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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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Kumar S, Sherman MY. Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us. Int J Mol Sci 2023; 24:ijms24087233. [PMID: 37108395 PMCID: PMC10138578 DOI: 10.3390/ijms24087233] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Irinotecan (SN-38) is a potent and broad-spectrum anticancer drug that targets DNA topoisomerase I (Top1). It exerts its cytotoxic effects by binding to the Top1-DNA complex and preventing the re-ligation of the DNA strand, leading to the formation of lethal DNA breaks. Following the initial response to irinotecan, secondary resistance is acquired relatively rapidly, compromising its efficacy. There are several mechanisms contributing to the resistance, which affect the irinotecan metabolism or the target protein. In addition, we have demonstrated a major resistance mechanism associated with the elimination of hundreds of thousands of Top1 binding sites on DNA that can arise from the repair of prior Top1-dependent DNA cleavages. Here, we outline the major mechanisms of irinotecan resistance and highlight recent advancements in the field. We discuss the impact of resistance mechanisms on clinical outcomes and the potential strategies to overcome resistance to irinotecan. The elucidation of the underlying mechanisms of irinotecan resistance can provide valuable insights for the development of effective therapeutic strategies.
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Affiliation(s)
- Santosh Kumar
- Department of Molecular Biology, Ariel University, Ariel 40700, Israel
| | - Michael Y Sherman
- Department of Molecular Biology, Ariel University, Ariel 40700, Israel
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3
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Polymer Thin Film Promotes Tumor Spheroid Formation via JAK2-STAT3 Signaling Primed by Fibronectin-Integrin α5 and Sustained by LMO2-LDB1 Complex. Biomedicines 2022; 10:biomedicines10112684. [DOI: 10.3390/biomedicines10112684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer stem-like cells (CSCs) are considered promising targets for anti-cancer therapy owing to their role in tumor progression. Extensive research is, therefore, being carried out on CSCs to identify potential targets for anti-cancer therapy. However, this requires the availability of patient-derived CSCs ex vivo, which remains restricted due to the low availability and diversity of CSCs. To address this limitation, a functional polymer thin-film (PTF) platform was invented to induce the transformation of cancer cells into tumorigenic spheroids. In this study, we demonstrated the functionality of a new PTF, polymer X, using a streamlined production process. Polymer X induced the formation of tumor spheroids with properties of CSCs, as revealed through the upregulated expression of CSC-related genes. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in the cancer cells cultured on polymer X was upregulated by the fibronectin-integrin α5-Janus kinase 2 (JAK2) axis and maintained by the cytosolic LMO2/LBD1 complex. In addition, STAT3 signaling was critical in spheroid formation on polymer X. Our PTF platform allows the efficient generation of tumor spheroids from cancer cells, thereby overcoming the existing limitations of cancer research.
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Ozawa S, Miura T, Terashima J, Habano W. Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:946-964. [PMID: 35582377 PMCID: PMC8992440 DOI: 10.20517/cdr.2021.82] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022]
Abstract
Treatment with pharmacological drugs for colorectal cancer (CRC) remains unsatisfactory. A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs, creating an urgent issue. In this review, we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness. Our review presents the following five major causes of irinotecan resistance in human CRC: (1) cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter, ABCG2; (2) cellular irinotecan resistance is also induced in association with a nuclear receptor, pregnane/steroid X receptor (PXR/SXR), which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38; (3) irinotecan-resistant cells possess either reduced DNA topoisomerase I (Top1) expression at both the mRNA and protein levels or Top1 missense mutations; (4) alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs; and (5) CRC stem cells are the most difficult targets to successfully treat CRC. In the clinical setting, CRC gradually develops resistance to initially effective irinotecan-based therapy. To solve this problem, several clinical trials, such as irinotecan plus cetuximab vs. cetuximab monotherapy, have been conducted. Another clinical trial on irinotecan plus guadecitabine, a DNA-methyltransferase inhibitor, has also been conducted.
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Affiliation(s)
- Shogo Ozawa
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Toshitaka Miura
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Jun Terashima
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Wataru Habano
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
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Mastri M, Ramakrishnan S, Shah SD, Karasik E, Gillard BM, Moser MT, Farmer BK, Azabdaftari G, Chatta GS, Woloszynska A, Eng KH, Foster BA, Huss WJ. Patient derived models of bladder cancer enrich the signal of the tumor cell transcriptome facilitating the analysis of the tumor cell compartment. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY 2021; 9:416-434. [PMID: 34993263 PMCID: PMC8727788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/06/2021] [Indexed: 06/14/2023]
Abstract
The evolving paradigm of the molecular classification of bladder cancer requires models that represent the classifications with less heterogeneity. Robust transcriptome based molecular classifications are essential to address tumor heterogeneity. Patient derived models (PDMs) are a powerful preclinical tool to study specific tumor compartments. We tested if the consensus molecular subtype analysis was applicable to PDMs and evaluated the tumor compartment each model represents. PDMs derived from surgical specimens were established as xenografts (PDX), organoids (PDO), and spheroids (PDS). The surgical specimens and PDMs were molecularly characterized by RNA sequencing. PDMs that were established in immune deficient mice or in vitro significantly downregulated transcripts related to the immune and stromal compartments compared to the surgical specimens. However, PDMs upregulate a patient-specific bladder cancer cell signal which allowed for analysis of cancer cell pathways independent of the tumor microenvironment. Based on transcriptomic signatures, PDMs are more similar to their surgical specimen than the model type; indicating that the PDMs retained unique features of the tumor from which the PDM was derived. When comparing models, PDX models were the most similar to the surgical specimen, while PDO and PDS models were most similar to each other. When the consensus molecular subtype classification system was applied to both the surgical samples and the three PDMs, good concordance was found between all samples indicating that this system of classification can be applied to PDO and PDS models. PDMs reduce tumor heterogeneity and allow analysis of tumor cells while maintaining the gene expression profile representative of the original tumor.
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Affiliation(s)
- Michalis Mastri
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Swathi Ramakrishnan
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Shruti D Shah
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Ellen Karasik
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Bryan M Gillard
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Michael T Moser
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Bailey K Farmer
- Department of Medicine, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Gissou Azabdaftari
- Department of Pathology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Gurkamal S Chatta
- Department of Medicine, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Anna Woloszynska
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Kevin H Eng
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Barbara A Foster
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
| | - Wendy J Huss
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
- Department of Dermatology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, NY, USA
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6
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Huang B, Yan X, Li Y. Cancer Stem Cell for Tumor Therapy. Cancers (Basel) 2021; 13:cancers13194814. [PMID: 34638298 PMCID: PMC8508418 DOI: 10.3390/cancers13194814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Although many methods have been applied in clinical treatment for tumors, they still always show a poor prognosis. Molecule targeted therapy has revolutionized tumor therapy, and a proper target must be found urgently. With a crucial role in tumor development, metastasis and recurrence, cancer stem cells have been found to be a feasible and potential target for tumor therapy. We list the unique biological characteristics of cancer stem cells and summarize the recent strategies to target cancer stem cells for tumor therapy, through which we hope to provide a comprehensive understanding of cancer stem cells and find a better combinational strategy to target cancer stem cells for tumor therapy. Abstract Tumors pose a significant threat to human health. Although many methods, such as operations, chemotherapy and radiotherapy, have been proposed to eliminate tumor cells, the results are unsatisfactory. Targeting therapy has shown potential due to its specificity and efficiency. Meanwhile, it has been revealed that cancer stem cells (CSCs) play a crucial role in the genesis, development, metastasis and recurrence of tumors. Thus, it is feasible to inhibit tumors and improve prognosis via targeting CSCs. In this review, we provide a comprehensive understanding of the biological characteristics of CSCs, including mitotic pattern, metabolic phenotype, therapeutic resistance and related mechanisms. Finally, we summarize CSCs targeted strategies, including targeting CSCs surface markers, targeting CSCs related signal pathways, targeting CSC niches, targeting CSC metabolic pathways, inducing differentiation therapy and immunotherapy (tumor vaccine, CAR-T, oncolytic virus, targeting CSCs–immune cell crosstalk and immunity checkpoint inhibitor). We highlight the potential of immunity therapy and its combinational anti-CSC therapies, which are composed of different drugs working in different mechanisms.
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Affiliation(s)
- Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Xin Yan
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
- Correspondence: ; Tel.: +86-138-9361-5421
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Horst EN, Bregenzer ME, Mehta P, Snyder CS, Repetto T, Yang-Hartwich Y, Mehta G. Personalized models of heterogeneous 3D epithelial tumor microenvironments: Ovarian cancer as a model. Acta Biomater 2021; 132:401-420. [PMID: 33940195 PMCID: PMC8969826 DOI: 10.1016/j.actbio.2021.04.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
Intractable human diseases such as cancers, are context dependent, unique to both the individual patient and to the specific tumor microenvironment. However, conventional cancer treatments are often nonspecific, targeting global similarities rather than unique drivers. This limits treatment efficacy across heterogeneous patient populations and even at different tumor locations within the same patient. Ultimately, this poor efficacy can lead to adverse clinical outcomes and the development of treatment-resistant relapse. To prevent this and improve outcomes, it is necessary to be selective when choosing a patient's optimal adjuvant treatment. In this review, we posit the use of personalized, tumor-specific models (TSM) as tools to achieve this remarkable feat. First, using ovarian cancer as a model disease, we outline the heterogeneity and complexity of both the cellular and extracellular components in the tumor microenvironment. Then we examine the advantages and disadvantages of contemporary cancer models and the rationale for personalized TSM. We discuss how to generate precision 3D models through careful and detailed analysis of patient biopsies. Finally, we provide clinically relevant applications of these versatile personalized cancer models to highlight their potential impact. These models are ideal for a myriad of fundamental cancer biology and translational studies. Importantly, these approaches can be extended to other carcinomas, facilitating the discovery of new therapeutics that more effectively target the unique aspects of each individual patient's TME. STATEMENT OF SIGNIFICANCE: In this article, we have presented the case for the application of biomaterials in developing personalized models of complex diseases such as cancers. TSM could bring about breakthroughs in the promise of precision medicine. The critical components of the diverse tumor microenvironments, that lead to treatment failures, include cellular- and extracellular matrix- heterogeneity, and biophysical signals to the cells. Therefore, we have described these dynamic components of the tumor microenvironments, and have highlighted how contemporary biomaterials can be utilized to create personalized in vitro models of cancers. We have also described the application of the TSM to predict the dynamic patterns of disease progression, and predict effective therapies that can produce durable responses, limit relapses, and treat any minimal residual disease.
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Affiliation(s)
- Eric N Horst
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Michael E Bregenzer
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Pooja Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Catherine S Snyder
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Taylor Repetto
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Yang Yang-Hartwich
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, CT 06510, United States
| | - Geeta Mehta
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States; Precision Health, University of Michigan, Ann Arbor, MI 48109, United States.
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8
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Gisina A, Novikova S, Kim Y, Sidorov D, Bykasov S, Volchenko N, Kaprin A, Zgoda V, Yarygin K, Lupatov A. CEACAM5 overexpression is a reliable characteristic of CD133-positive colorectal cancer stem cells. Cancer Biomark 2021; 32:85-98. [PMID: 34092615 DOI: 10.3233/cbm-203187] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND CD133 (prominin-1) is the most commonly used molecular marker of the cancer stem cells (CSCs) that maintain tumor progression and recurrence in colorectal cancer. However, the proteome of CSCs directly isolated from colorectal tumors based on CD133 expression has never been investigated. OBJECTIVE To reveal biomarkers of CD133-positive colorectal CSCs. METHODS Thirty colorectal tumor samples were collected from patients undergoing bowel resection. CD133-positive and CD133-negative cells were isolated by FACS. Comparative proteomic profiling was performed by LC-MS/MS analysis combined with label-free quantification. Verification of differentially expressed proteins was performed by flow cytometry or ELISA. CD133-knockout Caco-2 and HT-29 cell lines were generated using CRISPR-Cas9 gene editing. RESULTS LC-MS/MS analysis identified 29 proteins with at least 2.5-fold higher expression in CD133-positive cells versus CD133-negative cells. Flow cytometry confirmed CEACAM5 overexpression in CD133-positive cells in all clinical samples analyzed. S100A8, S100A9, and DEFA1 were differentially expressed in only a proportion of the samples. CD133 knockout in the colon cancer cell lines Caco-2 and HT-29 did not affect the median level of CEACAM5 expression, but led to higher variance of the percentage of CEACAM5-positive cells. CONCLUSIONS High CEACAM5 expression in colorectal cancer cells is firmly associated with the CD133-positive colorectal CSC phenotype, but it is unlikely that CD133 directly regulates CEACAM5 expression.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Svetlana Novikova
- Laboratory of Systems Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Yan Kim
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Dmitry Sidorov
- Department of Abdominal Surgery, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Stanislav Bykasov
- Department of Abdominal Surgery, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Nadezhda Volchenko
- Department of Oncomorphology, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Andrey Kaprin
- P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Victor Zgoda
- Laboratory of Systems Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Konstantin Yarygin
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
| | - Alexey Lupatov
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, Moscow, Russia
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Tampakis A, Tampaki EC, Nonni A, Kontos M, Tsourouflis G, Posabella A, Fourie L, Bolli M, Kouraklis G, von Flüe M, Felekouras E, Nikiteas N. MAP17 Expression in Colorectal Cancer Is a Prognostic Factor for Disease Recurrence and Dismal Prognosis Already in Early Stage Disease. Oncology 2021; 99:471-482. [PMID: 33853080 DOI: 10.1159/000515596] [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: 11/26/2020] [Accepted: 02/23/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Disease recurrence in colorectal cancer constitutes a major cause of significant cancer-associated morbidity and mortality. MAP17 is a small protein, and its overexpression in malignant tumors has been correlated with aggressive tumor phenotypes. The aim of the present study was to investigate the expression patterns of MAP17 in colorectal cancer specimens and to assess its clinical significance. PATIENTS AND METHODS Surgical specimens of 111 patients with primary resectable colorectal cancer constituted the study population. Expression of MAP17 was assessed by immunohistochemistry, and the results were correlated with clinical and survival data. RESULTS MAP17 was expressed in cancer cells and endothelial cells of tumor blood vessels. Expression of MAP17 more than 10% was correlated with advanced disease stage (p < 0.001), higher T classification (p = 0.007), the presence of lymph node metastasis (p < 0.001), vascular (p = 0.013) and perineural invasion (p = 0.012). Patients exhibiting MAP17 expression of more than 30% in cancer cells compared to those expressing MAP17 less than 10% demonstrated a significantly worse 3-year progression-free survival (35.2 vs. 91%, p < 0.001) and 5-year overall survival (40.8 vs. 91%, p < 0.001). Cox regression analysis confirmed MAP17 expression of more than 30% as a prognostic marker of progression free survival (HR 0.136, 95% CI = 0.056-0.329, p < 0.001) and overall survival (HR 0.144 [95% CI) = 0.049-0.419, p < 0.001) independent of other clinicopathological characteristics. Statistically significantly worse 3-year progression-free survival and 5-year overall survival was demonstrated in the subgroup analysis of patients with early stage cancer only and high expression of MAP17. CONCLUSIONS High MAP17 expression in patients with colorectal cancer is a significant risk factor for cancer-associated morbidity and mortality already in early stage disease.
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Affiliation(s)
- Athanasios Tampakis
- Clarunis, University Center for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland.,2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Ekaterini Christina Tampaki
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Afroditi Nonni
- 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Kontos
- 1st Department of Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Gerasimos Tsourouflis
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Alberto Posabella
- Clarunis, University Center for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Lana Fourie
- Clarunis, University Center for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Martin Bolli
- Clarunis, University Center for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Gregory Kouraklis
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Markus von Flüe
- Clarunis, University Center for Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital of Basel, Basel, Switzerland
| | - Evangelos Felekouras
- 1st Department of Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Nikolaos Nikiteas
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
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10
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Kim J, Choi KW, Lee J, Lee J, Lee S, Sun R, Kim J. Wnt/β-catenin Signaling Inhibitors suppress the Tumor-initiating properties of a CD44 +CD133 + subpopulation of Caco-2 cells. Int J Biol Sci 2021; 17:1644-1659. [PMID: 33994850 PMCID: PMC8120464 DOI: 10.7150/ijbs.58612] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 03/26/2021] [Indexed: 01/15/2023] Open
Abstract
Tumor-initiating cells or cancer stem cells are a subset of cancer cells that have tumorigenic potential in human cancer. Although several markers have been proposed to distinguish tumor-initiating cells from colorectal cancer cells, little is known about how this subpopulation contributes to tumorigenesis. Here, we characterized a tumor-initiating cell subpopulation from Caco-2 colorectal cancer cells. Based on the findings that Caco-2 cell subpopulations express different cell surface markers, we were able to discriminate three main fractions, CD44-CD133-, CD44-CD133+, and CD44+CD133+ subsets, and characterized their biochemical and tumorigenic properties. Our results show that CD44+CD133+ cells possessed an unusual capacity to proliferate and could form tumors when transplanted into NSG mice. Additionally, primary tumors grown from CD44+CD133+ Caco-2 cells contained mixed populations of CD44+CD133+ and non-CD44+CD133+ Caco-2 cells, indicating that the full phenotypic heterogeneity of the parental Caco-2 cells was re-created. Notably, only the CD44+CD133+ subset of Caco-2-derived primary tumors had tumorigenic potential in NSG mice, and the tumor growth of CD44+CD133+ cells was faster in secondary xenografts than in primary transplants. Gene expression analysis revealed that the Wnt/β-catenin pathway was over-activated in CD44+CD133+ cells, and the growth and tumorigenic potential of this subpopulation were significantly suppressed by small-molecule Wnt/β-catenin signaling inhibitors. Our findings suggest that the CD44+CD133+ subpopulation from Caco-2 cells was highly enriched in tumorigenic cells and will be useful for investigating the mechanisms leading to human colorectal cancer development.
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Affiliation(s)
| | | | | | | | | | | | - Jungho Kim
- Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul 04107, Korea
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11
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Yu ZL, Chen YF, Zheng B, Cai ZR, Zou YF, Ke J, Lan P, Gao F, Wu XJ. Protein-protein interaction analysis reveals a novel cancer stem cell related target TMEM17 in colorectal cancer. Cancer Cell Int 2021; 21:94. [PMID: 33549114 PMCID: PMC7868027 DOI: 10.1186/s12935-021-01794-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/27/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/β-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).
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Affiliation(s)
- Zhao-Liang Yu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China
| | - Yu-Feng Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China
| | - Bin Zheng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Ze-Rong Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China
| | - Yi-Feng Zou
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China
| | - Jia Ke
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Feng Gao
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangzhou, China.
| | - Xiao-Jian Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangzhou, China.
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12
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AlMusawi S, Ahmed M, Nateri AS. Understanding cell-cell communication and signaling in the colorectal cancer microenvironment. Clin Transl Med 2021; 11:e308. [PMID: 33635003 PMCID: PMC7868082 DOI: 10.1002/ctm2.308] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/31/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
Carcinomas are complex heterocellular systems containing epithelial cancer cells, stromal fibroblasts, and multiple immune cell-types. Cell-cell communication between these tumor microenvironments (TME) and cells drives cancer progression and influences response to existing therapies. In order to provide better treatments for patients, we must understand how various cell-types collaborate within the TME to drive cancer and consider the multiple signals present between and within different cancer types. To investigate how tissues function, we need a model to measure both how signals are transferred between cells and how that information is processed within cells. The interplay of collaboration between different cell-types requires cell-cell communication. This article aims to review the current in vitro and in vivo mono-cellular and multi-cellular cultures models of colorectal cancer (CRC), and to explore how they can be used for single-cell multi-omics approaches for isolating multiple types of molecules from a single-cell required for cell-cell communication to distinguish cancer cells from normal cells. Integrating the existing single-cell signaling measurements and models, and through understanding the cell identity and how different cell types communicate, will help predict drug sensitivities in tumor cells and between- and within-patients responses.
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Affiliation(s)
- Shaikha AlMusawi
- Cancer Genetics & Stem Cell Group, BioDiscovery Institute, Division of Cancer & Stem Cells, School of MedicineUniversity of NottinghamNottinghamUK
| | - Mehreen Ahmed
- Cancer Genetics & Stem Cell Group, BioDiscovery Institute, Division of Cancer & Stem Cells, School of MedicineUniversity of NottinghamNottinghamUK
- Department of Laboratory Medicine, Division of Translational Cancer ResearchLund UniversityLundSweden
| | - Abdolrahman S. Nateri
- Cancer Genetics & Stem Cell Group, BioDiscovery Institute, Division of Cancer & Stem Cells, School of MedicineUniversity of NottinghamNottinghamUK
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13
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Yoon C, Lu J, Yi BC, Chang KK, Simon MC, Ryeom S, Yoon SS. PI3K/Akt pathway and Nanog maintain cancer stem cells in sarcomas. Oncogenesis 2021; 10:12. [PMID: 33468992 PMCID: PMC7815726 DOI: 10.1038/s41389-020-00300-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022] Open
Abstract
The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)-Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination reduced tumor growth by 74%. Using a human phospho-kinase antibody array, Akt1/2 signaling, known to regulate Nanog, was found to be highly activated in sarcoma spheroid cells compared with monolayer cells. Pharmacologic inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs decreased Nanog expression and spheroid formation and reversed chemotherapy resistance. Akt1/2 inhibition combined with doxorubicin treatment of HT1080 flank xenografts reduced tumor growth by 73%. Finally, in a human sarcoma tumor microarray, expression of CD133, Nanog, and phospho-Akt were 1.8- to 6.8-fold higher in tumor tissue compared with normal tissue. Together, these results indicate that the Akt1/2-Nanog pathway is critical for maintenance of sarcoma CSCs and spheroid-forming cells, supporting further exploration of this pathway as a therapeutic target in sarcoma.
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Affiliation(s)
- Changhwan Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jun Lu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian, China
| | - Brendan C Yi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin K Chang
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sandra Ryeom
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sam S Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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14
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Fujiwara-Tani R, Sasaki T, Fujii K, Luo Y, Mori T, Kishi S, Mori S, Matsushima-Otsuka S, Nishiguchi Y, Goto K, Kawahara I, Kondoh M, Sho M, Kuniyasu H. Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma. Oncotarget 2020; 11:2982-2994. [PMID: 32821344 PMCID: PMC7415403 DOI: 10.18632/oncotarget.27674] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/20/2020] [Indexed: 12/17/2022] Open
Abstract
High morbidity and mortality of cancer, especially colorectal cancer (CRC), in diabetic patients have been reported. In this study, we investigated the relationship between the presence of diabetes mellitus (blood hemoglobin A1C was 6.5% or higher at the time of diagnosis of CRC) and the progression and liver metastasis of CRC. Histopathological findings in the primary lesions, which were preferential to diabetes-complicated CRC (DM-CRC) and the liver metastasis, were also investigated. Of the 473 CRC patients who underwent curative surgical resection, 148 (31%) had diabetes. In DM-CRC cases, the stage was more advanced, with more cases in stage IV or postoperative disease recurrence. Histopathological findings correlated with liver metastasis in DM-CRC, including budding grade, perineural invasion, and myxomatous tumor stroma, and all were highly correlated with the stage. Additionally, myxomatous stroma showed the strongest correlation with liver metastasis in multivariate analysis. Myxomatous stroma in stage III cases correlated with liver recurrence. The myxomatous stroma was abundant in biglycan protein and contained numerous CD90-positive mesenchymal stem cells (MSCs). In human colon cancer cell line HT29, biglycan expression was induced by high sugar concentration, fatty acids, and insulin, and its contact co-culture with MSCs resulted in enhanced stemness and epithelial-mesenchymal transition phenotype. Thus, DM-CRC has higher malignant phenotypes compared to non-DM-CRC, and the involvement of diabetes-induced biglycan may act as a pathogenic factor.
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Affiliation(s)
- Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Takamitsu Sasaki
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kiyomu Fujii
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yi Luo
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Takuya Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | | | - Yukiko Nishiguchi
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kei Goto
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Isao Kawahara
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Masuo Kondoh
- Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
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15
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Zhang B, Wang HY, Wang DX, Zeng Q, Fan Z, Xi JF, Nan X, He LJ, Zhou JN, Pei XT, Yue W. A new protocol for long-term culture of a specific subpopulation of liver cancer stem cells enriched by cell surface markers. FEBS Open Bio 2020; 10:1737-1747. [PMID: 32662250 PMCID: PMC7459405 DOI: 10.1002/2211-5463.12932] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/01/2020] [Accepted: 07/10/2020] [Indexed: 01/02/2023] Open
Abstract
Liver cancer stem cells (L‐CSCs) are considered to be an important therapeutic target for hepatocellular carcinoma (HCC). This study provides a new in vitro long‐term culture model for a specific subpopulation of L‐CSCs enriched by cell surface markers. We combined CD13, CD133 and EpCAM to selectively enrich L‐CSCs, which we then cultured in modified chemically defined medium. The enriched L‐CSCs exhibited enhanced proliferation, self‐renewal and long‐term clonal maintenance ability as compared with non‐CSCs. Compared with wild‐type hepatocellular carcinoma, the expression of stemness surface markers, oncogenes, drug resistance and tumorigenicity in enriched L‐CSCs was significantly increased. In summary, the subpopulation of L‐CSCs still maintains cancer stem cell‐related phenotypes after 14 days of culture.
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Affiliation(s)
- Biao Zhang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Hai-Yang Wang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Dong-Xing Wang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Quan Zeng
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Zeng Fan
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Jia-Fei Xi
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Xue Nan
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Li-Juan He
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Jun-Nian Zhou
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China.,Experimental Hematology and Biochemistry Lab, Beijing Institute of Radiation Medicine, Beijing, China
| | - Xue-Tao Pei
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
| | - Wen Yue
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing, China.,South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou, China
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16
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Zheng W, Yang C, Qiu L, Feng X, Sun K, Deng H. Transcriptional information underlying the generation of CSCs and the construction of a nine-mRNA signature to improve prognosis prediction in colorectal cancer. Cancer Biol Ther 2020; 21:688-697. [PMID: 32453965 PMCID: PMC7515529 DOI: 10.1080/15384047.2020.1762419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Despite recent progress in screening survival-related genes, there have been few attempts to apply methods based on cancer stem cells (CSCs) for prognosis. We aimed to identify a CSC-based model to predict survival in colorectal cancer (CRC) patients. MATERIAL/METHODS Differentially expressed genes between CRC and normal tissues and between CD133- and CD133+ cells were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, and intersections were evaluated. Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyzes were performed. STRING was used to investigate interactions between the encoded proteins and the Kaplan-Meier method to verify mRNAs associated with survival. A prognostic model based on CSCs was established via univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was conducted to test the model's sensitivity and specificity. The KS test was applied to provide evidence for relationships between expression levels of nine mRNAs in our model and pathological stage. RESULTS In total, 155 common differentially expressed mRNAs were identified, and nine (AOC1, UCN, MTUS1, CDC20, SNCB, MAT1A, TUBB2B, GABRA4 and ALPP) were screened after regression analyses to establish a predictive model for classifying patients into high- and low-risk groups with significantly different overall survival times, especially for stage II and IV patients. CONCLUSIONS We developed a novel model that provides additional and powerful prognostic information beyond conventional clinicopathological factors for CRC survival prediction. It also provides new insight into the molecular mechanisms underlying the transition from normal tissues to CSCs and formation of tumor tissues.
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Affiliation(s)
- Wenbo Zheng
- Department of General Surgery, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
| | - Chunzhao Yang
- Department of General Surgery, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
| | - Ling Qiu
- Department of General Surgery, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
| | - Xiaochuang Feng
- Department of General Surgery, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
| | - Kai Sun
- Department of General Surgery, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
| | - Haijun Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University , Guangzhou, Guangdong, China
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17
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Mohd-Zahid MH, Mohamud R, Che Abdullah CA, Lim J, Alem H, Wan Hanaffi WN, Z. A. I. Colorectal cancer stem cells: a review of targeted drug delivery by gold nanoparticles. RSC Adv 2020. [DOI: 10.1039/c9ra08192e] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The proposed schematic mechanismviawhich 5-fluorouracil-loaded gold nanoparticles conjugated with CD133 antibody target colorectal cancer stem cells.
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Affiliation(s)
- Manali Haniti Mohd-Zahid
- Department of Chemical Pathology
- School of Medical Sciences
- Universiti Sains Malaysia
- 16150 Kubang Kerian
- Malaysia
| | - Rohimah Mohamud
- Department of Immunology
- School of Medical Sciences
- Universiti Sains Malaysia
- 16150 Kubang Kerian
- Malaysia
| | | | - JitKang Lim
- School of Chemical Engineering
- Universiti Sains Malaysia
- 14300 Nibong Tebal
- Malaysia
| | - Halima Alem
- Institut Jean Lamour (IJL, UMR 7198)
- Université de Lorraine
- CNRS
- F-54011 Nancy Cedex
- France
| | | | - Iskandar Z. A.
- Department of Chemical Pathology
- School of Medical Sciences
- Universiti Sains Malaysia
- 16150 Kubang Kerian
- Malaysia
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18
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Yang Y, Nguyen TT, Pereira I, Hur JS, Kim H. Lichen Secondary Metabolite Physciosporin Decreases the Stemness Potential of Colorectal Cancer Cells. Biomolecules 2019; 9:E797. [PMID: 31795147 PMCID: PMC6995618 DOI: 10.3390/biom9120797] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 11/24/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
Secondary metabolites of lichens are promising bioresources for candidate anti-cancer drugs. Accordingly, several approaches have been proposed for screening these molecules for novel anti-cancer lead compounds. In this study, we found that a non-toxic concentration of physciosporin, a compound isolated from Pseudocyphellaria granulata, significantly decreased colony formation on soft agar and spheroid formation by CSC221 cancer stem-like cells. Physciosporin also decreased spheroid formation in other colorectal cancer cell lines, including DLD1, Caco2, and HT29. Aldehyde dehydrogenase-1 (ALDH1), the most important cancer stem marker, was sharply downregulated at both the protein and mRNA level following treatment with physciosporin. Physciosporin also decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli), as well as the Hes1 and CSL promoters, in reporter assays. Moreover, the drug significantly suppressed spheroid formation in CSC221 cells overexpressing Gli1/2 or EN1 (an S2-cleaved but membrane-tethered form of human Notch1) but did not suppress spheroid formation in cells overexpressing both Gli1/2 and ∆EN1, suggesting that physciosporin suppresses colon cancer cell stemness through the Sonic hedgehog and Notch signaling pathways. Together, these results demonstrate for the first time that physciosporin is a potent inhibitor of colorectal cancer cell stemness.
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Affiliation(s)
- Yi Yang
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Korea; (Y.Y.); (T.T.N.)
- Korean Lichen Research Institute, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Korea;
- Department of Pharmacology, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Korea
| | - Thanh Thi Nguyen
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Korea; (Y.Y.); (T.T.N.)
- Korean Lichen Research Institute, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Korea;
- Faculty of Natural Science and Technology, Tay Nguyen University, Buon Ma Thout 630000, Vietnam
| | - Iris Pereira
- Institute of Biological Sciences, Universidad de Talca, Talca 747-721, Chile;
| | - Jae-Seoun Hur
- Korean Lichen Research Institute, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Korea;
| | - Hangun Kim
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Korea; (Y.Y.); (T.T.N.)
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19
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Nallanthighal S, Heiserman JP, Cheon DJ. The Role of the Extracellular Matrix in Cancer Stemness. Front Cell Dev Biol 2019; 7:86. [PMID: 31334229 PMCID: PMC6624409 DOI: 10.3389/fcell.2019.00086] [Citation(s) in RCA: 233] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 05/03/2019] [Indexed: 12/12/2022] Open
Abstract
As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called "cancer stem cells" (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.
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Affiliation(s)
| | | | - Dong-Joo Cheon
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
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20
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Shahid A, Bharadwaj M. The connection between the Th17 cell related cytokines and cancer stem cells in cancer: Novel therapeutic targets. Immunol Lett 2019; 213:9-20. [PMID: 31278971 DOI: 10.1016/j.imlet.2019.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/25/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
Abstract
Cancer Stem Cells (CSCs) are the subpopulation of cells present in the different types of cancers with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. The research work on the CSC has been providing a promising approach for the improvement of cancer therapies in the future. The CSCs have a close connection with the cytokines related with the T helper 17 (Th17) cell and other factors present in the tumor microenvironment, and these play a pivotal role in tumor progression and metastasis. The properties of CSCs are well defined in various type of tumor which is mainly developed by chemically and spontaneously in murine cancer model but in human defined primarily on acute myeloid leukemia, glioma, and breast cancer. The role of Th1, Th2, Natural Killer cells are well described in the cancer biology, but the Th17 cells are the subset which is recently exploited, and lots of research are going on. In this Review, we summarize current findings of the characteristics and functions of the Th17 cell and its signature cytokines in different cancers and their interconnections with cancer stem cells and with their markers. We have also discussed the functional properties of CSCs and how the CSCs markers can be distinguished from normal stem cells markers. We have also talked about the strategies that are efficiently targeting of CSCs and Th17 cells in different cancers.
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Affiliation(s)
- Ayaz Shahid
- Molecular Biology Group, National Institute of Cancer Prevention and Research, Indian Council of Medical Research (ICMR), Department of Health Research, Noida, 201301, India
| | - Mausumi Bharadwaj
- Molecular Biology Group, National Institute of Cancer Prevention and Research, Indian Council of Medical Research (ICMR), Department of Health Research, Noida, 201301, India.
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Tang Z, Ma H, Mao Y, Ai S, Zhang P, Nie C, Gao Y, Lu R. Identification of stemness in primary retinoblastoma cells by analysis of stem-cell phenotypes and tumorigenicity with culture and xenograft models. Exp Cell Res 2019; 379:110-118. [DOI: 10.1016/j.yexcr.2019.03.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/14/2019] [Accepted: 03/27/2019] [Indexed: 10/27/2022]
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22
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Capture and Analysis of Cell Surface N-Glycans by Hydrazide-Modified Magnetic Beads and CE-LIF. Chromatographia 2019. [DOI: 10.1007/s10337-019-03742-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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23
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Tampakis A, Tampaki EC, Nonni A, Droeser R, Posabella A, Tsourouflis G, Kontzoglou K, Patsouris E, von Flüe M, Kouraklis G. Nectin-1 Expression in Colorectal Cancer: Is There a Group of Patients with High Risk for Early Disease Recurrence? Oncology 2019; 96:318-325. [PMID: 30917374 DOI: 10.1159/000499569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/07/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes. OBJECTIVES The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance. METHODS Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study. RESULTS Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47-70, vs. 82.1%, 95% CI = 69-93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156-0.972, p = 0.043). CONCLUSION Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence.
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Affiliation(s)
- Athanasios Tampakis
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland, .,2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece,
| | - Ekaterini Christina Tampaki
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Afroditi Nonni
- 1st Department of Pathology, School of Medicine, National University of Athens, Athens, Greece
| | - Raoul Droeser
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Alberto Posabella
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Gerasimos Tsourouflis
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Konstantinos Kontzoglou
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Efstratios Patsouris
- 1st Department of Pathology, School of Medicine, National University of Athens, Athens, Greece
| | - Markus von Flüe
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Gregory Kouraklis
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
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Khelwatty SA, Essapen S, Bagwan I, Green M, Seddon AM, Modjtahedi H. Co-expression and prognostic significance of putative CSC markers CD44, CD133, wild-type EGFR and EGFRvIII in metastatic colorectal cancer. Oncotarget 2019; 10:1704-1715. [PMID: 30899442 PMCID: PMC6422200 DOI: 10.18632/oncotarget.26722] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/15/2019] [Indexed: 12/24/2022] Open
Abstract
The presence of colorectal cancer stem cells (CSCs) have been associated with tumour initiation and resistance to therapy. This study investigated the co-expression and prognostic significance of the CSCs biomarkers CD44 and CD133 with wild-type EGFR (wtEGFR) and EGFRvIII in colorectal cancer (CRC). The expression of these biomarkers were determined in tumours from 70 patients with metastatic CRC by immunohistochemistry, and in a panel of human CRC cell lines, and their variants with acquired-resistance to EGFR inhibitors, by flow cytometry. The expression of CD44, CD133, wtEGFR and EGFRvIII were present in 17%, 23%, 26% and 13% of cases and the co-expression of CD44/CD133 with wtEGFR and EGFRvIII were present in 9% and 3% of the cases respectively. Only co-expression of CSCs/EGFRvIII (P = 0.037), and amphiregulin (P = 0.017) were associated with worse overall survival. Interestingly, disease-free survival was improved in BTC expressing patients (P = 0.025). In vitro CD133 expression and its co-expression with CD44 were associated with primary-resistance to irinotecan and acquired-resistance to anti-EGFR inhibitors respectively. Our results suggest co-expression of CSCs and EGFRvIII could be potential biomarkers of worse overall survival and resistance to therapy in patients with mCRC and warrants further validation in a larger cohort.
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Affiliation(s)
| | - Sharadah Essapen
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK.,St. Luke's Cancer Centre, Royal Surrey County Hospital, Guildford, Surrey, UK
| | - Izhar Bagwan
- Department of Histopathology, Royal Surrey County Hospital, Guildford, Surrey, UK
| | - Margaret Green
- Department of Histopathology, Royal Surrey County Hospital, Guildford, Surrey, UK
| | - Alan M Seddon
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK
| | - Helmout Modjtahedi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston, UK
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25
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Zhang HL, Wang P, Lu MZ, Zhang SD, Zheng L. c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells. Oncol Lett 2019; 17:4487-4493. [PMID: 30944638 PMCID: PMC6444394 DOI: 10.3892/ol.2019.10081] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 12/18/2018] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) are responsible for cancer formation, recurrence and drug resistance. c-Myc, one of the core markers for stem cells, has recently been considered to serve as a link between malignancy and ‘stemness’. However, the precise function of c-Myc in colon CSCs is still unclear. In the present study, a subpopulation of colon CSCs expressing a CD133 surface phenotype was isolated from the human HT-29 cell line, which possess greater tumor sphere-forming efficiency and have higher expression of ‘stemness’-associated genes compared with CD133-negative cells. Furthermore, it was demonstrated that c-Myc was highly expressed in CD133+ colon CSCs. Knockdown of c-Myc expression with small interfering RNA in colon CSCs can significantly inhibit tumor sphere formation, reduce the invasive and migratory capacity of CD133+ cells in vitro, and suppress the tumorigenicity of colon CSCs in vivo. In addition, it was suggested that c-Myc silencing may sensitize colon CSCs to chemotherapy-induced cytotoxicity via the downregulation of ABCG2 and ABCB5. These findings support a central role for c-Myc in maintaining the self-renewing and chemoresistant properties of colon CSCs.
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Affiliation(s)
- Huan-Le Zhang
- Department of Oncology, Lihuili Hospital of Ningbo Medical Center, Ningbo, Zhejiang 315000, P.R. China
| | - Ping Wang
- Department of Molecular Biology, Ningbo University School of Medicine, Ningbo, Zhejiang 315000, P.R. China
| | - Miao-Zhen Lu
- Department of Oncology, Lihuili Hospital of Ningbo Medical Center, Ningbo, Zhejiang 315000, P.R. China
| | - San-Dian Zhang
- Department of Oncology, Lihuili Hospital of Ningbo Medical Center, Ningbo, Zhejiang 315000, P.R. China
| | - Lu Zheng
- Department of Oncology, Lihuili Hospital of Ningbo Medical Center, Ningbo, Zhejiang 315000, P.R. China
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MEK5/ERK5 activation regulates colon cancer stem-like cell properties. Cell Death Discov 2019; 5:68. [PMID: 30774996 PMCID: PMC6370793 DOI: 10.1038/s41420-019-0150-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/21/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023] Open
Abstract
Colon cancer has been proposed to be sustained by a small subpopulation of stem-like cells with unique properties allowing them to survive conventional therapies and drive tumor recurrence. Identification of targetable signaling pathways contributing to malignant stem-like cell maintenance may therefore translate into new therapeutic strategies to overcome drug resistance. Here we demonstrated that MEK5/ERK5 signaling activation is associated with stem-like malignant phenotypes. Conversely, using a panel of cell line-derived three-dimensional models, we showed that ERK5 inhibition markedly suppresses the molecular and functional features of colon cancer stem-like cells. Particularly, pharmacological inhibition of ERK5 using XMD8-92 reduced the rate of primary and secondary sphere formation, the expression of pluripotency transcription factors SOX2, NANOG, and OCT4, and the proportion of tumor cells with increased ALDH activity. Notably, this was further associated with increased sensitivity to 5-fluorouracil-based chemotherapy. Mechanistically, ERK5 inhibition resulted in decreased IL-8 expression and NF-κB transcriptional activity, suggesting a possible ERK5/NF-κB/IL-8 signaling axis regulating stem-like cell malignancy. Taken together, our results provide proof of principle that ERK5-targeted inhibition may be a promising therapeutic approach to eliminate drug-resistant cancer stem-like cells and improve colon cancer treatment.
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27
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Abbasian M, Baharlouei A, Arab-Bafrani Z, Lightfoot DA. Combination of gold nanoparticles with low-LET irradiation: an approach to enhance DNA DSB induction in HT29 colorectal cancer stem-like cells. J Cancer Res Clin Oncol 2019; 145:97-107. [PMID: 30341685 DOI: 10.1007/s00432-018-2769-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 10/11/2018] [Indexed: 01/05/2023]
Abstract
PURPOSE High-linear energy transfer (high LET) irradiation has significant cytotoxic effects on different cancerous stem-like cells (CSLCs) such as colorectal CSLCs. A review of the literature has indicated that the presence of gold nanoparticles (GNPs) enables low-LET irradiation to produce highly non-homogeneous dose distributions like high-LET irradiation. The purpose of this study was to evaluate the radioresponsiveness of HT29 colorectal CSLCs under low-LET irradiation (X-ray) and in the presence of GNPs. METHODS Radioresponsiveness was evaluated using the ϒ-H2AX foci formation assay, the clonogenic assay, the cell cycle progression assay and analyses of radiobiological parameters. RESULTS In the presence of GNPs, the survival fraction of HT29 CSLCs was significantly reduced and caused significant changes in the radiobiological parameters after irradiation. In addition, ϒ-H2AX assay showed that in the presence of GNPs, the persistent DNA double-strand breaks were significantly increased in irradiated HT29 CSLCs. The relative biological effectiveness value of GNPs with X-rays was about 1.6 for HT-29 CSLCs at the 10% of cell survival fraction (D10 level) when compared to X-rays alone. CONCLUSION Therefore, the combination of GNPs with X-ray irradiation has the potential to kill HT29 CSLCs greater than the X-ray alone, and may be considered as an alternative for high-LET irradiation.
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Affiliation(s)
- Mahdi Abbasian
- Stem Cell Research Center, Golestan University of Medical Science, Gorgān, Iran
- Department of Biotechnology, College of Agriculture, Isfahan University of Technology, Isfahan, Iran
| | - Azam Baharlouei
- Department of Biotechnology, College of Agriculture, Isfahan University of Technology, Isfahan, Iran
- Department of Microbiology, Southern Illinois University at Carbondale, Carbondale, IL, 62901, USA
| | - Zahra Arab-Bafrani
- Stem Cell Research Center, Golestan University of Medical Science, Gorgān, Iran.
- Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgān, Iran.
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgān, Iran.
| | - David A Lightfoot
- Department of Plant, Soil and Agricultural Systems, Plant Biotechnology and Genome Core-Facility, Southern Illinois University at Carbondale, Carbondale, IL, 62901, USA
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28
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Lang T, Ding X, Kong L, Zhou X, Zhang Z, Ju H, Ding S. NFATC2 is a novel therapeutic target for colorectal cancer stem cells. Onco Targets Ther 2018; 11:6911-6924. [PMID: 30410349 PMCID: PMC6199214 DOI: 10.2147/ott.s169129] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Colorectal cancer stem cells (CRC-SCs) contribute to the initiation and progression of colorectal cancer (CRC). However, the underlying mechanisms for the propagation of CRC-SCs have remained elusive. Purpose The objective of this study was to study the role of NFATC2 in maintenance of the stemness in CRC-SCs. Method The expression levels of mRNA and protein were determined by qRT-PCR and western-blot, respectively. CRC-SCs were isolated by spheroid formation assay and flowcytometry. The sphere-forming and self-renewal abilities of CRC-SCs were determined by spheroid formation assay. The tumorigenicity of CRC-SCs was determined by cell-derived xenograft model. Gene manipulation was performed by lentivirus-mediated delivery system. Results We first found that NFATC2 is upregulated in primary CRC-SCs. Overexpression of NFATC2 promotes self-renewal and the expression of stem cell markers of CRC-SCs. Conversely, knockdown of NFATC2 attenuates stem cell-like properties of CRC-SCs. Mechanistic analysis indicated that NFATC2 upregulates the expression of AJUBA, downregulates the phosphorylation level of YAP, and therefore activates the transcriptional activities of YAP and promotes the stemness of CRC-SCs. Conclusion Our findings demonstrate NFATC2 as an oncogene that can promote the stemness of CRC-SCs. This work suggests a novel therapeutic strategy against CRC caused by aberrant expression of NFATC2.
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Affiliation(s)
- Tingyuan Lang
- Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education of China), Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China, ,
| | - Xiaojuan Ding
- Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education of China), Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China, ,
| | - Liangsheng Kong
- Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education of China), Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China, ,
| | - Xiaoyan Zhou
- Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education of China), Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China, ,
| | - Zhiqi Zhang
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, People's Republic of China
| | - Huangxian Ju
- Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education of China), Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China, , .,State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, People's Republic of China,
| | - Shijia Ding
- Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education of China), Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China, ,
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Hosea R, Hardiany NS, Ohneda O, Wanandi SI. Glucosamine decreases the stemness of human ALDH + breast cancer stem cells by inactivating STAT3. Oncol Lett 2018; 16:4737-4744. [PMID: 30214607 PMCID: PMC6126220 DOI: 10.3892/ol.2018.9222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells responsible for tumor maintenance and relapse due to their ability to resist various anticancer effects. Owing to the resistance of CSCs to the effects of targeted therapy, an alternative strategy that targets post-translational glycosylation may be an improved approach to treat cancer as it disrupts multiple coordinated signaling that maintains the stemness of CSCs. Glucosamine acts as an anticancer agent possibly by inhibiting N-linked glycosylation. The aim of the present study was to investigate the effect of glucosamine on the stemness of breast CSCs, which is regulated by signal transducer and activator of transcription 3 (STAT3) signaling. Human aldehyde dehydrogenase-positive (ALDH+) breast CSCs and MCF7 cells were treated with various concentrations (0.25, 1 or 4 mM) of glucosamine for 24 h. Subsequently, cell viability was determined by performing a trypan blue exclusion assay, pluripotency gene [ALDH 1 family member A1 (ALDH1A1), octamer-binding transcription factor 4 (OCT-4), and Krüppel-like factor 4 (KLF4)] expression was determined using the reverse transcription-quantitative polymerase chain reaction, and STAT3 and phosphorylated STAT3 (pSTAT3) levels were determined by performing western blot analysis. Furthermore, the number of mammosphere-forming units (MFUs) in ALDH+ breast CSCs and MCF7 cells was determined. It was determined that glucosamine treatment decreased the viability of ALDH+ breast CSCs. Glucosamine treatment also decreased the stemness of ALDH+ breast CSCs and MCF7 cells, as indicated by decreased ALDH1A1, OCT-4 and KLF4 expression level, and a decreased number of MFUs. This effect of glucosamine may be associated with a decreased pSTAT3/STAT3 ratio, indicating that glucosamine inhibited STAT3 activation; therefore, the results of the present study indicated that glucosamine treatment may be an improved approach to target the stemness of CSCs.
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Affiliation(s)
- Rendy Hosea
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Novi Silvia Hardiany
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Osamu Ohneda
- Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Septelia Inawati Wanandi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
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30
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Grimes DR, Currell FJ. Oxygen diffusion in ellipsoidal tumour spheroids. J R Soc Interface 2018; 15:20180256. [PMID: 30111663 PMCID: PMC6127169 DOI: 10.1098/rsif.2018.0256] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/23/2018] [Indexed: 01/09/2023] Open
Abstract
Oxygen plays a central role in cellular metabolism, in both healthy and tumour tissue. The presence and concentration of molecular oxygen in tumours has a substantial effect on both radiotherapy response and tumour evolution, and as a result the oxygen micro-environment is an area of intense research interest. Multi-cellular tumour spheroids closely mimic real avascular tumours, and in particular they exhibit physiologically relevant heterogeneous oxygen distribution. This property has made them a vital part of in vitro experimentation. For ideal spheroids, their heterogeneous oxygen distributions can be predicted from theory, allowing determination of cellular oxygen consumption rate (OCR) and anoxic extent. However, experimental tumour spheroids often depart markedly from perfect sphericity. There has been little consideration of this reality. To date, the question of how far an ellipsoid can diverge from perfect sphericity before spherical assumptions break down remains unanswered. In this work, we derive equations governing oxygen distribution (and, more generally, nutrient and drug distribution) in both prolate and oblate tumour ellipsoids, and quantify the theoretical limits of the assumption that the spheroid is a perfect sphere. Results of this analysis yield new methods for quantifying OCR in ellipsoidal spheroids, and how this can be applied to markedly increase experimental throughput and quality.
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Affiliation(s)
- David Robert Grimes
- Centre for Advanced and Interdisciplinary Radiation Research (CAIRR) School of Mathematics and Physics, Queen's University Belfast, Belfast BT7 1NN, UK
- Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratory, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Frederick J Currell
- The Dalton Cumbrian Facility and School of Chemistry, University of Manchester, Westlakes Science and Technology Park, Moor Row, Whitehaven CA24 3HA, UK
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31
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Moore PA, Shah K, Yang Y, Alderson R, Roberts P, Long V, Liu D, Li JC, Burke S, Ciccarone V, Li H, Fieger CB, Hooley J, Easton A, Licea M, Gorlatov S, King KL, Young P, Adami A, Loo D, Chichili GR, Liu L, Smith DH, Brown JG, Chen FZ, Koenig S, Mather J, Bonvini E, Johnson S. Development of MGD007, a gpA33 x CD3-Bispecific DART Protein for T-Cell Immunotherapy of Metastatic Colorectal Cancer. Mol Cancer Ther 2018; 17:1761-1772. [PMID: 29866746 DOI: 10.1158/1535-7163.mct-17-1086] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 02/23/2018] [Accepted: 05/31/2018] [Indexed: 11/16/2022]
Abstract
We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART protein designed to redirect T cells to target gpA33 expressing colon cancer. The gpA33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. MGD007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 μg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33-expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD-1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 μg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together, MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer. Mol Cancer Ther; 17(8); 1761-72. ©2018 AACR.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Hua Li
- MacroGenics, Rockville, Maryland
| | | | - Jeff Hooley
- MacroGenics, South San Francisco, California
| | - Ann Easton
- MacroGenics, South San Francisco, California
| | | | | | | | - Peter Young
- MacroGenics, South San Francisco, California
| | | | - Deryk Loo
- MacroGenics, South San Francisco, California
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Slater C, De La Mare JA, Edkins AL. In vitro analysis of putative cancer stem cell populations and chemosensitivity in the SW480 and SW620 colon cancer metastasis model. Oncol Lett 2018; 15:8516-8526. [PMID: 29805588 PMCID: PMC5950524 DOI: 10.3892/ol.2018.8431] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 02/27/2018] [Indexed: 02/07/2023] Open
Abstract
The cancer stem cell (CSC) theory implicates a small subpopulation of cells with stem-like properties, which is responsible for tumour initiation, development and metastasis. The unique biological and functional characteristics of CSCs, widely associated with treatment resistance, indicate an association between metastasis and stemness. It was hypothesised that metastatic cell lines may be enriched in CSCs and that this would correlate with a more resistant tumour. In the present study, the SW480 and SW620 paired cell lines derived from a colon adenocarcinoma and its lymph node metastasis, respectively were compared as an in vitro model of cancer progression. Their chemosensitivity and CSC properties were investigated. A range of in vitro assays were performed, including the side population assay, ALDEFLUOR assay, tumoursphere assay and assessment of CSC-associated surface phenotypes. It was determined that the SW480 and SW620 cells exhibited similar growth rates, although the SW480 cells were more migratory in wound healing assays on collagen and fibronectin matrices. SW480 and SW620 cells displayed similar CSC profiles, however, SW480 cells demosntrated significantly greater tumoursphere forming efficiency over SW620 cells. Tumourspheres derived from SW480 and SW620 cells also displayed differential sensitivity to 5-fluorouracil, oxaliplatin, geldanamycin and novobiocin that was not apparent when cells were grown under adherent conditions. Taken together, these results suggest that although the two cell lines have similar levels of putative CSC populations, there are differences in their biology that cannot be explained by these CSC levels. To the best of our knowledge, this is the first study to conduct a detailed analysis of the CSC populations using multiple in vitro assays in a paired cell line model. These results have clinical relevance for the understanding of the differences between primary tumours and their metastatic counterparts.
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Affiliation(s)
- Cindy Slater
- The Biomedical Biotechnology Research Unit, Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
| | - Jo-Anne De La Mare
- The Biomedical Biotechnology Research Unit, Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
| | - Adrienne Lesley Edkins
- The Biomedical Biotechnology Research Unit, Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
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Liu B, Xu T, Xu X, Cui Y, Xing X. Biglycan promotes the chemotherapy resistance of colon cancer by activating NF-κB signal transduction. Mol Cell Biochem 2018; 449:285-294. [PMID: 29761248 DOI: 10.1007/s11010-018-3365-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 05/02/2018] [Indexed: 01/05/2023]
Abstract
Biglycan (BGN) is overexpressed in cancer stem cells of colon cancer and induces the activation of NF-κB pathway which contributes to the chemotherapy resistance of diverse cancer types. Therefore, we hypothesized that the overexpression of BGN also promoted the development of multiple drug resistance (MDR) in colon cancer via NF-κB pathway. The expression of BGN was bilaterally modulated in colon cancer cell lines HT-29 and SW-480 and the effect of treatments on the cell proliferation and resistance to 5-FU was assessed. Moreover, the role of NF-κB signaling in the BGN-mediated formation of MDR was further investigated by subjecting BGN-overexpressed SW-480 cells to the co-treatment of chemo-agents and NF-κB inhibitor, PDTC. The inhibition of BGN expression decreased the proliferation potential of HT-29 cells while the induction of BGN expression increased the potential of SW-480 cells. BGN knockdown increased HT-29 cells' sensitivity to 5-FU, represented by the lower colony number and higher apoptotic rate. To the contrary, BGN overexpression promoted the resistance of SW-480 cells to 5-FU. The effect of BGN modulation on colon cancer cells was associated with the changes in apoptosis and NF-κB pathways: BGN inhibition increased the expressions of pro-apoptosis indicators and suppressed NF-κB pathway activity while BGN overexpression had the opposite effect. It was also found that the BGN-mediated formation of MDR was impaired when NF-κB pathway was blocked. Findings outlined in the current study showed that BGN contributed to the formation of chemotherapy resistance in colon cancer cells by activating NF-κB signaling.
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Affiliation(s)
- Bin Liu
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People's Republic of China
| | - Tonghong Xu
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People's Republic of China
| | - Xinning Xu
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People's Republic of China
| | - Yuzhu Cui
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People's Republic of China
| | - Xiaojing Xing
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People's Republic of China.
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Sattiraju A, Sai KKS, Mintz A. Glioblastoma Stem Cells and Their Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1041:119-140. [PMID: 29204831 DOI: 10.1007/978-3-319-69194-7_7] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glioblastoma (GBM) is the most common primary malignant astrocytoma associated with a poor patient survival. Apart from arising de novo, GBMs also occur due to progression of slower growing grade III astrocytomas. GBM is characterized by extensive hypoxia, angiogenesis, proliferation and invasion. Standard treatment options such as surgical resection, radiation therapy and chemotherapy have increased median patient survival to 14.6 months in adults but recurrent disease arising from treatment resistant cancer cells often results in patient mortality. These treatment resistant cancer cells have been found to exhibit stem cell like properties. Strategies to identify or target these Glioblastoma Stem Cells (GSC) have proven to be unsuccessful so far. Studies on cancer stem cells (CSC) within GBM and other cancers have highlighted the importance of paracrine signaling networks within their microenvironment on the growth and maintenance of CSCs. The study of GSCs and their communication with various cell populations within their microenvironment is therefore not only important to understand the biology of GBMs but also to predict response to therapies and to identify novel targets which could stymy support to treatment resistant cancer cells and prevent disease recurrence. The purpose of this chapter is to introduce the concept of GSCs and to detail the latest findings indicating the role of various cellular subtypes within their microenvironment on their survival, proliferation and differentiation.
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Affiliation(s)
- Anirudh Sattiraju
- Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | | | - Akiva Mintz
- Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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Cyr61-positive cancer stem-like cells enhances distal metastases of pancreatic cancer. Oncotarget 2018; 7:73160-73170. [PMID: 27705906 PMCID: PMC5341970 DOI: 10.18632/oncotarget.12248] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 09/16/2016] [Indexed: 12/12/2022] Open
Abstract
Efficient inhibition of tumor metastasis after resection of primary tumors is critical for cancer therapy. We have recently shown that Cyr61 promotes growth of pancreatic ductal adenocarcinoma (PDAC) through PI3k/Akt signaling-enhanced nuclear exclusion of p27. Here, we report that administration of adeno-associated viral vectors carrying a short-hairpin interfering RNA (shRNA) for Cyr61 via pancreatic duct significantly decreased the distal tumor metastases after resection of primary pancreatic tumor in mice. Moreover, Cyr61 depletion in PDAC cells significantly inhibited the tumor sphere formation in vitro, significantly decreased the growth of the subcutaneously transplanted tumor, and significantly decreased the incidence of tumor formation after serial adoptive transplantation into NOD/SCID mice. Finally, higher Cyr61 levels were detected in the PDAC specimens from the patients with distal tumor metastasis, compared to PDAC without metastasis at diagnosis. Together, our study suggests that suppression of Cyr61 in cancer stem cell-like cells in PDAC may inhibit tumor cell metastasis after resection of the primary tumor.
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36
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Wu W, Cao J, Ji Z, Wang J, Jiang T, Ding H. Co-expression of Lgr5 and CXCR4 characterizes cancer stem-like cells of colorectal cancer. Oncotarget 2018; 7:81144-81155. [PMID: 27835894 PMCID: PMC5348382 DOI: 10.18632/oncotarget.13214] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 10/26/2016] [Indexed: 12/11/2022] Open
Abstract
Therapies designed to target cancer stem cells (CSCs) in colorectal cancer (CRC) may improve treatment outcomes. Different markers have been used to identify CSCs or CSC-like cells in CRC, but the enrichment of CSCs using these markers has yet to be optimized. We recently reported the importance of Lgr5-positive CRC cells in cancer growth. Here, we studied the possibility of using Lgr5 and CXCR4 as CSC markers for CRC. We detected high Lgr5 and CXCR4 levels in stage IV CRC specimens. Both high Lgr5 and CXCR4 levels were associated with poor prognosis in stage IV CRC patients. In vitro, Lgr5+CXCR4-, CXCR4+Lgr5- and Lgr5+CXCR4+ cells were purified in human CRC cell lines and examined for their CSC properties. We found that compared to the unsorted cells, CXCR4+Lgr5-, Lgr5+CXCR4-, and Lgr5+/CXCR4+ cells showed significantly greater cancer mass after subcutaneous transplantation, greater tumor sphere formation, higher resistance to chemotherapy, and higher incidence of tumor formation after serial adoptive transplantation into NOD/SCID mice. Taken together, our data suggest that the combined use of Lgr5 and CXCR4 may facilitate the enrichment of CSCs in CRC, and that treating Lgr5+/CXCR4+ CRC cells may improve the outcome of CRC therapy.
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Affiliation(s)
- Weidong Wu
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jun Cao
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zhengyi Ji
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jingjue Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Tao Jiang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Honghua Ding
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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Turetta M, Del Ben F, Brisotto G, Biscontin E, Bulfoni M, Cesselli D, Colombatti A, Scoles G, Gigli G, del Mercato LL. Emerging Technologies for Cancer Research: Towards Personalized Medicine with Microfluidic Platforms and 3D Tumor Models. Curr Med Chem 2018; 25:4616-4637. [PMID: 29874987 PMCID: PMC6302350 DOI: 10.2174/0929867325666180605122633] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 07/24/2017] [Accepted: 05/03/2018] [Indexed: 02/07/2023]
Abstract
In the present review, we describe three hot topics in cancer research such as circulating tumor cells, exosomes, and 3D environment models. The first section is dedicated to microfluidic platforms for detecting circulating tumor cells, including both affinity-based methods that take advantage of antibodies and aptamers, and "label-free" approaches, exploiting cancer cells physical features and, more recently, abnormal cancer metabolism. In the second section, we briefly describe the biology of exosomes and their role in cancer, as well as conventional techniques for their isolation and innovative microfluidic platforms. In the third section, the importance of tumor microenvironment is highlighted, along with techniques for modeling it in vitro. Finally, we discuss limitations of two-dimensional monolayer methods and describe advantages and disadvantages of different three-dimensional tumor systems for cell-cell interaction analysis and their potential applications in cancer management.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Loretta L. del Mercato
- Address correspondence to this author at the CNR NANOTEC - Institute of Nanotechnology c/o Campus Ecotekne, via Monteroni, 73100, Lecce, Italy; E-mail:
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Zou S, Wang C, Liu J, Wang Q, Zhang D, Zhu S, Xu S, Kang M, He S. Sox12 Is a Cancer Stem-Like Cell Marker in Hepatocellular Carcinoma. Mol Cells 2017; 40:847-854. [PMID: 29127951 PMCID: PMC5712514 DOI: 10.14348/molcells.2017.0129] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 08/15/2017] [Accepted: 08/25/2017] [Indexed: 02/07/2023] Open
Abstract
Recent studies on molecular carcinogenesis suggest that the chemo-resistance of some cancers is largely due to presence of cancer stem cells (CSCs), which affect the chemotherapy outcome for hepatocellular carcinoma (HCC). However, currently no consensus on a CSC phenotype in HCC has been obtained. Here, we examined Sox12 as a novel CSC marker in HCC. Sox12+ versus Sox12- cells were purified from HCC cell lines. The Sox12+ cells were compared with Sox12- HCC cells for tumor sphere formation, chemo-resistance, tumor formation after serial adoptive transplantations in nude mice, and the frequency of developing distal metastasis. We found that compared to Sox12- HCC cells, Sox12+ HCC cells generated significantly more tumor spheres in culture, were more chemo-resistant to cisplatin, were detected in circulation more frequently, and formed distal tumor more frequently. Moreover, Sox12 appeared to functionally contribute to the stemness of HCC cells. Thus, we conclude that Sox12 may be a novel marker for enriching CSCs in HCC.
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Affiliation(s)
- Song Zou
- Department of Interventional Oncology, the People’s Hospital of Ganzhou, Ganzhou 341000,
China
| | - Chen Wang
- Department of Oncology, the People’s Hospital of Ganzhou, Ganzhou 341000,
China
| | - Jiansheng Liu
- Department of Oncology, the People’s Hospital of Ganzhou, Ganzhou 341000,
China
| | - Qun Wang
- Department of Oncology, the Affiliated Hospital of Guilin Medical University, Guilin 541001,
China
| | - Dongdong Zhang
- Department of Oncology, the Affiliated Hospital of Guilin Medical University, Guilin 541001,
China
| | - Shengnan Zhu
- Department of Oncology, the Affiliated Hospital of Guilin Medical University, Guilin 541001,
China
| | - Shengyuan Xu
- Department of Oncology, the Affiliated Hospital of Guilin Medical University, Guilin 541001,
China
| | - Mafei Kang
- Department of Oncology, the Affiliated Hospital of Guilin Medical University, Guilin 541001,
China
| | - Shaozhong He
- Department of Oncology, the Affiliated Hospital of Guilin Medical University, Guilin 541001,
China
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Olejniczak A, Szaryńska M, Kmieć Z. In vitro characterization of spheres derived from colorectal cancer cell lines. Int J Oncol 2017; 52:599-612. [PMID: 29207035 DOI: 10.3892/ijo.2017.4206] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 10/08/2017] [Indexed: 11/06/2022] Open
Abstract
Spherical cultures (SCs) can be regarded in cancer research as a link between in vitro investigations on cancer lines and in vivo studies of tumor development. SCs are believed to mimic tumor architecture and to be enriched in cancer stem cell-like cells (CSC-like cells). In the present study we characterized colonospheres derived from colorectal cancer (CRC) cell lines, and we confirmed the ability of HCT116 and HT29 cell lines to form spheres within serum-free medium, however, the detailed analysis presented the major differences concerning their characteristics including morphology, phenotype, proliferative potential, distribution in the cell cycle phases and spherogenicity. Moreover, after we magnetically separated CD133+ and CD133- cells we could conduct the analogical analysis as we performed for the original cells. We observed that all cellular fractions unveiled sphere formation capacity, even when cultured in limited number of cells per well and only SCs originated from CD133+ fraction resembled morphologically the parental spheres. Both CD133+ and CD133- subsets derived from HCT116 line were more enriched in cells in G0/G1 phase of the cell cycle in comparison to their HT29 analogues. Additionally, proliferative potential also varied amongst all studied fractions. Surprisingly, 3-D invasion assay revealed that only HCT116-derived populations were able to migrate into extended regions of Matrigel Matrix confirming their higher aggressiveness. Our results provided comprehensive characterization of CRC cell lines culture in adherent and spherical forms and, what seems to be the most advantageous, the comparison of two distinct fractions after magnetic separation. As we found the specific features of cells presented line- and expansion mode-dependency, thus, such complete description might appear crucial before CRC lines would be involved into sophisticated assays, especially focused on potentially novel therapeutic agents targeting CSC-like cells.
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Affiliation(s)
- Agata Olejniczak
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Magdalena Szaryńska
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland
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Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review. Int J Mol Sci 2017; 18:ijms18091926. [PMID: 28880238 PMCID: PMC5618575 DOI: 10.3390/ijms18091926] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 08/30/2017] [Accepted: 09/02/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast cancer resistance protein (BRCP) through its function in xenobiotic clearance might play an important role in irinotecan resistance. With a goal to evaluate the clinical significance of ABCG2 measurements, we here review the current literature on ABCG2 in relation to irinotecan treatment in CRC patients. RESULTS Few studies have evaluated the association between ABCG2 gene or protein expression and prognosis in CRC patients. Discordant results were reported. The discrepancies might be explained by the use of different criteria for interpretation of results in the immunohistochemistry studies. Only one large study evaluated the ABCG2 protein expression and efficacy of irinotecan in mCRC (CAIRO study, n = 566). This study failed to demonstrate any correlation between ABCG2 protein expression in the primary tumor and response to irinotecan-based treatment. We recently raised questions on how to evaluate ABCG2 immunoreactivity patterns, and the results in the CAIRO study might be influenced by using a different scoring protocol than the one proposed by us. In contrast, our recent exploratory study of ABCG2 mRNA expression in 580 patients with stage III primary CRC (subgroup from the randomized PETACC-3 study) indicated that high ABCG2 tumor tissue mRNA expression might be predictive for lack of efficacy of irinotecan. CONCLUSION The biological role of ABCG2 in predicting clinical irinotecan sensitivity/resistance in CRC is uncertain. In particular, the significance of ABCG2 cellular localization needs to be established. Data concerning ABCG2 mRNA expression and prediction of adjuvant irinotecan efficacy are still sparse and need to be confirmed.
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Wahab SR, Islam F, Gopalan V, Lam AKY. The Identifications and Clinical Implications of Cancer Stem Cells in Colorectal Cancer. Clin Colorectal Cancer 2017; 16:93-102. [DOI: 10.1016/j.clcc.2017.01.011] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 11/16/2016] [Accepted: 01/13/2017] [Indexed: 12/18/2022]
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Choi SY, Kim HR, Ryu PD, Lee SY. Regulation of voltage-gated potassium channels attenuates resistance of side-population cells to gefitinib in the human lung cancer cell line NCI-H460. BMC Pharmacol Toxicol 2017. [DOI: 10.1186/s40360-017-0118-9 order by 25532--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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43
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Choi SY, Kim HR, Ryu PD, Lee SY. Regulation of voltage-gated potassium channels attenuates resistance of side-population cells to gefitinib in the human lung cancer cell line NCI-H460. BMC Pharmacol Toxicol 2017; 18:14. [PMID: 28219421 PMCID: PMC5319158 DOI: 10.1186/s40360-017-0118-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 01/28/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Side-population (SP) cells that exclude anti-cancer drugs have been found in various tumor cell lines. Moreover, SP cells have a higher proliferative potential and drug resistance than main population cells (Non-SP cells). Also, several ion channels are responsible for the drug resistance and proliferation of SP cells in cancer. METHODS To confirm the expression and function of voltage-gated potassium (Kv) channels of SP cells, these cells, as well as highly expressed ATP-binding cassette (ABC) transporters and stemness genes, were isolated from a gefitinib-resistant human lung adenocarcinoma cell line (NCI-H460), using Hoechst 33342 efflux. RESULTS In the present study, we found that mRNA expression of Kv channels in SP cells was different compared to Non-SP cells, and the resistance of SP cells to gefitinib was weakened with a combination treatment of gefitinib and Kv channel blockers or a Kv7 opener, compared to single-treatment gefitinib, through inhibition of the Ras-Raf signaling pathway. CONCLUSIONS The findings indicate that Kv channels in SP cells could be new targets for reducing the resistance to gefitinib.
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Affiliation(s)
- Seon Young Choi
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - Hang-Rae Kim
- Department of Anatomy and Cell Biology, and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea
| | - Pan Dong Ryu
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - So Yeong Lee
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea.
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44
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Choi SY, Kim HR, Ryu PD, Lee SY. Regulation of voltage-gated potassium channels attenuates resistance of side-population cells to gefitinib in the human lung cancer cell line NCI-H460. BMC Pharmacol Toxicol 2017. [DOI: 10.1186/s40360-017-0118-9 order by 21742--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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45
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Stankevicius V, Kunigenas L, Stankunas E, Kuodyte K, Strainiene E, Cicenas J, Samalavicius NE, Suziedelis K. The expression of cancer stem cell markers in human colorectal carcinoma cells in a microenvironment dependent manner. Biochem Biophys Res Commun 2017; 484:726-733. [PMID: 28174005 DOI: 10.1016/j.bbrc.2017.01.111] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 01/21/2017] [Indexed: 12/14/2022]
Abstract
Numerous lines of evidence support the hierarchical model of cancer development and tumor initiation. According to the theory, cancer stem cells play a crucial role in the formation of the tumor and should be targeted for more effective anticancer treatment. However, cancer stem cells quickly loose their characteristics when propagated as 2D cell culture, indicating that the 2D cell culture does not provide the appropriate settings to maintain an in vivo environment. In this study we have investigated the expression of self-renewal, cancer stem cell and epithelial to mesenchymal transition markers after the transfer of human colorectal carcinoma cell DLD1 and HT29 lines from 2D cell cultures to scaffold-attached laminin rich extracellular matrix and scaffold-free multicellular spheroid 3D culture models. Based on the up-regulated expression of multipotency, CSC and EMT markers, our data suggests that human colorectal carcinoma cells grown in 3D exhibit enhanced cancer stem cell characteristics. Therefore, in order to design more efficient targeted therapies, we suggest that 3D cell culture models should be employed in cancer stem cell research.
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Affiliation(s)
- Vaidotas Stankevicius
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania; Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
| | - Linas Kunigenas
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania; Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
| | - Edvinas Stankunas
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania; Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
| | - Karolina Kuodyte
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania; Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
| | - Egle Strainiene
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania; Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Vilnius, Lithuania.
| | - Jonas Cicenas
- Vetsuisse Faculty, Institute of Animal Pathology, University of Bern, 3012 Bern, Switzerland; MAP Kinase Resource, Bern, Switzerland; Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Sauletekio av. 7, Vilnius LT-10257, Lithuania.
| | - Narimantas E Samalavicius
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania.
| | - Kestutis Suziedelis
- Laboratory of Molecular Oncology, National Cancer Institute, Santariskiu str. 1, 08660 Vilnius, Lithuania; Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
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Corbo C, Cevenini A, Salvatore F. Biomarker discovery by proteomics-based approaches for early detection and personalized medicine in colorectal cancer. Proteomics Clin Appl 2017; 11. [PMID: 28019089 DOI: 10.1002/prca.201600072] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 11/29/2016] [Accepted: 12/22/2016] [Indexed: 12/14/2022]
Abstract
About one million people per year develop colorectal cancer (CRC) and approximately half of them die. The extent of the disease (i.e. local invasion at the time of diagnosis) is a key prognostic factor. The 5-year survival rate is almost 90% in the case of delimited CRC and 10% in the case of metastasized CRC. Hence, one of the great challenges in the battle against CRC is to improve early diagnosis strategies. Large-scale proteomic approaches are widely used in cancer research to search for novel biomarkers. Such biomarkers can help in improving the accuracy of the diagnosis and in the optimization of personalized therapy. Herein, we provide an overview of studies published in the last 5 years on CRC that led to the identification of protein biomarkers suitable for clinical application by using proteomic approaches. We discussed these findings according to biomarker application, including also the role of protein phosphorylation and cancer stem cells in biomarker discovery. Our review provides a cross section of scientific approaches and can furnish suggestions for future experimental strategies to be used as reference by scientists, clinicians and researchers interested in proteomics for biomarker discovery.
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Affiliation(s)
- Claudia Corbo
- CEINGE, Advanced Biotechnology s.c.a.r.l., Via G. Salvatore 486, Naples, Italy.,Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Armando Cevenini
- CEINGE, Advanced Biotechnology s.c.a.r.l., Via G. Salvatore 486, Naples, Italy.,Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Francesco Salvatore
- CEINGE, Advanced Biotechnology s.c.a.r.l., Via G. Salvatore 486, Naples, Italy
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Pereira JFS, Awatade NT, Loureiro CA, Matos P, Amaral MD, Jordan P. The third dimension: new developments in cell culture models for colorectal research. Cell Mol Life Sci 2016; 73:3971-89. [PMID: 27147463 PMCID: PMC11108567 DOI: 10.1007/s00018-016-2258-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 04/20/2016] [Accepted: 04/28/2016] [Indexed: 12/23/2022]
Abstract
Cellular models are important tools in various research areas related to colorectal biology and associated diseases. Herein, we review the most widely used cell lines and the different techniques to grow them, either as cell monolayer, polarized two-dimensional epithelia on membrane filters, or as three-dimensional spheres in scaffold-free or matrix-supported culture conditions. Moreover, recent developments, such as gut-on-chip devices or the ex vivo growth of biopsy-derived organoids, are also discussed. We provide an overview on the potential applications but also on the limitations for each of these techniques, while evaluating their contribution to provide more reliable cellular models for research, diagnostic testing, or pharmacological validation related to colon physiology and pathophysiology.
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Affiliation(s)
- Joana F S Pereira
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016, Lisbon, Portugal
- BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Nikhil T Awatade
- BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Cláudia A Loureiro
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016, Lisbon, Portugal
- BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Paulo Matos
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016, Lisbon, Portugal
- BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Margarida D Amaral
- BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Peter Jordan
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016, Lisbon, Portugal.
- BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
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Meng Q, Wu W, Pei T, Li L, Tang X, Sun H. Novel markers for circulating tumor stem cells in colorectal carcinoma. Am J Transl Res 2016; 8:4233-4241. [PMID: 27830007 PMCID: PMC5095316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 09/08/2016] [Indexed: 06/06/2023]
Abstract
Some colorectal carcinoma (CRC) invades into vessels and has distal metastasis, largely attributable to the dissemination of tumor cells into circulation as circulating tumor cells (CTCs). Moreover, cancer stem cells (CSCs) within CTCs, which are termed as circulating tumor stem-like cells (CTSCs), are critical for formation of distal metastatic tumors. Although different cell surface markers have been used to characterize and isolate CTCs or CSCs in CRC, no good marker has been identified so far for CTSCs. Here, we show evidence that CD262+ CRC cells appeared to be highly enriched for CTSCs in CRC. CD262+ CRC cells formed more tumor spheres in culture, exhibited higher chemo-resistance, had higher ratio of developing tumors after serial adoptive transplantation in nude mice, and had higher frequency of developing distal metastatic tumor, compared to traditional CD133+ or CD44+ CRC cells. Moreover, tumor cells were significantly more frequently detected in the circulation when CD262+ CRC cells were subcutaneously transplanted. Finally, we detected high CD262 levels in the stage IV CRC specimens, which were associated with poor prognosis of the patients. Together, these data suggest CD262+ may be a novel CTSC markers and selective elimination of CD262+ CRC cells may substantially improve the current CRC therapy.
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Affiliation(s)
- Qinghui Meng
- Department of General Surgery, The First Clinical Medical School of Harbin Medical UniversityHarbin 150001, China
| | - Weihua Wu
- Department of Endocrinology, The First Clinical Medical School of Harbin Medical UniversityHarbin 150001, China
| | - Tiemin Pei
- Department of General Surgery, The First Clinical Medical School of Harbin Medical UniversityHarbin 150001, China
| | - Long Li
- Department of General Surgery, The First Clinical Medical School of Harbin Medical UniversityHarbin 150001, China
| | - Xiaolong Tang
- Department of General Surgery, The First Clinical Medical School of Harbin Medical UniversityHarbin 150001, China
| | - Haobo Sun
- Department of General Surgery, The First Clinical Medical School of Harbin Medical UniversityHarbin 150001, China
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Verneuil L, Leboeuf C, Bousquet G, Brugiere C, Elbouchtaoui M, Plassa LF, Peraldi MN, Lebbé C, Ratajczak P, Janin A. Donor-derived stem-cells and epithelial mesenchymal transition in squamous cell carcinoma in transplant recipients. Oncotarget 2016; 6:41497-507. [PMID: 26594799 PMCID: PMC4747169 DOI: 10.18632/oncotarget.6359] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 11/16/2015] [Indexed: 12/18/2022] Open
Abstract
Background Skin squamous-cell-carcinoma (SCC), is the main complication in long-term kidney-transplant recipients, and it can include donor-derived cells. Preclinical models demonstrated the involvement of epithelial mesenchymal transition (EMT) in the progression of skin SCC, and the role of Snail, an EMT transcription factor, in cancer stem-cell survival and expansion. Here, we studied stem-cells and EMT expression in SCCs and concomitant actinic keratoses (AK) in kidney-transplant recipients. Methods In SCC and AK in 3 female recipients of male kidney-transplants, donor-derived Y chromosome in epidermal stem cells was assessed using combined XY-FISH/CD133 immunostaining, and digital-droplet-PCR on laser-microdissected CD133 expressing epidermal cells. For EMT study, double immunostainings of CD133 with vimentin or snail and slug, electron microscopy and immunostainings of keratinocytes junctions were performed. Digital droplet PCR was used to check CDH1 (E-cadherin) expression level in laser-microdissected cells co-expressing CD133 and vimentin or snail and slug. The numbers of Y-chromosome were assessed using digital droplet PCR in laser-microdissected cells co-expressing CD133 and vimentin, or snail and slug, and in CD133 positive cells not expressing any EMT maker. Results We identified donor-derived stem-cells in basal layers and invasive areas in all skin SCCs and in concomitant AKs, but not in surrounding normal skin. The donor-derived stem-cells expressed the EMT markers, vimentin, snail and slug in SCCs but not in AKs. The expression of the EMT transcription factor, SNAI1, was higher in stem-cells when they expressed vimentin. They were located in invasive areas of SCCs. In these areas, the expressions of claudin-1 and desmoglein 1 were reduced or absent, and within the basal layer there were features of basal membrane disappearance. Donor-derived stem cells were in larger numbers in stem cells co-expressing vimentin or snail and slug than in stem cells not expressing any EMT marker. Conclusion We identified here donor-derived stem cells within skin SCC in kidney-transplant recipients. They were located in invasive areas of SCC and had EMT characteristics.
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Affiliation(s)
- Laurence Verneuil
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France.,Department of Dermatology, CHU Caen, Caen, F-14033, France.,Université de Caen Normandie, Medical School, Caen, F-14000, France
| | - Christophe Leboeuf
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France
| | - Guilhem Bousquet
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France
| | - Charlotte Brugiere
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France.,Department of Dermatology, CHU Caen, Caen, F-14033, France.,Université de Caen Normandie, Medical School, Caen, F-14000, France
| | - Morad Elbouchtaoui
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France.,Department of Pathology, AP-HP, Hôpital Saint-Louis, Paris, F-75010, France
| | | | - Marie-Noelle Peraldi
- Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France.,Department of Dermatology, AP-HP, Hôpital Saint-Louis, Paris, F-75010, France
| | - Celeste Lebbé
- Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France.,Department of Dermatology, AP-HP, Hôpital Saint-Louis, Paris, F-75010, France
| | - Philippe Ratajczak
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France
| | - Anne Janin
- INSERM, UMR_S1165, Paris, F-75010, France.,Department of Pathology, Université Paris Diderot, UMR_S1165, F-75010 Paris, France.,Department of Pathology, AP-HP, Hôpital Saint-Louis, Paris, F-75010, France
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50
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CD51 correlates with the TGF-beta pathway and is a functional marker for colorectal cancer stem cells. Oncogene 2016; 36:1351-1363. [PMID: 27593923 DOI: 10.1038/onc.2016.299] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 07/08/2016] [Accepted: 07/15/2016] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the top three most prevalent and deadly cancers. A cancer stem cell (CSC) sub-population that is characterized by the abilities of tumor initiation, self-renewal, metastasis and resistance to chemotherapy can suggest new therapeutic targets. However, no such sub-population has been conclusively identified for CRC, and we lack any marker to identify cells with all of the above characteristics. Here, we report that CD51+ CRC cells displayed greater sphere-forming and tumorigenic capacities, increased migratory and invasive potentials, and enhanced chemoresistance compared with CD51- CRC cells. CD51 knockdown reduced the side population, sphere formation, cell motility and inhibited tumor incidence and metastasis in an in vivo tumor model. Furthermore, CD51 could bind transforming growth factor beta (TGF-β) receptors, and that it upregulated TGF-β/Smad signaling. These results indicate that CD51 is a novel functional marker for colorectal CSCs which may provide an therapeutic target for the efficient elimination of colorectal CSCs.
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