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Sawai K, Goi T, Kimura Y, Koneri K. Presence of CD44v9-Expressing Cancer Stem Cells in Circulating Tumor Cells and Effects of Carcinoembryonic Antigen Levels on the Prognosis of Colorectal Cancer. Cancers (Basel) 2024; 16:1556. [PMID: 38672639 PMCID: PMC11048819 DOI: 10.3390/cancers16081556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/15/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells released from the primary tumor into the bloodstream, and contain cancer stem cells that influence tumor survival, recurrence, and metastasis. Here, we investigated CD44v9 expression in CTCs and impact of preoperative carcinoembryonic antigen (CEA) levels on colorectal cancer (CRC) prognosis. We analyzed the expression of CD44v9 mRNA in CTCs using reverse transcription-polymerase chain reaction and preoperative CEA levels in blood samples obtained from 300 patients with CRC. Subsequently, we evaluated the association of CD44v9 expression and CEA levels with clinicopathological factors. CD44v9 mRNA was expressed in 31.3% of the patients, and was significantly associated with liver metastasis. Patients with positive CD44v9 expression had a lower 5-year survival rate (62.3%) than those with negative CD44v9 expression (82.8%, p < 0.001). Cox regression analysis identified CD44v9 expression and high CEA levels (≥5 ng/mL) as poor prognostic factors, while negative CD44v9 expression and low CEA levels (<5 ng/mL) were associated with favorable prognosis (hazard ratio = 0.285, p = 0.006). These results suggest that a combination of CD44v9 mRNA expression in CTCs and serum CEA levels could serve as a valuable prognostic marker for CRC, potentially enhancing the accuracy of prognosis predictions.
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Affiliation(s)
- Katsuji Sawai
- First Department of Surgery, University of Fukui, Fukui 910-1193, Japan; (T.G.); (Y.K.); (K.K.)
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Rao D, Lu H, Wang X, Lai Z, Zhang J, Tang Z. Tissue-derived exosome proteomics identifies promising diagnostic biomarkers for esophageal cancer. eLife 2023; 12:e86209. [PMID: 37966470 PMCID: PMC10651172 DOI: 10.7554/elife.86209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 10/17/2023] [Indexed: 11/16/2023] Open
Abstract
Esophageal cancer (EC) is a fatal digestive disease with a poor prognosis and frequent lymphatic metastases. Nevertheless, reliable biomarkers for EC diagnosis are currently unavailable. Accordingly, we have performed a comparative proteomics analysis on cancer and paracancer tissue-derived exosomes from eight pairs of EC patients using label-free quantification proteomics profiling and have analyzed the differentially expressed proteins through bioinformatics. Furthermore, nano-flow cytometry (NanoFCM) was used to validate the candidate proteins from plasma-derived exosomes in 122 EC patients. Of the 803 differentially expressed proteins discovered in cancer and paracancer tissue-derived exosomes, 686 were up-regulated and 117 were down-regulated. Intercellular adhesion molecule-1 (CD54) was identified as an up-regulated candidate for further investigation, and its high expression in cancer tissues of EC patients was validated using immunohistochemistry, real-time quantitative PCR (RT-qPCR), and western blot analyses. In addition, plasma-derived exosome NanoFCM data from 122 EC patients concurred with our proteomic analysis. The receiver operating characteristic (ROC) analysis demonstrated that the AUC, sensitivity, and specificity values for CD54 were 0.702, 66.13%, and 71.31%, respectively, for EC diagnosis. Small interference (si)RNA was employed to silence the CD54 gene in EC cells. A series of assays, including cell counting kit-8, adhesion, wound healing, and Matrigel invasion, were performed to investigate EC viability, adhesive, migratory, and invasive abilities, respectively. The results showed that CD54 promoted EC proliferation, migration, and invasion. Collectively, tissue-derived exosomal proteomics strongly demonstrates that CD54 is a promising biomarker for EC diagnosis and a key molecule for EC development.
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Affiliation(s)
- Dingyu Rao
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Hua Lu
- The First Clinical School of Medicine of Southern Medical UniversityGuangzhouChina
| | - Xiongwei Wang
- Department of Anesthesiology, Longhua District Central HospitalShenzhenChina
| | - Zhonghong Lai
- Department of Traumatology, First Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Jiali Zhang
- The First School of Clinical Medicine, Gannan Medical UniversityGanzhouChina
| | - Zhixian Tang
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical UniversityGanzhouChina
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Ahmadieh-Yazdi A, Mahdavinezhad A, Tapak L, Nouri F, Taherkhani A, Afshar S. Using machine learning approach for screening metastatic biomarkers in colorectal cancer and predictive modeling with experimental validation. Sci Rep 2023; 13:19426. [PMID: 37940644 PMCID: PMC10632378 DOI: 10.1038/s41598-023-46633-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 11/03/2023] [Indexed: 11/10/2023] Open
Abstract
Colorectal cancer (CRC) liver metastasis accounts for the majority of fatalities associated with CRC. Early detection of metastasis is crucial for improving patient outcomes but can be delayed due to a lack of symptoms. In this research, we aimed to investigate CRC metastasis-related biomarkers by employing a machine learning (ML) approach and experimental validation. The gene expression profile of CRC patients with liver metastasis was obtained using the GSE41568 dataset, and the differentially expressed genes between primary and metastatic samples were screened. Subsequently, we carried out feature selection to identify the most relevant DEGs using LASSO and Penalized-SVM methods. DEGs commonly selected by these methods were selected for further analysis. Finally, the experimental validation was done through qRT-PCR. 11 genes were commonly selected by LASSO and P-SVM algorithms, among which seven had prognostic value in colorectal cancer. It was found that the expression of the MMP3 gene decreases in stage IV of colorectal cancer compared to other stages (P value < 0.01). Also, the expression level of the WNT11 gene was observed to increase significantly in this stage (P value < 0.001). It was also found that the expression of WNT5a, TNFSF11, and MMP3 is significantly lower, and the expression level of WNT11 is significantly higher in liver metastasis samples compared to primary tumors. In summary, this study has identified a set of potential biomarkers for CRC metastasis using ML algorithms. The findings of this research may provide new insights into identifying biomarkers for CRC metastasis and may potentially lay the groundwork for innovative therapeutic strategies for treatment of this disease.
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Affiliation(s)
- Amirhossein Ahmadieh-Yazdi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Mahdavinezhad
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Leili Tapak
- Department of Biostatistics, School of Public Health and Modeling of Noncommunicable Diseases Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Nouri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Taherkhani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saeid Afshar
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran.
- Cancer Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
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Gómez-Gallegos AA, Ramírez-Vidal L, Becerril-Rico J, Pérez-Islas E, Hernandez-Peralta ZJ, Toledo-Guzmán ME, García-Carrancá A, Langley E, Hernández-Guerrero A, López-Casillas F, Herrera-Goepfert R, Oñate-Ocaña LF, Ortiz-Sánchez E. CD24+CD44+CD54+EpCAM+ gastric cancer stem cells predict tumor progression and metastasis: clinical and experimental evidence. Stem Cell Res Ther 2023; 14:16. [PMID: 36737794 PMCID: PMC9898964 DOI: 10.1186/s13287-023-03241-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Specific and thorough identification of cancer cell subsets with higher tumorigenicity and chemoresistance, such as cancer stem cells (CSCs), could lead to the development of new and promising therapeutic targets. For better CSC identification, a complete or extended surface marker phenotype is needed to provide increased specificity for new cell targeting approaches. Our goal is to identify and characterize a putative extended phenotype for CSCs derived from patients with GC before treatment, as well as to evaluate its clinical value. In addition, we aim to ensure that cells with this phenotype have stemness and self-renewal capabilities. METHODS This is a cohort study including 127 treatment-naïve patients with GC who attended the Instituto Nacional de Cancerología. Multiparametric flow cytometry analysis was performed to determine the extended phenotype of cells derived from gastric biopsies. The tumorigenic capability of cells identified in patients was assessed in a zebrafish model. RESULTS CD24+CD44+CD54+EpCAM+ cells were present in all treatment-naïve patients included, with a median abundance of 1.16% (0.57-1.89%). The percentage of CD24+CD44+CD54+EpCAM+ cells was categorized as high or low using 1.19% as the cutoff for the CD24+CD44+CD54+EpCAM+ cell subset. Additionally, a higher TNM stage correlated with a higher percentage of CD24+CD44+CD54+EpCAM+ cells (Rho coefficient 0.369; p < 0.0001). We also demonstrated that a higher percentage of CD24+CD44+CD54+EpCAM+ cells was positively associated with metastasis. The metastatic potential of these cells was confirmed in a zebrafish model. Ultimately, under our conditions, we conclude that CD24+CD44+CD54+EpCAM+ cells are true gastric cancer stem cells (GCSCs). CONCLUSION The CD24+CD44+CD54+EpCAM+ cells present in tissue samples from patients are true GCSCs. This extended phenotype results in better and more specific characterization of these highly tumorigenic cells. The relative quantification of CD24+CD44+CD54+EpCAM+ cells has potential clinical value, as these cells are associated with metastatic disease, making their presence an additional prognostic marker and possibly a target for the design of new antineoplastic treatments in the era of precision oncology. Overall, the extended CD24+CD44+CD54+EpCAM+ phenotype of GCSCs could support their isolation for the study of their stemness mechanisms, leading to the identification of better molecular targets for the development of both new therapeutic approaches such as oncoimmunotherapy and new diagnostic and clinical prognostic strategies for GC.
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Affiliation(s)
- Angel A Gómez-Gallegos
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio A, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, C.P. 04510, Coyoacán, Distrito Federal, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Lizbeth Ramírez-Vidal
- Posgrado de Ciencias Biomédicas. Facultad de Medicina, Universidad Nacional Autónoma de México, Circuito Exterior s/n Ciudad Universitaria, Coyoacán, 04510, Mexico City, Mexico
| | - Jared Becerril-Rico
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio A, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, C.P. 04510, Coyoacán, Distrito Federal, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Elizabeth Pérez-Islas
- Departamento de Patología, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Zuly J Hernandez-Peralta
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Alejandro García-Carrancá
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
- Unidad de Investigación en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Elizabeth Langley
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Angélica Hernández-Guerrero
- Unidad de Endoscopia, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Fernando López-Casillas
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Exterior s/n Ciudad Universitaria, Coyoacán, 04510, Mexico City, Mexico
| | - Roberto Herrera-Goepfert
- Departamento de Patología, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Luis F Oñate-Ocaña
- Subdirección de Investigación Clínica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico.
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Pallares-Rusiñol A, Bernuz M, Moura SL, Fernández-Senac C, Rossi R, Martí M, Pividori MI. Advances in exosome analysis. Adv Clin Chem 2022; 112:69-117. [PMID: 36642486 DOI: 10.1016/bs.acc.2022.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
There is growing demand for novel biomarkers that detect early stage disease as well as monitor clinical management and therapeutic strategies. Exosome analysis could provide the next advance in attaining that goal. Exosomes are membrane encapsulated biologic nanometric-sized particles of endocytic origin which are released by all cell types. Unfortunately, exosomes are exceptionally challenging to characterize with current technologies. Exosomes are between 30 and 200nm in diameter, a size that makes them out of the sensitivity range to most cell-oriented sorting or analysis platforms, i.e., traditional flow cytometers. The most common methods for targeting exosomes to date typically involve purification followed by the characterization and the specific determination of their cargo. The whole procedure is time consuming, requiring thus skilled personnel as well as laboratory facilities and benchtop instrumentation. The most relevant methodology for exosome isolation, characterization and quantification is addressed in this chapter, including the most up-to-date approaches to explore the potential usefulness of exosomes as biomarkers in liquid biopsies and in advanced nanomedicine.
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Affiliation(s)
- Arnau Pallares-Rusiñol
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mireia Bernuz
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Silio Lima Moura
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carolina Fernández-Senac
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Rosanna Rossi
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mercè Martí
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - María Isabel Pividori
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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Liquid Biopsies: Flowing Biomarkers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1379:341-368. [DOI: 10.1007/978-3-031-04039-9_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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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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Li LS, Guo XY, Sun K. Recent advances in blood-based and artificial intelligence-enhanced approaches for gastrointestinal cancer diagnosis. World J Gastroenterol 2021; 27:5666-5681. [PMID: 34629793 PMCID: PMC8473600 DOI: 10.3748/wjg.v27.i34.5666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/14/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers are among the most common cancer types and leading causes of cancer-related deaths worldwide. There is a tremendous clinical need for effective early diagnosis for better healthcare of GI cancer patients. In this article, we provide a short overview of the recent advances in GI cancer diagnosis. In the first part, we discuss the applications of blood-based biomarkers, such as plasma circulating cell-free DNA, circulating tumor cells, extracellular vesicles, and circulating cell-free RNA, for cancer liquid biopsies. In the second part, we review the current trends of artificial intelligence (AI) for pathology image and tissue biopsy analysis for GI cancer, as well as deep learning-based approaches for purity assessment of tissue biopsies. We further provide our opinions on the future directions in blood-based and AI-enhanced approaches for GI cancer diagnosis, and we think that these fields will have more intensive integrations with clinical needs in the near future.
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Affiliation(s)
- Li-Shi Li
- School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, Guangdong Province, China
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong Province, China
| | - Xiang-Yu Guo
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong Province, China
| | - Kun Sun
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong Province, China
- BGI-Shenzhen, Shenzhen 518083, Guangdong Province, China
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Cortés-Hernández LE, Eslami-S Z, Costa-Silva B, Alix-Panabières C. Current Applications and Discoveries Related to the Membrane Components of Circulating Tumor Cells and Extracellular Vesicles. Cells 2021; 10:2221. [PMID: 34571870 PMCID: PMC8465935 DOI: 10.3390/cells10092221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies.
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Affiliation(s)
- Luis Enrique Cortés-Hernández
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, CEDEX 5, 34295 Montpellier, France; (L.E.C.-H.); (Z.E.-S.)
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, 34000 Montpellier, France
| | - Zahra Eslami-S
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, CEDEX 5, 34295 Montpellier, France; (L.E.C.-H.); (Z.E.-S.)
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, 34000 Montpellier, France
| | - Bruno Costa-Silva
- Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal;
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, CEDEX 5, 34295 Montpellier, France; (L.E.C.-H.); (Z.E.-S.)
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, 34000 Montpellier, France
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Menyailo ME, Bokova UA, Ivanyuk EE, Khozyainova AA, Denisov EV. Metastasis Prevention: Focus on Metastatic Circulating Tumor Cells. Mol Diagn Ther 2021; 25:549-562. [PMID: 34287797 DOI: 10.1007/s40291-021-00543-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2021] [Indexed: 12/13/2022]
Abstract
Metastasis is the main cause of cancer death. Metastatic foci are derived from tumor cells that detach from the primary tumor and then enter the circulation. Circulating tumor cells (CTCs) are generally associated with a high probability of distant metastasis and a negative prognosis. Most CTCs die in the bloodstream, and only a few cells form metastases. Such metastatic CTCs have a stem-like and hybrid epithelial-mesenchymal phenotype, can avoid immune surveillance, and show increased therapy resistance. Targeting metastatic CTCs and their progenitors in primary tumors and their descendants, particularly disseminated tumor cells, represents an attractive strategy for metastasis prevention. However, current therapeutic strategies mainly target the primary tumor and only indirectly affect metastasis-initiating cells. Here, we consider potential methods for preventing metastasis based on targeting molecular and cellular features of metastatic CTCs, including CTC clusters. Also, we emphasize current knowledge gaps in CTC biology that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.
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Affiliation(s)
- Maxim E Menyailo
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Ustinia A Bokova
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Elena E Ivanyuk
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Anna A Khozyainova
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny Str. 5, Tomsk, 634009, Russia
| | - Evgeny V Denisov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Kooperativny Str. 5, Tomsk, 634009, Russia.
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11
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Kim N, Gim JA, Lee BJ, Choi BI, Park SB, Yoon HS, Kang SH, Kim SH, Joo MK, Park JJ, Kim C, Kim HK. RNA-sequencing identification and validation of genes differentially expressed in high-risk adenoma, advanced colorectal cancer, and normal controls. Funct Integr Genomics 2021; 21:513-521. [PMID: 34273035 DOI: 10.1007/s10142-021-00795-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/14/2021] [Accepted: 06/22/2021] [Indexed: 12/18/2022]
Abstract
Distinct gene expression patterns that occur during the adenoma-carcinoma sequence need to be determined to analyze the underlying mechanism in each step of colorectal cancer progression. Elucidation of biomarkers for colorectal polyps that harbor malignancy potential is important for prevention of colorectal cancer. Here, we use RNA sequencing to determine gene expression profile in patients with high-risk adenoma treated with endoscopic submucosal dissection by comparing with gene expression in patients with advanced colorectal cancer and normal controls. We collected 70 samples, which consisted of 27 colorectal polyps, 24 cancer tissues, and 19 normal colorectal mucosa. RNA sequencing was performed on an Illumina platform to select differentially expressed genes (DEGs) between colorectal polyps and cancer, polyps and controls, and cancer and normal controls. The Kyoto Gene and Genome Encyclopedia (KEGG) and gene ontology (GO) analysis, gene-concept network, GSEA, and a decision tree were used to evaluate the DEGs. We selected the most highly expressed genes in high-risk polyps and validated their expression using real-time PCR and immunohistochemistry. Compared to patients with colorectal cancer, 82 upregulated and 24 downregulated genes were detected in high-risk adenoma. In comparison with normal controls, 33 upregulated and 79 downregulated genes were found in high-risk adenoma. In total, six genes were retrieved as the highest and second highest expressed in advanced polyps and cancers among the three groups. Among the six genes, ANAX3 and CD44 expression in real-time PCR for validation was in good accordance with RNA sequencing. We identified differential expression of mRNAs among high-risk adenoma, advanced colorectal cancer, and normal controls, including that of CD44 and ANXA3, suggesting that this cluster of genes as a marker of high-risk colorectal adenoma.
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Affiliation(s)
- Namjoo Kim
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Jeong-An Gim
- Medical Science Research Center, College of Medicine, Korea University Guro Hospital Seoul, Seoul, Republic of Korea
| | - Beom Jae Lee
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea.
| | - Byung Il Choi
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Seung Bin Park
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Hee Sook Yoon
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Sang Hee Kang
- Department of Surgery, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Seung Han Kim
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Moon Kyung Joo
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Jong-Jae Park
- Department of Gastroenterology, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Chungyeul Kim
- Department of Pathology, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Han-Kyeom Kim
- Department of Pathology, College of Medicine, Korea University, Seoul, Republic of Korea
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12
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Enkhbat M, Liu Y, Kim J, Xu Y, Yin Z, Liu T, Deng C, Zou C, Xie X, Li X, Wang P. Expansion of Rare Cancer Cells into Tumoroids for Therapeutic Regimen and Cancer Therapy. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Myagmartsend Enkhbat
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China
- University of Chinese Academy of Sciences Beijing 100049 China
| | - Yung‐Chiang Liu
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China
| | - Jua Kim
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China
| | - Yanshan Xu
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China
| | - Zongyi Yin
- Department of Hepatobiliary Surgery General Hospital of Shenzhen University Guangdong 518055 China
| | - Tzu‐Ming Liu
- Cancer Center, Faculty of Health Sciences University of Macau Macao 999078 China
| | - Chu‐Xia Deng
- Cancer Center, Faculty of Health Sciences University of Macau Macao 999078 China
| | - Chang Zou
- The First Affiliated Hospital of Southern University Shenzhen People's Hospital Shenzhen Guangdong 518020 China
| | - Xi Xie
- State Key Laboratory of Optoelectronic Materials and Technologies School of Electronics and Information Technology Sun Yat‐sen University Guangzhou 510275 China
| | - Xiaowu Li
- Department of Hepatobiliary Surgery General Hospital of Shenzhen University Guangdong 518055 China
| | - Peng‐Yuan Wang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China
- Department of Chemistry and Biotechnology Swinburne University of Technology Victoria 3122 Australia
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13
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Mohan A, Raj Rajan R, Mohan G, Kollenchery Puthenveettil P, Maliekal TT. Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells. Front Cell Dev Biol 2021; 9:668851. [PMID: 34150761 PMCID: PMC8209516 DOI: 10.3389/fcell.2021.668851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
A subpopulation within cancer, known as cancer stem cells (CSCs), regulates tumor initiation, chemoresistance, and metastasis. At a closer look, CSCs show functional heterogeneity and hierarchical organization. The present review is an attempt to assign marker profiles to define the functional heterogeneity and hierarchical organization of CSCs, based on a series of single-cell analyses. The evidences show that analogous to stem cell hierarchy, self-renewing Quiescent CSCs give rise to the Progenitor CSCs with limited proliferative capacity, and later to a Progenitor-like CSCs, which differentiates to Proliferating non-CSCs. Functionally, the CSCs can be tumor-initiating cells (TICs), drug-resistant CSCs, or metastasis initiating cells (MICs). Although there are certain marker profiles used to identify CSCs of different cancers, molecules like CD44, CD133, ALDH1A1, ABCG2, and pluripotency markers [Octamer binding transcriptional factor 4 (OCT4), SOX2, and NANOG] are used to mark CSCs of a wide range of cancers, ranging from hematological malignancies to solid tumors. Our analysis of the recent reports showed that a combination of these markers can demarcate the heterogeneous CSCs in solid tumors. Reporter constructs are widely used for easy identification and quantification of marker molecules. In this review, we discuss the suitability of reporters for the widely used CSC markers that can define the heterogeneous CSCs. Since the CSC-specific functions of CD44 and CD133 are regulated at the post-translational level, we do not recommend the reporters for these molecules for the detection of CSCs. A promoter-based reporter for ABCG2 may also be not relevant in CSCs, as the expression of the molecule in cancer is mainly regulated by promoter demethylation. In this context, a dual reporter consisting of one of the pluripotency markers and ALDH1A1 will be useful in marking the heterogeneous CSCs. This system can be easily adapted to high-throughput platforms to screen drugs for eliminating CSCs.
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Affiliation(s)
- Amrutha Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.,Manipal Academy of Higher Education, Manipal, India
| | - Reshma Raj Rajan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Gayathri Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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14
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Zheng W, Wu F, Fu K, Sun G, Sun G, Li X, Jiang W, Cao H, Wang H, Tang W. Emerging Mechanisms and Treatment Progress on Liver Metastasis of Colorectal Cancer. Onco Targets Ther 2021; 14:3013-3036. [PMID: 33986602 PMCID: PMC8110277 DOI: 10.2147/ott.s301371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is currently the third largest malignant tumor in the world, with high new cases and high mortality. Metastasis is one of the most common causes of death of colorectal cancer, of which liver metastasis is the most fatal. Since the beginning of the Human Genome Project in 2001, people have gradually recognized the 3 billion base pairs that make up the human genome, of which only about 1.5% of the nucleic acid sequences are used for protein coding, including proto-oncogenes and tumor suppressor genes. A large number of differences in the expression of proto-oncogenes and tumor suppressor genes have also been found in the study of colorectal cancer, which proves that they are also actively involved in the progression of colorectal cancer and promote the occurrence of liver metastasis. Except for 1.5% of the coding sequence, the rest of the nucleic acid sequence does not encode any protein, which is called non-coding RNA. With the deepening of research, genome sequences without protein coding potential that were originally considered “junk sequences” may have important biological functions. Many years of studies have found that a large number of abnormal expression of ncRNA in colorectal cancer liver metastasis, indicating that ncRNA plays an important role in it. To explore the role and mechanism of these coding sequences and non-coding RNA in liver metastasis of colorectal cancer is very important for the early diagnosis and treatment of liver metastasis of colorectal cancer. This article reviews the coding genes and ncRNA that have been found in the study of liver metastasis of colorectal cancer in recent years, as well as the mechanisms that have been identified or are still under study, as well as the clinical treatment of liver metastasis of colorectal cancer.
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Affiliation(s)
- Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Kai Fu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Wei Jiang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hanjin Wang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
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15
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Memarpour S, Khalili-Tanha G, Ghannad AA, Razavi MS, Joudi M, Joodi M, Ferns GA, Hassanian SM, Khazaei M, Avan A. The Clinical Application of Circulating Tumor Cells and DNAs as Prognostic and Predictive Biomarkers in Gastrointestinal Cancer. Curr Cancer Drug Targets 2021; 21:676-688. [PMID: 33719973 DOI: 10.2174/1568009621666210311090531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/21/2020] [Accepted: 01/31/2021] [Indexed: 11/22/2022]
Abstract
Gastrointestinal (GI) cancer is one of the most common cancers globally. Genetic and epigenetic mechanisms are involved in its pathogenesis. The conventional methods for diagnosis and screening for GI cancers are often invasive and have other limitations. In the era of personalized medicine, a novel non-invasive approach called liquid biopsy has been introduced for the detection and management of GI cancers, which focuses on the analysis of circulating tumor cells (CTCs) and circulating cell-free tumor DNA (ctDNA). Several studies have shown that this new approach allows for an improved understanding of GI tumor biology and will lead to an improvement in clinical management. The aim of the current review is to explore the clinical applications of CTCs and ctDNA in patients with GI cancer.
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Affiliation(s)
- Sara Memarpour
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Awa Alizadeh Ghannad
- Department of biological sciences, California state University, Sacramento, California. United States
| | - Masoud Sharifian Razavi
- Department of Gastroenterology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Mona Joudi
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Marjan Joodi
- Sarvar Children's Hospital, Endoscopic and Minimally Invasive Surgery Research Center, Mashhad. Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH. United Kingdom
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran
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16
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Asghari S, Mahmoudifard M. Core‐shell nanofibrous membrane of polycaprolactone‐hyaluronic acid as a promising platform for the efficient capture and release of circulating tumor cells. POLYM ADVAN TECHNOL 2020. [DOI: 10.1002/pat.5158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Sahar Asghari
- Department of Industrial and Environmental Biotechnology National Institute for Genetic Engineering and Biotechnology (NIGEB) Tehran Iran
| | - Matin Mahmoudifard
- Department of Industrial and Environmental Biotechnology National Institute for Genetic Engineering and Biotechnology (NIGEB) Tehran Iran
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17
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Tsai WS, Hung WS, Wang TM, Liu H, Yang CY, Wu SM, Hsu HL, Hsiao YC, Tsai HJ, Tseng CP. Circulating tumor cell enumeration for improved screening and disease detection of patients with colorectal cancer. Biomed J 2020; 44:S190-S200. [PMID: 35292267 PMCID: PMC9068522 DOI: 10.1016/j.bj.2020.09.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 09/21/2020] [Accepted: 09/27/2020] [Indexed: 12/13/2022] Open
Abstract
Background The immunochemical fecal occult blood test (iFOBT) for colorectal cancer (CRC) screening and the serum carcinoembryonic antigen (CEA) assay for disease detection of CRC is associated with a high false-positive rate and a low detection sensitivity, respectively. There is an unmet need to define additional modalities to complement these assays. Different subsets of circulating tumor cells (CTCs) are present in the peripheral blood of cancer patients. Whether or not CTCs testing supplements these clinical assays and is valuable for patients with CRC was investigated. Methods CTCs were enriched from pre-operative patients with CRC (n = 109) and the non-cancerous controls (n = 65). CTCs expressing either epithelial cell adhesion molecule (EpCAM) or podoplanin (PDPN, the marker associated with poor cancer prognosis) were defined by immunofluorescence staining and were analyzed alone or in combination with iFOBT or serum CEA. Results Patients with early or advanced stage of CRC can be clearly identified and differentiated from the non-cancerous controls (p < 0.001) by EpCAM+-CTC or PDPN+-CTC count. The sensitivity and specificity of EpCAM+-CTCs was 85.3% and 78.5%, respectively, when the cutoff value was 23 EpCAM+-CTCs/mL of blood; and the sensitivity and specificity of PDPN+-CTCs was 78.0% and 75.4%, respectively, when the cutoff value was 7 PDPN+-CTCs/mL of blood. Combined analysis of iFOBT with the EpCAM+-CTC and PDPN+-CTC count reduced the false-positive rate of iFOBT from 56.3% to 18.8% and 23.4%, respectively. Combined analysis of serum CEA with the EpCAM+-CTC and PDPN+-CTC count increased the disease detection rate from 30.3% to 89.9% and 86.2%, respectively. Conclusion CTC testing could supplement iFOBT to improve CRC screening and supplement serum CEA assay for better disease detection of patients with CRC.
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18
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Wu C, Zhang J, Li H, Xu W, Zhang X. The potential of liquid biopsies in gastrointestinal cancer. Clin Biochem 2020; 84:1-12. [PMID: 32540214 DOI: 10.1016/j.clinbiochem.2020.06.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/09/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liquid biopsy is a novel approach for cancer diagnosis, the value of which in human gastrointestinal (GI) cancer has been confirmed by the previous studies. This article summarized the recent advances in liquid biopsy with a focus on novel technologies and the use of it in the screening, monitoring, and treatment of human GI cancer. CONTENT The concept of liquid biopsy was first used to define the detection of circulating tumor cells (CTCs) in cancer patients, and has been expanded to other biomarkers in blood and body fluids, such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs) and circulating tumor RNA. If analyzed with proper and advanced techniques like next generation sequencing (NGS) or proteomics, liquid biopsies can open an enormous array of potential biomarkers. The amount changes of target biomarkers and the mutation of genetic materials provide quantitative and qualitative information, which can be utilized clinically for cancer diagnosis and disease monitoring. SUMMARY As a highly efficient, minimally invasive, and cost-effective approach to diagnose and evaluate prognosis of GI cancer, liquid biopsy has lots of advantages over traditional biopsy and is promising in future clinical utility. If the challenges are overcome in the near future, liquid biopsy will become a widely available and dependable option.
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Affiliation(s)
- Chenxi Wu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Jiayin Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Haibo Li
- Department of Clinical Laboratory, Nantong Maternal and Child Health Care Hospital, Nantong, Jiangsu 226000, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Xu Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.
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19
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Matrix Effect in the Isolation of Breast Cancer-Derived Nanovesicles by Immunomagnetic Separation and Electrochemical Immunosensing-A Comparative Study. SENSORS 2020; 20:s20040965. [PMID: 32054015 PMCID: PMC7071381 DOI: 10.3390/s20040965] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 01/16/2023]
Abstract
Exosomes are cell-derived nanovesicles released into biological fluids, which are involved in cell-to-cell communication. The analysis of the content and the surface of the exosomes allow conclusions about the cells they are originating from and the underlying condition, pathology or disease. Therefore, the exosomes are currently considered good candidates as biomarkers to improve the current methods for clinical diagnosis, including cancer. However, due to their low concentration, conventional procedures for exosome detection including biosensing usually require relatively large sample volumes and involve preliminary purification and preconcentration steps by ultracentrifugation. In this paper, the immunomagnetic separation is presented as an alternative method for the specific isolation of exosomes in serum. To achieve that, a rational study of the surface proteins in exosomes, which can be recognized by magnetic particles, is presented. The characterization was performed in exosomes obtained from cell culture supernatants of MCF7, MDA-MB-231 and SKBR3 breast cancer cell lines, including TEM and nanoparticle tracking analysis (NTA). For the specific characterization by flow cytometry and confocal microscopy, different commercial antibodies against selected receptors were used, including the general tetraspanins CD9, CD63 and CD81, and cancer-related receptors (CD24, CD44, CD54, CD326 and CD340). The effect of the serum matrix on the immunomagnetic separation was then carefully evaluated by spiking the exosomes in depleted human serum. Based on this study, the exosomes were preconcentrated by immunomagnetic separation on antiCD81-modified magnetic particles in order to achieve further magnetic actuation on the surface of the electrode for the electrochemical readout. The performance of this approach is discussed and compared with classical characterization methods.
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20
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Tsunedomi R, Yoshimura K, Suzuki N, Hazama S, Nagano H. Clinical implications of cancer stem cells in digestive cancers: acquisition of stemness and prognostic impact. Surg Today 2020; 50:1560-1577. [PMID: 32025858 DOI: 10.1007/s00595-020-01968-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023]
Abstract
Digestive system cancers are the most frequent cancers worldwide and often associated with poor prognosis because of their invasive and metastatic characteristics. Recent studies have found that the plasticity of cancer cells can impart cancer stem-like properties via the epithelial-mesenchymal transition (EMT). Cancer stem-like properties such as tumor initiation are integral to the formation of metastasis, which is the main cause of poor prognosis. Numerous markers of cancer stem cells (CSCs) have been identified in many types of cancer. Therefore, CSCs, via their stem cell-like functions, may play an important role in prognosis after surgery. While several reports have described prognostic analysis using CSC markers, few reviews have summarized CSCs and their association with prognosis. Herein, we review the prognostic potential of eight CSC markers, CD133, CD44, CD90, ALDH1A1, EPCAM, SOX2, SOX9, and LGR5, in digestive cancers including those of the pancreas, colon, liver, gastric, and esophagus.
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Affiliation(s)
- Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
| | - Kiyoshi Yoshimura
- Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
| | - Nobuaki Suzuki
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.,Faculty of Medicine, Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
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21
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Kapeleris J, Zou H, Qi Y, Gu Y, Li J, Schoning J, Monteiro MJ, Gu W. Cancer stemness contributes to cluster formation of colon cancer cells and high metastatic potentials. Clin Exp Pharmacol Physiol 2020; 47:838-847. [PMID: 31883392 DOI: 10.1111/1440-1681.13247] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/22/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022]
Abstract
The ability of cancer cells to form clusters is a characteristic feature in the development of metastatic tumours with drug resistance. Several studies demonstrated that clusters of circulating tumour cells (CTCs) have a greater metastatic potential to establish new tumours at secondary sites than single CTCs. However, the mechanism of cluster formation is not well understood. In this study, we investigated whether cancer stemness would contribute to cluster formation. We used a tumour sphere culture method to enrich cancer stem cells (CSCs) from colon cancer cells and found that during the second generation of sphere culture, clusters (between 3 and 5 cells) formed within the first 24 hours, whereas the rest remained as single cells. The clusters were analysed for stemness and metastatic potential, including gene expressions for cancer stemness (CD133 and Lgr5), epithelial-mesenchymal transition (E-cadherin and TGF-β 1-3) and hypoxia-induced factors (HIF-1α and HIF-2α). The results showed that the clusters expressed higher levels of these genes and colon CSC surface markers (including CD24, CD44 and CD133) than the single cells. Among these markers, CD24 seemed the major contributor linking the cells into the clusters. These clusters also showed a stronger ability to both form colonies and migrate. Our data collectively suggest that colon cancer stemness contributes to cluster formation and that clustered cells exhibit a great metastatic potential. Our study thus provides a method to study the CTC clusters and derive insight into oncogenesis and metastasis.
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Affiliation(s)
- Joanna Kapeleris
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Hong Zou
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia.,Department of Pathology, Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi University, Xinjiang, China
| | - Yan Qi
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia.,Department of Pathology, Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi University, Xinjiang, China
| | - Yushu Gu
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Jingyun Li
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Jennifer Schoning
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Michael J Monteiro
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
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22
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Rau KM, Liu CT, Hsiao YC, Hsiao KY, Wang TM, Hung WS, Su YL, Liu WC, Wang CH, Hsu HL, Chuang PH, Cheng JC, Tseng CP. Sequential Circulating Tumor Cell Counts in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: Monitoring the Treatment Response. J Clin Med 2020; 9:E188. [PMID: 32071283 PMCID: PMC7019972 DOI: 10.3390/jcm9010188] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/05/2020] [Accepted: 01/08/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common causes of cancer death in men. Whether or not a longitudinal follow-up of circulating tumor cells (CTCs) before and at different time points during systemic/targeted therapy is useful for monitoring the treatment response of patients with locally advanced or metastatic HCC has been evaluated in this study. Blood samples (n = 104) were obtained from patients with locally advanced or metastatic HCC (n = 30) for the enrichment of CTCs by a negative selection method. Analysis of the blood samples from patients with defined disease status (n = 81) revealed that those with progressive disease (PD, n = 37) had significantly higher CTC counts compared to those with a partial response (PR) or stable disease (SD; n = 44 for PR + SD, p = 0.0002). The median CTC count for patients with PD and for patients with PR and SD was 50 (interquartile range 21-139) and 15 (interquartile range 4-41) cells/mL of blood, respectively. A longitudinal analysis of patients (n = 17) after a series of blood collections demonstrated that a change in the CTC count correlated with the patient treatment response in most of the cases and was particularly useful for monitoring patients without elevated serum alpha-fetoprotein (AFP) levels. Sequential CTC enumeration during treatment can supplement standard medical tests and benefit the management of patients with locally advanced or metastatic HCC, in particular for the AFP-low cases.
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Affiliation(s)
- Kun-Ming Rau
- Department of Hematology-Oncology, E-Da Cancer Hospital, Kaohsiung 824, Taiwan;
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan
| | - Chien-Ting Liu
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (C.-T.L.); (K.-Y.H.); (Y.-L.S.); (W.-C.L.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Yu-Chiao Hsiao
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (Y.-C.H.); (T.-M.W.); (W.-S.H.); (H.-L.H.)
| | - Kai-Yin Hsiao
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (C.-T.L.); (K.-Y.H.); (Y.-L.S.); (W.-C.L.)
| | - Tzu-Min Wang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (Y.-C.H.); (T.-M.W.); (W.-S.H.); (H.-L.H.)
| | - Wei-Shan Hung
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (Y.-C.H.); (T.-M.W.); (W.-S.H.); (H.-L.H.)
| | - Yu-Li Su
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (C.-T.L.); (K.-Y.H.); (Y.-L.S.); (W.-C.L.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Wei-Ching Liu
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (C.-T.L.); (K.-Y.H.); (Y.-L.S.); (W.-C.L.)
| | - Cheng-Hsu Wang
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
- Division of Hematology/Oncology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
| | - Hsueh-Ling Hsu
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (Y.-C.H.); (T.-M.W.); (W.-S.H.); (H.-L.H.)
| | - Po-Heng Chuang
- Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan;
| | - Ju-Chien Cheng
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan;
| | - Ching-Ping Tseng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (Y.-C.H.); (T.-M.W.); (W.-S.H.); (H.-L.H.)
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Department of Laboratory Medicine, Linko Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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23
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Nanduri LK, Hissa B, Weitz J, Schölch S, Bork U. The prognostic role of circulating tumor cells in colorectal cancer. Expert Rev Anticancer Ther 2019; 19:1077-1088. [PMID: 31778322 DOI: 10.1080/14737140.2019.1699065] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Metastasis is the main cause of cancer-associated death in colorectal cancer (CRC). The presence of circulating tumor cells (CTC) in the blood is associated with an increased risk of recurrence and poor prognosis. The clinical significance of CTCs as a novel biomarker has been extensively studied in the last decade. It has been shown that CTC detection applies to early cancer detection. The presence of CTCs is associated with metastatic spread and poor survival and is also useful as a marker for therapy response.Areas covered: We summarize the role of CTC in CRC, their clinical significance, current methods for CTC detection and challenges as well as future perspectives of CTC research.Expert commentary: The clinical significance of CTC in CRC patients is well established. Although insightful, the available marker-based approaches hampered our understanding of the CTCs and their biology, as such approaches do not take into account the heterogeneity of these cell populations. New technologies should expand the marker-based detection to multi biomarker-based approaches together with recent technological advances in microfluidics for single cell enrichment and analysis.
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Affiliation(s)
- Lahiri Kanth Nanduri
- Department of Gastrointestinal-, Thoracic- and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium, Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara Hissa
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal-, Thoracic- and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium, Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Schölch
- Department of Gastrointestinal-, Thoracic- and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium, Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ulrich Bork
- Department of Gastrointestinal-, Thoracic- and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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24
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Ma L, Dong L, Chang P. CD44v6 engages in colorectal cancer progression. Cell Death Dis 2019; 10:30. [PMID: 30631039 PMCID: PMC6328617 DOI: 10.1038/s41419-018-1265-7] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/04/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023]
Abstract
CD44 is a transmembrane glycoprotein. When the CD44 gene is expressed, its pre-messenger RNA (mRNA) can be alternatively spliced into mature mRNAs that encode several CD44 isoforms. The mRNA assembles with ten standard exons, and the sixth variant exon encodes CD44v6, which engages in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. Mechanistically, CD44v6 interacts with hyaluronic acid (HA) or osteopontin, or it acts as a coreceptor for various cytokines, such as epidermal growth factor, vascular endothelial growth factor, hepatocyte growth factor, and C-X-C motif chemokine 12. In this context, the receptor tyrosine kinase or G protein-coupled receptor-associated signaling pathways, including mitogen-activated protein kinase/extracellular-signal-regulated kinase and phosphoinositide-3-kinase/Akt, are activated. Using these actions, homeostasis or regeneration can be facilitated among normal tissues. However, overexpression of the mature mRNA encoding CD44v6 can induce cancer progression. For example, CD44v6 assists colorectal cancer stem cells in colonization, invasion, and metastasis. Overexpression of CD44v6 predicts poor prognosis in patients with colorectal cancer, as patients with a large number of CD44v6-positive cells in their tumors are generally diagnosed at late stages. Thus, the clinical significance of CD44v6 in colorectal cancer deserves consideration. Preclinical results have indicated satisfactory efficacies of anti-CD44 therapy among several cancers, including prostate cancer, pancreatic cancer, and gastric cancer. Moreover, clinical trials aiming to evaluate the pharmacokinetics, pharmacodynamics, efficacy, and toxicity of a commercialized anti-CD44 monoclonal antibody developed by Roche (RO5429083) have been conducted among patients with CD44-expressing malignant tumors, and a clinical trial focusing on the dose escalation of this antibody is ongoing. Thus, we are hopeful that anti-CD44 therapy will be applied in the treatment of colorectal cancer in the future.
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Affiliation(s)
- Lixin Ma
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, 130021, Changchun, China
| | - Lihua Dong
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, 130021, Changchun, China.
| | - Pengyu Chang
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, 130021, Changchun, China.
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25
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Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma. Int J Mol Sci 2018; 19:ijms19103014. [PMID: 30282914 PMCID: PMC6213422 DOI: 10.3390/ijms19103014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/28/2018] [Accepted: 10/01/2018] [Indexed: 12/17/2022] Open
Abstract
Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and targeted therapy) led to the research of novel prognostic and predictive biomarkers in CRC liver metastases (CRCLM) patients. In this review, we seek to describe the current state of knowledge of CRCLM biomarkers and to outline impending clinical perspectives, in particular focusing on the cutting-edge tools available for their characterization.
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26
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Zhu B, Wang Y, Wang X, Wu S, Zhou L, Gong X, Song W, Wang D. Evaluation of the correlation of MACC1, CD44, Twist1, and KiSS-1 in the metastasis and prognosis for colon carcinoma. Diagn Pathol 2018; 13:45. [PMID: 30021598 PMCID: PMC6052590 DOI: 10.1186/s13000-018-0722-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 06/25/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Metastasis-associated in colon cancer 1 (MACC1) has been reported to promote tumor cell invasion and metastasis. Cancer stem cells and epithelial-mesenchymal transition (EMT) have also been reported to promote tumor cell proliferation, invasion, and metastasis. KiSS-1, a known suppressor of metastasis, has been reported to be down-regulated in various tumors. However, the associations of MACC1, CD44, Twist1, and KiSS-1 in colonic adenocarcinoma (CAC) invasion and metastasis remain unclear. The purpose of this study is to investigate the roles of MACC1, CD44, Twist1, and KiSS-1 in CAC invasion and metastasis and their associations with each other and with the clinicopathological characteristics of CAC patients. METHODS Immunohistochemistry and multivariate analysis were carried out to explore the expression of MACC1, CD44, Twist1, and KiSS-1 in 212 whole-CAC-tissue specimens and the corresponding normal colon mucosa tissues. Demographic, clinicopathological, and follow-up data were also collected. RESULTS The results of this study showed MACC1, CD44, and Twist1 expression to be up-regulated, and KiSS-1 expression was down-regulated in CAC tissues. Positive expression of MACC1, CD44, and Twist1 was found to be positively correlated with invasion, tumor grades, and lymph- node-metastasis (LNM) stages and tumor-node-metastasis (TNM) stages for patients with CAC. Positive expression of KiSS-1 was inversely associated with invasion, tumor size, LNM stage, and TNM stage. The KiSS-1-positive expression group had significantly more favorable OS than did the KiSS-1-negative group. Univariate analysis indicated that overexpression of MACC1, CD44, and Twists1 was negatively associated with longer overall survival (OS) time, and there was a positive relationship between KiSS-1-positive expression and OS time for patients with CAC. Multivariate Cox analysis demonstrated that overexpression of MACC1, CD44, Twist1, and low expression of KiSS-1 and LNM and TNM stages were independent predictors of prognosis in patients with CAC. CONCLUSIONS The results in this study indicated that levels of expression of MACC1, CD44, Twist1, and KiSS-1 are related to the duration of OS in patients with CAC. MACC1, CD44, Twist1, and KiSS-1 may be suitable for use as biomarkers and therapeutic targets in CAC.
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Affiliation(s)
- Bo Zhu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Yichao Wang
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Xiaolin Wang
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Shiwu Wu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Lei Zhou
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Xiaomeng Gong
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Wenqing Song
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
| | - Danna Wang
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Pathology, Bengbu Medical University, Bengbu, China
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27
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Burz C, Pop VV, Buiga R, Daniel S, Samasca G, Aldea C, Lupan I. Circulating tumor cells in clinical research and monitoring patients with colorectal cancer. Oncotarget 2018; 9:24561-24571. [PMID: 29849961 PMCID: PMC5966258 DOI: 10.18632/oncotarget.25337] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 04/24/2018] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer remains a frequent disease to which screening and target therapy exist, but despite this is still marked by a high mortality rate. Even though radical surgery may be performed in many cases, patients relapse with metastatic disease. Circulating tumor cells were incriminated for tumor recurrence, that's why vigorous research started on their field. Owning prognostic and predictive value, it was revealed their usefulness in disease monitoring. Moreover, they may serve as liquid biopsies for genetic tests in cases where tissue biopsy is contraindicated or cannot be performed. In spite of these advantages, they were not included in clinical guidelines, despite CellSearch and many other detection methods were developed to ease the identification of circulating tumor cells. This review highlights the implication of circulating tumor cells in metastasis cascade, intrinsic tumor cells mechanisms and correlations with clinical parameters along with their utility for medical practice and detection techniques.
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Affiliation(s)
- Claudia Burz
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania.,Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Vlad-Vasile Pop
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania
| | - Rares Buiga
- Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Sur Daniel
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania.,Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Gabriel Samasca
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania.,Emergency Hospital for Children, Cluj-Napoca, Romania
| | - Cornel Aldea
- Emergency Hospital for Children, Cluj-Napoca, Romania
| | - Iulia Lupan
- Babeş-Bolyai University, Department of Molecular Biology and Biotehnology, Cluj-Napoca, Romania.,Institute of Interdisciplinary Research in Bio-Nano-Sciences, Cluj-Napoca, Romania
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28
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Xu HL, Li M, Zhang RJ, Jiang HJ, Zhang MY, Li X, Wang YQ, Pan WB. Prediction of tumor biological characteristics in different colorectal cancer liver metastasis animal models using 18F-FDG and 18F-FLT. Hepatobiliary Pancreat Dis Int 2018; 17:140-148. [PMID: 29571649 DOI: 10.1016/j.hbpd.2018.03.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 03/06/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Positron emission tomography (PET) is a noninvasive method to characterize different metabolic activities of tumors, providing information for staging, prognosis, and therapeutic response of patients with cancer. The aim of this study was to evaluate the feasibility of 18F-fludeoxyglucose (18F-FDG) and 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET in predicting tumor biological characteristics of colorectal cancer liver metastasis. METHODS The uptake rate of 18F-FDG and 18F-FLT in SW480 and SW620 cells was measured via an in vitro cell uptake assay. The region of interest was drawn over the tumor and liver to calculate the maximum standardized uptake value ratio (tumor/liver) from PET images in liver metastasis model. The correlation between tracer uptake in liver metastases and VEGF, Ki67 and CD44 expression was evaluated by linear regression. RESULTS Compared to SW620 tumor-bearing mice, SW480 tumor-bearing mice presented a higher rate of liver metastases. The uptake rate of 18F-FDG in SW480 and SW620 cells was 6.07% ± 1.19% and 2.82% ± 0.15%, respectively (t = 4.69, P = 0.04); that of 18F-FLT was 24.81% ± 0.45% and 15.57% ± 0.66%, respectively (t = 19.99, P < 0.001). Micro-PET scan showed that all parameters of FLT were significantly higher in SW480 tumors than those in SW620 tumors. A moderate relationship was detected between metastases in the liver and 18F-FLT uptake in primary tumors (r = 0.73, P = 0.0019). 18F-FLT uptake was also positively correlated with the expression of CD44 in liver metastases (r = 0.81, P = 0.0049). CONCLUSIONS The uptake of 18F-FLT in metastatic tumor reflects different biological behaviors of colon cancer cells. 18F-FLT can be used to evaluate the metastatic potential of colorectal cancer in nude mice.
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Affiliation(s)
- Hai-Long Xu
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Man Li
- Endoscopy Center, the Third Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Rong-Jun Zhang
- Key Laboratory of Nuclear Medicine of the Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Wuxi 214063, China
| | - Hui-Jie Jiang
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
| | - Ming-Yu Zhang
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Xin Li
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Yi-Qiao Wang
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Wen-Bin Pan
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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29
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Cho KM, Park H, Oh DY, Kim TY, Lee KH, Han SW, Im SA, Kim TY, Bang YJ. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and their dynamic changes during chemotherapy is useful to predict a more accurate prognosis of advanced biliary tract cancer. Oncotarget 2018; 8:2329-2341. [PMID: 27911876 PMCID: PMC5356803 DOI: 10.18632/oncotarget.13731] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 11/24/2016] [Indexed: 01/15/2023] Open
Abstract
Background and Purpose Systemic inflammation is known to promote carcinogenesis in biliary tract cancer (BTC). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are indicative of systemic inflammation. We evaluated the clinical significance of systemic inflammation measured by NLR and PLR in patients with advanced BTC. Additionally, we also co-analyzed the dynamics of NLR and PLR during chemotherapy. Methods We reviewed 450 patients with unresectable BTC receiving palliative chemotherapy. NLR and PLR were obtained before initiation of palliative chemotherapy. Changes in NLR, PLR were obtained by subtracting the initial value from the value obtained after progression of chemotherapy. Results Higher systemic inflammation status also had relation with a primary tumor site (p = 0.003) and higher levels of CEA (p = 0.038). The ROC cut-off values of NLR and PLR for predicting overall survival (OS) were 3.8 and 121, respectively. Patients with a high NLR or PLR had worse OS independently in multivariate analysis (6.90 vs. 9.80 months, p =0.002; 7.83 vs. 9.90 months, p =0.041, respectively). High NLR with increased NLR after chemotherapy is associated with worse OS and progression-free survival (PFS) (p < 0.001, p = 0.013 respectively). Results are similar for PLR. Conclusion Systemic inflammation represented by NLR and PLR, predicts the OS of patients with advanced BTC who are receiving palliative chemotherapy. In addition, considering NLR/PLR with a dynamic change of NLR/PLR during chemotherapy might help to predict a more accurate prognosis.
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Affiliation(s)
- Kyoung-Min Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hyunkyung Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do-Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yung-Jue Bang
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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30
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Zhang HJ, Fang XH, Li J. Liquid biopsy in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2018; 26:182-189. [DOI: 10.11569/wcjd.v26.i3.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, liquid biopsy technology, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes, has been effectively used in the early diagnosis, relapse and drug resistance monitoring, and prognosis evaluation in colorectal cancer (CRC). In this paper, we review the basic research and clinical application of liquid biopsy in CRC.
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Affiliation(s)
- Hui-Juan Zhang
- Physical Examination Center, Zhengzhou Seventh People's Hospital, Zhengzhou 450003, He'nan Province, China
| | - Xin-Hui Fang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, He'nan Provincial People's Hospital, Zhengzhou 450003, He'nan Province, China
| | - Jian Li
- Department of Gastroenterology, People's Hospital of Zhengzhou University, He'nan Provincial People's Hospital, Zhengzhou 450003, He'nan Province, China
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31
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LncRNA HIF1A-AS2 positively affects the progression and EMT formation of colorectal cancer through regulating miR-129-5p and DNMT3A. Biomed Pharmacother 2017; 98:433-439. [PMID: 29278853 DOI: 10.1016/j.biopha.2017.12.058] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/07/2017] [Accepted: 12/14/2017] [Indexed: 02/08/2023] Open
Abstract
LncRNAs were a group of RNAs, which can be a regulator or master in biological activities of cancer cells. HIF1A-AS2 belongs to this group, and it has been verified to be able to affect cell activities in several kinds of cancers. In this study, we tried to study the functions of HIF1A-AS2 exerted in colorectal cancer. In order to clearly know about the expression of HIF1A-AS2, miR-129-5p and DNMT3A in CRC tissues and cells, we employed qRT-PCR. The relevance among those three genes was examined by the use of Pearson correlation analysis. With the aid of bioinformatics analysis and dual luciferase reporter assays, the combinations between them were verified one by one MTT, colony formation trans-well and western blotting, immunofluorescence, all those assays reflected a fact that as a ceRNA, HIF1A-AS2 could directly bind with miR-129-5p, and could positively affect cell proliferation, invasion and EMT formation by regulation of the expression of miR-129-5p and DNMT3A. Therefore, we obtained a conclusion that HIF1A-AS2 exerted the oncogenic functions in CRC through regulating miR-129-5p/DNMT3A axis, which indicates that HIF1A-AS2 might be a useful therapeutic target in CRC.
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32
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Fang C, Fan C, Wang C, Huang Q, Meng W, Yu Y, Yang L, Hu J, Li Y, Mo X, Zhou Z. Prognostic value of CD133 + CD54 + CD44 + circulating tumor cells in colorectal cancer with liver metastasis. Cancer Med 2017; 6:2850-2857. [PMID: 29105339 PMCID: PMC5727299 DOI: 10.1002/cam4.1241] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 09/28/2017] [Indexed: 02/05/2023] Open
Abstract
In the previous study, we had showed the expression of CD133+ CD54+ CD44+ cellular subpopulation of circulating tumor cells (CTCs) was significantly associated with liver metastasis of colorectal cancer (CRC). This study aimed to explore whether this subpopulation of CTCs have a prognostic value in CRC patients. Flow cytometry was used to detect the expression of cellular subpopulations of CTCs with CD133, CD54, and CD44 in 152 CRC patients, between December 2013 and October 2014. The impact of clinicopathological factors and the expression of cellular subpopulations of CTCs on overall survival were then analyzed. CRC patients with liver metastases who underwent resection of the primary tumor accompanied by surgical treatment for metastasis had a better survival than other patients (P < 0.001). The liver metastatic CRC patients with high expression of CD133+ CD54+ (P < 0.001), CD133- CD54+ (P = 0.004), and CD133+ CD44+ CD54+ (P = 0.003) cellular subpopulations of CTCs had a worse survival than those patients with low expression. Multivariable survival analyses identified carcinoembryonic antigen levels (hazard ratio [HR] = 3.056; 95% confidence interval [CI] = 1.354-6.897; P = 0.007), treatment strategy (HR = 0.212; 95% CI = 0.056-0.808; P = 0.023), and CD133+ CD44+ CD54+ cellular subpopulation of CTCs (HR = 6.459; 95% CI = 1.461-28.558; P = 0.014) as independent prognostic factors for CRC patients with liver metastasis. CD133+ CD44+ CD54+ cellular subpopulation of CTCs has a prognostic value in CRC patients with liver metastasis, especially in the survival of CRC patients with liver metastasis who did not undergo surgical treatment for metastasis.
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Affiliation(s)
- Chao Fang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.,Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Chuanwen Fan
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.,Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Cun Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Qiaorong Huang
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wentong Meng
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yongyang Yu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Lie Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiankun Hu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Li
- Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xianming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zongguang Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.,Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Chen D, Sun Q, Zhang L, Zhou X, Cheng X, Zhou D, Ye F, Lin J, Wang W. The lncRNA HOXA11-AS functions as a competing endogenous RNA to regulate PADI2 expression by sponging miR-125a-5p in liver metastasis of colorectal cancer. Oncotarget 2017; 8:70642-70652. [PMID: 29050308 PMCID: PMC5642583 DOI: 10.18632/oncotarget.19956] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/27/2017] [Indexed: 12/12/2022] Open
Abstract
Several long non-coding RNAs (lncRNAs) play important roles in the regulation of liver metastasis in colorectal cancer (CRC) patients. We previously described the potential involvement of HOMEOBOX A11 (HOXA11) antisense RNA (HOXA11-AS), miR-125a-5p, and peptidyl arginine deiminase 2 (PADI2) in promoting liver metastasis in CRC patients. In the present study, we verified the significant upregulation of HOXA11-AS and PADI2, as well as the downregulation of miR-125a-5p, in CRC patients with liver metastasis. Overexpression and knockdown studies of HOXA11-AS or PADI2, as well as gain-/loss-of-function studies of miR-125a-5p, revealed a positive correlation between HOXA11-AS and PADI2 and a negative correlation with miR-125a-5p in the regulation of liver metastasis in CRC cell lines. Overall, we conclude that HOXA11-AS promotes liver metastasis in CRC by functioning as a miR-125a-5p sponge and describe a novel HOXA11-AS-miR-125a-5p-PADI2 regulatory network involved in CRC liver metastasis.
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Affiliation(s)
- Dong Chen
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Sun
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lufei Zhang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohu Zhou
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofei Cheng
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongkai Zhou
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Ye
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianjiang Lin
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Lu G, Zhou L, Song W, Wu S, Zhu B, Wang D. Expression of ORAOV1, CD133 and WWOX correlate with metastasis and prognosis in gastric adenocarcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:8916-8924. [PMID: 31966760 PMCID: PMC6965444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/27/2017] [Indexed: 06/10/2023]
Abstract
BACKGROUND Oral cancer overexpressed 1 (ORAOV1) which is a novel candidate oncogene is a useful biomarker of metastasis and prognosis in various cancers. CD133 which is a biomarker of cancer stem cells is overexpressed in many cancers and promotes cancer cells growth and metastasis. WW domain-containing oxidoreductase (WWOX) which is a suppressor gene of tumor can inhibit proliferation and promote apoptosis in various cancers. However, associations among ORAOV1, CD133, and WWOX and their clinicopathological significance in gastric adenocarcionma (GAC) are unclear. In this study, we analyzed associations among ORAOV1, CD133, and WWOX in GAC, and their respective associations with clinicopathological characteristics and survival in GAC. METHOD Positive expression of ORAOV1, CD133, and WWOX in 236 whole GAC tissue samples were detected by immunohistochemistry staining. Patients' clinical data were also collected. RESULTS Levels of ORAOV1 and CD133 were significantly higher, and levels of WWOX significantly lower, in GAC tissues than in normal gastric tissues. Levels of ORAOV1 and CD133 were positively associated with tumor grade, invasion of depth, lymph node metastasis (LNM), and tumor-node metastasis (TNM) stages, and inversely with patients overall survival time; levels of WWOX was negatively correlated with tumor grade, invasion of depth, LNM, and TNM stages, and the WWOX-positive subgroup had significantly longer overall survival time than did the WWOX-negative subgroup. In multivariate analysis, high expression of ORAOV1 and CD133, invasion of depth, and TNM stages, and low expression of WWOX were potential to be independent prognostic factors for overall survival time in patients with GAC. CONCLUSIONS The expression of ORAOV1, CD133, and WWOX represent promising biomarkers for metastasis and prognosis, and potential therapeutic targets for GAC.
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Affiliation(s)
- Guoyu Lu
- Department of Emergence, The First Affiliated Hospital of Bengbu Medical CollegeAnhui, China
| | - Lei Zhou
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeAnhui, China
- Department of Pathology, Bengbu Medical CollegeAnhui, China
| | - Wenqing Song
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeAnhui, China
- Department of Pathology, Bengbu Medical CollegeAnhui, China
| | - Shiwu Wu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeAnhui, China
- Department of Pathology, Bengbu Medical CollegeAnhui, China
| | - Bo Zhu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeAnhui, China
- Department of Pathology, Bengbu Medical CollegeAnhui, China
| | - Danna Wang
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical CollegeAnhui, China
- Department of Pathology, Bengbu Medical CollegeAnhui, China
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Liu JX, Zhang ZC, Shao ZW, Pu FF, Wang BC, Zhang YK, Zeng XL, Guo XD, Yang SH, He TC. TRAIL-R1 as a novel surface marker for circulating giant cell tumor of bone. Oncotarget 2017; 8:50724-50730. [PMID: 28881598 PMCID: PMC5584197 DOI: 10.18632/oncotarget.17042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 03/29/2017] [Indexed: 12/30/2022] Open
Abstract
Giant cell tumor of bone (GCT), which frequently occurs in the patients’ spine, is relatively prevalent in Chinese population. A group of GCT invades into vessels and appears to be circulating tumor cells (CTCs) responsible for the distal metastasis of the primary tumor. So far the cell surface markers of GCT have not been determined. In the current study, we aimed to identify a novel CTC marker with higher specificity in GCT. TRAIL-R1+ cells were purified from GCT cell lines. The TRAIL-R1+ cells were compared with total GCT cells for tumor sphere formation, chemo-resistance, tumor formation in nude mice, and frequency of developing distal metastases. We found that TRAIL-R1+ GCT cells appeared to be highly enriched for CTCs in GCT. Compared to total GCT cells, TRAIL-R1+ GCT cells generated significantly more tumor spheres in culture, were higher chemo-resistant, and had a higher frequency of being detected in the circulation after subcutaneous transplantation as well as development of distal metastases. Thus, we conclude that TRAIL-R1+ may be a novel CTC marker in GCT. Selective elimination of TRAIL-R1+ GCT cells may improve the current GCT therapy.
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Affiliation(s)
- Jian-Xiang Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhi-Cai Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zeng-Wu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Fei-Fei Pu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bai-Chuan Wang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu-Kun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xian-Lin Zeng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiao-Dong Guo
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shu-Hua Yang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago 60637, IL, USA
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Zou J, Wang E. eTumorType, An Algorithm of Discriminating Cancer Types for Circulating Tumor Cells or Cell-free DNAs in Blood. GENOMICS PROTEOMICS & BIOINFORMATICS 2017; 15:130-140. [PMID: 28389380 PMCID: PMC5414714 DOI: 10.1016/j.gpb.2017.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 12/18/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023]
Abstract
With the technology development on detecting circulating tumor cells (CTCs) and cell-free DNAs (cfDNAs) in blood, serum, and plasma, non-invasive diagnosis of cancer becomes promising. A few studies reported good correlations between signals from tumor tissues and CTCs or cfDNAs, making it possible to detect cancers using CTCs and cfDNAs. However, the detection cannot tell which cancer types the person has. To meet these challenges, we developed an algorithm, eTumorType, to identify cancer types based on copy number variations (CNVs) of the cancer founding clone. eTumorType integrates cancer hallmark concepts and a few computational techniques such as stochastic gradient boosting, voting, centroid, and leading patterns. eTumorType has been trained and validated on a large dataset including 18 common cancer types and 5327 tumor samples. eTumorType produced high accuracies (0.86-0.96) and high recall rates (0.79-0.92) for predicting colon, brain, prostate, and kidney cancers. In addition, relatively high accuracies (0.78-0.92) and recall rates (0.58-0.95) have also been achieved for predicting ovarian, breast luminal, lung, endometrial, stomach, head and neck, leukemia, and skin cancers. These results suggest that eTumorType could be used for non-invasive diagnosis to determine cancer types based on CNVs of CTCs and cfDNAs.
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Affiliation(s)
- Jinfeng Zou
- National Research Council Canada, Montreal, QC H4P 2R2, Canada
| | - Edwin Wang
- National Research Council Canada, Montreal, QC H4P 2R2, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 2B2, Canada; Center for Bioinformatics, McGill University, Montreal, QC H3G 0B1, Canada; Center for Health Genomics and Informatics, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Biochemistry & Molecular Biology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Medical Genetics, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Department of Oncology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Calgary, AB T2N 4N1, Canada; Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N1, Canada; O'Brien Institute for Public Health, Calgary, AB T2N 4N1, Canada.
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