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Affiliation(s)
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Cited by Other Article(s) |
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1
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Yu R, Ji X, Zhang P, Zhang H, Qu H, Dong W. The potential of chimeric antigen receptor -T cell therapy for endocrine cancer. World J Surg Oncol 2025; 23:153. [PMID: 40264184 PMCID: PMC12012980 DOI: 10.1186/s12957-025-03745-x] [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: 12/20/2024] [Accepted: 03/07/2025] [Indexed: 04/24/2025] Open
Abstract
Endocrine cancer, a relatively rare and heterogeneous tumor with diverse clinical features. The facile synthesis of hormones further complicates endocrine cancer treatment. Thus, the development of safe and effective systemic treatment approaches, such as chimeric antigen receptor (CAR) T cell therapy, is imperative to enhance the prognosis of patients with endocrine cancer. Although this therapy has achieved good results in the treatment of hematological malignancies, it encounters diverse complications and challenges in the context of endocrine cancer. This review delineates the generation of CAR-T cells, examines the potential of CAR-T cell therapy for endocrine cancer, enumerates pivotal antigens linked to endocrine cancer, encapsulates the challenges confronted with CAR-T cell therapy for endocrine cancer, and expounds upon strategies to overcome these limitations. The primary objective is to provide insightful perspectives that can contribute to the advancement of CAR-T cell therapy in the field of endocrine cancer.
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Affiliation(s)
- Ruonan Yu
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Xiaoyu Ji
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Huiling Qu
- Department of Neurology, The General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, Liaoning, 110840, China.
| | - Wenwu Dong
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China.
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2
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Zhu Y, Abedini A, Rodriguez GM, McCloskey CW, Abou-Hamad J, Salah OS, Larocque J, Tsoi MF, Boerboom D, Cook D, Vanderhyden B. Loss of LATS1 and LATS2 promotes ovarian tumor formation by enhancing AKT activity and PD-L1 expression. Oncogene 2025:10.1038/s41388-025-03387-z. [PMID: 40221530 DOI: 10.1038/s41388-025-03387-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/14/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
High-grade serous ovarian cancer (HGSOC) is the deadliest and most common subtype of ovarian cancer. Unfortunately, most patients develop recurrence and, ultimately, resistance to standard platinum chemotherapy. Large tumor suppressors LATS1 and LATS2, the core Hippo signaling kinases, have been implicated in various cancer types, including ovarian cancer. The mechanism by which LATS1/2 suppresses ovarian cancer progression is currently elusive, but the expression of LATS1/2 is frequently reduced or lost in these cancers. In this study, we demonstrate that the inactivation of LATS1/2 is sufficient to transform normal mouse ovarian epithelium into tumorigenic cells associated with increased cell proliferation, invasion, and stemness and epithelial-mesenchymal transition (EMT) characteristics. The knockout of Lats1/2 in the epithelial cells also leads to higher expression levels of the immune checkpoint molecule PD-L1, suggesting a regulatory role of LATS1/2 in modulating immune responses and immune evasion. In addition to the loss of LATS1/2 activating the downstream transcriptional coactivators YAP and TAZ, PI3K-AKT activity was also increased, likely contributing to enhanced tumor proliferation and survival. The stimulatory effect of Lats1/2 knockout on cell proliferation can be partially reversed by treatment with the AKT inhibitor MK2206. Treatment with verteporfin, a potent inhibitor of YAP/TAZ, decreases ovarian tumor progression and reduces the activated AKT in the tumors. In summary, this study uncovers several biological mechanisms for the initiation of HGSOC and identifies LATS1/2 as potential prognostic indicators and therapeutic targets.
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Affiliation(s)
- Yalun Zhu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Atefeh Abedini
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Galaxia M Rodriguez
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Curtis W McCloskey
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - John Abou-Hamad
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Omar Salah Salah
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Janie Larocque
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Mayra F Tsoi
- Centre de Recherche en Reproduction et Fertilité (CRRF), Université de Montréal, Saint-Hyacinthe, QC, Canada
| | - Derek Boerboom
- Centre de Recherche en Reproduction et Fertilité (CRRF), Université de Montréal, Saint-Hyacinthe, QC, Canada
| | - David Cook
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Barbara Vanderhyden
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
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3
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Yuan J, Guan W, Li X, Wang F, Liu H, Xu G. RBM15‑mediating MDR1 mRNA m 6A methylation regulated by the TGF‑β signaling pathway in paclitaxel‑resistant ovarian cancer. Int J Oncol 2023; 63:112. [PMID: 37594126 PMCID: PMC10552772 DOI: 10.3892/ijo.2023.5560] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023] Open
Abstract
Ovarian cancer (OC) lacks effective biomarkers for diagnosis at an early stage and often develops chemoresistance after the initial treatment at an advanced stage. RNA‑binding motif protein 15 (RBM15) is an RNA m6A methylation mediator that serves an oncogenic role in some cancers. However, the function and molecular mechanisms of RBM15 in ovarian tumorigenesis and chemoresistance remain to be elucidated. The present study identified the overexpression of RBM15 in OC tissues and paclitaxel (PTX)‑resistant cells using reverse transcription‑quantitative (q)PCR, western blotting and immunohistochemistry. Clinical data analyses showed that high expression of RBM15 was associated with poor prognosis in patients with OC. Overexpression of RBM15 led to an increase in cell viability and colony formation and a decrease in cell sensitivity to PTX and apoptosis, whereas the knockdown of RBM15 resulted in the inhibition of cell viability and colony formation in vitro and tumor formation in vivo and increased cell apoptosis and sensitivity to PTX in a time‑ and dose‑dependent manner. Furthermore, RBM15 knockdown reduced the spheroid formation of PTX‑resistant OC cells. Silencing of RBM15 decreased multidrug resistance 1 (MDR1) mRNA m6A methylation detected by the methylated RNA immunoprecipitation‑qPCR assay and downregulated the expression of a chemo‑drug efflux pump MDR1 at the mRNA and protein levels. Finally, RBM15 expression was suppressed by the activation of the TGF‑β signaling pathway. Thus, the findings revealed a TGF‑β/RBM15/MDR1 regulatory mechanism. Targeting RBM15 may provide a novel therapeutic strategy for the treatment of PTX‑resistant OC.
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Affiliation(s)
- Jia Yuan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032
| | - Wencai Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508
| | - Xin Li
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032
| | - Fanchen Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032
| | - Huiqiang Liu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China
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4
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Chen PM, Wong CN, Wong CN, Chu PY. Actin-like Protein 6A Expression Correlates with Cancer Stem Cell-like Features and Poor Prognosis in Ovarian Cancer. Int J Mol Sci 2023; 24:ijms24032016. [PMID: 36768349 PMCID: PMC9916576 DOI: 10.3390/ijms24032016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023] Open
Abstract
Ovarian cancer has the highest mortality rate among gynecological cancers, often diagnosed at the late stage and lacking an effective targeted therapy. Although the study of malignant features of cancer, considered to be cancer stem cells (CSCs), is emerging, the aim of this study was to predict and explore the possible mechanism and clinical value of genetic markers in the development of ovarian cancer from a combined database with CSCs features. The common differentially expressed genes (DEGs) were selected in GSE185833 and GSE176246 datasets from the Gene Expression Omnibus (GEO). The GSE185833 dataset was created to reveal gene expression profiles of peritoneal metastasis tissues using single-cell sequencing, and the GSE176246 dataset was determined from gene expression profiles of chemotherapy-refractory ovarian cancer cell lines compared with ovarian cancer cell lines by RNA-seq analysis. By analyzing the correlation between common DEGs and prognosis of ovarian cancer and its possible pathways and functions were predicted by The Cancer Genome Atlas (TCGA) database. The expression levels of 11 genetic markers were significantly elevated in highly invasive and chemoresistant ovarian cancer. The expression of Actin-like protein 6A (ACTL6A) was found to be correlated with survival prognosis, and the total survival time of the patients with high expression of ACTL6A was shorter than those with low expression. Gene set enrichment analysis (GSEA) showed that ACTL6A positively enriched the gene set of 'Cell cycle' and ACTL6A negatively enriched the gene set of focal adhesion. CP724714, a human epidermal growth factor receptor 2 (HER2) inhibitor, could serve as a therapeutic option when ACTL6A levels are high in ovarian cancer cells. The high expression of ACTL6A is a poor prognostic factor in ovarian cancer and may serve as an effective biomarker for predicting treatment-refractory, metastasis, and prognosis of patients with ovarian cancer. The use of HER2 inhibitors is a promising therapeutic strategy against chemoresistant ovarian cancer.
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Affiliation(s)
- Po-Ming Chen
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
| | - Chui-Nguk Wong
- Department of Obstetrics and Gynecology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
| | - Chui-Na Wong
- Department of Obstetrics and Gynecology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
| | - Pei-Yi Chu
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan
- National Institute of Cancer Research, National Health Research Institute, Tainan 704, Taiwan
- Correspondence: ; Tel.: +886-4-7256166
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5
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Mesothelin Expression Is Not Associated with the Presence of Cancer Stem Cell Markers SOX2 and ALDH1 in Ovarian Cancer. Int J Mol Sci 2022; 23:ijms23031016. [PMID: 35162954 PMCID: PMC8834752 DOI: 10.3390/ijms23031016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/06/2022] [Accepted: 01/14/2022] [Indexed: 11/17/2022] Open
Abstract
Mesothelin (MSLN) overexpression (OE) is a frequent finding in ovarian carcinomas and increases cell survival and tumor aggressiveness. Since cancer stem cells (CSCs) contribute to pathogenesis, chemoresistance and malignant behavior in ovarian cancer (OC), we hypothesized that MSLN expression could be creating a favorable environment that nurtures CSCs. In this study, we analyzed the expression of MSLN and CSC markers SOX2 and ALDH1 by immunohistochemistry (IHC) in different model systems: primary high-grade serous carcinomas (HGSCs) and OC cell lines, including cell lines that were genetically engineered for MSLN expression by either CRISPR-Cas9-mediated knockout (Δ) or lentivirus-mediated OE. Cell lines, wild type and genetically engineered, were evaluated in 2D and 3D culture conditions and xenografted in nude mice. We observed that MSLN was widely expressed in HGSC, and restricted expression was observed in OC cell lines. In contrast, SOX2 and ALDH1 expression was limited in all tissue and cell models. Most importantly, the expression of CSC markers was independent of MSLN expression, and manipulation of MSLN expression did not affect CSC markers. In conclusion, MSLN expression is not involved in driving the CSC phenotype.
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6
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Gorczyca G, Wartalski K, Wiater J, Samiec M, Tabarowski Z, Duda M. Anabolic Steroids-Driven Regulation of Porcine Ovarian Putative Stem Cells Favors the Onset of Their Neoplastic Transformation. Int J Mol Sci 2021; 22:ijms222111800. [PMID: 34769230 PMCID: PMC8583785 DOI: 10.3390/ijms222111800] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Nandrolone (Ndn) and boldenone (Bdn), the synthetic testosterone analogues with strong anabolic effects, despite being recognized as potentially carcinogenic compounds, are commonly abused by athletes and bodybuilders, which includes women, worldwide. This study tested the hypothesis that different doses of Ndn and Bdn can initiate neoplastic transformation of porcine ovarian putative stem cells (poPSCs). Immunomagnetically isolated poPSCs were expanded ex vivo in the presence of Ndn or Bdn, for 7 and 14 days. Results show that pharmacological doses of both Ndn and Bdn, already after 7 days of poPSCs culture, caused a significant increase of selected, stemness-related markers of cancer cells: CD44 and CD133. Notably, Ndn also negatively affected poPSCs growth not only by suppressing their proliferation and mitochondrial respiration but also by inducing apoptosis. This observation shows, for the first time, that chronic exposure to Ndn or Bdn represents a precondition that might enhance risk of poPSCs neoplastic transformation. These studies carried out to accomplish detailed molecular characterization of the ex vivo expanded poPSCs and their potentially cancerous derivatives (PCDs) might be helpful to determine their suitability as nuclear donor cells (NDCs) for further investigations focused on cloning by somatic cell nuclear transfer (SCNT). Such investigations might also be indispensable to estimate the capabilities of nuclear genomes inherited from poPSCs and their PCDs to be epigenetically reprogrammed (dedifferentiated) in cloned pig embryos generated by SCNT. This might open up new possibilities for biomedical research aimed at more comprehensively recognizing genetic and epigenetic mechanisms underlying not only tumorigenesis but also reversal/retardation of pro-tumorigenic intracellular events.
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Affiliation(s)
- Gabriela Gorczyca
- Department of Endocrinology, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9 Street, 30-387 Krakow, Poland;
| | - Kamil Wartalski
- Department of Histology, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7 Street, 31-034 Krakow, Poland; (K.W.); (J.W.)
| | - Jerzy Wiater
- Department of Histology, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7 Street, 31-034 Krakow, Poland; (K.W.); (J.W.)
| | - Marcin Samiec
- Department of Reproductive Biotechnology and Cryoconservation, National Research Institute of Animal Production, Krakowska 1 Street, 32-083 Balice near Kraków, Poland
- Correspondence: (M.S.); (M.D.)
| | - Zbigniew Tabarowski
- Department of Experimental Hematology, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9 Street, 30-387 Krakow, Poland;
| | - Małgorzata Duda
- Department of Endocrinology, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9 Street, 30-387 Krakow, Poland;
- Correspondence: (M.S.); (M.D.)
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7
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NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44. Biomedicines 2021; 9:biomedicines9101339. [PMID: 34680456 PMCID: PMC8533227 DOI: 10.3390/biomedicines9101339] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 12/09/2022] Open
Abstract
Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment.
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8
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Kim DK, Ham MH, Lee SY, Shin MJ, Kim YE, Song P, Suh DS, Kim JH. CD166 promotes the cancer stem-like properties of primary epithelial ovarian cancer cells. BMB Rep 2021. [PMID: 32843129 PMCID: PMC7781915 DOI: 10.5483/bmbrep.2020.53.12.102] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) or tumor-initiating cells are thought to play critical roles in tumorigenesis, metastasis, drug resistance, and tumor recurrence. For the diagnosis and targeted therapy of CSCs, the molecular identity of biomarkers or therapeutic targets for CSCs needs to be clarified. In this study, we identified CD166 as a novel marker expressed in the sphere-forming CSC population of A2780 epithelial ovarian cancer cells and primary ovarian cancer cells. The CD166+ cells isolated from A2780 cells and primary ovarian cancer cells highly expressed CSC markers, including ALDH1a1, OCT4, and SOX2, and ABC transporters, which are implicated in the drug resistance of CSCs. The CD166+ cells exhibited enhanced CSC-like properties, such as increased sphere-forming ability, cell migration and adhesion abilities, resistance to conventional anti-cancer drugs, and high tumorigenic potential in a xenograft mouse model. Knockdown of CD166 expression in the sphere-forming ovarian CSCs abrogated their CSC-like properties. Moreover, silencing of CD166 expression in the sphere-forming CSCs suppressed the phosphorylation of focal adhesion kinase, paxillin, and SRC. These results suggest that CD166 plays a key role in the regulation of CSC-like properties and focal adhesion kinase signaling in ovarian cancer.
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Affiliation(s)
- Dae Kyoung Kim
- Departments of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Min Hee Ham
- Departments of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Seo Yul Lee
- Departments of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Min Joo Shin
- Departments of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Ye Eun Kim
- Departments of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Parkyong Song
- Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Dong-Soo Suh
- Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 50612, Korea
| | - Jae Ho Kim
- Departments of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea; Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea
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9
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Bindhya S, Sidhanth C, Krishnapriya S, Garg M, Ganesan TS. Development and in vitro characterisation of an induced pluripotent stem cell model of ovarian cancer. Int J Biochem Cell Biol 2021; 138:106051. [PMID: 34343671 DOI: 10.1016/j.biocel.2021.106051] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 07/06/2021] [Accepted: 07/29/2021] [Indexed: 12/27/2022]
Abstract
Ovarian cancer recurs despite advances in treatment and is due to drug resistance. The persistence of cancer stem cells (CSCs) is one of the causes. It has been challenging to maintain CSCs long term in culture from primary malignant cells. Reprogramming cancer cells into induced pluripotent stem cells (iPSCs) could be an approach to achieve this. An ovarian cancer cell line, PEO4, was initially reprogrammed into iPSCs using the classical four factors OCT4, SOX2, KLF4 and MYC (OSKM) using lentivirus transduction. The PEO4-OSKM-cells had all the hallmarks of iPSCs. As MYC is oncogenic, we have replaced it with GLIS1 and show that PEO4 cells could be transformed into iPSCs. The transfection efficiency was two-fold better with OCT4-SOX2-KLF4-GLIS1 (OSKG) with larger colonies. Further, normal fallopian tube epithelial cells were also transformed using OSKG into iPSCs. iPSCs expressed CSCs markers such as CD133, EPHA1, ALDH1A1 and LGR5 prominently and were more resistant to cisplatin and taxol as compared to parental PEO4 cells. PEO4-OSKM-iPSCs cells formed more colonies in a clonogenic assay as compared to PEO4-OSKG-iPSCs and parental cells. These results provide a first insight that both an ovarian cancer cell line and fallopian tube epithelial cells can be reprogrammed and GLIS1 can successfully replace MYC as a transcription factor. This in vitro model is useful for future experiments to understand the characteristics of CSCs in the pathogenesis of ovarian cancer.
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Affiliation(s)
- S Bindhya
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Chennai, India
| | - C Sidhanth
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Chennai, India
| | - S Krishnapriya
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Chennai, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Uttar Pradesh, India
| | - T S Ganesan
- Laboratory for Cancer Biology, Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Chennai, India.
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10
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A Keratin 7 and E-Cadherin Signature Is Highly Predictive of Tubo-Ovarian High-Grade Serous Carcinoma Prognosis. Int J Mol Sci 2021; 22:ijms22105325. [PMID: 34070214 PMCID: PMC8158692 DOI: 10.3390/ijms22105325] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 01/06/2023] Open
Abstract
During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10−4) by Kaplan–Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10−4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10−4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.
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11
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Wesley T, Berzins S, Kannourakis G, Ahmed N. The attributes of plakins in cancer and disease: perspectives on ovarian cancer progression, chemoresistance and recurrence. Cell Commun Signal 2021; 19:55. [PMID: 34001250 PMCID: PMC8127266 DOI: 10.1186/s12964-021-00726-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/20/2021] [Indexed: 02/06/2023] Open
Abstract
The plakin family of cytoskeletal proteins play an important role in cancer progression yet are under-studied in cancer, especially ovarian cancer. These large cytoskeletal proteins have primary roles in the maintenance of cytoskeletal integrity but are also associated with scaffolds of intermediate filaments and hemidesmosomal adhesion complexes mediating signalling pathways that regulate cellular growth, migration, invasion and differentiation as well as stress response. Abnormalities of plakins, and the closely related spectraplakins, result in diseases of the skin, striated muscle and nervous tissue. Their prevalence in epithelial cells suggests that plakins may play a role in epithelial ovarian cancer progression and recurrence. In this review article, we explore the roles of plakins, particularly plectin, periplakin and envoplakin in disease-states and cancers with emphasis on ovarian cancer. We discuss the potential role the plakin family of proteins play in regulating cancer cell growth, survival, migration, invasion and drug resistance. We highlight potential relationships between plakins, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) and discuss how interaction of these processes may affect ovarian cancer progression, chemoresistance and ultimately recurrence. We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease. In this review, attempts have been made to understand the crucial changes in plakin expression in relation to progression and recurrence of ovarian cancer.
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Video Abstract
- Tamsin Wesley
- Fiona Elsey Cancer Research Institute, Ballarat Technology Central Park, Suites 23-26, 106-110 Lydiard Street South, Ballarat, VIC, 3353, Australia.,School of Science, Psychology and Sport, Federation University Australia, Ballarat, VIC, 3010, Australia
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- Stuart Berzins
- Fiona Elsey Cancer Research Institute, Ballarat Technology Central Park, Suites 23-26, 106-110 Lydiard Street South, Ballarat, VIC, 3353, Australia.,School of Science, Psychology and Sport, Federation University Australia, Ballarat, VIC, 3010, Australia
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- George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat Technology Central Park, Suites 23-26, 106-110 Lydiard Street South, Ballarat, VIC, 3353, Australia.,School of Science, Psychology and Sport, Federation University Australia, Ballarat, VIC, 3010, Australia
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- Nuzhat Ahmed
- Fiona Elsey Cancer Research Institute, Ballarat Technology Central Park, Suites 23-26, 106-110 Lydiard Street South, Ballarat, VIC, 3353, Australia. .,School of Science, Psychology and Sport, Federation University Australia, Ballarat, VIC, 3010, Australia. .,Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, 3052, Australia. .,Centre for Reproductive Health, The Hudson Institute of Medical Research and Department of Translational Medicine, Monash University, Melbourne, VIC, 3168, Australia.
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12
Etzerodt A, Moulin M, Doktor TK, Delfini M, Mossadegh-Keller N, Bajenoff M, Sieweke MH, Moestrup SK, Auphan-Anezin N, Lawrence T. Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer.
J Exp Med 2020;
217:133611. [PMID:
31951251 PMCID:
PMC7144521 DOI:
10.1084/jem.20191869]
[Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/23/2019] [Accepted: 12/16/2019] [Indexed: 12/17/2022] Open
Abstract
Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.
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Affiliation(s)
- Anders Etzerodt
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.,Department of Biomedicine, University of Aarhus, Aarhus, Denmark
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- Morgane Moulin
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.,Centre for Inflammation Biology and Cancer Immunology, School of Immunology & Microbial Sciences, King's College London, London, UK
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- Thomas Koed Doktor
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
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- Marc Bajenoff
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France
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- Michael H Sieweke
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.,Centre for Regenerative Therapies, TU Dresden, Dresden, Germany
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- Søren Kragh Moestrup
- Department of Biomedicine, University of Aarhus, Aarhus, Denmark.,Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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- Toby Lawrence
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.,Centre for Inflammation Biology and Cancer Immunology, School of Immunology & Microbial Sciences, King's College London, London, UK.,Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
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13
Cook DP, Vanderhyden BC. Ovarian cancer and the evolution of subtype classifications using transcriptional profiling†.
Biol Reprod 2020;
101:645-658. [PMID:
31187121 DOI:
10.1093/biolre/ioz099]
[Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/23/2019] [Accepted: 06/09/2019] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer is a complex disease with multiple subtypes, each having distinct histopathologies and variable responses to treatment. This review highlights the technological milestones and the studies that have applied them to change our definitions of ovarian cancer. Over the past 50 years, technologies such as microarrays and next-generation sequencing have led to the discovery of molecular alterations that define each of the ovarian cancer subtypes and has enabled further subclassification of the most common subtype, high-grade serous ovarian cancer (HGSOC). Improvements in mutational profiling have provided valuable insight, such as the ubiquity of TP53 mutations in HGSOC tumors. However, the information derived from these technological advances has also revealed the immense heterogeneity of this disease, from variation between patients to compositional differences within single masses. In looking forward, the emerging technologies for single-cell and spatially resolved transcriptomics will allow us to better understand the cellular composition and structure of tumors and how these contribute to the molecular subtypes. Attempts to incorporate the complexities ovarian cancer has resulted in increasing sophistication of model systems, and the increased precision in molecular profiling of ovarian cancers has already led to the introduction of inhibitors of poly (ADP-ribose) polymerases as a new class of treatments for ovarian cancer with DNA repair deficiencies. Future endeavors to define increasingly accurate classification strategies for ovarian cancer subtypes will allow for confident prediction of disease progression and provide important insight into potentially targetable molecular mechanisms specific to each subtype.
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Affiliation(s)
- David P Cook
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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- Barbara C Vanderhyden
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada
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14
Bukovsky A. Immunology of tissue homeostasis, ovarian cancer growth and regression, and long lasting cancer immune prophylaxis - review of literature.
Histol Histopathol 2020;
36:31-46. [PMID:
32896865 DOI:
10.14670/hh-18-261]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Data on the substantial physiological role of the immune system in the organism's ability to manage proper differentiation and function of normal tissues (tissue homeostasis), and detailed causes of the immune system's essential role for the in-vivo stimulation of cancer growth, are severely lacking. This results in a lack of effective cancer immunotherapy without adverse events, and in the lack of long-lasting cancer immune prophylaxes, particularly in ovarian cancers. Elimination of blood auto-antibodies blocking anti-cancer T cell effectors by intermittent moderate doses of cyclophosphamide, facilitation of the immune system reactivity against alloantigens of cancer cells by two subsequent blood transfusions, and augmentation of anticancer immunity by weekly intradermal injections of bacterial toxins, caused during the subsequent treatment-free period, lasting for two to four weeks, regression of inoperable epithelial ovarian cancers and regeneration of the tremendously metastatically altered abdominal tissues into normal healthy conditions without multivisceral cytoreductive surgery, which can result in life-threatening consequences. An otherwise untreated rectal cancer, progressing over 3 years, regressed after severe toxic dermatitis lasting over one week. This was caused by an accidental consumption of a large raw shiitake mushroom. Subsequent daily consumptions of 2 g Metformin ER and honeybee propolis ethanol extract, and weekly single larger raw shiitake mushroom, which all stimulate immune system reactivity against cancer stem cells, prevented malignant recurrence over the next 29 years without recurring dermatitis, and maintained healthy organism's conditions. These observations indicate that regression of advanced inoperable cancers and long-lasting cancer immune prophylaxis can be reached by simple approaches.
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Affiliation(s)
- Antonin Bukovsky
- Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, Vestec, Czech Republic.
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15
Behera A, Ashraf R, Srivastava AK, Kumar S. Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells.
Heliyon 2020;
6:e04820. [PMID:
32984578 PMCID:
PMC7492822 DOI:
10.1016/j.heliyon.2020.e04820]
[Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/01/2020] [Accepted: 08/26/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND
Epithelial ovarian cancer (EOC) is a lethal and aggressive gynecological malignancy. Despite recent advances, existing therapies are challenged by a high relapse rate, eventually resulting in disease recurrence and chemoresistance. Emerging evidence indicates that a subpopulation of cells known as cancer stem-like cells (CSLCs) exists with non-tumorigenic cancer cells (non-CSCs) within a bulk tumor and is thought to be responsible for tumor recurrence and drug-resistance. Therefore, identifying the molecular drivers for cancer stem cells (CSCs) is critical for the development of novel therapeutic strategies for the treatment of EOC.
METHODS
Two gene datasets were downloaded from the Gene Expression Omnibus (GEO) database based on our search criteria. Differentially expressed genes (DEGs) in both datasets were obtained by the GEO2R web tool. Based on log2 (fold change) >2, the top thirteen up-regulated genes and log2 (fold change) < -1.5 top thirteen down-regulated genes were selected, and the association between their expressions and overall survival was analyzed by OncoLnc web tool. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways analysis, and protein-protein interaction (PPI) networks were performed for all the common DEGs found in both datasets. SK-OV-3 cells were cultured in an adherent culture medium and spheroids were generated in suspension culture with CSCs specific medium. RNA from both cell population was extracted to validate the selected DEGs expression by q-PCR. Growth inhibition assay was performed in SK-OV-3 cells after carboplatin treatment.
RESULTS
A total of 200 DEGs, 117 up-regulated and 83 down-regulated genes were commonly identified in both datasets. Analysis of pathways and enrichment tests indicated that the extracellular matrix part, cell proliferation, tissue development, and molecular function regulation were enriched in CSCs. Biological pathways such as interferon-alpha/beta signaling, molecules associated with elastic fibers, and synthesis of bile acids and bile salts were significantly enriched in CSCs. Among the top 13 up-regulated and down-regulated genes, MMP1 and PPFIBP1 expression were associated with overall survival. Higher expression of ADM, CXCR4, LGR5, and PTGS2 in carboplatin treated SK-OV-3 cells indicate a potential role in drug resistance.
CONCLUSIONS
The molecular signature and signaling pathways enriched in ovarian CSCs were identified by bioinformatics analysis. This analysis could provide further research ideas to find the new mechanism and novel potential therapeutic targets for ovarian CSCs.
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Affiliation(s)
- Abhijeet Behera
- Division of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh, India
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- Rahail Ashraf
- Division of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh, India
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- Amit Kumar Srivastava
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India
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- Sanjay Kumar
- Division of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati, Andhra Pradesh, India
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16
Cho Y, Kim YK. Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance.
Front Oncol 2020;
10:764. [PMID:
32582535 PMCID:
PMC7280434 DOI:
10.3389/fonc.2020.00764]
[Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/21/2020] [Indexed: 12/21/2022] Open
Abstract
Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to various defensive mechanisms in cancer. Initially, overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) was considered the most important mechanism for drug resistance; hence, many investigators for a long time focused on the development of specific ABC transporter inhibitors. However, to date their efforts have failed to develop a clinically applicable drug, leaving only a number of problems. The concept of cancer stem cells (CSCs) has provided new directions for both cancer and MDR research. MDR is known to be one of the most important features of CSCs and thus plays a crucial role in cancer recurrence and exacerbation. Therefore, in recent years, research targeting CSCs has been increasing rapidly in search of an effective cancer treatment. Here, we review the drugs that have been studied and developed to overcome MDR and CSCs, and discuss the limitations and future perspectives.
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Affiliation(s)
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- Yong Kee Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, South Korea
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17
Maenhoudt N, Defraye C, Boretto M, Jan Z, Heremans R, Boeckx B, Hermans F, Arijs I, Cox B, Van Nieuwenhuysen E, Vergote I, Van Rompuy AS, Lambrechts D, Timmerman D, Vankelecom H. Developing Organoids from Ovarian Cancer as Experimental and Preclinical Models.
Stem Cell Reports 2020;
14:717-729. [PMID:
32243841 PMCID:
PMC7160357 DOI:
10.1016/j.stemcr.2020.03.004]
[Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 03/03/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer (OC) represents the most dismal gynecological cancer. Pathobiology is poorly understood, mainly due to lack of appropriate study models. Organoids, defined as self-developing three-dimensional in vitro reconstructions of tissues, provide powerful tools to model human diseases. Here, we established organoid cultures from patient-derived OC, in particular from the most prevalent high-grade serous OC (HGSOC). Testing multiple culture medium components identified neuregulin-1 (NRG1) as key factor in maximizing OC organoid development and growth, although overall derivation efficiency remained moderate (36% for HGSOC patients, 44% for all patients together). Established organoid lines showed patient tumor-dependent morphology and disease characteristics, and recapitulated the parent tumor's marker expression and mutational landscape. Moreover, the organoids displayed tumor-specific sensitivity to clinical HGSOC chemotherapeutic drugs. Patient-derived OC organoids provide powerful tools for the study of the cancer's pathobiology (such as importance of the NRG1/ERBB pathway) as well as advanced preclinical tools for (personalized) drug screening and discovery.
Organoids are established from ovarian cancer (OC)
Neuregulin-1 (NRG1) is identified as key component for OC organoid growth
OC organoids capture disease hallmarks and recapitulate patient tumor characteristics
OC organoids are amenable to drug screening and mechanistic (NRG1/ERBB) research
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Affiliation(s)
- Nina Maenhoudt
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
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- Charlotte Defraye
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
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- Matteo Boretto
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
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- Ziga Jan
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium; Cluster Woman and Child, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Cancer Centre Carinthia, 9020 Klagenfurt, Austria
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- Ruben Heremans
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium; Cluster Woman and Child, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Gynecology and Obstetrics, University Hospitals Leuven (UZ Leuven), 3000 Leuven, Belgium
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- Bram Boeckx
- Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium
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- Florian Hermans
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium; Department of Morphology, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium
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- Ingrid Arijs
- Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium
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- Benoit Cox
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium
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- Els Van Nieuwenhuysen
- Cluster Woman and Child, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Gynecology and Obstetrics, University Hospitals Leuven (UZ Leuven), 3000 Leuven, Belgium
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- Ignace Vergote
- Cluster Woman and Child, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Gynecology and Obstetrics, University Hospitals Leuven (UZ Leuven), 3000 Leuven, Belgium
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- Anne-Sophie Van Rompuy
- Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, 3000 Leuven, Belgium
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- Diether Lambrechts
- Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium
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- Dirk Timmerman
- Cluster Woman and Child, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Gynecology and Obstetrics, University Hospitals Leuven (UZ Leuven), 3000 Leuven, Belgium
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- Hugo Vankelecom
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium.
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18
Belur Nagaraj A, Joseph P, Ponting E, Fedorov Y, Singh S, Cole A, Lee W, Yoon E, Baccarini A, Scacheri P, Buckanovich R, Adams DJ, Drapkin R, Brown BD, DiFeo A. A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs.
Stem Cell Reports 2020;
12:122-134. [PMID:
30629937 PMCID:
PMC6335585 DOI:
10.1016/j.stemcr.2018.12.002]
[Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 12/06/2018] [Accepted: 12/06/2018] [Indexed: 01/11/2023] Open
Abstract
Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3' UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181ahigh subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs.
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Affiliation(s)
- Anil Belur Nagaraj
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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- Peronne Joseph
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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- Erin Ponting
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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- Yuriy Fedorov
- Small Molecules Drug Development Core Facility, Office of Research Administration, Case Western Reserve University, Cleveland, OH 44106, USA
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- Salendra Singh
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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- Alex Cole
- Department of Electrical Engineering and Computer Science, Center for Wireless Integrated MicroSensing and Systems (WIMS2), The University of Michigan, Ann Arbor, MI, USA
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- Woncheol Lee
- Department of Electrical Engineering and Computer Science, Center for Wireless Integrated MicroSensing and Systems (WIMS2), The University of Michigan, Ann Arbor, MI, USA
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- Euisik Yoon
- Department of Electrical Engineering and Computer Science, Center for Wireless Integrated MicroSensing and Systems (WIMS2), The University of Michigan, Ann Arbor, MI, USA
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- Alessia Baccarini
- Department of Genetics and Multiscale Biology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA
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- Peter Scacheri
- Department of Genetics and Genomic Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
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- Ronald Buckanovich
- Department of Medicine, Magee Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
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- Drew J Adams
- Small Molecules Drug Development Core Facility, Office of Research Administration, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Genetics and Genomic Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
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- Ronny Drapkin
- Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA
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- Brian D Brown
- Department of Genetics and Multiscale Biology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA
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- Analisa DiFeo
- Rogel Cancer Center, The University of Michigan, Michigan Medicine, Ann Arbor, MI, USA; Department of Obstetrics and Gynecology, The University of Michigan, Michigan Medicine, Ann Arbor, MI, USA; Department of Pathology, The University of Michigan, Michigan Medicine, Ann Arbor, MI, USA.
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19
Nguyen VHL, Hough R, Bernaudo S, Peng C. Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis.
J Ovarian Res 2019;
12:122. [PMID:
31829231 PMCID:
PMC6905042 DOI:
10.1186/s13048-019-0596-z]
[Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023] Open
Abstract
Epithelial ovarian cancer (EOC) is the deadliest female malignancy. The Wnt/β-catenin pathway plays critical roles in regulating embryonic development and physiological processes. This pathway is tightly regulated to ensure its proper activity. In the absence of Wnt ligands, β-catenin is degraded by a destruction complex. When the pathway is stimulated by a Wnt ligand, β-catenin dissociates from the destruction complex and translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate target gene expression. Aberrant activation of this pathway, which leads to the hyperactivity of β-catenin, has been reported in ovarian cancer. Specifically, mutations of CTNNB1, AXIN, or APC, have been observed in the endometrioid and mucinous subtypes of EOC. In addition, upregulation of the ligands, abnormal activation of the receptors or intracellular mediators, disruption of the β-catenin destruction complex, inhibition of the association of β-catenin/E-cadherin on the cell membrane, and aberrant promotion of the β-catenin/TCF transcriptional activity, have all been reported in EOC, especially in the high grade serous subtype. Furthermore, several non-coding RNAs have been shown to regulate EOC development, in part, through the modulation of Wnt/β-catenin signalling. The Wnt/β-catenin pathway has been reported to promote cancer stem cell self-renewal, metastasis, and chemoresistance in all subtypes of EOC. Emerging evidence also suggests that the pathway induces ovarian tumor angiogenesis and immune evasion. Taken together, these studies demonstrate that the Wnt/β-catenin pathway plays critical roles in EOC development and is a strong candidate for the development of targeted therapies.
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Affiliation(s)
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- Rebecca Hough
- Department of Biology, York University, Toronto, Ontario, Canada
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- Chun Peng
- Department of Biology, York University, Toronto, Ontario, Canada. .,Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada.
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20
Keyvani V, Farshchian M, Esmaeili SA, Yari H, Moghbeli M, Nezhad SRK, Abbaszadegan MR. Ovarian cancer stem cells and targeted therapy.
J Ovarian Res 2019;
12:120. [PMID:
31810474 PMCID:
PMC6896744 DOI:
10.1186/s13048-019-0588-z]
[Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/04/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND
Ovarian cancer has the highest ratio of mortality among gynecologic malignancies. Chemotherapy is one of the most common treatment options for ovarian cancer. However, tumor relapse in patients with advanced tumor stage is still a therapeutic challenge for its clinical management.
MAIN BODY
Therefore, it is required to clarify the molecular biology and mechanisms which are involved in chemo resistance to improve the survival rate of ovarian cancer patients. Cancer stem cells (CSCs) are a sub population of tumor cells which are related to drug resistance and tumor relapse.
CONCLUSION
In the present review, we summarized the recent findings about the role of CSCs in tumor relapse and drug resistance among ovarian cancer patients. Moreover, we focused on the targeted and combinational therapeutic methods against the ovarian CSCs.
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Affiliation(s)
- Vahideh Keyvani
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
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- Moein Farshchian
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR), Khorasan Razavi Branch, Mashhad, Iran
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- Seyed-Alireza Esmaeili
- Immunology Research Center, Bu‐Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Science, Mashhad, Iran
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- Hadi Yari
- Human Genetics Division, Medical Biotechnology Department, National Institute of Genetics Engineering and Biotechnology, Tehran, Iran
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- Meysam Moghbeli
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
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21
Kenda Suster N, Virant-Klun I. Presence and role of stem cells in ovarian cancer.
World J Stem Cells 2019;
11:383-397. [PMID:
31396367 PMCID:
PMC6682502 DOI:
10.4252/wjsc.v11.i7.383]
[Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/23/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023] Open
Abstract
Ovarian cancer is the deadliest gynecological malignancy. It is typically diagnosed at advanced stages of the disease, with metastatic sites disseminated widely within the abdominal cavity. Ovarian cancer treatment is challenging due to high disease recurrence and further complicated pursuant to acquired chemoresistance. Cancer stem cell (CSC) theory proposes that both tumor development and progression are driven by undifferentiated stem cells capable of self-renewal and tumor-initiation. The most recent evidence revealed that CSCs in terms of ovarian cancer are not only responsible for primary tumor growth, metastasis and relapse of disease, but also for the development of chemoresistance. As the elimination of this cell population is critical for increasing treatment success, a deeper understanding of ovarian CSCs pathobiology, including epithelial-mesenchymal transition, signaling pathways and tumor microenvironment, is needed. Finally, before introducing new therapeutic agents for ovarian cancer, targeting CSCs, accurate identification of different ovarian stem cell subpopulations, including the very small embryonic-like stem cells suggested as progenitors, is necessary. To these ends, reliable markers of ovarian CSCs should be identified. In this review, we present the current knowledge and a critical discussion concerning ovarian CSCs and their clinical role.
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Affiliation(s)
- Natasa Kenda Suster
- Department of Gynecology, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia
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- Irma Virant-Klun
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia
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22
Ovarian Cancer Stemness: Biological and Clinical Implications for Metastasis and Chemotherapy Resistance.
Cancers (Basel) 2019;
11:cancers11070907. [PMID:
31261739 PMCID:
PMC6678827 DOI:
10.3390/cancers11070907]
[Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 06/24/2019] [Accepted: 06/26/2019] [Indexed: 01/04/2023] Open
Abstract
Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.
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23
Klapdor R, Wang S, Morgan M, Dörk T, Hacker U, Hillemanns P, Büning H, Schambach A. Characterization of a Novel Third-Generation Anti-CD24-CAR against Ovarian Cancer.
Int J Mol Sci 2019;
20:ijms20030660. [PMID:
30717444 PMCID:
PMC6387114 DOI:
10.3390/ijms20030660]
[Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 01/25/2019] [Accepted: 01/30/2019] [Indexed: 01/07/2023] Open
Abstract
Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach against OC cells and cancer stem cells (CSC). CSC represents a subpopulation of the tumor characterized by enhanced chemoresistance as well as the increased capability of self-renewal and metastasis. We designed a codon-optimized third-generation CAR containing the highly active single chain variable fragment (scFv) “SWA11” against CD24. We equipped the human NK-cell line NK-92 with the anti-CD24 CAR and an anti-CD19 control CAR using lentiviral transduction. Engineered NK-92 cells showed high cytotoxic activity against CD24-positive OC cell lines (SKOV3, OVCAR3). This effect was restricted to CD24-expressing cells as shown after lentiviral transduction of CD24-negative cell lines (A2780, HEK-293T) with CD24 transmembrane proteins. Additionally, NK-92 cells equipped with our novel anti-CD24 CAR were highly effective against patient-derived primary ovarian cancer cells. The activation of NK cells was shown by specific IFNγ secretion upon antigen stimulation. To further reduce possible off-target effects in vivo, we applied a dual-CAR approach using an anti-CD24-CD28-41BB fusion protein linked via a 2A sequence to an anti-mesothelin-CD3ζ-CAR. The dual-CAR was simultaneously active against CD24 and mesothelin expressing cells. Our novel anti-CD24-CAR showed a highly cytotoxic effect against OC cell lines and primary OC cells and will be evaluated in future in vivo trials as a promising immunotherapeutic approach against OC.
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Affiliation(s)
- Rüdiger Klapdor
- Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany.
- Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
- Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany.
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- Shuo Wang
- Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany.
- Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
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- Michael Morgan
- Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
- Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany.
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- Thilo Dörk
- Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany.
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- Ulrich Hacker
- Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, 04103 Leipzig, Germany.
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- Peter Hillemanns
- Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany.
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- Hildegard Büning
- Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
- Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany.
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- Axel Schambach
- Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
- Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany.
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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24
Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer.
Int J Mol Sci 2019;
20:ijms20010229. [PMID:
30626133 PMCID:
PMC6337358 DOI:
10.3390/ijms20010229]
[Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 12/20/2018] [Accepted: 12/23/2018] [Indexed: 01/06/2023] Open
Abstract
Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression.
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25
Belur Nagaraj A, Joseph P, Kovalenko O, Wang Q, Xu R, DiFeo A. Evaluating class III antiarrhythmic agents as novel MYC targeting drugs in ovarian cancer.
Gynecol Oncol 2018;
151:525-532. [PMID:
30301560 PMCID:
PMC6526024 DOI:
10.1016/j.ygyno.2018.09.019]
[Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 09/07/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE
To evaluate the utility of amiodarone and its derivative dronedarone as novel drug repositioning candidates in EOC and to determine the potential pathways targeted by these drugs.
METHODS
Drug-predict bioinformatics platform was used to assess the utility of amiodarone as a novel drug-repurposing candidate in EOC. EOC cells were treated with amiodarone and dronedarone. Cell death was assessed by Annexin V staining. Cell viability and cell survival were assessed by MTT and clonogenics assays respectively. c-MYC and mTOR/Akt axis were evaluated as potential targets. Effect on autophagy was determined by autophagy flux flow cytometry.
RESULTS
"DrugPredict" bioinformatics platform ranked Class III antiarrhythmic drug amiodarone within the top 3.9% of potential EOC drug repositioning candidates which was comparable to carboplatin ranking in the top 3.7%. Amiodarone and dronedarone were the only Class III antiarrhythmic drugs that decreased the cellular survival of both cisplatin-sensitive and cisplatin-resistant primary EOC cells. Interestingly, both drugs induced degradation of c-MYC protein and decreased the expression of known transcriptional targets of c-MYC. Furthermore, stable overexpression of non-degradable c-MYC partially rescued the effects of amiodarone and dronedarone induced cell death. Dronedarone induced higher autophagy flux in EOC cells as compared to amiodarone with decreased phospho-AKT and phospho-4EBP1 protein expression, suggesting autophagy induction due to inhibition of AKT/mTOR axis with these drugs. Lastly, both drugs also inhibited the survival of EOC tumor-initiating cells (TICs).
CONCLUSIONS
We provide the first evidence of class III antiarrhythmic agents as novel c-MYC targeting drugs and autophagy inducers in EOC. Since c-MYC is amplified in >40% ovarian tumors, our results provide the basis for repositioning amiodarone and dronedarone as novel c-MYC targeting drugs in EOC with potential extension to other cancers.
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Affiliation(s)
- Anil Belur Nagaraj
- Case Comprehensive Cancer Center, Cleveland, OH, USA; Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55904, USA
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- Olga Kovalenko
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
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- QuanQiu Wang
- Dept. of Population and Quantitative Health Sciences, Case Western Reserve University, USA
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- Rong Xu
- Dept. of Population and Quantitative Health Sciences, Case Western Reserve University, USA
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- Analisa DiFeo
- Case Comprehensive Cancer Center, Cleveland, OH, USA; Department of Pathology and Department of Obstetrics and Gynecology, University of Michigan, USA.
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26
Zhao L, Wang ZG, Zhang P, Yu XF, Su XJ. Poly r(C) Binding Protein 1 Regulates Posttranscriptional Expression of the Ubiquitin Ligase TRIM56 in Ovarian Cancer.
IUBMB Life 2018;
71:177-182. [DOI:
10.1002/iub.1948]
[Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 08/09/2018] [Accepted: 09/03/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Lei Zhao
- College of Medical Laboratory Science and Technology; Harbin Medical University at Daqing; Daqing Heilongjiang 163319 China
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- Zhi-gang Wang
- College of Medical Laboratory Science and Technology; Harbin Medical University at Daqing; Daqing Heilongjiang 163319 China
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- Ping Zhang
- College of Medical Laboratory Science and Technology; Harbin Medical University at Daqing; Daqing Heilongjiang 163319 China
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- Xiu-feng Yu
- College of Medical Laboratory Science and Technology; Harbin Medical University at Daqing; Daqing Heilongjiang 163319 China
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- Xiao-jie Su
- College of Medical Laboratory Science and Technology; Harbin Medical University at Daqing; Daqing Heilongjiang 163319 China
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27
Parte SC, Batra SK, Kakar SS. Characterization of stem cell and cancer stem cell populations in ovary and ovarian tumors.
J Ovarian Res 2018;
11:69. [PMID:
30121075 PMCID:
PMC6098829 DOI:
10.1186/s13048-018-0439-3]
[Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 08/05/2018] [Indexed: 02/07/2023] Open
Abstract
Background
Ovarian cancer is a complicated malady associated with cancer stem cells (CSCs) contributing to 238,700 estimated new cases and 151,900 deaths per year, worldwide. CSCs comprise a tiny fraction of tumor-bulk responsible for cancer recurrence and eventual mortality. CSCs or tumor initiating cells are responsible for self-renewal, differentiation and proliferative potential, tumor initiation capability, its progression, drug resistance and metastatic spread. Although several biomarkers are implicated in these processes, their distribution within the ovary and association with single cell type has neither been established nor demonstrated across ovarian tumor developmental stages. Therefore, precise identification, thorough characterization and effective targeted destruction of dormant and highly proliferating potent CSC populations is an immediate need.
Results
In view of this, distribution of various CSC (ALDH1/2, C-KIT, CD133, CD24 and CD44) and cell proliferation (KI67) specific markers in the ovarian surface epithelium (OSE) and cortex regions in normal ovary, and benign, borderline and high grade metastatic ovarian tumors by immuno-histochemistry and confocal microscopy was studied. We further confirmed their expression by RT-PCR analysis. Co-expression analysis of stem cell (OCT4, SSEA4) and CSC (ALDH1/2, CD44 and LGR5) markers with proliferation marker (KI67) in HG tumors revealed dual positive proliferating stem and CSCs, few non-proliferating stem/CSC (SSEA4+/KI67− and ALDH1/2+/KI67−) and only KI67+ cells in cortex, signifying dynamic populations and interesting cellular hierarchy in cortex region. Smaller spherical (≤ 5 μm) and larger spindle/elliptical shaped (~ 10 μm) cell populations with high nucleo-cytoplasmic ratio were detected across all samples (including normal ovaries) but with variable distribution and characteristic stage-wise marker expression across different tumor stages.
Conclusions
Diverse stem and CSC populations expressing characteristic markers revealing distinct phenotypes (spherical ≤5 μm and spindle/elliptical ~ 10 μm) were distributed within different tumor stages studied signifying dynamic and probable functional hierarchy within these cell types. Involvement of extra-ovarian sites of origin of stem and CSCs requires rigorous evaluation. Quantitative analysis of potent CSC populations, their mechanisms and pathways for self-renewal, chemo-resistance, metastatic spread etc. with respect to various markers studied, will provide better insights and targets for developing effective therapeutics to prevent metastasis and eventually help improve patient mortality.
Electronic supplementary material
The online version of this article (10.1186/s13048-018-0439-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Seema C Parte
- Department of Physiology, University of Louisville, 505 South Hancock Street, CTRB, Room 322, Louisville, 40202, KY, USA.,James Graham Brown Cancer Center, University of Louisville, Louisville, 40202, KY, USA
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- Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska, Omaha, 68198, NE, USA
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- Sham S Kakar
- Department of Physiology, University of Louisville, 505 South Hancock Street, CTRB, Room 322, Louisville, 40202, KY, USA. .,James Graham Brown Cancer Center, University of Louisville, Louisville, 40202, KY, USA.
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28
Can Stemness and Chemoresistance Be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?
Cancers (Basel) 2018;
10:cancers10080241. [PMID:
30042330 PMCID:
PMC6116003 DOI:
10.3390/cancers10080241]
[Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 07/12/2018] [Accepted: 07/17/2018] [Indexed: 12/12/2022] Open
Abstract
Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, is often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons, personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to target in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.
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29
Stadnicka K, Sławińska A, Dunisławska A, Pain B, Bednarczyk M. Molecular signatures of epithelial oviduct cells of a laying hen (Gallus gallus domesticus) and quail (Coturnix japonica).
BMC DEVELOPMENTAL BIOLOGY 2018;
18:9. [PMID:
29614966 PMCID:
PMC5883888 DOI:
10.1186/s12861-018-0168-2]
[Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 03/21/2018] [Indexed: 12/30/2022]
Abstract
Background
In this work we have determined molecular signatures of oviduct epithelial and progenitor cells. We have proposed a panel of selected marker genes, which correspond with the phenotype of oviduct cells of a laying hen (Gallus gallus domesticus) and quail (Coturnix japonica). We demonstrated differences in characteristics of those cells, in tissue and in vitro, with respect to different anatomical and functional parts of the oviduct (infundibulum (INF), distal magnum (DM, and proximal magnum (PM)). The following gene expression signatures were studied: (1) oviduct markers (estrogen receptor 1, ovalbumin, and SPINK7 - ovomucoid), (2) epithelial markers (keratin 5, keratin 14, and occludin) and (3) stem-like/progenitor markers (CD44 glycoprotein, LGR5, Musashi-1, and sex determining region Y-box 9, Nanog homebox, OCT4/cPOUV gene encoding transcription factor POU5F3).
Results
In chicken, the expression of oviduct markers increased toward the proximal oviduct. Epithelial markers keratin14 and occludin were high in distal oviduct and decreased toward the proximal magnum. In quail oviduct tissue, the gene expression pattern of oviduct/epithelial markers was similar to chicken. The markers of progenitors/stemness in hen oviduct (Musashi-1 and CD44 glycoprotein) had the highest relative expression in the infundibulum and decreased toward the proximal magnum. In quail, we found significant expression of four progenitor markers (LGR5 gene, SRY sex determining region Y-box 9, OCT4/cPOUV gene, and CD44 glycoprotein) that were largely present in the distal oviduct. After in vitro culture of oviduct cells, the gene expression pattern has changed. High secretive potential of magnum-derived cells diminished by using decreased abundance of mRNA. On the other hand, chicken oviduct cells originating from the infundibulum gained ability to express OVM and OVAL. Epithelial character of the cells was maintained in vitro. Among progenitor markers, both hen and quail cells expressed high level of SOX9, LGR5 and Musashi-1.
Conclusion
Analysis of tissue material revealed gradual increase/decrease pattern in majority of the oviduct markers in both species. This pattern changed after the oviductal cells have been cultured in vitro. The results can provide molecular tools to validate the phenotype of in vitro biological models from reproductive tissue.
Electronic supplementary material
The online version of this article (10.1186/s12861-018-0168-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Katarzyna Stadnicka
- Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, Mazowiecka 28, 85-084, Bydgoszcz, Poland.
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- Anna Sławińska
- Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, Mazowiecka 28, 85-084, Bydgoszcz, Poland
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- Aleksandra Dunisławska
- Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, Mazowiecka 28, 85-084, Bydgoszcz, Poland
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- Bertrand Pain
- University of Lyon, Université Lyon 1, INSERM, INRA, Stem Cell and Brain Research Institute, U1208, USC1361, Bron, France
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- Marek Bednarczyk
- Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, Mazowiecka 28, 85-084, Bydgoszcz, Poland
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30
Mitra T, Prasad P, Mukherjee P, Chaudhuri SR, Chatterji U, Roy SS. Stemness and chemoresistance are imparted to the OC cells through TGFβ1 driven EMT.
J Cell Biochem 2018. [PMID:
29537103 DOI:
10.1002/jcb.26753]
[Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ovarian cancer (OC) is the fourth most common gynecological malignancy due to its highly aggressive, recurrent, and drug-resistant nature. The last two features are rendered by the presence of cancer stem cells (CSCs). Factors like TGFβ1 and their downstream signaling pathways are upregulated in most cancers and are known to induce EMT and stemness, but the exact mechanisms underlying the process remain unelucidated. In our study, TGFβ1 induced enhanced stem-like properties like high expression of the pluripotent markers SOX2, OCT4a, and NANOG, along with CD44, and CD117 in the OC cells. In addition, increased activity of the aldehyde dehydrogenase enzyme, formation of compact spheroids, and a quiescent phenotype were observed. In deciphering the mechanism behind it, our data propose ZEB1 transcription factor to play a substantial role in inducing the EMT-mediated stemness and chemoresistance. Further, in our study, we elucidated the significant contribution of both Smad and non-Smad pathways like ERK, JNK, and P38 MAPK pathways in the induction of stem-like characteristics. The novelty of the study also resides with the fact in the expression of different lineage-specific markers, like CD31, CD45, and CD117 along with CD44 in the TGFβ1-induced epithelial ovarian cancer spheroids. This suggests a tendency of the spheroidal cells towards differentiating into heterogenic populations, which is a distinctive feature of a stem cell. Taken together, the present study provides an insight to the molecular cues involved in the acquisition of stemness and chemoresistance along with tumor heterogeneity in TGFβ1-induced OC cells.
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Affiliation(s)
- Tulika Mitra
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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- Parash Prasad
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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- Pritha Mukherjee
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India
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- Susri Ray Chaudhuri
- Tata Translational Cancer Research Centre, Tata Medical Centre, Kolkata, India
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- Urmi Chatterji
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India
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- Sib S Roy
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,Academy of Scientific & Innovative Research, CSIR-Indian Institute of Chemical Biology Campus, Kolkata, India
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31
Lee YJ, Wu CC, Li JW, Ou CC, Hsu SC, Tseng HH, Kao MC, Liu JY. A rational approach for cancer stem-like cell isolation and characterization using CD44 and prominin-1(CD133) as selection markers.
Oncotarget 2018;
7:78499-78515. [PMID:
27655682 PMCID:
PMC5346656 DOI:
10.18632/oncotarget.12100]
[Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 09/12/2016] [Indexed: 12/18/2022] Open
Abstract
The availability of adequate cancer stem cells or cancer stem-like cell (CSC) is important in cancer study. From ovarian cancer cell lines, SKOV3 and OVCAR3, we induced peritoneal ascites tumors in immunodeficient mice. Among the cells (SKOV3.PX1 and OVCAR3.PX1) from those tumors, we sorted both CD44 and CD133 positive cells (SKOV3.PX1_133+44+, OVCAR3.PX1_133+44+), which manifest the characteristics of self-renewal, multi-lineage differentiation, chemoresistance and tumorigenicity, those of cancer stem-like cells (CSLC). Intraperitoneal transplantation of these CD44 and CD133 positive cells resulted in poorer survival in the engrafted animals. Clinically, increased CD133 expression was found in moderately and poorly differentiated (grade II and III) ovarian serous cystadenocarcinomas. The ascites tumor cells from human ovarian cancers demonstrated more CD133 and CD44 expressions than those from primary ovarian or metastatic tumors and confer tumorigenicity in immunodeficient mice. Compared to their parental cells, the SKOV3.PX1_133+44+ and OVCAR3.PX1_133+44+ cells uniquely expressed 5 CD markers (CD97, CD104, CD107a, CD121a, and CD125). Among these markers, CD97, CD104, CD107a, and CD121a are significantly more expressed in the CD133+ and CD44+ double positive cells of human ovarian ascites tumor cells (Ascites_133+44+) than those from primary ovarian or metastatic tumors. The cancer stem-like cells were enriched from 3% to more than 70% after this manipulation. This intraperitoneal enrichment of cancer stem-like cells, from ovarian cancer cell lines or primary ovarian tumor, potentially provides an adequate amount of ovarian cancer stem-like cells for the ovarian cancer study and possibly benefits cancer therapy.
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Affiliation(s)
- Yi-Jen Lee
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
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- Chang-Cheng Wu
- Chief of Obstetrics and Gynecology, Tri-Service General Hospital Penghu Branch, Penghu, Taiwan
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- Jhy-Wei Li
- Chief of Pathology, Da-Chien General Hospital, Miaoli, Taiwan.,Department of Rehabilitation science, Jente Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
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- Chien-Chih Ou
- Obstetrics and Gynecology, Tri-Service General Hospital, Taipei, Taiwan
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- Shih-Chung Hsu
- Medical Care and Management, Kang-Ning Junior College, Taipei, Taiwan
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- Hsiu-Hsueh Tseng
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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- Ming-Ching Kao
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.,Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
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- Jah-Yao Liu
- Department of Obstetrics and Gynecology, National Defense Medical Center, Taipei, Taiwan.,Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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32
Seo EJ, Kim DK, Jang IH, Choi EJ, Shin SH, Lee SI, Kwon SM, Kim KH, Suh DS, Kim JH. Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer.
Oncotarget 2018;
7:55624-55638. [PMID:
27489349 PMCID:
PMC5342441 DOI:
10.18632/oncotarget.10954]
[Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 07/18/2016] [Indexed: 12/18/2022] Open
Abstract
Hypoxia and NOTCH signaling have been reported to be associated with the self-renewal and drug resistance of cancer stem cells (CSCs). However, the molecular mechanisms by which hypoxia and NOTCH signaling stimulate the self-renewal and drug resistance of ovarian CSCs are poorly understood. In the present study, we identified SOX2 as a key transcription factor for CSC-like characteristics in the downstream of hypoxia-induced NOTCH signaling in epithelial ovarian cancer cells. Hypoxic treatment or overexpression of intracellular domain of NOTCH1 (NICD1) in ovarian cancer cells increased sphere formation, drug resistance, and expression of CSC-associated genes such as SOX2, ALDH, and ABC transporters. Hypoxic treatment increased the expression of NICD1, and hypoxic treatment or NICD1 overexpression increased SOX2 promoter activity, which was inhibited by deletion of HIF-1 or CSL binding sites. Furthermore, DAPT treatment decreased the effect of hypoxic treatment, and SOX2 knockdown decreased the effect of hypoxic treatment and NICD overexpression on sphere formation and drug resistance in established ovarian cancer cell lines and primary ovarian cancer cells. These results suggest that hypoxia-NOTCH1-SOX2 signaling axis is important for activation of ovarian CSCs, which may provide a novel opportunity for developing therapeutics to eradicate CSCs in ovarian cancer patients.
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Affiliation(s)
- Eun Jin Seo
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Dae Kyoung Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Il Ho Jang
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Eun Jung Choi
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Sang Hun Shin
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Su In Lee
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Sang-Mo Kwon
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Ki-Hyung Kim
- Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Dong-Soo Suh
- Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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- Jae Ho Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
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33
de Lima AB, Silva LM, Gonçales NG, Carvalho MRS, da Silva Filho AL, da Conceição Braga L. Three-Dimensional Cellular Arrangement in Epithelial Ovarian Cancer Cell Lines TOV-21G and SKOV-3 is Associated with Apoptosis-Related miRNA Expression Modulation.
CANCER MICROENVIRONMENT 2018;
11:85-92. [PMID:
29307001 DOI:
10.1007/s12307-017-0203-z]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 11/29/2017] [Indexed: 12/21/2022]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the lack of chemoresistance biomarkers contributes to the poor prognosis. Cancer stem cells (CSC) have been investigated in EOC to understand its relationship with chemoresistance and recurrence. In this context, in vitro cultivation-models are important tools for CSC studies. MicroRNAs (miRNAs) play key roles in cancer, CSC regulation and apoptosis. Thus, this study aims to evaluate the tumorsphere model as CSC-enrichment method in EOC studies and investigate apoptosis-related miRNAs in tumorspheres-derived EOC cell lines. TOV-21G and SKOV-3 were cultured in monolayer and tumorspheres. Genetic profiles of cell lines were obtained using COSMIC database. CD24/CD44/CD146/CD177 and ALDH1 markers were evaluated in cell lines and tumorspheres-derived by flow cytometry. Eleven miRNAs were selected by in silico analysis for qPCR analysis. According to COSMIC, TOV-21G and SKOV-3 have eight and nine cancer-related mutations, respectively. TOV-21G showed a CD44+/high/CD24-/low/CD117-/low/CD146-/low/ALDH1low profile in both culture models; thus, no significant difference between cultivation models was identified. SKOV-3 showed a CD44+/high/CD24+/high/ CD117-/low/CD146-/low/ALDH1low profile in both culture models, although the tumorsphere model showed a significant increase in CD24+/high subpopulation (ovarian CSC-like). Among eleven miRNAs, we observed differences in miRNA expression between culture models. MiR-26a was overexpressed in TOV-21G tumorspheres, albeit downregulated in SKOV-3 tumorspheres. MiR-125b-5p, miR-17-5p and miR-221 was downregulated in tumorsphere model in both cell lines. Given that tumorsphere-derived SKOV-3 had a higher ratio of CD24+/high cells, we suggest that miR-26a, miR-125b-5p, miR-17-5p and miR-221 downregulation could be related to poor EOC prognosis.
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Affiliation(s)
- Aline Brito de Lima
- Serviço de Biologia Celular, Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, Brazil.,Laboratório de Genética Humana e Médica, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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- Luciana Maria Silva
- Serviço de Biologia Celular, Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, Brazil
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- Maria Raquel Santos Carvalho
- Laboratório de Genética Humana e Médica, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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- Agnaldo Lopes da Silva Filho
- Departamento de Ginecologia e Obstetrícia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
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- Letícia da Conceição Braga
- Serviço de Biologia Celular, Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, Brazil.,Departamento de Ginecologia e Obstetrícia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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34
Bhattacharya R, Mitra T, Ray Chaudhuri S, Roy SS. Mesenchymal splice isoform of CD44 (CD44s) promotes EMT/invasion and imparts stem‐like properties to ovarian cancer cells.
J Cell Biochem 2018;
119:3373-3383. [DOI:
10.1002/jcb.26504]
[Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/09/2017] [Indexed: 12/18/2022]
Affiliation(s)
- Rahul Bhattacharya
- Cell Biology and Physiology DivisionCSIR‐Indian Institute of Chemical BiologyKolkataWest BengalIndia
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- Tulika Mitra
- Cell Biology and Physiology DivisionCSIR‐Indian Institute of Chemical BiologyKolkataWest BengalIndia
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- Susri Ray Chaudhuri
- Tata Translational Cancer Research CentreTata Medical CentreKolkataWest BengalIndia
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- Sib Sankar Roy
- Cell Biology and Physiology DivisionCSIR‐Indian Institute of Chemical BiologyKolkataWest BengalIndia
- Academy of Scientific and Innovative ResearchCSIR‐Indian Institute of Chemical Biology CampusKolkataWest BengalIndia
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35
Diagnostic and Prognostic Biomarkers in ovarian cancer and the potential roles of cancer stem cells – An updated review.
Exp Cell Res 2018;
362:1-10. [DOI:
10.1016/j.yexcr.2017.10.018]
[Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 10/20/2017] [Indexed: 01/06/2023]
36
Motohara T, Katabuchi H. Emerging Role of CD44 Variant 6 in Driving the Metastatic Journey of Ovarian Cancer Stem Cells.
CELL BIOLOGY OF THE OVARY 2018:73-88. [DOI:
10.1007/978-981-10-7941-2_6]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
37
Reimer D, Boesch M, Wolf D, Marth C, Sopper S, Hatina J, Altevogt P, Parson W, Hackl H, Zeimet AG. Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum-response.
Int J Cancer 2017;
142:1640-1651. [DOI:
10.1002/ijc.31186]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 11/01/2017] [Accepted: 11/16/2017] [Indexed: 01/04/2023]
Affiliation(s)
- Daniel Reimer
- Department of Obstetrics and Gynecology; Medical University Innsbruck; 6020 Innsbruck Austria
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- Maximilian Boesch
- Institute of Immunobiology, Kantonsspital St. Gallen; 9007 St. Gallen Switzerland
- Internal Medicine V, Innsbruck Medical University; 6020 Innsbruck Austria
- Tyrolean Cancer Research Institute; 6020 Innsbruck Austria
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- Dominik Wolf
- Internal Medicine V, Innsbruck Medical University; 6020 Innsbruck Austria
- Medical Clinic 3, Oncology, Hematology, Immunology and Rheumatology; University Clinic Bonn (UKB); 53127 Bonn Germany
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- Christian Marth
- Department of Obstetrics and Gynecology; Medical University Innsbruck; 6020 Innsbruck Austria
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- Sieghart Sopper
- Internal Medicine V, Innsbruck Medical University; 6020 Innsbruck Austria
- Tyrolean Cancer Research Institute; 6020 Innsbruck Austria
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- Jiri Hatina
- Department of Biology and Biomedical Centre; Faculty of Medicine Pilsen, Charles University Prague; 30100 Pilsen Czech Republic
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- Peter Altevogt
- Skin Cancer Unit; German Cancer Research Center (DKFZ); 69120 Heidelberg Germany
- Department of Dermatology, Venereology and Allergology; University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg; 68167 Mannheim Germany
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- Walther Parson
- Institute of Legal Medicine, Medical University Innsbruck; 6020 Innsbruck Austria
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- Hubert Hackl
- Division of Bioinformatics; Biocenter, Medical University Innsbruck; 6020 Innsbruck Austria
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- Alain G. Zeimet
- Department of Obstetrics and Gynecology; Medical University Innsbruck; 6020 Innsbruck Austria
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38
Zhao L, Zhang P, Su XJ, Zhang B. The ubiquitin ligase TRIM56 inhibits ovarian cancer progression by targeting vimentin.
J Cell Physiol 2017;
233:2420-2425. [PMID:
28771721 DOI:
10.1002/jcp.26114]
[Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 08/01/2017] [Indexed: 01/06/2023]
Abstract
Tumor metastasis is responsible for 90% of all cancer-related deaths. Epithelial to mesenchymal transition (EMT) is an important prerequisite for tumor metastasis. One of the important mediators of EMT and cancer progression in ovarian cancer is the vimentin protein. The objective of the current study was to evaluate the molecular mechanism that regulates vimentin expression in ovarian cancer cells. Vimentin was robustly induced in the ovarian cancer cell line SKOV-3 compared to normal ovarian epithelial cell line Moody and the induction was not due to transcriptional upregulation. Treatment with the proteasomal inhibitor MG-132 revealed that vimentin is actively degraded by the proteasome in Moody cells and stabilized in the SKOV-3 cell line. Mass spectrometric analysis of vimentin immunoprecipitate of MG-132 treated Moody cells revealed candidate ubiquitin ligases associated with vimentin. RNAi mediated silencing of the candidate ubiquitin in Moody cells and concurrent overexpression of the candidate ubiquitin ligases in SKOV-3 confirmed that TRIM56 is the ubiquitin ligase that is degrading vimentin in Moody cells. RNAi mediated silencing of TRIM56 in Moody cells and ectopic overexpression of TRIM56 in SKOV-3 cells, respectively, significantly up- and down-regulated in vitro migration and invasion in these cells. Analysis of TRIM56 transcript level and vimentin protein expression in 25 patients with ovarian carcinoma confirmed an inverse correlation between TRIM56 and vimentin expression. Cumulatively, our data reveals for the first time a novel post-translational regulatory mechanism of regulating vimentin expression, EMT, and metastatic progression in ovarian cancer cells.
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Affiliation(s)
- Lei Zhao
- College of Medical Laboratory Science and Technology, Harbin Medical University at Daqing, Daqing, Heilongjiang, China
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- Ping Zhang
- College of Medical Laboratory Science and Technology, Harbin Medical University at Daqing, Daqing, Heilongjiang, China
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- Xiao-Jie Su
- College of Medical Laboratory Science and Technology, Harbin Medical University at Daqing, Daqing, Heilongjiang, China
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- Bing Zhang
- College of Medical Laboratory Science and Technology, Harbin Medical University at Daqing, Daqing, Heilongjiang, China
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39
Roy M, Connor J, Al-Niaimi A, Rose SL, Mahajan A. Aldehyde dehydrogenase 1A1 (ALDH1A1) expression by immunohistochemistry is associated with chemo-refractoriness in patients with high-grade ovarian serous carcinoma.
Hum Pathol 2017;
73:1-6. [PMID:
28851663 DOI:
10.1016/j.humpath.2017.06.025]
[Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 06/09/2017] [Accepted: 06/29/2017] [Indexed: 01/09/2023]
Abstract
Aldehyde dehydrogenase-1A1 (ALDH1A1), CD133, CD44, and CD24 have been reported as cancer stem cell markers in ovarian cancers. The goal of our study was to assess the prognostic significance of these markers in patients with advanced serous ovarian cancer. Formalin-fixed, paraffin-embedded tissues from 347 ovarian cancers were used to construct a microarray. Immunohistochemical studies for ALDH1A1, CD133, CD44, and CD24 were performed and scored semiquantitatively by 2 pathologists based on intensity and percent of positive immunoreactive cells. Immunohistochemistry was compared to clinical parameters and survival. Of the 347 cases, early stage disease, nonserous tumors, cases with incomplete therapy, and cores with no tumor were excluded. Immunohistochemistry was interpretable in 124 of the 136 stage III and IV ovarian serous carcinoma. ALDH1A1, CD24, and CD44 were variably detected in both tumor and stromal cells, and immunoreactivity in tumor was stronger than in stromal cells. CD133 immunoreactivity was not quantified due to nonspecific staining in tumor and stroma. Statistical analyses using χ2 and Student t test revealed that ALDH1A1-positive (n=53) carcinoma were 3 times more likely to demonstrate platinum refractoriness than ALDH1A1-negative (n=71) tumors (17% vs. 6%, respectively; p=.04); however, neither progression free nor overall survival was influenced by ALDH1A1 status in this cohort. The expression of CD44 and CD24 had no clinicopathological associations in the present study. Our study supports that ALDH1A1 expression is associated with poor response to platinum-based therapy in patients with high-grade ovarian serous carcinoma. Further study of this relationship is needed to understand how this could impact clinical care.
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Affiliation(s)
- Madhuchhanda Roy
- Department of Pathology, University of Wisconsin Hospital and Clinics, Madison, WI 53792
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- Joseph Connor
- Department of Pathology, University of Wisconsin Hospital and Clinics, Madison, WI 53792
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- Ahmed Al-Niaimi
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Wisconsin Hospital and Clinics, Madison, WI 53792
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- Stephen L Rose
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Wisconsin Hospital and Clinics, Madison, WI 53792
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- Aparna Mahajan
- Department of Pathology, University of Wisconsin Hospital and Clinics, Madison, WI 53792.
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40
Klapdor R, Wang S, Hacker U, Büning H, Morgan M, Dörk T, Hillemanns P, Schambach A. Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor-Based Immunotherapy and Chemotherapy.
Hum Gene Ther 2017;
28:886-896. [PMID:
28836469 DOI:
10.1089/hum.2017.168]
[Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer represents the most lethal gynecological cancer. Although cytoreductive chemotherapy and surgery lead to complete macroscopic tumor removal, most of the patients in advanced stages suffer from recurrent disease and subsequently die. This may be explained by the activity of cancer stem cells (CSC), which are a subpopulation of cells with an elevated chemoresistance and an increased capacity for self-renewal and metastatic spread. Specifically targeting these cells by adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. This study selected the widely accepted CSC marker CD133 as a target for a chimeric antigen receptor (CAR)-based immunotherapeutic approach to treat ovarian cancer. A lentiviral vector was generated encoding a third-generation anti-CD133-CAR, and clinically used NK92 cells were transduced. These engineered natural killer (NK) cells showed specific killing against CD133-positive ovarian cancer cell lines and primary ovarian cancer cells cultured from sequential ascites harvests. Additionally, specific activation of these engineered NK cells was demonstrated via interferon-gamma secretion assays. To improve clinical efficacy of ovarian cancer treatment, the effect of the chemotherapeutic agent cisplatin was evaluated together with CAR-transduced NK cell treatment. It was demonstrated that NK cells remain cytotoxic and active under cisplatin treatment and, importantly, that sequential treatment with cisplatin followed by CAR-NK cells led to the strongest killing effect. The specific eradication of ovarian CSCs by anti-CD133-CAR expressing NK92 cells represents a promising strategy and, when confirmed in vivo, shall be the basis of future clinical studies with the aim to prevent recurrent disease.
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Affiliation(s)
- Rüdiger Klapdor
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany .,2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany
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- Shuo Wang
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany .,2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany
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- Ulrich Hacker
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,4 University Cancer Center Leipzig (UCCL), University Hospital Leipzig , Leipzig, Germany
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- Hildegard Büning
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany
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- Michael Morgan
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany
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- Thilo Dörk
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany
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- Peter Hillemanns
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany
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- Axel Schambach
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany .,5 Division of Hematology/Oncology, Boston Children's Hospital , Harvard Medical School, Boston, Massachusetts
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41
Bartakova A, Michalova K, Presl J, Vlasak P, Kostun J, Bouda J. CD44 as a cancer stem cell marker and its prognostic value in patients with ovarian carcinoma.
J OBSTET GYNAECOL 2017;
38:110-114. [PMID:
28816557 DOI:
10.1080/01443615.2017.1336753]
[Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The aim of our study was to clarify whether the CD44 adhesion molecule as a cancer stem cell marker could also serve as a prognostic factor in patients with epithelial ovarian cancer (EOC). A retrospective study was performed on 87 patients with histologically verified EOC. Specimens of both primary tumour and implantation metastases were tested from 48 of them. CD44 expression was detected by immunohistochemistry. We looked for the cut-off levels of CD44 expression using the Cox regression model. We confirmed statistically significant prognostic factors for overall survival (OS) and disease-free interval (DFI) to be: stage of the disease, postoperative residual tumour and papillary serous histological type. We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%. CD44 was neither a prognostic factor of OS nor of DFI. IMPACT STATEMENT What is already known about this subject: Epithelial ovarian cancer is the second most common gynaecological cancer in developed countries. Despite great efforts devoted to ovarian cancer research during past decades, levels of patient mortality have changed very little. Cancer stem cells (CSCs) are subpopulations of cells with typical characteristics of stem cells - i.e. the ability to self-renew and differentiate in a variety of cell types. The main surface marker typical for CSCs is CD44. The aim of our study was to clarify whether the CD44 as a CSCs marker could serve as a prognostic factor in patients with epithelial ovarian cancer. Previous studies published on this topic revealed controversial results. The novelty of our study lies in looking for the cut-off using the Cox regression model.
WHAT THIS STUDY ADDS
We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%, however, CD44 was neither a prognostic factor of overall survival nor of disease-free interval. We propose to investigate other markers including other CSCs as a prognostic factors or potential aims for targeted therapy in ovarian cancer.
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Affiliation(s)
- Alena Bartakova
- a Department of Gynaecology and Obstetrics , University Hospital Pilsen, Charles University , Prague , Czech Republic
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- Kveta Michalova
- b Sikl's Department of Pathology , University Hospital Pilsen, Charles University , Prague , Czech Republic
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- Jiri Presl
- a Department of Gynaecology and Obstetrics , University Hospital Pilsen, Charles University , Prague , Czech Republic
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- Pavel Vlasak
- a Department of Gynaecology and Obstetrics , University Hospital Pilsen, Charles University , Prague , Czech Republic
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- Jan Kostun
- a Department of Gynaecology and Obstetrics , University Hospital Pilsen, Charles University , Prague , Czech Republic
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- Jiri Bouda
- a Department of Gynaecology and Obstetrics , University Hospital Pilsen, Charles University , Prague , Czech Republic
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42
Alwosaibai K, Abedini A, Al-Hujaily EM, Tang Y, Garson K, Collins O, Vanderhyden BC. PAX2 maintains the differentiation of mouse oviductal epithelium and inhibits the transition to a stem cell-like state.
Oncotarget 2017;
8:76881-76897. [PMID:
29100356 PMCID:
PMC5652750 DOI:
10.18632/oncotarget.20173]
[Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 07/18/2017] [Indexed: 12/18/2022] Open
Abstract
Recent studies have provided evidence that the secretory cells of the fallopian tube (oviduct) are a probable origin for high-grade serous ovarian carcinoma. In addition to secretory cells, the fallopian tube epithelium consists of ciliated cells and CD44+ undifferentiated stem-like cells. Loss of PAX2 expression is recognized as an early event in epithelial transformation, but the specific role of PAX2 in this transition is unknown. The aim of this study was to define the role of PAX2 in oviductal epithelial (OVE) cells and its response to transforming growth factor β1 (TGFβ), characterizing specifically its potential involvement in regulating stem cell-like behaviors that may contribute to formation of cancer-initiating cells. Treatment of primary cultures of mouse OVE cells with TGFβ induced an epithelial-mesenchymal transition (EMT) associated with decreased expression of PAX2 and an increase in the fraction of cells expressing CD44. PAX2 knockdown in OVE cells and overexpression in ovarian epithelial cells confirmed that PAX2 inhibits stem cell characteristics and regulates the degree of epithelial differentiation of OVE cells. These results suggest that loss of PAX2, as occurs in serous tubal intraepithelial carcinomas, may shift secretory cells to a more mesenchymal phenotype associated with stem-like features.
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Affiliation(s)
- Kholoud Alwosaibai
- Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ontario, Canada.,King Fahad Specialist Hospital, Dammam, Saudi Arabia
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- Atefeh Abedini
- Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ontario, Canada
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- Ensaf M Al-Hujaily
- Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ontario, Canada
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- Yong Tang
- Department of Urology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China
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- Kenneth Garson
- Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ontario, Canada
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- Olga Collins
- Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ontario, Canada
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- Barbara C Vanderhyden
- Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.,Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ontario, Canada.,Department of Obstetrics and Gynecology, University of Ottawa, Ontario, Canada
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43
Xie X, Yang M, Ding Y, Chen J. Microbial infection, inflammation and epithelial ovarian cancer.
Oncol Lett 2017;
14:1911-1919. [PMID:
28789426 PMCID:
PMC5529868 DOI:
10.3892/ol.2017.6388]
[Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 04/13/2017] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer is the most common, and life-threatening, type of female gynecological cancer. The etiology of ovarian cancer remains unclear, and there are currently no effective screening or treatment methods for the disease. Microbial infection serves a marked function in inducing carcinogenesis. A number of studies have identified pelvic inflammatory disease as a risk factor for epithelial ovarian cancer. Thus, it is hypothesized that microbial infection may contribute to ovarian cancer. In the present review, the microorganisms that have been identified to be associated with ovarian cancer and the underlying molecular mechanisms involved are discussed. Infection-induced chronic inflammation is considered an important process for carcinogenesis, cancer progression and metastasis. Therefore, the pathological process and associated inflammatory factors are reviewed in the present paper.
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Affiliation(s)
- Xiaohui Xie
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410001, P.R. China
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- Mengyuan Yang
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410001, P.R. China
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- Yiling Ding
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410001, P.R. China
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- Jianlin Chen
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410001, P.R. China
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44
miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway.
Oncogenesis 2017;
6:e326. [PMID:
28459431 PMCID:
PMC5525454 DOI:
10.1038/oncsis.2017.25]
[Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/24/2017] [Accepted: 03/09/2017] [Indexed: 12/22/2022] Open
Abstract
Epithelial ovarian cancer is the most lethal gynecological cancer mainly due to late diagnosis, easy spreading and rapid development of chemoresistance. Cancer stem cells are considered to be one of the main mechanisms for chemoresistance, as well as metastasis and recurrent disease. To explore the stemness characteristics of ovarian cancer stem cells, we successfully enriched ovarian cancer stem-like cells from an established ovarian cancer cell line (SKOV-I6) and a fresh ovarian tumor-derived cell line (OVS1). These ovarian cancer stem-like cells possess important cancer stemness characteristics including sphere-forming and self-renewing abilities, expressing important ovarian cancer stem cell and epithelial–mesenchymal transition markers, as well as increased drug resistance and potent tumorigenicity. Microarray analysis of OVS1-derived sphere cells revealed increased expression of amphiregulin (AREG) and decreased expression of its conserved regulatory microRNA, miR-34c-5p, when compared with the OVS1 parental cells. Overexpression of AREG and decreased miR-34c-5p expression in SKOV-I6 and OVS1 sphere cells were confirmed by quantitative real-time PCR analysis. Luciferase reporter assay and mutant analysis confirmed that AREG is a direct target of miR-34c-5p. Furthermore, AREG-mediated increase of sphere formation, drug resistance toward docetaxel and carboplatin, as well as tumorigenicity of SKOV-I6 and OVS1 cells could be abrogated by miR-34c-5p. We further demonstrated that miR-34c-5p inhibited ovarian cancer stemness through downregulation of the AREG-EGFR-ERK pathway. Overexpression of AREG was found to be correlated with advanced ovarian cancer stages and poor prognosis. Taken together, our data suggest that AREG promotes ovarian cancer stemness and drug resistance via the AREG-EGFR-ERK pathway and this is inhibited by miR-34c-5p. Targeting AREG, miR-34c-5p could be a potential strategy for anti-cancer-stem cell therapy in ovarian cancer.
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45
NANOG regulates epithelial-mesenchymal transition and chemoresistance in ovarian cancer.
Biosci Rep 2017;
37:BSR20160247. [PMID:
27884977 PMCID:
PMC5223747 DOI:
10.1042/bsr20160247]
[Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 11/11/2016] [Accepted: 11/24/2016] [Indexed: 01/06/2023] Open
Abstract
A key transcription factor associated with poor prognosis and resistance to chemotherapy in ovarian cancer is NANOG. However, the mechanism by which NANOG functions remains undefined. It has been suggested that epithelial-to-mesenchymal transition (EMT) also contributes to development of drug resistance in different cancers. We thus determined whether NANOG expression was associated with EMT and chemoresistance in epithelial ovarian cancer cells. NANOG expression was increased in epithelial ovarian cancer cell lines compared with its expression in normal epithelial ovarian cell lines. NANOG expression in SKOV-3 or OV2008 cells directly correlated with high expression of mesenchymal cell markers and inversely with low expression of epithelial cell marker. RNAi-mediated silencing of NANOG in SKOV-3 reversed the expression of mesenchymal cell markers and restored expression of E-cadherin. Reversibly, stable overexpression of NANOG in Moody cells increased expression of N-cadherin whereas down-regulating expression of E-cadherin, cumulatively indicating that NANOG plays an important role in maintaining the mesenchymal cell markers. Modulating NANOG expression did not have any effect on proliferation or colony formation. Susceptibility to cisplatin increased in SKOV-3 cells on down-regulating NANOG and reversible results were obtained in Moody cells post-overexpression of NANOG. NANOG silencing in SKOV-3 and OV2008 robustly attenuated in vitro migration and invasion. NANOG expression exhibited a biphasic pattern in patients with ovarian cancer and expression was directly correlated to chemoresistance retrospectively. Cumulatively, our data demonstrate that NANOG expression modulates chemosensitivity and EMT resistance in ovarian cancer.
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Choi EJ, Seo EJ, Kim DK, Lee SI, Kwon YW, Jang IH, Kim KH, Suh DS, Kim JH. FOXP1 functions as an oncogene in promoting cancer stem cell-like characteristics in ovarian cancer cells.
Oncotarget 2016;
7:3506-19. [PMID:
26654944 PMCID:
PMC4823123 DOI:
10.18632/oncotarget.6510]
[Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 11/21/2015] [Indexed: 12/18/2022] Open
Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers with a high recurrence rate. It is important to understand the nature of recurring cancer cells to terminally eliminate ovarian cancer. The winged helix transcription factor Forkhead box P1 (FOXP1) has been reported to function as either oncogene or tumor-suppressor in various cancers. In the current study, we show that FOXP1 promotes cancer stem cell-like characteristics in ovarian cancer cells. Knockdown of FOXP1 expression in A2780 or SKOV3 ovarian cancer cells decreased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment, whereas overexpression of FOXP1 in A2780 or SKOV3 ovarian cancer cells increased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment. In addition, overexpression of FOXP1 increased promoter activity of ABCG2, OCT4, NANOG, and SOX2, among which the increases in ABCG2, OCT4, and SOX2 promoter activity were dependent on the presence of FOXP1-binding site. In xenotransplantation of A2780 ovarian cancer cells into nude mice, knockdown of FOXP1 expression significantly decreased tumor size. These results strongly suggest FOXP1 functions as an oncogene by promoting cancer stem cell-like characteristics in ovarian cancer cells. Targeting FOXP1 may provide a novel therapeutic opportunity for developing a relapse-free treatment for ovarian cancer patients.
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Affiliation(s)
- Eun Jung Choi
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Eun Jin Seo
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Dae Kyoung Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Su In Lee
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Yang Woo Kwon
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Il Ho Jang
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Ki-Hyung Kim
- Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Dong-Soo Suh
- Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea
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- Jae Ho Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 626-770, Gyeongsangnam-do, Republic of Korea
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Davidson B. CD24 is highly useful in differentiating high-grade serous carcinoma from benign and malignant mesothelial cells.
Hum Pathol 2016;
58:123-127. [PMID:
27589896 DOI:
10.1016/j.humpath.2016.08.005]
[Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 07/30/2016] [Accepted: 08/18/2016] [Indexed: 12/14/2022]
Abstract
CD24 was previously shown to be overexpressed in high-grade serous carcinoma (HGSC) effusions compared to malignant mesothelioma (MM) in gene expression array analysis. The present study validated this observation in a large series consisting of both effusions and surgical specimens. Effusions (n = 206; 100 HGSC, 16 ovarian carcinomas of other histological types, 54 breast carcinomas, 36 MM) and surgical specimens (n = 182; 117 ovarian carcinomas, 65 MM) were analyzed for CD24 expression using immunohistochemistry. CD24 was expressed in 105/116 (91%) ovarian carcinoma and 16/54 (30%) breast carcinoma effusions, while it was uniformly absent in MM (0/36; 0%; P < .001). Reactive mesothelial cells were CD24-negative in all carcinoma specimens. Comparative analysis of 117 solid primary (n = 43) and metastatic (n = 74) ovarian carcinomas and 65 solid MM specimens showed CD24 expression in 46% (54/117) of the former compared to 3% (2/65) of the latter (P < .001). Comparative analysis of ovarian carcinomas at different anatomic sites showed significantly higher CD24 expression in effusions compared to solid ovarian and metastatic lesions (P < .001), with similar results when analysis was limited to HGSC (P < .001). In conclusion, CD24 is a highly sensitive and specific marker of ovarian carcinoma in the differential diagnosis from MM and reactive mesothelium in effusions. CD24 is similarly a specific marker in surgical specimens, though with lower sensitivity. The overexpression of CD24 in ovarian carcinoma effusions compared to solid lesions may be due to the acquisition of cancer stem cell characteristics.
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Affiliation(s)
- Ben Davidson
- Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310, Oslo, Norway; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316, Oslo, Norway.
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ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells.
Tumour Biol 2016;
37:12889-12896. [DOI:
10.1007/s13277-016-5209-5]
[Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 07/13/2016] [Indexed: 12/20/2022] Open
49
Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M. Therapies targeting cancer stem cells: Current trends and future challenges.
World J Stem Cells 2015;
7:1185-1201. [PMID:
26516409 PMCID:
PMC4620424 DOI:
10.4252/wjsc.v7.i9.1185]
[Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 08/02/2015] [Accepted: 09/08/2015] [Indexed: 02/07/2023] Open
Abstract
Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers.
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50
Abstract
The mammalian ovary is covered by a single-layered epithelium that undergoes rupture and remodelling following each ovulation. Although resident stem cells are presumed to be crucial for this cyclic regeneration, their identity and mode of action have been elusive. Surrogate stemness assays and in vivo fate-mapping studies using recently discovered stem cell markers have identified stem cell pools in the ovary and fimbria that ensure epithelial homeostasis. Recent findings provide insights into intrinsic mechanisms and local extrinsic cues that govern the function of ovarian and fimbrial stem cells. These discoveries have advanced our understanding of stem cell biology in the ovary and fimbria, and lay the foundations for evaluating the contribution of resident stem cells to the initiation and progression of human epithelial ovarian cancer.
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