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1
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Hakala S, Hämäläinen A, Sandelin S, Giannareas N, Närvä E. Detection of Cancer Stem Cells from Patient Samples. Cells 2025; 14:148. [PMID: 39851576 PMCID: PMC11764358 DOI: 10.3390/cells14020148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/26/2025] Open
Abstract
The existence of cancer stem cells (CSCs) in various tumors has become increasingly clear in addition to their prominent role in therapy resistance, metastasis, and recurrence. For early diagnosis, disease progression monitoring, and targeting, there is a high demand for clinical-grade methods for quantitative measurement of CSCs from patient samples. Despite years of active research, standard measurement of CSCs has not yet reached clinical settings, especially in the case of solid tumors. This is because detecting this plastic heterogeneous population of cells is not straightforward. This review summarizes various techniques, highlighting their benefits and limitations in detecting CSCs from patient samples. In addition, methods designed to detect CSCs based on secreted and niche-associated signaling factors are reviewed. Spatial and single-cell methods for analyzing patient tumor tissues and noninvasive techniques such as liquid biopsy and in vivo imaging are discussed. Additionally, methods recently established in laboratories, preclinical studies, and clinical assays are covered. Finally, we discuss the characteristics of an ideal method as we look toward the future.
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Affiliation(s)
| | | | | | | | - Elisa Närvä
- Institute of Biomedicine and FICAN West Cancer Centre Laboratory, University of Turku and Turku University Hospital, FI-20520 Turku, Finland; (S.H.); (A.H.); (S.S.); (N.G.)
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2
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Wang Q, Zhang Q, Wang X, Luo H, Du T, Wu L, Tan M, Chen Y, Wu X, Sun S, Liu Z, Xie Y, Yuan W. TGM2-Mediated Autophagy Contributes to the Radio-Resistance of Non-Small Cell Lung Cancer Stem-like Cells. Biomedicines 2024; 12:2231. [PMID: 39457544 PMCID: PMC11504678 DOI: 10.3390/biomedicines12102231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024] Open
Abstract
Objectives: Cancer cells with 'stemness' are generally resistant to chemoradiotherapy. This study aims to compare the differences in radiation sensitivity of A549 and CD44+A549 stem-like cells to X-rays and carbon ion radiation (C-ions), and to find a target that can kill cancer stem-like cells (CSCs) of non-small cell lung cancer (NSCLC). Methods: The study used two cell lines (A549 and CD44+A549). The tumorigenicity of cells was tested with animal experiments. The cells were irradiated with X-rays and C-ions. Cell viability was detected using the CCK-8 and EdU assay. A liquid chromatograph-mass spectrometer (LC-MS) helped detect metabolic differences. Protein and mRNA expression were detected using a Western blot, reverse transcription-quantitative (RT-qPCR), and PCR array. The autophagic activity was monitored with a CYTO-ID® Autophagy Detection Kit 2.0. Immunofluorescence and co-immunoprecipitation helped to observe the localization and interaction relationships. Results: First, we verified the radio-resistance of CD44+A549 stem-like cells. LC-MS indicated the difference in autophagy between the two cells, followed by establishing a correlation between the radio-resistance and autophagy. Subsequently, the PCR array proved that TGM2 is significantly upregulated in CD44+A549 stem-like cells. Moreover, the TGM2 knockdown by small interfering RNA could decrease the radio-resistance of CD44+A549 cells. Bioinformatic analyses and experiments showed that TGM2 is correlated with the expression of CD44 and LC3B. Additionally, TGM2 could directly interact with LC3B. Conclusions: We established the CD44-TGM2-LC3 axis: CD44 mediates radio-resistance of CD44+A549 stem-like cells through TGM2 regulation of autophagy. Our study may provide new biomarkers and strategies to alleviate the radio-resistance of CSCs in NSCLC.
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Affiliation(s)
- Qian Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
| | - Qiuning Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
- Graduate School of the Chinese Academy of Sciences, Beijing 101499, China
| | - Xiaohu Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
| | - Hongtao Luo
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
- Graduate School of the Chinese Academy of Sciences, Beijing 101499, China
| | - Tianqi Du
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
| | - Luyao Wu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
- Graduate School of the Chinese Academy of Sciences, Beijing 101499, China
| | - Mingyu Tan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
| | - Yanliang Chen
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
| | - Xun Wu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
| | - Shilong Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
- Graduate School of the Chinese Academy of Sciences, Beijing 101499, China
| | - Zhiqiang Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
- Graduate School of the Chinese Academy of Sciences, Beijing 101499, China
| | - Yi Xie
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China
- Graduate School of the Chinese Academy of Sciences, Beijing 101499, China
| | - Wenzhen Yuan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China; (Q.W.)
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3
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Phadte P, Bishnu A, Dey P, M M, Mehrotra M, Singh P, Chakrabarty S, Majumdar R, Rekhi B, Patra M, De A, Ray P. Autophagy-mediated ID1 turnover dictates chemo-resistant fate in ovarian cancer stem cells. J Exp Clin Cancer Res 2024; 43:222. [PMID: 39123206 PMCID: PMC11316295 DOI: 10.1186/s13046-024-03147-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND The mechanisms enabling dynamic shifts between drug-resistant and drug-sensitive states in cancer cells are still underexplored. This study investigated the role of targeted autophagic protein degradation in regulating ovarian cancer stem cell (CSC) fate decisions and chemo-resistance. METHODS Autophagy levels were compared between CSC-enriched side population (SP) and non-SP cells (NSP) in multiple ovarian cancer cell lines using immunoblotting, immunofluorescence, and transmission electron microscopy. The impact of autophagy modulation on CSC markers and differentiation was assessed by flow cytometry, immunoblotting and qRT-PCR. In silico modeling and co-immunoprecipitation identified ID1 interacting proteins. Pharmacological and genetic approaches along with Annexin-PI assay, ChIP assay, western blotting, qRT-PCR and ICP-MS were used to evaluate effects on cisplatin sensitivity, apoptosis, SLC31A1 expression, promoter binding, and intracellular platinum accumulation in ID1 depleted backdrop. Patient-derived tumor spheroids were analyzed for autophagy and SLC31A1 levels. RESULTS Ovarian CSCs exhibited increased basal autophagy compared to non-CSCs. Further autophagy stimulation by serum-starvation and chemical modes triggered proteolysis of the stemness regulator ID1, driving the differentiation of chemo-resistant CSCs into chemo-sensitive non-CSCs. In silico modeling predicted TCF12 as a potent ID1 interactor, which was validated by co-immunoprecipitation. ID1 depletion freed TCF12 to transactivate the cisplatin influx transporter SLC31A1, increasing intracellular cisplatin levels and cytotoxicity. Patient-derived tumor spheroids exhibited a functional association between autophagy, ID1, SLC31A1, and platinum sensitivity. CONCLUSIONS This study reveals a novel autophagy-ID1-TCF12-SLC31A1 axis where targeted autophagic degradation of ID1 enables rapid remodeling of CSCs to reverse chemo-resistance. Modulating this pathway could counter drug resistance in ovarian cancer.
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Affiliation(s)
- Pratham Phadte
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Aniketh Bishnu
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Pranay Dey
- Molecular Functional Imaging Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Manikandan M
- Laboratory of Medicinal Chemistry and Cell Biology, Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India
| | - Megha Mehrotra
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Prerna Singh
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Shritama Chakrabarty
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
- Indian Institute of Science Education and Research, Bhopal, 462066, India
| | - Rounak Majumdar
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
- Indian Institute of Science Education and Research, Kolkata, 741246, India
| | - Bharat Rekhi
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
- Department of Pathology, Tata Memorial Hospital, Mumbai, 400012, India
| | - Malay Patra
- Laboratory of Medicinal Chemistry and Cell Biology, Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India
| | - Abhijit De
- Molecular Functional Imaging Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Pritha Ray
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India.
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India.
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Mallika L, Rajarathinam M, Thangavel S. Cancer stem cells in head and neck squamous cell carcinoma and its associated markers: A review. INDIAN J PATHOL MICR 2024; 67:250-258. [PMID: 38394427 DOI: 10.4103/ijpm.ijpm_467_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/30/2023] [Indexed: 02/25/2024] Open
Abstract
ABSTRACT Evidences of the current research say that cancer is multifactorial with varied mechanisms of origin. Most theories evolve either intrinsic (genetic) or extrinsic factors like tobacco and alcoholism as the major cause of oral cancer in India. There is growing evidence that human papilloma virus may act as a co-carcinogen, along with tobacco, in the causation of cancers. The cells being triggered by the agents may be somatic (differentiated functional cell) or a normal stem cell with multipotency or even the transient proliferative cells derived from the stem cells. These stem cells possess several features like slow cell cycle, ability to extrude chemotherapeutic drugs, exhibit epithelial mesenchymal transition, and inhibit apoptosis. Targeting these progenitor stem cells may aid in improving the overall prognosis of the patient. These cancer stem cells are targeted using various markers that are apparently more or less specific to various types of stem cells.
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Affiliation(s)
- Lavanya Mallika
- Department of Microbiology, Government Mohan Kumaramangalam Medical College, Salem, Tamil Nadu, India
| | - Mani Rajarathinam
- Dean, Government Mohan Kumaramangalam Medical College, Salem, Tamil Nadu, India
| | - Sundararajan Thangavel
- Associate Professor and Principal Investigator, Viral Research Diagnostic Laboratory, Department of Microbiology, Government Mohan Kumaramangalam Medical College, Salem, Tamil Nadu, India
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5
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Beninato T, Lo Russo G, Leporati R, Roz L, Bertolini G. Circulating tumor cells in lung cancer: Integrating stemness and heterogeneity to improve clinical utility. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 392:1-66. [PMID: 40287216 DOI: 10.1016/bs.ircmb.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Circulating tumor cells (CTC), released by primary tumors into the bloodstream, represent a valuable source to inform on cancer heterogeneity, cancer progression, metastatic disease and therapy efficacy without the need of invasive tumor biopsies. However, the extreme rarity and heterogeneity of CTCs, occurring at genotypic, phenotypic and functional levels, poses a major challenge for the study of this population and explains the lack of standardized strategies of CTC isolation. Lung cancer, the leading causes of cancer-related death worldwide, is a paradigmatic example of how CTC heterogeneity can undermine the clinical utility of this biomarker, since contrasting data have been reported using different isolation technologies. Some evidences suggest that only a fraction of CTC, characterized by stem-like feature and partial epithelial-mesenchymal transition (EMT) phenotype, can sustain metastasis initiation. Cancer stem cells (CSCs) have the potential to maintain primary tumors, initiate metastasis and escape both chemotherapy and immunotherapy treatments. Moreover, a close connection has been reported in several tumor types among hybrid phenotype, characterized by retention of epithelial and mesenchymal traits, acquisition of CSC feature and increased metastatic potential. This review focuses on the phenotypic and functional heterogeneity of CTCs and the resulting implications for their isolation and clinical validation, especially in the setting of non-small cell lung cancer (NSCLC). In particular, we discuss the most relevant studies providing evidence for the presence and prognostic/predictive value of CTC subsets characterized by stem-like and hybrid EMT phenotype. Despite technical and conceptual issues, tracking circulating CSCs has the potential to improve the prognostic/predictive value of CTCs in NSCLC setting and could provide novel insights into the comprehension of the metastatic process and identification of novel therapeutic targets.
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Affiliation(s)
- Teresa Beninato
- Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giuseppe Lo Russo
- Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Rita Leporati
- Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Roz
- Unit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giulia Bertolini
- Unit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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6
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Duvivier L, Gerard L, Diaz A, Gillet JP. Linking ABC transporters to the hallmarks of cancer. Trends Cancer 2024; 10:124-134. [PMID: 37884430 DOI: 10.1016/j.trecan.2023.09.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/28/2023]
Abstract
Human ATP-binding cassette (ABC) transporters are ubiquitously expressed and transport a broad range of endogenous and xenobiotic substrates across extra- and intracellular membranes. Mutations in ABC genes cause 21 monogenic diseases, and polymorphisms in these genes are associated with susceptibility to complex diseases. ABC transporters also play a major role in drug bioavailability, and they mediate multidrug resistance in cancer. At least 13 ABC transporters were shown to be involved in drug resistance in vitro. In the past decade, efforts have been made to elucidate their roles in tumor biology. Herein, we explore their involvement in tumorigenesis, focusing on the hallmarks of cells as they make their way from normalcy to neoplastic growth states.
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Affiliation(s)
- Laurent Duvivier
- Laboratory of Molecular Cancer Biology, URPhyM, NARILIS, University of Namur, Namur, Belgium
| | - Louise Gerard
- Laboratory of Molecular Cancer Biology, URPhyM, NARILIS, University of Namur, Namur, Belgium
| | - Adriana Diaz
- Laboratory of Molecular Cancer Biology, URPhyM, NARILIS, University of Namur, Namur, Belgium
| | - Jean-Pierre Gillet
- Laboratory of Molecular Cancer Biology, URPhyM, NARILIS, University of Namur, Namur, Belgium.
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7
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Rehman A, Panda SK, Tirino V, Del Vecchio V. Cancer Stem Cells: Detection and Characterization from Solid Tumors. Methods Mol Biol 2024; 2835:215-228. [PMID: 39105918 DOI: 10.1007/978-1-0716-3995-5_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2024]
Abstract
Cancer stem cells (CSCs) have emerged as an attractive research interest due to their prominent role in development of the tumors. CSCs are rare dormant cells that can self-renew and maintain tumor development and heterogeneity. A better understanding of CSCs can improve tumor classification and contribute toward the development of novel therapeutic approaches to fight cancer. Hence, it is of immense importance to comprehend the basic function of CSCs in tumor formation, which can only be possible by devising perfected methodologies to isolate, detect, and characterize them. In this chapter, we outline the key protocols to culture, identify, and isolate CSCs from solid tumors to further advance basic and clinical investigation related to CSCs and their role in tumor biology.
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Affiliation(s)
- A Rehman
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy
| | - S Kumar Panda
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy
| | - V Tirino
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy
| | - V Del Vecchio
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy.
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8
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Vukovic Đerfi K, Vasiljevic T, Matijevic Glavan T. Recent Advances in the Targeting of Head and Neck Cancer Stem Cells. APPLIED SCIENCES 2023; 13:13293. [DOI: 10.3390/app132413293] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous cancer with a poor overall response to therapy. One of the reasons for this therapy resistance could be cancer stem cells (CSCs), a small population of cancer cells with self-renewal and tumor-initiating abilities. Tumor cell heterogeneity represents hurdles for therapeutic elimination of CSCs. Different signaling pathway activations, such as Wnt, Notch, and Sonic-Hedgehog (SHh) pathways, lead to the expression of several cancer stem factors that enable the maintenance of CSC features. Identification and isolation of CSCs are based either on markers (CD133, CD44, and aldehyde dehydrogenase (ALDH)), side populations, or their sphere-forming ability. A key challenge in cancer therapy targeting CSCs is overcoming chemotherapy and radiotherapy resistance. However, in novel therapies, various approaches are being employed to address this hurdle such as targeting cell surface markers, other stem cell markers, and different signaling or metabolic pathways, but also, introducing checkpoint inhibitors and natural compounds into the therapy can be beneficial.
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Affiliation(s)
- Kristina Vukovic Đerfi
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tea Vasiljevic
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tanja Matijevic Glavan
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
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9
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de Albuquerque Dias R, Balbinot KM, da Silva Kataoka MS, de Melo Alves Júnior S, de Jesus Viana Pinheiro J. Expression of stem cell markers SALL4, LIN28A, and KLF4 in ameloblastoma. Diagn Pathol 2023; 18:92. [PMID: 37559082 PMCID: PMC10413759 DOI: 10.1186/s13000-023-01379-9] [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: 07/14/2023] [Accepted: 08/02/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Ameloblastoma (AME) is a benign odontogenic tumour of epithelial origin characterised by slow but aggressive growth, infiltration, and recurrence; it is capable of reaching large dimensions and invading adjacent structures. Stem cell research has proven to be significant in the sphere of tumour biology through these cells' possible involvement in the aetiopathogenesis of this tumour. METHODS Immunohistochemistry was performed on AME, dentigerous cyst (DC), and dental follicle (DF) samples, and indirect immunofluorescence was performed on the AME-hTERT cell line to determine the expression of SALL4, LIN28A, and KLF4. RESULTS Expression of proteins related to cellular pluripotency was higher in AME cells than in DC and DF cells. The analysis revealed that the proteins in question were mainly expressed in the parenchyma of AME tissue samples and were detected in the nuclei of AME-hTERT cells. CONCLUSIONS Stem cells may be related to the origin and progression of AME.
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Affiliation(s)
- Rafaela de Albuquerque Dias
- Laboratory of Pathological Anatomy and Immunohistochemistry, Federal University of Pará, Belém, Pará, Brazil.
| | - Karolyny Martins Balbinot
- Laboratory of Pathological Anatomy and Immunohistochemistry, Federal University of Pará, Belém, Pará, Brazil
| | | | - Sérgio de Melo Alves Júnior
- Laboratory of Pathological Anatomy and Immunohistochemistry, Federal University of Pará, Belém, Pará, Brazil
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10
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Chen M, Jiang J, Hou J. Single-cell technologies in multiple myeloma: new insights into disease pathogenesis and translational implications. Biomark Res 2023; 11:55. [PMID: 37259170 PMCID: PMC10234006 DOI: 10.1186/s40364-023-00502-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/12/2023] [Indexed: 06/02/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of plasma cells. Although therapeutic advances have been made to improve clinical outcomes and to prolong patients' survival in the past two decades, MM remains largely incurable. Single-cell sequencing (SCS) is a powerful method to dissect the cellular and molecular landscape at single-cell resolution, instead of providing averaged results. The application of single-cell technologies promises to address outstanding questions in myeloma biology and has revolutionized our understanding of the inter- and intra-tumor heterogeneity, tumor microenvironment, and mechanisms of therapeutic resistance in MM. In this review, we summarize the recently developed SCS methodologies and latest MM research progress achieved by single-cell profiling, including information regarding the cancer and immune cell landscapes, tumor heterogeneities, underlying mechanisms and biomarkers associated with therapeutic response and resistance. We also discuss future directions of applying transformative SCS approaches with contribution to clinical translation.
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Affiliation(s)
- Mengping Chen
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jinxing Jiang
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jian Hou
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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11
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Wang Q, Liu R, Zhang Q, Luo H, Wu X, Du T, Chen Y, Tan M, Liu Z, Sun S, Yang K, Tian J, Wang X. Biological effects of cancer stem cells irradiated by charged particle: a systematic review of in vitro studies. J Cancer Res Clin Oncol 2023:10.1007/s00432-022-04561-6. [PMID: 36611110 DOI: 10.1007/s00432-022-04561-6] [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: 11/10/2022] [Accepted: 12/24/2022] [Indexed: 01/09/2023]
Abstract
PURPOSE The existence of cancer stem cells (CSCs) is closely related to tumor recurrence, metastasis, and resistance to chemoradiotherapy. In addition, given the unique physical and biological advantages of charged particle, we hypothesized that charged particle irradiation would produce strong killing effects on CSCs. The purpose of our systematic review is to evaluate the biological effects of CSCs irradiated by charged particle, including proliferation, invasion, migration, and changes in the molecular level. METHODS We searched PubMed, EMBASE, and Web of Science until 17 march 2022 according to the key words. Included studies have to be vitro studies of CSCs irradiated by charged particle. Outcomes included one or more of radiation sensitivity, proliferation, metastasis, invasion, and molecular level changes, like DNA damage after been irradiated. RESULTS Eighteen studies were included in the final analysis. The 18 articles include 12-carbon ion irradiation, 4-proton irradiation, 1 α-particle irradiation, 1-carbon ion combine proton irradiation. CONCLUSION Through the extraction and analysis of data, we came to this conclusion: CSCs have obvious radio-resistance compared with non-CSCs, and charged particle irradiation or in combination with drugs could overcome this resistance, specifically manifested in inhibiting CSCs' proliferation, invasion, migration, and causing more and harder to repair DNA double-stranded breaks (DSB) of CSCs.
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Affiliation(s)
- Qian Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, China
| | - Ruifeng Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, 730030, China.,Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, 730030, China
| | - Qiuning Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, 730030, China.,Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, 730030, China
| | - Hongtao Luo
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, 730030, China.,Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, 730030, China
| | - Xun Wu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, China
| | - Tianqi Du
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, China
| | - Yanliang Chen
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, China
| | - Mingyu Tan
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, China
| | - Zhiqiang Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, 730030, China.,Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, 730030, China
| | - Shilong Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China.,Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, 730030, China.,Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, 730030, China
| | - Kehu Yang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730030, China
| | - Jinhui Tian
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730030, China
| | - Xiaohu Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, China. .,Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, 730030, China. .,Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, 730030, China.
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12
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Effects of Berberine against Pancreatitis and Pancreatic Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238630. [PMID: 36500723 PMCID: PMC9738201 DOI: 10.3390/molecules27238630] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/28/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
The pancreas is a glandular organ with endocrine and exocrine functions necessary for the maintenance of blood glucose homeostasis and secretion of digestive enzymes. Pancreatitis is characterized by inflammation of the pancreas leading to temporary or permanent pancreatic dysfunction. Inflammation and fibrosis caused by chronic pancreatitis exacerbate malignant transformation and significantly increase the risk of developing pancreatic cancer, the world's most aggressive cancer with a 5-year survival rate less than 10%. Berberine (BBR) is a naturally occurring plant-derived polyphenol present in a variety of herbal remedies used in traditional medicine to treat ulcers, infections, jaundice, and inflammation. The current review summarizes the existing in vitro and in vivo evidence on the effects of BBR against pancreatitis and pancreatic cancer with a focus on the signalling mechanisms underlying the effects of BBR.
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13
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Redox-Regulation in Cancer Stem Cells. Biomedicines 2022; 10:biomedicines10102413. [PMID: 36289675 PMCID: PMC9598867 DOI: 10.3390/biomedicines10102413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.
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14
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Chen L, Yang F, Chen S, Tai J. Mechanisms on chemotherapy resistance of colorectal cancer stem cells and research progress of reverse transformation: A mini-review. Front Med (Lausanne) 2022; 9:995882. [PMID: 36172536 PMCID: PMC9510709 DOI: 10.3389/fmed.2022.995882] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
Tumor recurrence and chemotherapy resistance are mainly responsible for poor prognosis in colorectal cancer (CRC) patients. Cancer stem cell (CSC) has been identified in many solid tumors, including CRC. Additionally, CSC cannot be completely killed during chemotherapy and develops resistance to chemotherapeutic drugs, which is the main reason for tumor recurrence. This study reviews the main mechanisms of CSC chemotherapy resistance in CRC, including activation of DNA damage checkpoints, epithelial-mesenchymal transition (EMT), inhibition of the overexpression of antiapoptotic regulatory factors, overexpression of ATP-binding cassette (ABC) transporters, maintenance of reactive oxygen species (ROS) levels, and the dormant state of CSC. Advances in research to reverse chemotherapy resistance are also discussed. Our study can provide the promising potential for eliminating CSC and preventing tumor progression for CRC treatment.
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Affiliation(s)
- Lei Chen
- Department of Colorectal and Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Funing Yang
- Pediatric Outpatient Clinic, First Hospital of Jilin University, Changchun, China
| | - Si Chen
- Department of Colorectal and Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Jiandong Tai
- Department of Colorectal and Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
- *Correspondence: Jiandong Tai
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15
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Serizawa K, Tanaka H, Ueda T, Fukui A, Kakutani H, Taniguchi T, Inoue H, Kumode T, Taniguchi Y, Rai S, Hirase C, Morita Y, Espinoza JL, Tatsumi Y, Ashida T, Matsumura I. CD34 + myeloma cells with self-renewal activities are therapy-resistant and persist as MRD in cell cycle quiescence. Int J Hematol 2022; 115:336-349. [PMID: 35133572 DOI: 10.1007/s12185-021-03261-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/12/2021] [Accepted: 11/12/2021] [Indexed: 01/13/2023]
Abstract
Side population (SP) is known to include therapy-resistant cells in various cancers. Here, we analyzed SP using multiple myeloma (MM) samples. The SP accounted for 2.96% in MM cells from newly diagnosed MM (NDMM). CD34 was expressed in 47.8% of SP cells, but only in 2.11% of bulk MM cells. CD34+ MM cells expressed more immature cell surface markers and a gene signature than CD34- MM cells. CD34+ but not CD34- MM cells possessed clonogenic activities and showed long-term self-renewal activities in xenotransplantation assays. Similarly, whereas 2.20% of MM cells were CD34+ in NDMM (n = 38), this proportion increased to 42.6% in minimal residual disease (MRD) samples (n = 16) (p < 0.001) and to 17.7% in refractory/relapsed MM (RRMM) (n = 30) (p < 0.01). Cell cycle analysis showed that 24.7% of CD34+ MM cells from NDMM were in G0 phase while this proportion was 54.9% in MRD (p < 0.05) and 14.5% in RRMM, reflecting the expansion of MM. Together, CD34+ MM cells with long-term self-renewal activities persist as MRD in cell cycle quiescence or remain as therapy-resistant cells in RRMM, substantiating the necessity of targeting this population to improve clinical outcomes of MM.
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Affiliation(s)
- Kentaro Serizawa
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Hirokazu Tanaka
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan.
| | - Takeshi Ueda
- Department of Biochemistry, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Ayano Fukui
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Hiroaki Kakutani
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Takahide Taniguchi
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Hiroaki Inoue
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Takahiro Kumode
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Yasuhiro Taniguchi
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Shinya Rai
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Chikara Hirase
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Yasuyoshi Morita
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - J Luis Espinoza
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Yoichi Tatsumi
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Takashi Ashida
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, Japan
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16
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Huang S, Song Y, Liang T, Zhang JR, Zhu JJ. CRISPR System-Linked Self-Assembling Nanoplatforms for Inspection and Screening of Gastric Cancer Stem Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2104622. [PMID: 34874610 DOI: 10.1002/smll.202104622] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/10/2021] [Indexed: 06/13/2023]
Abstract
Cancer stem cells (CSCs) possess a high degree of plasticity, constituting a formidable challenge to identify and screen CSCs in situ with outstanding specificity and sensitivity. To overcome this limitation, a self-assembled heterodimer consisting of clustered regularly interspaced short palindromic repeats/Cas12a (named A-CCA) linkage is designed for in situ identification and screening of gastric CSCs (GCSCs) from gastric cancer cells (GCCs). In this system, the editable character of crRNA performs recognition of dual-targets in GCSCs, effectively boosting the specificity of identification, while the enzymatic reaction of Cas12a contributes meaningfully to the sensitivity of sensing, enabling in situ examination and screening of GCSCs. Specifically, the A-CCA nanoplatforms hybridized with ABCG 2 and ABCB 1 overexpress in GCSCs, which can generate heterodimers and simultaneously restore the function of trans-cleavage. At this time, the asymmetry of the heterodimer causes a circular dichroism signal, which together with the recovered fluorescence signal form a dual-signals output system that can further ensure the precision of screening GCSC. Therefore, fluorescence-enhanced GCSCs can be sorted out from GCCs by flow cytometry. Furthermore, GCSCs screened by this assay possess extremely aggressive tumorigenic efficiency, providing a fundamental research object for further developing CSC targeted drugs in vivo.
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Affiliation(s)
- Shan Huang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China
| | - Yuexin Song
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China
| | - Tingxizi Liang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China
| | - Jian-Rong Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China
- School of Chemistry and Life Science, Nanjing University Jinling College, Nanjing, 210089, P. R. China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China
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17
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Huang R, Meens J, Yuzwa S, Ailles L, Ohh M, Robinson CM. Side population analysis in clear cell renal cell carcinoma. Biochem Biophys Res Commun 2021; 585:196-202. [PMID: 34813980 DOI: 10.1016/j.bbrc.2021.11.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 11/12/2021] [Indexed: 10/19/2022]
Abstract
Cancer stem cells have an important role in tumour biology. While their identity in haematological malignancies is clearly defined, stem cell identity remains elusive in some solid tumours. Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer, but the identity or existence of ccRCC stem cells remains unknown. We aimed to discern their existence using the widely utilised side population approach in ccRCC cell lines. In all cells tested, a well-defined side population was identified, and cell-based assays suggested stem-like properties. However, limiting dilution assays revealed comparable tumour initiating abilities and tumour histology of side and non-side populations, and single cell RNA-sequencing revealed minimal differences between these populations. The results indicate that the side population approach is not sufficient for cancer stem cell discovery in ccRCC.
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Affiliation(s)
- Richard Huang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1M1, Canada.
| | - Jalna Meens
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
| | - Scott Yuzwa
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1M1, Canada.
| | - Laurie Ailles
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
| | - Michael Ohh
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1M1, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, M5G 1M1, Canada.
| | - Claire M Robinson
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1M1, Canada; Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, H91 FD82, Ireland.
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18
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Zhang W, Wei L, Weng J, Yu F, Qin H, Wang D, Zeng H. Advances in the Research of Osteosarcoma Stem Cells and its Related Genes. Cell Biol Int 2021; 46:336-343. [PMID: 34941001 DOI: 10.1002/cbin.11752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 11/29/2021] [Accepted: 12/12/2021] [Indexed: 11/07/2022]
Abstract
Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need of new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell theory states that cancer stem cells represent a small proportion of cancer cells. These cancer stem cells have self-renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and its related genes. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Weifei Zhang
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Liangchen Wei
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Jian Weng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Fei Yu
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Haotian Qin
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Deli Wang
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Hui Zeng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
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19
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Albendazole inhibits NF-κB signaling pathway to overcome tumor stemness and bortezomib resistance in multiple myeloma. Cancer Lett 2021; 520:307-320. [PMID: 34390764 DOI: 10.1016/j.canlet.2021.08.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 11/23/2022]
Abstract
Multiple myeloma (MM) is incurable and the second most common hematologic malignancy in plasma cells. Multiple myeloma stem cell-like cells (MMSCs), a rare population of MM cells, are believed to be the major cause of drug resistance and high recurrence rates in patients with MM. Therefore, developing novel strategies to eradicate MMSCs may favor myeloma treatment. In this study, based on the drug repositioning strategy, we found that albendazole (ABZ), a broad-spectrum antiparasitic drug, selectively suppresses the proliferation of multiple myeloma cells in vitro and in vivo and decreases number of aldehyde dehydrogenase (ALDH)-positive MMSCs in MM. Furthermore, RNA-seq of MM cells after ABZ treatment revealed that inhibition of the nuclear factor kappa-B (NF-κB) pathway is a key mediator of ABZ against MM. Moreover, we demonstrated that ABZ can resensitize cells resistant to bortezomib and overcome MMSCs-induced bortezomib resistance by decreasing ALDH1+ MMSCs numbers. Our findings provide preclinical evidence for utilizing the previously known pharmacologically active drug albendazole for the treatment of multiple myeloma.
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20
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Preferential interaction of platelets with prostate cancer cells with stem cell markers. Thromb Res 2021; 206:42-51. [PMID: 34403851 DOI: 10.1016/j.thromres.2021.08.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 07/29/2021] [Accepted: 08/10/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Prostate cancer (PCa) may be initiated by CD133+/CD44+ expressing stem cell-like cells (PCSC), which are also thought to drive metastasis. Platelets also contribute to metastasis via tumor cell-induced platelet aggregation (TCIPA), which in part enhances cancer cell invasion. Moreover, activated platelets secrete stromal derived growth factor-1α (SDF-1α) that can mobilize CSCs via the CXCR4 receptor. However, the potential reciprocal interactions between CSCs and platelets have not been investigated. OBJECTIVE To characterize the mechanisms behind PCSC-platelet interaction. METHODS Fluorescence Activated Cell Sorting was utilized to separate DU145 and PC3 PCa cells into CD133+/CD44+, CD133+/CD44-, CD44+/CD133-, and CD133-/CD44- subpopulations and to measure their CXCR4 surface expression. PCa subpopulation TCIPA experiments were performed using aggregometry and immunoblot was used to measure prothrombin. Platelet SDF-1α secretion was measured by ELISA. Modified-Boyden chamber assays were used to assess the role of SDF-1α:CXCR4 pathway in platelet-PCSC interactions. RESULTS DU145 and PC3 expressing both CD133 and CD44 stem cell markers accounted for only small fractions of total cells (DU145: CD133+/CD44+ 3.44 ± 1.45% vs. CD133+/CD44- 1.56 ± 0.45% vs. CD44+/CD133- 68.19 ± 6.25% vs. CD133-/CD44- 20.36 ± 4.51%). However, CD133+ subpopulations induced the greatest amount of aggregation compared to CD44+/CD133- and double-negative DU145, and this aggregation potency of CD133+ PCa cells corresponded with high levels of prothrombin expression. Additionally, CD133+ subpopulations expressed significantly higher level of CXCR4 compared to CD133-/CD44- and CD44+/CD133-. Disruption of SDF-1α:CXCR4 pathway reduced platelet-induced PCSC invasion. CONCLUSIONS CD133+/CD44+ and CD133+/CD44- PCSCs have highest platelet aggregation potency, which could be attributed to their increased prothrombin expression. Reciprocally, platelet-derived SDF-1α stimulates PCSC invasion.
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21
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Liverani C, De Vita A, Spadazzi C, Miserocchi G, Cocchi C, Bongiovanni A, De Lucia A, La Manna F, Fabbri F, Tebaldi M, Amadori D, Tasciotti E, Martinelli G, Mercatali L, Ibrahim T. Lineage-specific mechanisms and drivers of breast cancer chemoresistance revealed by 3D biomimetic culture. Mol Oncol 2021; 16:921-939. [PMID: 34109737 PMCID: PMC8847989 DOI: 10.1002/1878-0261.13037] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 01/16/2023] Open
Abstract
To improve the success rate of current preclinical drug trials, there is a growing need for more complex and relevant models that can help predict clinical resistance to anticancer agents. Here, we present a three‐dimensional (3D) technology, based on biomimetic collagen scaffolds, that enables the modeling of the tumor hypoxic state and the prediction of in vivo chemotherapy responses in terms of efficacy, molecular alterations, and emergence of resistance mechanisms. The human breast cancer cell lines MDA‐MB‐231 (triple negative) and MCF‐7 (luminal A) were treated with scaling doses of doxorubicin in monolayer cultures, 3D collagen scaffolds, or orthotopically transplanted murine models. Lineage‐specific resistance mechanisms were revealed by the 3D tumor model. Reduced drug uptake, increased drug efflux, and drug lysosomal confinement were observed in triple‐negative MDA‐MB‐231 cells. In luminal A MCF‐7 cells, the selection of a drug‐resistant subline from parental cells with deregulation of p53 pathways occurred. These cells were demonstrated to be insensitive to DNA damage. Transcriptome analysis was carried out to identify differentially expressed genes (DEGs) in treated cells. DEG evaluation in breast cancer patients demonstrated their potential role as predictive biomarkers. High expression of the transporter associated with antigen processing 1 (TAP1) and the tumor protein p53‐inducible protein 3 (TP53I3) was associated with shorter relapse in patients affected by ER+ breast tumor. Likewise, the same clinical outcome was associated with high expression of the lysosomal‐associated membrane protein 1 LAMP1 in triple‐negative breast cancer. Hypoxia inhibition by resveratrol treatment was found to partially re‐sensitize cells to doxorubicin treatment. Our model might improve preclinical in vitro analysis for the translation of anticancer compounds as it provides: (a) more accurate data on drug efficacy and (b) enhanced understanding of resistance mechanisms and molecular drivers.
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Affiliation(s)
- Chiara Liverani
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro De Vita
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Chiara Spadazzi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giacomo Miserocchi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Claudia Cocchi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Anna De Lucia
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Federico La Manna
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Francesco Fabbri
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Michela Tebaldi
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Dino Amadori
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Ennio Tasciotti
- Center for Biomimetic Medicine, Houston Methodist Research Institute (HMRI), TX, USA.,IRCCS San Raffaele Pisana, Rome Sclavo Research Center, Siena, Italy
| | - Giovanni Martinelli
- Scientific Directory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Laura Mercatali
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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22
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Koshkin SA, Anatskaya OV, Vinogradov AE, Uversky VN, Dayhoff GW, Bystriakova MA, Pospelov VA, Tolkunova EN. Isolation and Characterization of Human Colon Adenocarcinoma Stem-Like Cells Based on the Endogenous Expression of the Stem Markers. Int J Mol Sci 2021; 22:4682. [PMID: 33925224 PMCID: PMC8124683 DOI: 10.3390/ijms22094682] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer stem cells' (CSCs) self-maintenance is regulated via the pluripotency pathways promoting the most aggressive tumor phenotype. This study aimed to use the activity of these pathways for the CSCs' subpopulation enrichment and separating cells characterized by the OCT4 and SOX2 expression. METHODS To select and analyze CSCs, we used the SORE6x lentiviral reporter plasmid for viral transduction of colon adenocarcinoma cells. Additionally, we assessed cell chemoresistance, clonogenic, invasive and migratory activity and the data of mRNA-seq and intrinsic disorder predisposition protein analysis (IDPPA). RESULTS We obtained the line of CSC-like cells selected on the basis of the expression of the OCT4 and SOX2 stem cell factors. The enriched CSC-like subpopulation had increased chemoresistance as well as clonogenic and migration activities. The bioinformatic analysis of mRNA seq data identified the up-regulation of pluripotency, development, drug resistance and phototransduction pathways, and the downregulation of pathways related to proliferation, cell cycle, aging, and differentiation. IDPPA indicated that CSC-like cells are predisposed to increased intrinsic protein disorder. CONCLUSION The use of the SORE6x reporter construct for CSCs enrichment allows us to obtain CSC-like population that can be used as a model to search for the new prognostic factors and potential therapeutic targets for colon cancer treatment.
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Affiliation(s)
- Sergei A. Koshkin
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Ste. 1024, Philadelphia, PA 19107, USA
| | - Olga V. Anatskaya
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Alexander E. Vinogradov
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Vladimir N. Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Guy W. Dayhoff
- Department of Chemistry, College of Art and Sciences, University of South Florida, Tampa, FL 33620, USA;
| | - Margarita A. Bystriakova
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Valery A. Pospelov
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Elena N. Tolkunova
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
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23
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Pak PJ, Lee DG, Sung JH, Jung SH, Han TY, Park SH, Chung N. Synergistic effect of the herbal mixture C5E on gemcitabine treatment in PANC‑1 cells. Mol Med Rep 2021; 23:315. [PMID: 33760105 PMCID: PMC7974510 DOI: 10.3892/mmr.2021.11954] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 09/28/2020] [Indexed: 12/18/2022] Open
Abstract
The present study aimed to determine the anticancer effect of the herbal mixture extract C5E in the pancreatic cancer cell line, PANC-1, in the absence or presence of gemcitabine treatment, a chemotherapeutic drug used for the treatment of pancreatic cancer. The anticancer effects of C5E, gemcitabine and C5E plus gemcitabine in PANC-1 cells following 72 h of treatment were investigated. The effect of each treatment on cell cycle arrest, apoptosis and the proportion of side population (SP) cells was determined using flow cytometric analysis following propidium iodide (PI), Annexin V-FITC/PI double staining and Hoechst 33342 staining, respectively. SP cells share similar characteristics to cancer stem-like cells, and a reduction in the SP is considered to be indicative of an anticancer effect. The percentage of SP cells and the cell viability of general PANC-1 cells were significantly decreased in response to all treatments. The percentage of SP cells was reduced from 8.2% (control) to 3.9, 7.2 and 5.1% following the treatment with C5E, gemcitabine and the co-treatment, respectively. All three treatments were discovered to inhibit cell viability by arresting the cell cycle at the S phase and promoted cell death by inducing early apoptosis, with the levels of apoptosis being increased from 1.9% (control) to 7.3, 2.5 and 12.0% following the treatment with C5E, gemcitabine and the co-treatment, respectively. The mRNA expression levels of sonic hedgehog, which is implicated in the development of certain types of cancer, were downregulated to a greater extent following the co-treatment with C5E and gemcitabine compared with the treatment with either C5E or gemcitabine alone. As the co-treatment with gemcitabine and C5E was more effective than each individual treatment, the present study suggested that the combined treatment may exhibit synergistic effects in PANC-1 cells.
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Affiliation(s)
- Pyo June Pak
- Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Dong Gun Lee
- Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Ji Hyun Sung
- Flow Cytometry Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03082, Republic of Korea
| | - Seung Hyun Jung
- School of Oriental Medicine, Dongguk University, Ilsan 10326, Republic of Korea
| | - Tae-Young Han
- BanryongInsu Herb Clinic, Seoul 06099, Republic of Korea
| | - Sung Hyo Park
- Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Namhyun Chung
- Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
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24
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FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells. Int J Mol Sci 2021; 22:ijms22020753. [PMID: 33451103 PMCID: PMC7828641 DOI: 10.3390/ijms22020753] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.
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25
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Reversal of cisplatin sensitization and abrogation of cisplatin-enriched cancer stem cells in 5-8F nasopharyngeal carcinoma cell line through a suppression of Wnt/β-catenin-signaling pathway. Mol Cell Biochem 2021; 476:1663-1672. [PMID: 33423190 DOI: 10.1007/s11010-020-04045-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 12/26/2020] [Indexed: 10/22/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is one of the rare cancers in western countries but predominant in Southeast Asian countries including Thailand. One major cause for failure of NPC chemotherapeutic treatments is reportedly correlated with the elevation of cancer stem cell (CSC) fractions. Thus, this present study aims to investigate the effect of cisplatin (CDDP) treatment on the enrichment of cancer stem-like cells (CSCs) and its associated signaling pathway in EBV-negative NPC cells. Cisplatin-pretreated 5-8F NPC cells (5-8F CDDP) were first generated by treating the cells with 0.5 μM cisplatin for 48 h. After the instant treatment, 5-8F CDDP showed increased IC50 values, demonstrating a decrease in CDDP sensitization. Besides, the proportion of NPC cells with cancer stem-like phenotypes comprising side population (SP), key stemness-related gene expressions including SOX2, ALDH1, CD24 was significantly enhanced. Additionally, 5-8F CDDP displayed the upregulation of β-catenin gene, suggesting its association with the CSC-initiating mechanism. Furthermore, a tankyrase inhibitor for Wnt/β-catenin pathway, XAV939, substantially reduced CSCs and retrieved the cisplatin sensitivity in 5-8F CDDP. This confirms that the Wnt/β-catenin signaling is accountable for rising of the CSC population in EBV-negative NPC. Finally, the combined treatment of CDDP and XAV939 exhibited lower 5-8F CDDP cell viability compared to the treatment of CDDP alone, suggesting the reversal of cisplatin sensitization. In conclusion, the enhancement of CSCs in 5-8F NPC cells caused by the instant cisplatin treatment is initially mediated through the upregulation of β-catenin and activation of Wnt/β-catenin signaling pathway. As a result, a primary chemotherapeutic treatment with closely monitoring the targeted Wnt/β-catenin signaling pathway could potentially prevent the development of CSCs and improve the treatment efficiency in NPC.
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26
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Zhang X, Powell K, Li L. Breast Cancer Stem Cells: Biomarkers, Identification and Isolation Methods, Regulating Mechanisms, Cellular Origin, and Beyond. Cancers (Basel) 2020; 12:E3765. [PMID: 33327542 PMCID: PMC7765014 DOI: 10.3390/cancers12123765] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/03/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Despite recent advances in diagnosis and treatment, breast cancer (BC) is still a major cause of cancer-related mortality in women. Breast cancer stem cells (BCSCs) are a small but significant subpopulation of heterogeneous breast cancer cells demonstrating strong self-renewal and proliferation properties. Accumulating evidence has proved that BCSCs are the driving force behind BC tumor initiation, progression, metastasis, drug resistance, and recurrence. As a heterogeneous disease, BC contains a full spectrum of different BC subtypes, and different subtypes of BC further exhibit distinct subtypes and proportions of BCSCs, which correspond to different treatment responses and disease-specific outcomes. This review summarized the current knowledge of BCSC biomarkers and their clinical relevance, the methods for the identification and isolation of BCSCs, and the mechanisms regulating BCSCs. We also discussed the cellular origin of BCSCs and the current advances in single-cell lineage tracing and transcriptomics and their potential in identifying the origin and lineage development of BCSCs.
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Affiliation(s)
- Xiaoli Zhang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH 43210, USA;
| | | | - Lang Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH 43210, USA;
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27
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Alzeeb G, Metges JP, Corcos L, Le Jossic-Corcos C. Three-Dimensional Culture Systems in Gastric Cancer Research. Cancers (Basel) 2020; 12:E2800. [PMID: 33003476 PMCID: PMC7601358 DOI: 10.3390/cancers12102800] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC), which includes cancer of the esophagus, the oesophagogastric junction, and the stomach fundus, is highly deadly with strong regional influence, Asia being the most affected. GC is often detected at late stages, with 30% of metastatic cases at diagnosis. Many authors have devised models to both unravel the mechanisms of GC development and to evaluate candidate therapeutics. Among these models, 2D-cell cultures are progressively replaced by 3D-cell cultures that recapitulate, much more comprehensively, tumor cellular and genetic heterogeneity, as well as responsiveness to environmental changes, such as exposure to drugs or irradiation. With respect to the specifics of GC, there are high hopes from such model systems, especially with the aim of identifying prognostic markers and novel drug targets.
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Affiliation(s)
- George Alzeeb
- Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France; (G.A.); (L.C.)
| | - Jean-Philippe Metges
- CHU de Brest, Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France;
| | - Laurent Corcos
- Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France; (G.A.); (L.C.)
- CHU de Brest, Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France;
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28
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Qallandar OB, Ebrahimi F, Islam F, Wahab R, Qiao B, Reher P, Gopalan V, Lam AKY. Bone Invasive Properties of Oral Squamous Cell Carcinoma and its Interactions with Alveolar Bone Cells: An In Vitro Study. Curr Cancer Drug Targets 2020; 19:631-640. [PMID: 30387395 DOI: 10.2174/1568009618666181102144317] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 10/01/2018] [Accepted: 10/14/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Co-culture of cancer cells with alveolar bone cells could modulate bone invasion and destructions. However, the mechanisms of interaction between oral squamous cell carcinoma (OSCC) and bone cells remain unclear. OBJECTIVE The aim of this study is to analyse the direct and indirect effects of OSCC cells in the stimulation of osteolytic activity and bone invasion. METHODS Direct co-culture was achieved by culturing OSCC (TCA8113) with a primary alveolar bone cell line. In the indirect co-culture, the supernatant of TCA8113 cells was collected to culture the alveolar bone cells. To assess the bone invasion properties, in vitro assays were performed. RESULTS The proliferation of co-cultured cancer cells was significantly (p<0.05) higher in comparison to the monolayer control cells. However, the proliferation rates were not significantly different between direct and indirect co-cultured cells with indirect co-cultured cells proliferated slightly more than the direct co-cultured cells. Invasion and migration capacities of co-cultured OSCC and alveolar bone cells enhanced significantly (p<0.05) when compared to that of control monolayer counterparts. Most importantly, we noted that OSCC cells directly co-cultured with alveolar bone cells stimulated pronounced bone collagen destruction. In addition, stem cells and epithelialmesenchymal transition markers have shown significant changes in their expression in co-cultured cells. CONCLUSION In conclusion, the findings of this study highlight the importance of the interaction of alveolar bone cells and OSCC cells in co-culture setting in the pathogenesis of bone invasion. This may help in the development of potential future biotherapies for bone invasion in OSCC.
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Affiliation(s)
- Omel Baneen Qallandar
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.,School of Dentistry and Oral Health, Griffith University, Gold Coast, Queensland, Australia
| | - Faeza Ebrahimi
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| | - Farhadul Islam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.,Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Riajul Wahab
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| | - Bin Qiao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, China
| | - Peter Reher
- School of Dentistry and Oral Health, Griffith University, Gold Coast, Queensland, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia
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29
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Lee SH, Reed-Newman T, Anant S, Ramasamy TS. Regulatory Role of Quiescence in the Biological Function of Cancer Stem Cells. Stem Cell Rev Rep 2020; 16:1185-1207. [DOI: 10.1007/s12015-020-10031-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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30
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Kihira K, Chelakkot VS, Kainuma H, Okumura Y, Tsuboya N, Okamura S, Kurihara K, Iwamoto S, Komada Y, Hori H. Close interaction with bone marrow mesenchymal stromal cells induces the development of cancer stem cell-like immunophenotype in B cell precursor acute lymphoblastic leukemia cells. Int J Hematol 2020; 112:795-806. [PMID: 32862292 DOI: 10.1007/s12185-020-02981-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/05/2020] [Accepted: 08/25/2020] [Indexed: 12/15/2022]
Abstract
Minimal residual disease of leukemia may reside in the bone marrow (BM) microenvironment and escape the effects of chemotherapeutic agents. This study investigated interactions between B cell precursor (BCP)-acute lymphoblastic leukemia (ALL) cells and BM mesenchymal stromal cells (BM-MSCs) in vitro. Five BCP-ALL cell lines established from pediatric patients and primary samples from a BCP-ALL patient were examined by flow cytometry and immunocytochemistry for expression of specific cell surface markers and cell adhesion proteins. The cell lines developed chemoresistance to commonly used anti-leukemic agents through adhesion to MSC-TERT cells in long-term culture. The change in chemosensitivity after adhering to BM-MSCs was associated with the expression of CD34, CD133, P-glycoprotein and BCRP/ABCG2, and downregulation of CD38. Similar phenotypic changes were observed in primary samples obtained by marrow aspiration or biopsy from a BCP-ALL patient. BM-MSC-adhering leukemia cells also showed deceleration of cell proliferation and expressed proteins in the Cadherin and Integrin pathways. These results suggest that BCP-ALL cells residing in the BM microenvironment may acquire chemoresistance by altering their phenotype to resemble that of cancer stem cells. Our results indicate that cell adhesion could be potentially targeted to improve the chemosensitivity of residual BCP-ALL cells in the BM microenvironment.
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Affiliation(s)
- Kentaro Kihira
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | | | - Hiroki Kainuma
- Department of Medical Education, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan
| | - Yosuke Okumura
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Naoki Tsuboya
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Satoshi Okamura
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan.,Department of Medical Education, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan
| | - Kosuke Kurihara
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan.,Department of Medical Education, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan
| | - Shotaro Iwamoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yoshihiro Komada
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hiroki Hori
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan. .,Department of Medical Education, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan.
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31
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Tong Y, Gao WQ, Liu Y. Metabolic heterogeneity in cancer: An overview and therapeutic implications. Biochim Biophys Acta Rev Cancer 2020; 1874:188421. [PMID: 32835766 DOI: 10.1016/j.bbcan.2020.188421] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022]
Abstract
Recent research on cancer metabolism has revealed that individual tumors have highly heterogeneous metabolic profiles that contribute to the connective metabolic networks within the tumor and its environment. Indeed, tumor-associated cells types, including tumor cells, cancer-associated fibroblasts (CAFs) and immune cells, reprogram their metabolism in many different ways due to diverse genetic backgrounds and complex environmental stimuli. This intratumoral metabolic heterogeneity and the derived metabolic interactions play an instrumental role in cancer progression. Understanding how this heterogeneity occurs may provide promising therapeutic strategies. Here, we review the diverse metabolic profiles of several important cell subpopulations in tumors and their impact on tumor progression and discuss the consequent metabolic interactions as well as the related therapeutic concerns.
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Affiliation(s)
- Yu Tong
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
| | - Yanfeng Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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32
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Mechanisms of cancer stem cell therapy. Clin Chim Acta 2020; 510:581-592. [PMID: 32791136 DOI: 10.1016/j.cca.2020.08.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are responsible for carcinogenesis and tumorigenesis and are involved in drug and radiation resistance, metastasis, tumor relapse and initiation. Remarkably, they have other abilities such as inheritance of self-renewal and de-differentiation. Hence, targeting CSCs is considered a potential anti-cancer therapeutic strategy. Recent advances in the identification of biomarkers to recognize CSCs and the development of new techniques to evaluate tumorigenic and carcinogenic roles of CSCs are instrumental to this approach. Elucidation of signaling pathways that regulate CSCs colony progression and drug resistance are critical in establishing effective targeted therapies. CSCs play a central key role in immunomodulation, immune evasion and effector immunity, which alters immune system balancing. These include mTOR, SHH, NOTCH and Wnt/β-catering in cancer progression. In this review article, we discuss the importance of these CSCs pathways in cancer therapy.
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33
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Soltanian S, Sheikhbahaei M, Ziasistani M. Phytol Down-Regulates Expression of Some Cancer Stem Cell Markers and Decreases Side Population Proportion in Human Embryonic Carcinoma NCCIT Cells. Nutr Cancer 2020; 73:1520-1533. [PMID: 32700607 DOI: 10.1080/01635581.2020.1795695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cancer stem cells (CSCs), a subgroup of cancer cells, have self-renewal capacity and differentiation potential and drive tumor growth. CSCs are highly-resistant to conventional chemo-radio therapy. Phytochemicals were shown to be able to eliminate CSCs. Phytol is a diterpene alcohol with demonstrated anticancer effects. The current study compared the effect of phytol with retinoic acid (RA) as a well-known inducers of CSC differentiation and cisplatin, a common chemotherapy drug, on CSC markers in human embryonic carcinoma NCCIT cells. NCCIT cells were exposed to 10 mM RA for 14 day to induce differentiation. Moreover, NCCIT cells were treated with IC50 dose of cisplatin (12 µM) and phytol (40 µM) for 7 day. Real-time PCR showed that phytol was more effective that RA and cisplatin in down-regulating the CSC markers OCT4, NANOG, SOX2, ALDH1, ABCB1, CD44 and CD133. Percentage of SP (13%) and ABCB1+ (0.34%) in NCCIT cells decreased to 7% and 0.1% respectively after treatment with phytol. A very small proportion of NCCIT cells were positive for CD44 (0.2%) and CD133 (0.48%) and this fraction did not change significantly after treatment with three agents. In conclusion, phytol has the greatest inhibitory effect on CSC population and markers than RA and cisplatin.
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Affiliation(s)
- Sara Soltanian
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Mahboubeh Sheikhbahaei
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Mahsa Ziasistani
- Pathology and Stem Cell Research Center, Afzalipour Medical School, Kerman University of Medical Sciences, Kerman, Iran
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34
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Liang L, He Y, Wang H, Zhou H, Xiao L, Ye M, Kuang Y, Luo S, Zuo Y, Feng P, Yang C, Cao W, Liu T, Roy M, Xiao X, Liu J. The Wee1 kinase inhibitor MK1775 suppresses cell growth, attenuates stemness and synergises with bortezomib in multiple myeloma. Br J Haematol 2020; 191:62-76. [PMID: 32314355 DOI: 10.1111/bjh.16614] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 03/05/2020] [Indexed: 12/16/2022]
Abstract
Multiple myeloma stem-like cells (MMSCs) are responsible for initiation and relapse, though novel treatment paradigms that effectively eradicate MMSCs are yet to be developed. Selective inhibition of the cell cycle regulatory kinase Wee1 by MK1775 is being explored as a potential anti-cancer therapeutic. We report that higher expression of Wee1 is correlated with poor survival in multiple myeloma (MM). The MM models and patient-derived CD138+ plasma cells are particularly sensitive to the growth-inhibitory effects of the Wee1 inhibitor MK1775. MK1775 induces Mus81-Eme1 endonuclease-mediated DNA damage in S-phase cell cycle that results in a blockade of replication and then apoptosis. Furthermore, MK1775 strongly suppresses the features of stemness in vitro, in vivo and in primary CD138+ cells by decreasing ALDH1+ cell fraction and the expression of ALDH1. In addition, co-treatment of MK1775 with bortezomib is synergistic in vitro and in vivo. Bortezomib, although it enhances ALDH1+ cells, when combined with MK1775 abrogates this stimulatory effect on stemness. Considering MM as an invariably incurable malignancy due to the presence of heterogenic myeloma stem-like cells, our study presents inhibition of Wee1 as a promising targeted therapy for MM and provides a compelling rationale to further investigate the activity of MK1775 against myeloma in clinical settings.
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Affiliation(s)
- Long Liang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.,Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Yanjuan He
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Haiqin Wang
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Hui Zhou
- Lymphoma & Hematology Department, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Ling Xiao
- Department of Histology and Embryology of School of Basic Medical Sciences, Central South University, Changsha, China
| | - Mao Ye
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Yijin Kuang
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Saiqun Luo
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Yuna Zuo
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Peifu Feng
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Chaoying Yang
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Wenjie Cao
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China.,Department of Histology and Embryology of School of Basic Medical Sciences, Central South University, Changsha, China
| | - Taohua Liu
- Department of Clinical Medicine, Xiangya Medical School, Changsha, China
| | - Mridul Roy
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Xiaojuan Xiao
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Jing Liu
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
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Wang H, Gong Y, Liang L, Xiao L, Yi H, Ye M, Roy M, Xia J, Zhou W, Yang C, Shen X, Zhang B, Li Z, Liu J, Zhou H, Xiao X. Lycorine targets multiple myeloma stem cell-like cells by inhibition of Wnt/β-catenin pathway. Br J Haematol 2020; 189:1151-1164. [PMID: 32167591 DOI: 10.1111/bjh.16477] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022]
Abstract
Multiple myeloma (MM) is characterised by the proliferation and accumulation of malignant plasma cells in the bone marrow. Despite the progress in treatment over the last few years, MM remains incurable and the majority of patients relapse. MM stem-like cells (MMSCs) have been considered as the main reason for drug resistance and eventual relapse. Currently, therapeutic agents are not enough to eradicate MMSCs, and finding effective strategies to eradicate MMSCs may improve the outcome of patients. Here we showed that lycorine, a natural compound from the Amaryllidaceae species, effectively inhibits the proliferation of myeloma cells from cell lines or patients, mainly through decreasing ALDH1+ cells. Mechanistically, lycorine decreases the MMSC population through inhibition of the Wnt/β-catenin pathway by reducing the β-catenin protein level. Moreover, lycorine could overcome the increasing proportion of ALDH1+ cells caused by bortezomib (BTZ) treatment, and a combination BTZ and lycorine have a synergistic effect on anti-myeloma cells. Furthermore, we found a similar reduction of MMSC characteristics by lycorine in BTZ-resistant MM cells and primary CD138+ plasma cells. Collectively, our findings indicate lycorine as a promising agent to target MMSCs to overcome the drug resistance of BTZ, and that, alone or in combination with BTZ, lycorine is a potential therapeutic strategy for MM treatments.
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Affiliation(s)
- Haiqin Wang
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Yanfei Gong
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Long Liang
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China.,Hematology Department, Xiangya Hospital, Central South University, Changsha, China
| | - Ling Xiao
- Department of Histology and Embryology of School of Basic Medical Sciences, Central South University, Changsha, China
| | - Hui Yi
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Mao Ye
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Mridul Roy
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China.,Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Jiliang Xia
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China
| | - Wen Zhou
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China
| | - Chaoying Yang
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Xiaokai Shen
- Xiangya Medical School, Central South University, Changsha, China
| | - Boxin Zhang
- Xiangya Medical School, Central South University, Changsha, China
| | - Zhenzhen Li
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Jing Liu
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Hui Zhou
- Lymphoma & Hematology Department, the Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, China
| | - Xiaojuan Xiao
- Molecular Biology Research Center & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
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Abstract
Cancer stem cells (CSCs) are a small subpopulation of cells associated with cancer initiation, progression, metastasis, therapy resistant, and recurrence. In esophageal squamous cell carcinoma (ESCC), several cell surface and intracellular markers, for example, CD44, ALDH, Pygo2, MAML1, Twist1, Musashi1, side population (SP), CD271, and CD90, have been proposed to identify CSCs. In addition, stem cell markers such as ALDH1, HIWI, Oct3/4, ABCG2, SOX2, SALL4, BMI-1, NANOG, CD133, and podoplanin were associated with pathological stages of cancer, cancer recurrence, prognosis, and therapy resistance of patients with ESCC. Identification and isolation of CSCs could play an important part of improved cancer management regime in ESCC. Furthermore, CSCs may be used as the predictive tool for chemoradiotherapy response in ESCC. Different methods such as in vitro functional assays, cell sorting using various intracellular, and cell surface markers and xenotransplantation techniques are frequently used for the identification and isolation of CSCs in different cancers, including ESCC. However, none of these methods solely can guarantee complete isolation of CSC population. Therefore, a combination of methods is used for reliable detection and isolation of CSCs. Herein, we describe the identification and isolation of CSCs from ESCC cells by cell sorting after Hoechst 33342 staining followed by in vitro functional assays and in vivo mouse xenotransplantation techniques.
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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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Mendoza-Almanza G, Ortíz-Sánchez E, Rocha-Zavaleta L, Rivas-Santiago C, Esparza-Ibarra E, Olmos J. Cervical cancer stem cells and other leading factors associated with cervical cancer development. Oncol Lett 2019; 18:3423-3432. [PMID: 31516560 PMCID: PMC6733009 DOI: 10.3892/ol.2019.10718] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 06/06/2019] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer (CC) is one of the leading causes of cancer-associated mortalities in women from developing countries. Similar to other types of cancer, CC is considered to be a multifactorial disease, involving socioeconomic, cultural, immunological and epigenetic factors, as well as persistent human papilloma virus (HPV) infection. It has been well established that cancer stem cells (CSCs) play an important role in defining tumor size, the speed of development and the level of regression following treatment; therefore, CSCs are associated with a poor prognosis. CSCs have been detected in many types of cancer, including leukemia, pancreatic, colon, esophagus, liver, prostate, breast, gastric and lung cancer. In cervical cancer, CSCs have been associated with resistance to normally used drugs such as cisplatin. The present review summarizes the strategies that high-risk HPV viruses (HPV-16 and HPV-18) have developed to transform normal epithelial cells into cancer cells, as well as the cellular pathways and studies associated with the identification of cervical cancer stem cell biomarkers. In this sense, the present review provides state of the art information regarding CC development.
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Affiliation(s)
- Gretel Mendoza-Almanza
- National Council for Science and Technology, Autonomous University of Zacatecas, Zacatecas 98060, Mexico
| | | | - Leticia Rocha-Zavaleta
- Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - César Rivas-Santiago
- National Council for Science and Technology, Autonomous University of Zacatecas, Zacatecas 98060, Mexico
| | - Edgar Esparza-Ibarra
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98060, Mexico
| | - Jorge Olmos
- Department of Marine Biotechnology, Center for Scientific Research and Higher Education, Ensenada 22860, Mexico
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Miranda R, Farina E, Farina MA. Micrografting chronic lower extremity ulcers with mechanically disaggregated skin using a micrograft preparation system. J Wound Care 2019; 27:60-65. [PMID: 29424645 DOI: 10.12968/jowc.2018.27.2.60] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE The Rigenera system is a new standardised micrograft preparation system. It works by means of automated mechanical disaggregation of small tissue samples, extracting only the smallest cells (<50µm). The aim of this study was to retrospectively evaluate patients affected by chronic ulcers and who were treated with the micrograft preparation method. METHOD Chronic ulcers have been included regardless of the cause. The specimen was collected with a 3mm diameter biopsy punch and immediately dissociated by means of the Rigenera System. The obtained suspension was placed on a scaffold of equine collagen. RESULTS We included 15 patients (four males, 11 females) with a mean age of 72.2±8.41 (mean±standard deviation) years. In seven patients the ulcers were related to the complications of diabetes, post-traumatic in a further three diabetic patients, vasculitis in one patient, and four patients had venous leg ulcers (VLUs). The median main diameter was 5.0cm and the median estimated area was 43.96cm2. The ulcers were present from a mean of 4.50±2.30 months before inclusion in this study. At the second week the wounds were reduced by 37.33%±19.35%, at the week eight, nine patients (60.0%) were healed, and at week 16, 13 (86.7%) were healed. The quality of scars was good and did not deteriorate at the six month follow-up. CONCLUSION The simplicity of the approach, the minimal invasiveness of the specimen collection, and the good quality of scarring of healed wounds, confirmed in the follow-up, makes this micrograft preparation method a useful tool to use on large or complex wounds.
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Affiliation(s)
- Rosario Miranda
- Medical Angiologist, Specialista Ambulatoriale Branca di Angiologia - Azienda Sanitaria Locale NA3-Sud Distretto di Nola (NA), Italy
| | - Eleonora Farina
- Vascular Surgeon, Clinica Minerva - Santa Maria Capua Vetere (CE), Italy
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40
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Ward Rashidi MR, Mehta P, Bregenzer M, Raghavan S, Fleck EM, Horst EN, Harissa Z, Ravikumar V, Brady S, Bild A, Rao A, Buckanovich RJ, Mehta G. Engineered 3D Model of Cancer Stem Cell Enrichment and Chemoresistance. Neoplasia 2019; 21:822-836. [PMID: 31299607 PMCID: PMC6624324 DOI: 10.1016/j.neo.2019.06.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 06/03/2019] [Accepted: 06/12/2019] [Indexed: 12/14/2022] Open
Abstract
Intraperitoneal dissemination of ovarian cancers is preceded by the development of chemoresistant tumors with malignant ascites. Despite the high levels of chemoresistance and relapse observed in ovarian cancers, there are no in vitro models to understand the development of chemoresistance in situ. Method: We describe a highly integrated approach to establish an in vitro model of chemoresistance and stemness in ovarian cancer, using the 3D hanging drop spheroid platform. The model was established by serially passaging non-adherent spheroids. At each passage, the effectiveness of the model was evaluated via measures of proliferation, response to treatment with cisplatin and a novel ALDH1A inhibitor. Concomitantly, the expression and tumor initiating capacity of cancer stem-like cells (CSCs) was analyzed. RNA-seq was used to establish gene signatures associated with the evolution of tumorigenicity, and chemoresistance. Lastly, a mathematical model was developed to predict the emergence of CSCs during serial passaging of ovarian cancer spheroids. Results: Our serial passage model demonstrated increased cellular proliferation, enriched CSCs, and emergence of a platinum resistant phenotype. In vivo tumor xenograft assays indicated that later passage spheroids were significantly more tumorigenic with higher CSCs, compared to early passage spheroids. RNA-seq revealed several gene signatures supporting the emergence of CSCs, chemoresistance, and malignant phenotypes, with links to poor clinical prognosis. Our mathematical model predicted the emergence of CSC populations within serially passaged spheroids, concurring with experimentally observed data. Conclusion: Our integrated approach illustrates the utility of the serial passage spheroid model for examining the emergence and development of chemoresistance in ovarian cancer in a controllable and reproducible format.
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Affiliation(s)
- Maria R Ward Rashidi
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Pooja Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Michael Bregenzer
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Shreya Raghavan
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Elyse M Fleck
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Eric N Horst
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Zainab Harissa
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Visweswaran Ravikumar
- Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samuel Brady
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
| | - Andrea Bild
- Division of Molecular Pharmacology, Department of Medical Oncology and Therapeutics, City of Hope Cancer Institute, Duarte, CA, USA
| | - Arvind Rao
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Radiation Oncology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Ronald J Buckanovich
- Director of Ovarian Cancer Research, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Geeta Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI, USA..
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MicroRNA-192-5p Promote the Proliferation and Metastasis of Hepatocellular Carcinoma Cell by Targeting SEMA3A. Appl Immunohistochem Mol Morphol 2019; 25:251-260. [PMID: 26580097 DOI: 10.1097/pai.0000000000000296] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Side population (SP) cells are a small subset of cells isolated from a cultured cancer cell line with characteristics similar to those of cancer stem cells, such as high metastatic and tumorigenic potentials. However, the molecular mechanisms remain unclear for the malignant properties of SP cells. In this study, SP cells were isolated by staining cultured HCCLM3 cells with fluorescent DNA-binding dye Hoechst 33342 and sorted by flow cytometry. The proportion of SP cells was 2.79%±0.19% in the HCCLM3 cell line. Compared with non-SP cells, SP cells possessed stronger capability of sphere formation and tumorigenicity, and expressed higher levels of CD133 and CD90. Then, we found that SP cells possessed 25 upregulated and 34 downregulated microRNAs with differences of >3-fold. As one of the upregulated microRNAs, miR-192-5p was computationally predicted to target semaphorin 3A (SEMA3A), a potent suppressor of tumor angiogenesis in various cancer models. Luciferase reporter assay showed that SEMA3A was a direct target of miR-192-5p. Overexpression of miR-192-5p promoted cell proliferation and metastasis targeting SEMA3A in HCCLM3 cells. Immunohistochemical staining revealed that SEMA3A expression was significantly reverse associated with metastasis in hepatocellular carcinoma tissues. The results indicate that miR-192-5p contributes to targeting SEMA3A in HCCLM3 cells, and this may be used as a target in targeted therapy and a marker for cancer behavior and prognosis.
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42
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Cai W, Wang Z, Wei C, Wu M, Zheng W, Zhang H, Liu C, Liu L. Prognostic evaluation of NANOG and OCT4 expression for posttransplantation hepatocellular carcinoma recurrence. J Cell Biochem 2019; 120:8419-8429. [PMID: 30506712 DOI: 10.1002/jcb.28128] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 10/31/2018] [Indexed: 01/24/2023]
Abstract
Postoperative hepatocellular carcinoma (HCC) recurrence and metastasis throw great threaten to its overall survival (OS). This paper focus on exploring the prognostic significance of NANOG and OCT4 expression in HCC recurrence and OS after liver transplantation. Eighty-six patients who meet University of California San Francisco (UCSF) criteria and underwent liver transplantation in Tianjin First Central Hospital between August 2010 and August 2013 were included. Expression of NANOG and OCT4 was determined by immunohistochemistry. The relationships between NANOG and OCT4 expression with tumor recurrence, tumor count, histology stage, lymph node metastasis (LNM) and microvascular invasion (MVI) were explored through the χ2 test and Cox regression analysis. We found that 19/26 and 20/24 patients with positive expression of NANOG and OCT4 relapsed. Combination of NANOG and OCT4 expression was indicated as valuable prognostic signature for HCC recurrence prediction (P < 0.0011). Besides, we identified other key factors with significant correlations with recurrence, such as LNM (P = 0.011) and MVI (P = 0.024). Strikingly, recurrence sites could significantly affect recurrence time (P = 0.0062) and patients with recurrence in transplanted liver have longer recurrence time. In conclusions, we analyzed the relationships between NANOG/OCT4 expression, clinicopathology features, HCC recurrence, and OS after liver transplantation for the first time. Combination of NANOG, OCT4, LNM, histopathological stage, and MVI may be predictor for HCC recurrence posttransplantation. Comprehensive of histopathological stage grade and LNM were considered as prognosis factor for OS after liver transplantation. This should be helpful for treatment method selection for HCC patients after liver transplantation.
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Affiliation(s)
- Wenjuan Cai
- Pathology Department, Tianjin First Center Hospital, Tianjin, China
| | - Zhenglu Wang
- Pathology Department, Tianjin First Center Hospital, Tianjin, China.,Biobank, Tianjin First Center Hospital, Tianjin, China
| | - Chunfang Wei
- School of Medicine, Nankai University, Tianjin, China
| | - Meng Wu
- School of Medicine, Nankai University, Tianjin, China
| | - Weiping Zheng
- Organ Transplant Center, Tianjin First Center Hospital, Tianjin, China
| | - Haiming Zhang
- Key Lab for Critical Care Medicine of the Ministry of Health, Tianjin First Center Hospital, Tianjin, China
| | - Chenghu Liu
- School of Medicine, Nankai University, Tianjin, China
| | - Lei Liu
- Tianjin Key Laboratory of Organ Transplantation, Tianjin, China.,Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
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Zhou X, Ma Y, Liu F, Gu C, Wang X, Xia H, Zhou G, Huang J, Luo X, Yang J. Melanocyte Chitosan/Gelatin Composite Fabrication with Human Outer Root Sheath-Derived Cells to Produce Pigment. Sci Rep 2019; 9:5198. [PMID: 30914712 PMCID: PMC6435804 DOI: 10.1038/s41598-019-41611-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 03/11/2019] [Indexed: 12/26/2022] Open
Abstract
The hair follicle serves as a melanocyte reservoir for both hair and skin pigmentation. Melanocyte stem cells (MelSCs) and melanocyte progenitors reside in the bulge/sub-bulge region of the lower permanent portion of the hair follicle and play a vital role for repigmentation in vitiligo. It would be beneficial to isolate MelSCs in order to further study their function in pigmentary disorders; however, due to the lack of specific molecular surface markers, this has not yet been successfully accomplished in human hair follicles (HuHF). One potential method for MelSCs isolation is the “side population” technique, which is frequently used to isolate hematopoietic and tumor stem cells. In the present study, we decided to isolate HuHF MelSCs using “side population” to investigate their melanotic function. By analyzing mRNA expression of TYR, SOX10, and MITF, melanosome structure, and immunofluorescence with melanocyte-specific markers, we revealed that the SP-fraction contained MelSCs with an admixture of differentiated melanocytes. Furthermore, our in vivo studies indicated that differentiated SP-fraction cells, when fabricated into a cell-chitosan/gelatin composite, could transiently repopulate immunologically compromised mice skin to regain pigmentation. In summary, the SP technique is capable of isolating HuHF MelSCs that can potentially be used to repopulate skin for pigmentation.
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Affiliation(s)
- Xianyu Zhou
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Yan Ma
- Division of Plastic Surgery, Xinjiang Korla Bazhou People's Hospital, Xinjiang, People's Republic of China
| | - Fei Liu
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Chuan Gu
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Xiuxia Wang
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Huitang Xia
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Guangdong Zhou
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Jinny Huang
- Department of Transplantation, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xusong Luo
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
| | - Jun Yang
- Department of Plastic and Reconstructive Surgery, the Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
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Lin HW, Chiang YC, Sun NY, Chen YL, Chang CF, Tai YJ, Chen CA, Cheng WF. CHI3L1 results in poor outcome of ovarian cancer by promoting properties of stem-like cells. Endocr Relat Cancer 2019; 26:73-88. [PMID: 30121622 DOI: 10.1530/erc-18-0300] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/13/2018] [Indexed: 12/15/2022]
Abstract
The role of chitinase-3-like protein 1 (CHI3L1) in ovarian cancer and the possible mechanisms were elucidated. CHI3L1 is a secreted glycoprotein and associated with inflammation, fibrosis, asthma, extracellular tissue remodeling and solid tumors. Our previous study showed CHI3L1 could be a potential prognostic biomarker for epithelial ovarian cancer and could protect cancer cells from apoptosis. Therefore, clinical data and quantitation of CHI3L1 of ovarian cancer patients, tumor spheroid formation, side-population assays, Aldefluor and apoptotic assays, ELISA, RT-PCR, immunoblotting and animal experiments were performed in two ovarian cancer cells lines, OVCAR3 and CA5171, and their CHI3L1-overexpressing and -knockdown transfectants. High expression of CHI3L1 was associated with poor outcome and chemoresistance in ovarian cancer patients. The mRNA expression of CHI3L1 in CA5171 ovarian cancer stem-like cells was 3-fold higher than in CA5171 parental cells. CHI3L1 promoted the properties of ovarian cancer stem-like cells including generating more and larger tumor spheroids and a higher percentage of ALDH+ in tumor cells and promoting resistance to cytotoxic drug-induced apoptosis. CHI3L1 could induce both the Akt (essential) and Erk signaling pathways, and then enhance expression of β-catenin followed by SOX2, and finally promote tumor spheroid formation and other properties of ovarian cancer stem-like cells. OVCAR3 CHI3L1-overexpressing transfectants were more tumorigenic in vivo, whereas CA5171 CHI3L1-knockdown transfectants were not tumorigenic in vivo. CHI3L1 critically enhances the properties of ovarian cancer stem-like cells. CHI3L1 or CHI3L1-regulated signaling pathways and molecules could be potential therapeutic targets in ovarian cancer.
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Affiliation(s)
- Han-Wei Lin
- Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan
| | - Ying-Cheng Chiang
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Nai-Yun Sun
- Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan
| | - Yu-Li Chen
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Chi-Fang Chang
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Yi-Jou Tai
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Chi-An Chen
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Wen-Fang Cheng
- Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Ruan Z, Yang X, Cheng W. OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells. Cancer Manag Res 2018; 11:389-399. [PMID: 30643464 PMCID: PMC6314052 DOI: 10.2147/cmar.s180418] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Although surgery, chemotherapy, and radiotherapy eliminate clinically apparent ovarian tumor, the 5-year survival rate is no more than 45%. Cancer stem cells (CSCs) have been identified for precaution of tumor metastasis and recurrence in many kinds of cancers including ovarian cancer. AIM This study aims to explore the function of OCT4, a CSC marker, in ovarian cancer progression and to investigate its underlying mechanism. MATERIALS AND METHODS By Hoechst side population (SP) technique, CSC-like SP cells from human ovarian cancer SKOV3 and A2780 cells were isolated and used for this study. shRNA and lentivirus targeting human OCT4 gene were used to knock down OCT4 in SP cells and upregulate OCT4 in non-SP (NSP) cells stably. Peficitinib was used to inhibit JAK/STAT signaling. Cell counting kit-8, flow cytometry, and in vivo xenograft model were used to evaluate the effects of OCT4/JAK/STAT on the viability, drug resistance, apoptosis, cycle, and tumorigenesis of the SP cells. Immunofluorescence staining was used to detect the location of STAT6. RESULTS Results showed that OCT4 was upregulated in the SP of SKOV3 and A2780 cells when compared with the NSP cells. Downregulation of OCT4 inhibited SP cell viability, tumorigenesis, and reduced cell drug resistance and induced a G2/M phase arrest, while upregulation of OCT4 conferred NSP cell malignant features. Besides, OCT4 upregulation in NSP cells increased the phosphorylated levels of proteins in JAK and STAT families, especially in JAK1 and STAT6. Furthermore, the roles of apoptosis inhibition and viability, invasion, and tumorigenesis promotions induced by OCT4 in NSP cells were all abolished when adding peficitinib. CONCLUSION Our study demonstrated that OCT4 accelerated ovarian cancer progression through activating JAK/STAT signaling pathway.
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Affiliation(s)
- Zhengyi Ruan
- Department of Obstetrics and Gynaecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,
| | - Xingyu Yang
- Department of Obstetrics and Gynaecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,
| | - Weiwei Cheng
- Department of Obstetrics and Gynaecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China,
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Ring A, Nguyen C, Smbatyan G, Tripathy D, Yu M, Press M, Kahn M, Lang JE. CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer. Cancers (Basel) 2018; 10:cancers10120525. [PMID: 30572639 PMCID: PMC6315782 DOI: 10.3390/cancers10120525] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/11/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022] Open
Abstract
Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials.
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Affiliation(s)
- Alexander Ring
- Department of Oncology and Hematology, UniversitätsSpital Zürich, Rämistrasse 100, 0832 Zürich 1, The Netherlands.
| | - Cu Nguyen
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Goar Smbatyan
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Debu Tripathy
- Department of Breast Medical Oncology, UT-MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Min Yu
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Michael Press
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Julie E Lang
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
- Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA.
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Nakagawa M, Fujita S, Katsumoto T, Yamagata K, Ogawara Y, Hattori A, Kagiyama Y, Honma D, Araki K, Inoue T, Kato A, Inaki K, Wada C, Ono Y, Yamamoto M, Miura O, Nakashima Y, Kitabayashi I. Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma. Cancer Sci 2018; 110:194-208. [PMID: 30343511 PMCID: PMC6317945 DOI: 10.1111/cas.13840] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 12/19/2022] Open
Abstract
Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug‐resistant myeloma stem cells. Side population (SP) cells show cancer stem cell‐like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non‐SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient‐derived xenograft model. Moreover, long‐term continuous dosing of OR‐S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR‐S1, leading to significant advances in the treatment of MM.
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Affiliation(s)
- Makoto Nakagawa
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.,Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shuhei Fujita
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
| | - Takuo Katsumoto
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazutsune Yamagata
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoko Ogawara
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
| | - Ayuna Hattori
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuki Kagiyama
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.,Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Daisuke Honma
- Oncology Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Kazushi Araki
- Oncology Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Tatsuya Inoue
- Functional Genomics and Proteomics Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan
| | - Ayako Kato
- Functional Genomics and Proteomics Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan
| | - Koichiro Inaki
- Functional Genomics and Proteomics Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan
| | - Chisa Wada
- Functional Genomics and Proteomics Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan
| | - Yoshimasa Ono
- Functional Genomics and Proteomics Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan
| | - Masahide Yamamoto
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Osamu Miura
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuharu Nakashima
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Issay Kitabayashi
- Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
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Soltanian S, Riahirad H, Pabarja A, Jafari E, Khandani BK. Effect of Cinnamic acid and FOLFOX in diminishing side population and downregulating cancer stem cell markers in colon cancer cell line HT-29. Daru 2018; 26:10.1007/s40199-018-0210-8. [PMID: 30209760 PMCID: PMC6154487 DOI: 10.1007/s40199-018-0210-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/06/2018] [Indexed: 12/26/2022] Open
Abstract
PURPOSE There is a lot of evidence suggesting that a small subset of cancer cells resistant to conventional chemotherapy and radiotherapy and known as cancer stem cells (CSCs) is responsible for promoting metastasis and cancer relapse. Therefore, targeting and eliminating the CSCs could lead to higher survival rates and a better quality of life. In comparison with conventional chemical drugs that may not be effective against CSCs, phytochemicals are strong anti-CSCs agents. The current study examines the effect of 5-fluorouracil plus oxaliplatin (FOLFOX) as a common chemotherapy drug on colorectal cancer as well as the influence of Cinnamic acid (CINN) as a plant-derived phytochemical on colon cancer stem-like cells in HT-29 adenocarcinoma cell line. METHODS The anti-proliferative effect of FOLFOX and CINN was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Flow cytometry analysis was used for the identification of side population (SP), CD44, and CD133 positive cells. The expression of OCT4, NANOG, ABCB1, and ALDH1A was assessed by RT-PCR. RESULTS The FOLFOX and CINN decreased cell viability in certain drug concentrations: IC50 = 5,40 μM oxaliplatin +220 μM 5-fluorouracil, and 13,50 mM for CINN. The CSC-associated markers (OCT4, NANOG, ABCB1, and ALDH1A) and the proportion of cancer stem-like cells (SP cells, CD44, and CD133 positive cells) were downregulated following the treatment of HT-29 adenocarcinoma cell line with IC50 concentrations of FOLFOX and CINN. CONCLUSION Our data suggests that CINN, a naturally occurring component, could be more effective than FOLFOX treatment in reducing the cancer stem-like cells and expression of CSC markers from HT-29 colon cancer cells. Graphical abstract ᅟ.
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Affiliation(s)
- Sara Soltanian
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Helia Riahirad
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Athareh Pabarja
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Elham Jafari
- Pathology and Stem Cell Research Center, Kerman University of Medical Science, Kerman, Iran
| | - Behjat Kalantari Khandani
- Department of Internal Medicine, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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Ren YM, Duan YH, Sun YB, Yang T, Zhao WJ, Zhang DL, Tian ZW, Tian MQ. Exploring the key genes and pathways of side population cells in human osteosarcoma using gene expression array analysis. J Orthop Surg Res 2018; 13:153. [PMID: 29921292 PMCID: PMC6006685 DOI: 10.1186/s13018-018-0860-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 06/08/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human osteosarcoma (OS) is one of the most common primary bone sarcoma, because of early metastasis and few treatment strategies. It has been reported that the tumorigenicity and self-renewal capacity of side population (SP) cells play roles in human OS via regulating of target genes. This study aims to complement the differentially expressed genes (DEGs) that regulated between the SP cells and the non-SP cells from primary human OS and identify their functions and molecular pathways associated with OS. METHODS The gene expression profile GSE63390 was downloaded, and bioinformatics analysis was made. RESULTS One hundred forty-one DEGs totally were identified. Among them, 72 DEGs (51.06%) were overexpressed, and the remaining 69 DEGs (48.94%) were underexpressed. Gene ontology (GO) and pathway enrichment analysis of target genes were performed. We furthermore identified some relevant core genes using gene-gene interaction network analysis such as EIF4E, FAU, HSPD1, IL-6, and KISS1, which may have a relationship with the development process of OS. We also discovered that EIF4E/mTOR signaling pathway could be a potential research target for therapy and tumorigenesis of OS. CONCLUSION This analysis provides a comprehensive understanding of the roles of DEGs coming from SP cells in the development of OS. However, these predictions need further experimental validation in future studies.
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Affiliation(s)
- Yi-Ming Ren
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Yuan-Hui Duan
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Yun-Bo Sun
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Tao Yang
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Wen-Jun Zhao
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Dong-Liang Zhang
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Zheng-Wei Tian
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
| | - Meng-Qiang Tian
- Department of Joint and Sport Medicine, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121 People’s Republic of China
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