-PCR were performed with blood samples from healthy volunteers spiked with six CRC cell lines to generate an algorithm, herein called the Six-gene Assay, based on six genes (CEA, EpCAM, CK19, MUC1, EGFR and C-Met) for CTC detection. The CTCs of 50 relapsed CRC patients were then respectively measured by CEA Gene Assay (single-gene assay control) and Six-gene Assay. Subsequently, receiver operating characteristic analysis of the CTC panel performance in diagnosing CRC was conducted for both assays. Moreover, the 2-year progression-free survival (PFS) of all patients was collected, and the application of CEA Gene Assay and Six-gene Assay in predicting PFS was carefully evaluated with different CTC cutoff values. Encouragingly, we successfully constructed the first multiple gene-based algorithm, named the Six-gene Assay, for CTC detection in CRC patients. Six-gene Assay was more sensitive than CEA Gene Assay; for instance, in 50 CRC patients, the positive rate of Six-gene Assay in CTC detection was 82%, whereas that of CEA Gene Assay was only 70%. Moreover, Six-gene Assay was more sensitive and accurate than CEA Gene Assay in diagnosing CRC as well as predicting the 2-year PFS of CRC patients. Statistical analysis demonstrated that CTC numbers measured by Six-gene Assay were significantly associated with 2-year PFS. This novel Six-gene Assay improves the definition of disease status and correlates with PFS in relapsed CRC, and thus holds promise for future clinical applications.
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Affiliation(s)
- Xin Shou
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yong Li
- Department of Medical Oncology, Shanghai Gongli Hospital, Second Military Medical University, Shanghai, China
| | - Weilei Hu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Tingting Ye
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Guosheng Wang
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Xu
- Department of Medical Oncology, Shanghai Gongli Hospital, Second Military Medical University, Shanghai, China
| | - Meihua Sui
- Center for Cancer Biology and Innovative Therapeutics, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, China
| | - Yibing Xu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
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14
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Gao G, Liu C, Jain S, Li D, Wang H, Zhao Y, Liu J. Potential use of aptamers for diagnosis and treatment of pancreatic cancer. J Drug Target 2019; 27:853-865. [PMID: 30596288 DOI: 10.1080/1061186x.2018.1564924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pancreatic cancer (PC) is highly malignant with a low 5-year survival rate. PC currently does not have good early diagnostic markers and responses poorly to chemotherapeutic drugs. The search for better biomarkers and developing more effective chemotherapy are important ways to improve the healthcare of PC patients. Aptamers are single-stranded nucleic acids with high binding affinity and specificity to target molecules. Many aptamers against different forms of cancer including PC have been selected for both diagnostic and therapeutic use. Aptamers can work as ligands to distinguish tumour cells from normal cells. Using cells as selection targets, the obtained aptamers have been used to discover new cancer biomarkers after identification of the binding target. Aptamers have been shown to have antagonists effect on cancer cell proliferation, apoptosis, and metastasis. In addition, aptamers have been used as carriers to deliver therapeutic agents to selectively kill PC cells. This review summarises the potential use of aptamers in the diagnosis and treatment of PC.
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Affiliation(s)
- Ge Gao
- a Faculty of Laboratory Medicine , Xiangya Medical College, Central South University , Changsha , China.,b Department of Clinical Laboratory , Third Xiangya Hospital, Central South University , Changsha , China
| | - Can Liu
- a Faculty of Laboratory Medicine , Xiangya Medical College, Central South University , Changsha , China.,b Department of Clinical Laboratory , Third Xiangya Hospital, Central South University , Changsha , China
| | - Sona Jain
- c Department of Chemistry , Waterloo Institute for Nanotechnology, University of Waterloo , Waterloo , Canada
| | - Dai Li
- c Department of Chemistry , Waterloo Institute for Nanotechnology, University of Waterloo , Waterloo , Canada.,d Department of Pharmacology , Xiangya Hospital, Central South University , Changsha , China
| | - Hai Wang
- a Faculty of Laboratory Medicine , Xiangya Medical College, Central South University , Changsha , China.,b Department of Clinical Laboratory , Third Xiangya Hospital, Central South University , Changsha , China
| | - Yongxin Zhao
- a Faculty of Laboratory Medicine , Xiangya Medical College, Central South University , Changsha , China.,b Department of Clinical Laboratory , Third Xiangya Hospital, Central South University , Changsha , China
| | - Juewen Liu
- c Department of Chemistry , Waterloo Institute for Nanotechnology, University of Waterloo , Waterloo , Canada
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15
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Kawamura S, Iinuma H, Wada K, Takahashi K, Minezaki S, Kainuma M, Shibuya M, Miura F, Sano K. Exosome‐encapsulated microRNA‐4525, microRNA‐451a and microRNA‐21 in portal vein blood is a high‐sensitive liquid biomarker for the selection of high‐risk pancreatic ductal adenocarcinoma patients. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2019; 26:63-72. [DOI: 10.1002/jhbp.601] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Sachiyo Kawamura
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Hisae Iinuma
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Keita Wada
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Kunihiko Takahashi
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Shunryo Minezaki
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Masahiko Kainuma
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Makoto Shibuya
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Fumihiko Miura
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
| | - Keiji Sano
- Department of Surgery Teikyo University School of Medicine 2‐11‐1 Kaga Itabashi Tokyo 173‐0003 Japan
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16
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Bahnassy AA, Salem SE, Mohanad M, Abulezz NZ, Abdellateif MS, Hussein M, Zekri CAN, Zekri ARN, Allahloubi NMA. Prognostic significance of circulating tumor cells (CTCs) in Egyptian non-metastatic colorectal cancer patients: A comparative study for four different techniques of detection (Flowcytometry, CellSearch, Quantitative Real-time PCR and Cytomorphology). Exp Mol Pathol 2018; 106:90-101. [PMID: 30578762 DOI: 10.1016/j.yexmp.2018.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/16/2018] [Accepted: 12/17/2018] [Indexed: 12/21/2022]
Abstract
PURPOSE We assessed CTCs counts in NMCRC patients using four different techniques. METHODS CTCs were detected in 63 NMCRC patients, 40 benign bowel diseases (BBD) and 40 normal controls (NC) using, flow-cytometry (FCM), CellSearch (CS), cytomorphology and quantitative real time (qPCR) for CK19, MUC1, CD44, CD133, ALDH1 expression. Results were correlated to progression free (PFS) and overall (OS). RESULTS Positive CTCs (≥4 cells /7.5 mL blood) were detected in 50.8% (32/63) NMCRC by FCM and 7.5% (3/40) BBD (p < .001). CTCs were detected in 34/63 (54%) NMCRC, 4/40 (10%) BBD (p < .001) by CS. CK19, MUC1, CD44, CD133 and ALDH1 were expressed in 35 (55.6%), 29 (46.0%), 28 (44.4%), 26 (41.3%) and 25 (41.3%) cases of NMCRC. In BBD 4/40 (10%) cases expressed CK19, MUC1 and CD44, while 2/40 (5%) expressed CD133. Cytomorphology showed the lowest sensitivity (47.6%) and specificity (90%) for CTCs detection. The combined use of FCM or CS with CTCs-mRNA markers improved the sensitivity and specificity to 68.3%, and 95.0%; respectively. Positive CTCs and mRNA markers expression were significantly associated with shorter 5-yr PFS and OS. In multivariate analysis, CTCs mRNA markers were independent prognostic factors for PFS and OS. CONCLUSIONS Enumeration of CTCs by FCM and RNA expression for specific colon cancer markers are comparable to CS regarding sensitivity and specificity. CTCs also represent novel therapeutic targets for NMCRC cases.
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Affiliation(s)
- Abeer A Bahnassy
- Tissue culture and Cytogenetics Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt.
| | - Salem E Salem
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Marwa Mohanad
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6(th) of October 12945, Egypt
| | - Nermeen Z Abulezz
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6(th) of October 12945, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Marwa Hussein
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Chahd A N Zekri
- Faculty of Medicine, 6(th) of October University, 6(th) of October, Egypt
| | - Abdel-Rahman N Zekri
- Virology and Immunology unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Nasr M A Allahloubi
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
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Ding C, Zhou X, Xu C, Chen J, Ju S, Chen T, Liang Z, Cui Z, Li C, Zhao J. Circulating tumor cell levels and carcinoembryonic antigen: An improved diagnostic method for lung adenocarcinoma. Thorac Cancer 2018; 9:1413-1420. [PMID: 30178907 PMCID: PMC6209798 DOI: 10.1111/1759-7714.12851] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/27/2018] [Accepted: 07/27/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The aim of this study was to determine a correlation between benign and malignant lung solitary pulmonary nodules (SPN), and analyze the association between circulating tumor cell (CTC) levels and different subtypes of lung adenocarcinoma. METHODS A total of 200 patients (80 with SPNs and 120 diagnosed with lung cancer) were included in the study. The CTC levels were quantified by identifying the folate receptor on the surface of tumor cells; clinical tumor specific markers were detected by biochemical immunization. The content of peripheral blood CTCs in benign and malignant lung SPN patients was detected and the differences in preoperative CTC levels in different pathological subtypes were analyzed. Based on the collected data, receiver operating characteristic curves were calculated and the rate of lung cancer was predicted. RESULTS The peripheral blood CTC levels in patients with malignant lung SPNs were higher than in patients with benign SPNs. The maximum nodule diameter, carcinoembryonic antigen, and CTC levels were independent risk factors for malignant lung SPNs. The peripheral blood CTC levels in patients with stage III-IV lung adenocarcinoma were higher than in stage I-II patients. The peripheral blood CTC levels in patients with microinvasive and invasive adenocarcinoma were higher than in adenocarcinoma in situ patients. The CTC levels in the peripheral blood of patients with maximum tumor diameter > 2 cm were higher than in patients with tumors < 2 cm. CONCLUSION The detection of CTCs can be used as a biomarker for screening SPNs and diagnosing early-stage lung cancer. Using the combination of CTC levels and CEA significantly improves the efficacy of lung adenocarcinoma diagnosis.
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Affiliation(s)
- Cheng Ding
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Xiaofei Zhou
- Department of RadiologyThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Chun Xu
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Jun Chen
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Shen Ju
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Tengfei Chen
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Zhipan Liang
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Zihan Cui
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Chang Li
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
| | - Jun Zhao
- Department of Thoracic SurgeryThe First Affiliated Hospital of Soochow University, Medical College of Soochow UniversitySuzhouChina
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Wang H, Stoecklein NH, Lin PP, Gires O. Circulating and disseminated tumor cells: diagnostic tools and therapeutic targets in motion. Oncotarget 2018; 8:1884-1912. [PMID: 27683128 PMCID: PMC5352105 DOI: 10.18632/oncotarget.12242] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 09/20/2016] [Indexed: 12/16/2022] Open
Abstract
Enumeration of circulating tumor cells (CTCs) in peripheral blood with the gold standard CellSearchTM has proven prognostic value for tumor recurrence and progression of metastatic disease. Therefore, the further molecular characterization of isolated CTCs might have clinical relevance as liquid biopsy for therapeutic decision-making and to monitor disease progression. The direct analysis of systemic cancer appears particularly important in view of the known disparity in expression of therapeutic targets as well as epithelial-to-mesenchymal transition (EMT)-based heterogeneity between primary and systemic tumor cells, which all substantially complicate monitoring and therapeutic targeting at present. Since CTCs are the potential precursor cells of metastasis, their in-depth molecular profiling should also provide a useful resource for target discovery. The present review will discuss the use of systemically spread cancer cells as liquid biopsy and focus on potential target antigens.
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Affiliation(s)
- Hongxia Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Nikolas H Stoecklein
- Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | | | - Olivier Gires
- Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University of Munich, Munich, Germany.,Clinical Cooperation Group Personalized Radiotherapy of Head and Neck Tumors, Helmholtz, Germany
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19
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Yang C, Zou K, Zheng L, Xiong B. Prognostic and clinicopathological significance of circulating tumor cells detected by RT-PCR in non-metastatic colorectal cancer: a meta-analysis and systematic review. BMC Cancer 2017; 17:725. [PMID: 29115932 PMCID: PMC5688806 DOI: 10.1186/s12885-017-3704-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 10/25/2017] [Indexed: 01/08/2023] Open
Abstract
Background Circulating tumor cells (CTCs) have been accepted as a prognostic marker in patients with metastatic colorectal cancer (mCRC, UICC stage IV). However, the prognostic value of CTCs in patients with non-metastatic colorectal cancer (non-mCRC, UICC stage I-III) still remains in dispute. A meta-analysis was performed to investigate the prognostic significance of CTCs detected by the RT-PCR method in patients diagnosed with non-mCRC patients. Methods A comprehensive literature search for relevant articles was performed in the EmBase, PubMed, Ovid, Web of Science, Cochrane library and Google Scholar databases. The studies were selected according to predetermined inclusion/exclusion criteria. Using the random-effects model of Stata software, version12.0 (2011) (Stata Corp, College Station, TX, USA), to conduct the meta-analysis, and the hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were regarded as the effect measures. Subgroup analyses and meta-regression were also conducted to clarify the heterogeneity. Results Twelve eligible studies, containing 2363 patients with non-mCRC, were suitable for final analyses. The results showed that the overall survival (OS) (HR = 3.07, 95% CI: [2.05–4.624], P < 0.001; I2 = 55.7%, P = 0.008) and disease-free survival (DFS) (HR = 2.58, 95% CI: [2.00–3.32], P < 0.001; I2 = 34.0%, P = 0.085) were poorer in patients with CTC-positive, regardless of the sampling time, adjuvant therapy and TNM stage. CTC-positive was also significantly associated with regional lymph nodes (RLNs) metastasis (RR = 1.62, 95% CI: [1.17–2.23], P = 0.003; I2 = 74.6%, P<0.001), depth of infiltration (RR = 1.41, 95% CI: [1.03–1.92], P = 0.03; I2 = 38.3%, P = 0.136), vascular invasion (RR = 1.66, 95% CI: [1.17–2.36], P = 0.004; I2 = 46.0%, P = 0.135), tumor grade (RR = 1.19, 95% CI: [1.02–1.40], P = 0.029; I2 = 0%, P = 0.821) and tumor-node-metastasis (TNM) stage(I, II versus III) (RR = 0.76, 95% CI 0.71–0.81, P < 0.001; I2 = 0%, P = 0.717). However, there was no significant relationship between CTC-positive and tumor size (RR = 1.08, 95% CI: [0.94–1.24], P = 0.30; I2 = 0%, P = 0.528). Conclusions Detection of CTCs by RT-PCR method has prognostic value for non-mCRC patients, and CTC-positive was associated with poor prognosis and poor clinicopathological prognostic factors. However, the prognostic value of CTCs supports the use of CTCs as an indicator of metastatic disease prior to the current classification of mCRC meaning it is detectable by CT/MRI.
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Affiliation(s)
- Chaogang Yang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Kun Zou
- Department of Oncology, Central Hospital of Wuhan, No.16 Gusaoshu Road, Jianghan District, Wuhan, 430014, China
| | - Liang Zheng
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
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Werner S, Stenzl A, Pantel K, Todenhöfer T. Expression of Epithelial Mesenchymal Transition and Cancer Stem Cell Markers in Circulating Tumor Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 994:205-228. [DOI: 10.1007/978-3-319-55947-6_11] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Kim YJ, Lee HS, Jung DE, Kim JM, Song SY. The DNA aptamer binds stemness-enriched cancer cells in pancreatic cancer. J Mol Recognit 2016; 30. [PMID: 27891685 DOI: 10.1002/jmr.2591] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 10/20/2016] [Accepted: 10/20/2016] [Indexed: 11/07/2022]
Abstract
Pancreatic cancer remains one of the most common and lethal cancers. Most patients (80%) present with inoperable advanced pancreatic cancer at initial diagnosis, and their early diagnosis is a significant unmet challenge. Recent studies indicate that cancer, including pancreatic cancer, is initiated and propagated by cancer stem cells (CSCs). CSCs are responsible not only for the pathogenesis of cancer but also for the heterogeneity, malignant degree, anticancer therapy resistance, and recurrence of tumors. Therefore, the identification of CSCs may be a crucial stepping stone for overcoming this disastrous pancreatic cancer. Here, we investigated pancreatic CSC-associated aptamers as a novel tool for diagnosis and therapeutic agents. Aptamers that bind to stemness-enriched cancer cells in pancreatic cancer were developed by modified Cell-SELEX method. Positive selection was performed by the sphere cells generated by pancreatic cancer cell line, HPAC, and then the aptamer pool was negatively selected by pancreatic normal cell line, HPDE. Aptamers 1 and 146 showing high specificity upon the KD values with 22.18 and 22.62 nM were selected. These 2 aptamers were validated by binding to HPAC sphere cells and to HPDE cells, and both aptamers showed specificity to HPAC sphere cells only. Aptamer-positive cells showed high expression levels of CSC-associated genes compared with the aptamer-negative cells by FACS analysis. The colocalization of CD44, CD24, ESA, and CD133 was also observed in the aptamer-positive cells by confocal microscopy. In the present study, these 2 pancreatic CSC-associated aptamers may be potential candidates for novel diagnostic markers, CSC-targeting drug delivery, or circulating tumor cell detection.
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Affiliation(s)
- Yoon-Jin Kim
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea.,Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Dawoon E Jung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Jeong Mi Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Si Young Song
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea.,Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.,Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
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22
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Effects of surgery on the cancer stem cell niche. Eur J Surg Oncol 2016; 42:319-25. [DOI: 10.1016/j.ejso.2015.12.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 11/24/2015] [Accepted: 12/09/2015] [Indexed: 01/12/2023] Open
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23
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Lianidou ES. Gene expression profiling and DNA methylation analyses of CTCs. Mol Oncol 2016; 10:431-42. [PMID: 26880168 DOI: 10.1016/j.molonc.2016.01.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/19/2016] [Accepted: 01/25/2016] [Indexed: 01/26/2023] Open
Abstract
A variety of molecular assays have been developed for CTCs detection and molecular characterization. Molecular assays are based on the nucleic acid analysis in CTCs and are based on total RNA isolation and subsequent mRNA quantification of specific genes, or isolation of genomic DNA that can be for DNA methylation studies and mutation analysis. This review is mainly focused on gene expression and methylation studies in CTCs in various types of cancer.
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Affiliation(s)
- Evi S Lianidou
- Analysis of Circulating Tumor Cells Lab, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, 15771, Greece.
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24
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Kekilli KE, Abakay CD, Tezcan G, Tunca B, Egeli U, Saraydaroglu O, Esbah O, Ekinci AS, Arslan S, Uslu N, Ozkan L. Effects of EGFR, CK19, CK20 and Survinin Gene Expression on Radiotherapy Results in Patients with Locally Advanced Head and Neck Cancer. Asian Pac J Cancer Prev 2015; 16:3023-7. [DOI: 10.7314/apjcp.2015.16.7.3023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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25
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Grover PK, Cummins AG, Price TJ, Roberts-Thomson IC, Hardingham JE. Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research. Ann Oncol 2014; 25:1506-16. [PMID: 24651410 DOI: 10.1093/annonc/mdu018] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence suggests that circulating tumour cells (CTCs) are responsible for metastatic relapse and this has fuelled interest in their detection and quantification. Although numerous methods have been developed for the enrichment and detection of CTCs, none has yet reached the 'gold' standard. Since epithelial cell adhesion molecule (EpCAM)-based enrichment of CTCs offers several advantages, it is one of the most commonly used and has been adapted for high-throughput technology. However, emerging evidence suggests that CTCs are highly heterogeneous: they consist of epithelial tumour cells, epithelial-to-mesenchymal transition (EMT) cells, hybrid (epithelial/EMT(+)) tumour cells, irreversible EMT(+) tumour cells, and circulating tumour stem cells (CTSCs). The EpCAM-based approach does not detect CTCs expressing low levels of EpCAM and non-epithelial phenotypes such as CTSCs and those that have undergone EMT and no longer express EpCAM. Thus, the approach may lead to underestimation of the significance of CTCs, in general, and CTSCs and EMT(+) tumour cells, in particular, in cancer dissemination. Here, we provide a critical review of research literature on the evolving concept of CTCs and the inadequacy of their enrichment by EpCAM-based technology for basic and clinical cancer research. The review also outlines future perspectives in the field.
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Affiliation(s)
| | | | - T J Price
- Haematology-Oncology, The Queen Elizabeth Hospital, Woodville South, Australia
| | | | - J E Hardingham
- Haematology-Oncology, The Queen Elizabeth Hospital, Woodville South, Australia
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26
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The Clinical Potential of Circulating Tumor Cells and Circulating Tumor-Associated Cellular Elements in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2013. [DOI: 10.1007/s11888-013-0193-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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27
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Kin C, Kidess E, Poultsides GA, Visser BC, Jeffrey SS. Colorectal cancer diagnostics: biomarkers, cell-free DNA, circulating tumor cells and defining heterogeneous populations by single-cell analysis. Expert Rev Mol Diagn 2013; 13:581-99. [PMID: 23895128 DOI: 10.1586/14737159.2013.811896] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Reliable biomarkers are needed to guide treatment of colorectal cancer, as well as for surveillance to detect recurrence and monitor therapeutic response. In this review, the authors discuss the use of various biomarkers in addition to serum carcinoembryonic antigen, the current surveillance method for metastatic recurrence after resection. The clinical relevance of mutations including microsatellite instability, KRAS, BRAF and SMAD4 is addressed. The role of circulating tumor cells and cell-free DNA with regards to their implementation into clinical use is discussed, as well as how single-cell analysis may fit into a monitoring program. The detection and characterization of circulating tumor cells and cell-free DNA in colorectal cancer patients will not only improve the understanding of the development of metastasis, but may also supplant the use of other biomarkers.
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Affiliation(s)
- Cindy Kin
- Department of Surgery, Stanford University School of Medicine, CA, USA.
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28
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Torino F, Bonmassar E, Bonmassar L, De Vecchis L, Barnabei A, Zuppi C, Capoluongo E, Aquino A. Circulating tumor cells in colorectal cancer patients. Cancer Treat Rev 2013; 39:759-72. [PMID: 23375250 DOI: 10.1016/j.ctrv.2012.12.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2012] [Revised: 12/10/2012] [Accepted: 12/12/2012] [Indexed: 12/11/2022]
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29
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Falci C, Gianesin K, Sergi G, Giunco S, De Ronch I, Valpione S, Soldà C, Fiduccia P, Lonardi S, Zanchetta M, Keppel S, Brunello A, Zafferri V, Manzato E, De Rossi A, Zagonel V. Immune senescence and cancer in elderly patients: results from an exploratory study. Exp Gerontol 2013; 48:1436-42. [PMID: 24120567 DOI: 10.1016/j.exger.2013.09.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 09/16/2013] [Accepted: 09/30/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND The challenge of immune senescence has never been addressed in elderly cancer patients. This study compares the thymic output and peripheral blood telomere length in ≥70year old cancer patients. PATIENTS AND METHODS Fifty-two elderly cancer patients and 39 age-matched controls without personal history of cancer were enrolled. All patients underwent a Comprehensive Geriatric Assessment (CGA), from which a multidimensional prognostic index (MPI) score was calculated. Peripheral blood samples were studied for naïve and recent thymic emigrant (RTE) CD4(+) and CD8(+) cells by flow cytometry. T-cell receptor rearrangement excision circle (TREC) levels, telomere length and telomerase activity in peripheral blood cells were quantified by real-time PCR. RESULTS The percentages of CD8(+) naïve and CD8(+) RTE cells and TREC levels were significantly lower in cancer patients than in controls (p=0.003, p=0.004, p=0.031, respectively). Telomere lengths in peripheral blood cells were significantly shorter in cancer patients than in controls (p=0.046) and did not correlate with age in patients, whereas it did in controls (r=-0.354, p=0.031). Short telomere (≤median)/low TREC (≤median) profile was associated with higher risk of cancer (OR=3.68 [95% CI 1.22-11.11]; p=0.021). Neither unfitness on CGA nor MPI score were significantly related to thymic output or telomere length in either group. CONCLUSIONS Immune senescence is significantly worse in elderly cancer patients than in age-matched controls. The low thymic output and the shorter telomeres in peripheral blood cells of cancer patients may reflect a pre-existing condition which facilitates the onset of malignancies in elderly people.
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Affiliation(s)
- Cristina Falci
- Medical Oncology Unit II, Istituto Oncologico Veneto (IOV), IRCCS, Padova, Italy
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30
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Kuan WC, Horák D, Plichta Z, Lee WC. Immunocapture of CD133-positive cells from human cancer cell lines by using monodisperse magnetic poly(glycidyl methacrylate) microspheres containing amino groups. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2013; 34:193-200. [PMID: 24268249 DOI: 10.1016/j.msec.2013.09.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 08/14/2013] [Accepted: 09/08/2013] [Indexed: 12/01/2022]
Abstract
Magnetic poly(glycidyl methacrylate)-based macroporous microspheres with an average particle size of 4.2μm were prepared using a modified multi-step swelling polymerization method and by introducing amino functionality on their surfaces. Antibody molecules were oxidized on their carbohydrate moieties and bound to the amino-containing magnetic microspheres via a site-directed procedure. CD133-positive cells could be effectively captured from human cancer cell lines (HepG2, HCT116, MCF7, and IMR-32) by using magnetic microspheres conjugated to an anti-human CD133 antibody. After further culture, the immunocaptured CD133-expressing cells from IMR-32 proliferated and gradually detached from the magnetic microspheres. Flow-cytometric analysis confirmed the enrichment of CD133-expressing cells by using the antibody-bound magnetic microspheres. Such microspheres suitable for immunocapture are very promising for cancer diagnosis because the CD133-expressing cells in cancer cell lines have been suggested to be cancer stem cells.
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Affiliation(s)
- Wei-Chih Kuan
- Department of Chemical Engineering, Systems Biology and Tissue Engineering Research Center, National Chung Cheng University, Minhisung 621, Taiwan
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31
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Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 2013; 32:643-71. [DOI: 10.1007/s10555-013-9444-6] [Citation(s) in RCA: 288] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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32
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Pericleous P, Gazouli M, Lyberopoulou A, Rizos S, Nikiteas N, Efstathopoulos EP. Detection of colorectal circulating cancer cells with the use of a quantum dot labelled magnetic immunoassay method. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s13126-013-0025-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Essentials of circulating tumor cells for clinical research and practice. Crit Rev Oncol Hematol 2013; 88:338-56. [PMID: 23830807 DOI: 10.1016/j.critrevonc.2013.05.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Revised: 03/17/2013] [Accepted: 05/02/2013] [Indexed: 02/06/2023] Open
Abstract
The major cause of death due to cancer is its metastatic deposit in numerous tissues and organs. The metastatic process requires the migration of malignant cells from primary sites to distant environments. Even for tumors initially spreading through lymphatic vessels, hematogenous transport is the most common metastatic pathway. The detachment of cancer cells from a primary tumor into the blood stream is called epithelial-mesenchymal transition (EMT). As these cells circulate further in the bloodstream they are known as circulating tumor cells (CTCs). The CTC population is highly resilient, enabling the cells to colonize a foreign microenvironment. Alternatively, cancer stem cells (CSCs) may arise from differentiated cancer cells through EMT and an embryonic transdifferentiation process. The presence of CTCs/CSCs in blood seems to be a determining factor of metastasis. This paper reviews various methods of clinical cancer detection as well as the biology and molecular characterization of CTCs/CSCs. Our goal was to summarize clinical studies which used CTC/CSCs for prognosis in patients with breast, colorectal, prostate, lung, ovarian, and bladder cancer.
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Akagi Y, Kinugasa T, Adachi Y, Shirouzu K. Prognostic significance of isolated tumor cells in patients with colorectal cancer in recent 10-year studies. Mol Clin Oncol 2013; 1:582-592. [PMID: 24649214 DOI: 10.3892/mco.2013.116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 04/18/2013] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) that detach from the primary tumor and move into the circulation are detected in patients with metastatic cancer. The discovery of such cancer cells has been used as a predictor of recurrence and prognosis, although a consensus regarding such applications has not been reached. Peritoneal cytology may be used for identifying high risk of recurrence or mortality, whereas the intraoperative presence of tumor cells in drainage veins, bone marrow, or the liver is not always useful for evaluating the prognosis. The reported positive rate for tumor cells in the peripheral blood of patients with colorectal cancer, including metastasis, has varied from 10 to 80%; however, numerous studies have demonstrated significant differences in the recurrence and mortality rates between patients with and without isolated tumor cells (ITCs) in the peripheral blood. However, the clinical significance of CTCs as an absolute prognostic factor has not been elucidated, since the measurement methodologies and/or the number of cases differed between the studies. Future prospective studies including larger patient populations may elucidate the utility of routine detection of ITCs in daily practice.
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Affiliation(s)
- Yoshito Akagi
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Tetsushi Kinugasa
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yosuke Adachi
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Kazuo Shirouzu
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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35
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Kim JW, Galanzha EI, Zaharoff DA, Griffin RJ, Zharov VP. Nanotheranostics of circulating tumor cells, infections and other pathological features in vivo. Mol Pharm 2013; 10:813-30. [PMID: 23379366 DOI: 10.1021/mp300577s] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Many life-threatening diseases are disseminated through biological fluids, such as blood, lymph, and cerebrospinal fluid. The migration of tumor cells through the vascular circulation is a mandatory step in metastasis, which is responsible for ∼90% of cancer-associated mortality. Circulating pathogenic bacteria, viruses, or blood clots lead to other serious conditions including bacteremia, sepsis, viremia, infarction, and stroke. Therefore, technologies capable of detecting circulating tumor cells (CTCs), circulating bacterial cells (CBCs), circulating endothelial cells (CECs), circulating blood clots, cancer biomarkers such as microparticles and exosomes, which contain important microRNA signatures, and other abnormal features such as malaria parasites in biological fluids may facilitate early diagnosis and treatment of metastatic cancers, infections, and adverse cardiovascular events. Unfortunately, even in a disease setting, circulating abnormal cells are rare events that are easily obscured by the overwhelming background material in whole blood. Existing detection methods mostly rely on ex vivo analyses of limited volumes (a few milliliters) of blood samples. These small volumes limit the probability of detecting CTCs, CECs, CBCs and other rare phenomena. In vivo detection platforms capable of continuously monitoring the entire blood volume may substantially increase the probability of detecting circulating abnormal cells and, in particular, increase the opportunity to identify exceedingly rare and potentially dangerous subsets of these cells, such as circulating cancer stem cells (CCSCs). In addition, in vivo detection technologies capable of destroying and/or capturing circulating abnormal cells may inhibit disease progression. This review focuses on novel therapeutic and diagnostic (theranostic) platforms integrating in vivo real-time early diagnosis and nano-bubble based targeted therapy of CTCs, CECs, CBCs and other abnormal objects in circulation. This critical review particularly focuses on nanotechnology-based theranostic (nanotheranostic) approaches, especially in vivo photoacoustic (PA) and photothermal (PT) nanotheranostic platforms. We emphasize an urgent need for in vivo platforms composed of multifunctional contrast nanoagents, which utilize diverse modalities to realize a breakthrough for early detection and treatment of harmful diseases disseminated through the circulation.
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Affiliation(s)
- Jin-Woo Kim
- Bio/Nano Technology Laboratory, Institute for Nanoscience and Engineering, University of Arkansas, Fayetteville, Arkansas 72701, USA.
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36
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Chen S, Song X, Chen Z, Li X, Li M, Liu H, Li J. CD133 expression and the prognosis of colorectal cancer: a systematic review and meta-analysis. PLoS One 2013; 8:e56380. [PMID: 23409180 PMCID: PMC3569427 DOI: 10.1371/journal.pone.0056380] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 01/08/2013] [Indexed: 12/25/2022] Open
Abstract
Objective CD133 has recently been reported as a marker of cancer stem-like cells in colorectal cancer (CRC). However, its predictive value in CRC still remains controversial. In this study, we aimed to evaluate the association between the expression of CD133 and clinicopathological features and the outcome of CRC patients by performing a meta-analysis. Methods A comprehensive literature search for relevant studies published up to December 2012 was performed using PubMed, MEDLINE and ISI Web of Science. Only articles in which CD133 antigen was detected in situ localisation by immunohistochemical staining were included. This meta-analysis was done using RevMan 4.2 software. Results We found that a total of 15 studies involving 810 CD133-high and 1487 CD133-low patients met the inclusion criteria for the analysis of 5-year overall survival (OS) rate. In a random-effects model, the results showed that CD133-high expression in colorectal cancer was an independent prognostic marker correlating with both OS rate (RR = 0.67, 95%CI 0.54–0.82, P<0.01) and disease free survival (DFS) rate (RR = 0.71, 95%CI 0.52–0.96, P = 0.03). CD133-high expression was also associated with more T3,4 tumor invasion, N positive and vascular invasion cases, corresponding to a risk difference of 1.12 (95%CI 1.01–1.23, P = 0.03), 1.31 (95%CI 1.06–1.63, P = 0.01) and 1.24 (95%CI 1.08–1.41, P<0.01), respectively. However, when types of histology, lymphatic invasion and distant metastasis were considered, CD133 overexpression was not significantly related with these clinicopathological parameters. Conclusion Our meta-analysis results suggest that CD133 is an efficient prognostic factor in CRC. Higher CD133 expression is significantly associated with poorer clinical outcome and some clinicopathological factors such as T category, N category and vascular invasion in CRC patients.
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Affiliation(s)
- Shicai Chen
- Department of Gastrointestinal Tumor Surgery, Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, China
| | - Xinming Song
- Department of Gastrointestinal and Pancreatic Surgery of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- * E-mail:
| | - Zhihui Chen
- Department of Gastrointestinal and Pancreatic Surgery of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xinxin Li
- Department of Gastrointestinal and Pancreatic Surgery of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingzhe Li
- Department of Gastrointestinal and Pancreatic Surgery of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haiying Liu
- Department of Gastrointestinal Tumor Surgery, Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, China
| | - Jianchang Li
- Department of Gastrointestinal Tumor Surgery, Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, China
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da Paz MC, Santos MDFMA, Santos CMB, da Silva SW, de Souza LB, Lima ECD, Silva RC, Lucci CM, Morais PC, Azevedo RB, Lacava ZGM. Anti-CEA loaded maghemite nanoparticles as a theragnostic device for colorectal cancer. Int J Nanomedicine 2012; 7:5271-82. [PMID: 23055733 PMCID: PMC3468277 DOI: 10.2147/ijn.s32139] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Nanosized maghemite particles were synthesized, precoated (with dimercaptosuccinic acid) and surface-functionalized with anticarcinoembryonic antigen (anti-CEA) and successfully used to target cell lines expressing the CEA, characteristic of colorectal cancer (CRC) cells. The as-developed nanosized material device, consisting of surface decorated maghemite nanoparticles suspended as a biocompatible magnetic fluid (MF) sample, labeled MF-anti-CEA, was characterized and tested against two cell lines: a high-CEA expressing cell line (LS174T) and a low-CEA expressing cell line (HCT116). Whereas X-ray diffraction was used to assess the average core size of the as-synthesized maghemite particles (average 8.3 nm in diameter), dynamic light scattering and electrophoretic mobility measurements were used to obtain the average hydrodynamic diameter (550 nm) and the zeta-potential (−38 mV) of the as-prepared and maghemite-based nanosized device, respectively. Additionally, surface-enhanced Raman spectroscopy (SERS) was used to track the surface decoration of the nanosized maghemite particles from the very first precoating up to the attachment of the anti-CEA moiety. The Raman peak at 1655 cm−1, absent in the free anti-CEA spectrum, is the signature of the anti-CEA binding onto the precoated magnetic nanoparticles. Whereas MTT assay was used to confirm the low cell toxicity of the MF-anti-CEA device, ELISA and Prussian blue iron staining tests performed with both cell lines (LS174T and HCT116) confirm that the as-prepared MF-anti- CEA is highly specific for CEA-expressing cells. Finally, transmission electron microscopy analyses show that the association with anti-CEA seems to increase the number of LS174T cells with internalized maghemite nanoparticles, whereas no such increase seems to occur in the HCT116 cell line. In conclusion, the MF-anti-CEA sample is a biocompatible device that can specifically target CEA, suggesting its potential use as a theragnostic tool for CEA-expressing tumors, micrometastasis, and cancer-circulating cells.
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Nanog: a potential biomarker for liver metastasis of colorectal cancer. Dig Dis Sci 2012; 57:2340-6. [PMID: 22562535 DOI: 10.1007/s10620-012-2182-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/12/2012] [Indexed: 01/10/2023]
Abstract
BACKGROUND At present, the relationship between Nanog expression and the biological behavior and prognosis of colorectal cancer is still unclear. AIM The purpose of this study was to evaluate the expression and regulatory effects of Nanog in colorectal cancer and the correlation between Nanog protein expression and the prognosis of patients with colorectal cancer. MATERIALS AND METHODS The differential expression of genes between CD133+ tumor cells and CD133- tumor cells were detected using RT(2) Profiler™ PCR Array. The Nanog mRNA expression level was detected by RT-PCR and the protein level was detected using immunohistochemistry staining. The relationship between Nanog expression and clinicopathological parameters of colorectal cancer was determined. RESULTS Nanog were expressed significantly higher in CD133+ tumor cells compared to CD133- tumor cells. It was observed that 72 (20.00 %) of the 360 cases positively expressed Nanog. Univariate analyses indicated that Nanog expression was related to histological grade, lymph node metastasis, TNM stage, and liver metastasis (P = 0.005, 0.001, 0.001 and 0.012, respectively). Spearman correlation analysis showed that Nanog expression has a linear correlation to liver metastasis (P = 0.001). After conducting multivariate analysis, histological grade, TNM stage, and Nanog were found to be related to liver metastasis (P = 0.020, 0.01 and 0.001, respectively). In the Cox regression test, the histological grade, Lymph node metastasis, TNM stage, liver metastasis, and Nanog were detected as the independent prognostic factors (P = 0.02, 0.045, 0.01, 0.001 and 0.001, respectively). CONCLUSIONS Nanog protein may be a potential biomarker for postoperative liver metastasis of colorectal cancer.
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Gazouli M, Lyberopoulou A, Pericleous P, Rizos S, Aravantinos G, Nikiteas N, Anagnou NP, Efstathopoulos EP. Development of a quantum-dot-labelled magnetic immunoassay method for circulating colorectal cancer cell detection. World J Gastroenterol 2012; 18:4419-26. [PMID: 22969208 PMCID: PMC3436060 DOI: 10.3748/wjg.v18.i32.4419] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 08/14/2012] [Accepted: 08/18/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect of colorectal cancer (CRC) circulating tumour cells (CTCs) surface antigens, we present an assay incorporating cadmium selenide quantum dots (QDs) in these paper.
METHODS: The principle of the assay is the immunomagnetic separation of CTCs from body fluids in conjunction with QDs, using specific antibody biomarkers: epithelial cell adhesion molecule antibody, and monoclonal cytokeratin 19 antibody. The detection signal was acquired from the fluorescence signal of QDs. For the evaluation of the performance, the method under study was used to isolate the human colon adenocarcinoma cell line (DLD-1) and CTCs from CRC patients’ peripheral blood.
RESULTS: The minimum detection limit of the assay was defined to 10 DLD-1 CRC cells/mL as fluorescence was measured with a spectrofluorometer. Fluorescence-activated cell sorting analysis and Real Time RT-PCR, they both have also been used to evaluate the performance of the described method. In conclusion, we developed a simple, sensitive, efficient and of lower cost (than the existing ones) method for the detection of CRC CTCs in human samples. We have accomplished these results by using magnetic bead isolation and subsequent QD fluorescence detection.
CONCLUSION: The method described here can be easily adjusted for any other protein target of either the CTC or the host.
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