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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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Zisis V, Giannakopoulos NN, Schmitter M, Poulopoulos A, Andreadis D. Cancer Stem Cells' Biomarker ALDH1&2 Increased Expression in Erosive Oral Lichen Planus Compared to Oral Leukoplakia. Cureus 2023; 15:e44278. [PMID: 37772212 PMCID: PMC10532032 DOI: 10.7759/cureus.44278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
INTRODUCTION ALDH1&2 has been considered an oral cancer stem cell (CSC) marker. Oral carcinogenesis is a process that usually passes through oral potentially malignant disorders (OPMD). Oral lichen planus (OLP) consists of immune-related chronic disorders that have been included in the OPMDs due to their possible transformation into oral cancer. The aim of this study was to investigate the early presence of ALDH1&2 in OLP compared to early oral leukoplakias (OL), especially mildly and non-dysplastic OL. MATERIALS AND METHODS The study type is experimental, and the study design is characterized as semiquantitative research which belongs to the branch of experimental research. The study sample consisted of paraffin-embedded OLP biopsy samples from the archives of the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece, during the period 2009-2019. The study sample contained 24 cases of OLP (14 erosive and 10 reticular) and 30 cases of OL (16 cases of moderately and severely dysplastic OL and 14 cases of mildly and non-dysplastic OL). The CSC-related biomarker ALDH1&2 was examined using semiquantitative immunohistochemistry (monoclonal antibody sc-166362, Santa Cruz Biotechnology, Dallas, Texas, USA, 1:100). ALDH1&2 expression was evaluated through a scale of 1 to 3 depending on the percentage of positive epithelial cells and was compared to normal epithelium as well as cases of OL (the most prominent OPMD). The statistical analysis was performed with the Pearson chi-square test and the significance level was set at p≤0.05. RESULTS The cytoplasmic staining of ALDH1&2 was observed mostly in the epithelial cells of the basal layer of the epithelium of OLP. Overall, this expression was significantly increased compared to normal epithelium. In addition, statistically significantly higher expression of ALDH1&2 was observed in the erosive form of OLP. Interestingly, this OLP positivity was higher compared to mild and non-dysplastic leukoplakias (p<0.001). CONCLUSIONS ALDH1&2 is a confirmed CSC marker that was found to be clearly increased in OLP and characteristically in erosive OLP epithelium for the first time. Noteworthy, it was more prominent in erosive OLP rather than in mildly and non-dysplastic OL. Whether this pattern of expression raises the red flag of an early epithelial "CSC" phenotype in OLP or that ALDH1&2 expression indicates a response to the OLP inflammatory process requires further investigation.
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Affiliation(s)
- Vasileios Zisis
- Prosthodontics, Julius-Maximilians-Universität, Würzburg, DEU
- Oral Medicine/Pathology, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | | | - Marc Schmitter
- Prosthodontics, Julius-Maximilians-Universität, Würzburg, DEU
| | | | - Dimitrios Andreadis
- Oral Medicine/Pathology, Aristotle University of Thessaloniki, Thessaloniki, GRC
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Zisis V, Paraskeuopoulos K, Athanasios P, Panta P, Dimitrios A. Altered Presence of Cancer Stem Cell ALDH1/2 in Oral Leukoplakias and Squamous Cell Carcinomas. Cureus 2023; 15:e40836. [PMID: 37489188 PMCID: PMC10363262 DOI: 10.7759/cureus.40836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2023] [Indexed: 07/26/2023] Open
Abstract
INTRODUCTION Cancer stem cells (CSCs) are responsible for initiating the process of carcinogenesis by enabling the self-renewal and self-proliferation of the cancer cells. This study aimed to investigate the presence of epithelial cells with cancer stem cells characteristics (ALDH+) in the early stages of oral precancerous lesions (Oral Leukoplakias) and the frequency of these cells in the different stages of oral squamous cell carcinomas (OSCCs). MATERIALS & METHODS The aim of this study was the detection of the immunohistochemical pattern of expression of CSC protein-biomarker ALDH1&2 (sc-166362, Santa Cruz Co, Dallas, Texas, USA) in paraffin-embedded samples of 30 cases of leukoplakia of all degrees of dysplasia and 21 cases of oral squamous cell carcinomas (OSCC) of all degrees of differentiation compared to the histologically normal oral epithelium. The samples were retrieved from 2009-2019 from the archives of the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece. The samples were evaluated through a three-tier scale (positive cells Ι: 6-35%, ΙΙ: 36-70%, ΙΙΙ: 71-100%). Statistical analysis was performed through SPSS Pearson Chi-square, and the significance level was set at 0.05 (p=0.05). Results: The staining of ALDH1&2 was observed mildly in the cell membrane of cells in the stratum spinosum of the normal epithelium and the cell membrane of cells in the stratum basale of the normal epithelium, characteristically at the interface point with the basal membrane. ALDH1&2 were expressed significantly more in the OSCC than in the leukoplakia (p-value=0.0001) and the normal epithelium (p-value=0.0001). Mainly, ALDH1&2 were expressed significantly more in the severely and moderately dysplastic oral leukoplakia compared to the mildly dysplastic and non-dysplastic leukoplakia (p-value=0.001). DISCUSSION The characteristic expression of ALDH in potentially malignant oral and OSCC lesions suggests the presence of CSCs and their possible implication in the early stages of oral tumorigenesis, even at the stage of oral leukoplakia.
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Affiliation(s)
- Vasileios Zisis
- Oral Medicine/ Pathology, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | | | | | - Prashanth Panta
- Oral Medicine and Radiology, Malla Reddy Institute of Dental Sciences, Hyderabad, IND
| | - Andreadis Dimitrios
- Oral Medicine/ Pathology, Aristotle University of Thessaloniki, Thessaloniki, GRC
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Joshi P, Waghmare S. Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges. World J Stem Cells 2023; 15:438-452. [PMID: 37342225 PMCID: PMC10277967 DOI: 10.4252/wjsc.v15.i5.438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
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Affiliation(s)
- Priyanka Joshi
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjeev Waghmare
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
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Xu C, Yang HL, Yang YK, Pan L, Chen HY. Zinc-finger protein 750 mitigates malignant biological behavior of oral CSC-like cells enriched from parental CAL-27 cells. Oncol Lett 2022; 23:28. [PMID: 34868365 PMCID: PMC8630818 DOI: 10.3892/ol.2021.13146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 11/05/2021] [Indexed: 11/06/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the most commonly occurring oral malignancy. Cancer stem cells (CSCs) are known to be responsible for cancer recurrence and metastasis. Zinc-finger protein 750 (ZNF750) has been reported to inhibit OSCC cell proliferation and invasion. The present study aimed to elucidate the role of ZNF750 in the inhibition of the renewal ability of CSCs derived from the OSCC cell line, CAL-27. The effects of ZNF750 on CSC-like properties were examined using aldehyde dehydrogenase (ALDH), tumor sphere formation and colony formation assays. Reverse transcription-quantitative PCR and western blotting were performed to detect the expression levels of octamer-binding transcription factor 4, sex-determining region Y-box 2, the enhancer of zeste homolog 2 (Ezh2), embryonic ectoderm development (EED) and SUZ12 polycomb repressive complex 2 subunit (SUZ12), and for the identification of genes associated with metastasis. ZNF750 effectively attenuated CSC-like cell self-renewal abilities; ZNF750 decreased the ALDH-positive cell population, tumor sphere and colony formation abilities, cell viability and stemness factors. Furthermore, the expression levels of Ezh2, EED and SUZ12 were decreased by ZNF750. ZNF750 inhibited MMP1, 3, 9 and 13 expression levels, and decreased the cell invasion and migratory abilities. Moreover, the expression of tissue inhibitors of matrix metalloproteinases-1 was increased by ZNF750. However, opposite effects were observed following the knockdown of the ZNF750 gene. Overall, the present study demonstrated that ZNF750 has the potential to inhibit the renewal of CSC-like cells enriched from parental CAL-27 cells.
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Affiliation(s)
- Cong Xu
- Central Laboratory of Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Hong-Li Yang
- Central Laboratory of Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Yi-Kun Yang
- Central Laboratory of Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Li Pan
- Central Laboratory of Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Hai-Ying Chen
- Central Laboratory of Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
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Moosavi MS, Tavakol F. Literature review of cancer stem cells in oral lichen planus: a premalignant lesion. Stem Cell Investig 2021; 8:25. [PMID: 35071586 PMCID: PMC8743864 DOI: 10.21037/sci-2020-049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/09/2021] [Indexed: 11/14/2023]
Abstract
OBJECTIVE As there is no review study about cancer stem cells (CSCs) involved in the pathogenesis of oral lichen planus (OLP), for the first time we review the role of these cells in OLP and this hypothesis may be a clue for the evaluation of the premalignancy of OLP. BACKGROUND Cellular mediated immune responses are the main etiopathogenesis in OLP and it is a potentially premalignant lesion. One of the factors proposed in the pathogenesis of OLP and the comparable trend of this autoimmune disease to squamous cell carcinoma (SCC) are CSCs. CSCs have been detected in several solid tumors including head and neck cancers, and have special characteristics including metastasis and resistance to chemotherapy. METHODS Related keywords were searched and risk of bias assessment was done for each study. CONCLUSIONS Among all of the studies reviewed in this article, all markers had increased expression in OLP compared to controls that are consistent with SCC. Only CD44 was in contradiction to other papers, in which different expression of CD44 strains was measured in different samples such as saliva and tissue. Based on the results of this review and more studies in the future by investigating the levels of these markers in OLP, it may be possible to determine the prognosis and course of the disease for each patient individually.
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Affiliation(s)
- Mahdieh-Sadat Moosavi
- Dental Research Center, Dentistry Research Institute, Department of Oral and Maxillofacial Medicine, Faculty of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tavakol
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Lorestan University of Medical Sciences, Khorramabad, Iran
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Lee JW, Lee HY. Targeting Cancer Stem Cell Markers or Pathways: A Potential Therapeutic Strategy for Oral Cancer Treatment. Int J Stem Cells 2021; 14:386-399. [PMID: 34711702 PMCID: PMC8611309 DOI: 10.15283/ijsc21084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/14/2021] [Accepted: 06/05/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cancer cells with stem cell-like properties, self-renewal potential, and differentiation capacity into multiple cell types. Critical genetic alterations or aberrantly activated signaling pathways associated with drug resistance and recurrence have been observed in multiple types of CSCs. In this context, CSCs are considered to be responsible for tumor initiation, growth, progression, therapeutic resistance, and metastasis. Therefore, to effectively eradicate CSCs, tremendous efforts have been devoted to identify specific target molecules that play a critical role in regulating their distinct functions and to develop novel therapeutics, such as proteins, monoclonal antibodies, selective small molecule inhibitors, and small antisense RNA (asRNA) drugs. Similar to other CSC types, oral CSCs can be characterized by certain pluripotency-associated markers, and oral CSCs can also survive and form 3D tumor spheres in suspension culture conditions. These oral CSC-targeting therapeutics selectively suppress specific surface markers or key signaling components and subsequently inhibit the stem-like properties of oral CSCs. A large number of new therapeutic candidates have been tested, and some products are currently in the pre-clinical or clinical development phase. In the present study, we review new oral CSC-targeted therapeutic strategies and discuss the various specific CSC surface markers and key signaling components involved in the stem-like properties, growth, drug resistance, and tumorigenicity of oral CSCs.
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Affiliation(s)
- Jin Woo Lee
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Korea
| | - Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, Goesan, Korea.,Division of Science Education, Kangwon National University, Chuncheon, Korea
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Hsueh WT, Chen SH, Chien CH, Chou SW, Chi PI, Chu JM, Chang KY. SOD2 Enhancement by Long-Term Inhibition of the PI3K Pathway Confers Multi-Drug Resistance and Enhanced Tumor-Initiating Features in Head and Neck Cancer. Int J Mol Sci 2021; 22:ijms222011260. [PMID: 34681918 PMCID: PMC8537886 DOI: 10.3390/ijms222011260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/15/2021] [Accepted: 10/16/2021] [Indexed: 11/16/2022] Open
Abstract
The phosphoinositide-3-kinase (PI3K) pathway has widely been considered as a potential therapeutic target for head and neck cancer (HNC); however, the application of PI3K inhibitors is often overshadowed by the induction of drug resistance with unknown mechanisms. In this study, PII3K inhibitor resistant cancer cells were developed by prolonged culturing of cell lines with BEZ235, a dual PI3K and mammalian target of rapamycin (mTOR) inhibitor. The drug resistant HNC cells showed higher IC50 of the proliferation to inhibitors specifically targeting PI3K and/or mTOR, as compared to their parental cells. These cells also showed profound resistance to drugs of other classes. Molecular analysis revealed persistent activation of phosphorylated AKT at threonine 308 in the drug resistant cells and increased expression of markers for tumor-initiating cells. Interestingly, increased intra-cellular ROS levels were observed in the drug resistant cells. Among anti-oxidant molecules, the expression of SOD2 was increased and was associated with the ALDH-positive tumor-initiating cell features. Co-incubation of SOD inhibitors and BEZ235 decreased the stemness feature of the cells in vitro, as shown by results of the spheroid formation assay. In conclusion, dysregulation of SOD2 might contribute to the profound resistance to PI3K inhibitors and the other drugs in HNC cells.
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Affiliation(s)
- Wei-Ting Hsueh
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan; (W.-T.H.); (S.-H.C.)
| | - Shang-Hung Chen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan; (W.-T.H.); (S.-H.C.)
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; (C.-H.C.); (S.-W.C.); (P.-I.C.); (J.-M.C.)
| | - Chia-Hung Chien
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; (C.-H.C.); (S.-W.C.); (P.-I.C.); (J.-M.C.)
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
| | - Shao-Wen Chou
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; (C.-H.C.); (S.-W.C.); (P.-I.C.); (J.-M.C.)
| | - Pei-I Chi
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; (C.-H.C.); (S.-W.C.); (P.-I.C.); (J.-M.C.)
| | - Jui-Mei Chu
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; (C.-H.C.); (S.-W.C.); (P.-I.C.); (J.-M.C.)
| | - Kwang-Yu Chang
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan; (W.-T.H.); (S.-H.C.)
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan; (C.-H.C.); (S.-W.C.); (P.-I.C.); (J.-M.C.)
- Correspondence: ; Tel.: +886-6-208-3422
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Zhou T, Sang YH, Cai S, Xu C, Shi MH. The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth. Cell Death Dis 2021; 12:751. [PMID: 34326320 PMCID: PMC8322058 DOI: 10.1038/s41419-021-04039-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 07/15/2021] [Accepted: 07/19/2021] [Indexed: 12/25/2022]
Abstract
POLRMT (RNA polymerase mitochondrial) is responsible for the transcription of mitochondrial genome encoding key components of oxidative phosphorylation. This process is important for cancer cell growth. The current study tested expression and potential functions of POLRMT in non-small cell lung cancer (NSCLC). TCGA cohorts and the results from the local lung cancer tissues showed that POLRMT is overexpressed in human lung cancer tissues. In both primary human NSCLC cells and A549 cells, POLRMT silencing (by targeted lentiviral shRNAs) or knockout (through CRSIPR/Cas9 gene editing method) potently inhibited cell viability, proliferation, migration, and invasion, and induced apoptosis activation. On the contrast, ectopic overexpression of POLRMT using a lentiviral construct accelerated cell proliferation and migration in NSCLC cells. The mtDNA contents, mRNA levels of mitochondrial transcripts, and subunits of respiratory chain complexes, as well as S6 phosphorylation, were decreased in POLRMT-silenced or -knockout NSCLC cells, but increased after ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus (AAV) potently inhibited NSCLC xenograft growth in severe combined immune deficiency mice. The mtDNA contents, mRNA levels of mitochondria respiratory chain complex subunits, and S6 phosphorylation were decreased in POLRMT shRNA AAV-injected NSCLC xenograft tissues. These results show that POLRMT is a novel and important oncogene required for NSCLC cell growth in vitro and in vivo.
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Affiliation(s)
- Tong Zhou
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yong-Hua Sang
- Department of Thoracic Surgery, The Second affiliated Hospital of Soochow University, Suzhou, China
| | - Shang Cai
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chun Xu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Min-Hua Shi
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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Gupta S, Kumar P, Das BC. HPV +ve/-ve oral-tongue cancer stem cells: A potential target for relapse-free therapy. Transl Oncol 2021; 14:100919. [PMID: 33129107 PMCID: PMC7590584 DOI: 10.1016/j.tranon.2020.100919] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/27/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
The tongue squamous cell carcinoma (TSCC) is a highly prevalent head and neck cancer often associated with tobacco and/or alcohol abuse or high-risk human papillomavirus (HR-HPV) infection. HPV positive TSCCs present a unique mechanism of tumorigenesis as compared to tobacco and alcohol-induced TSCCs and show a better prognosis when treated. The poor prognosis and/or recurrence of TSCC is due to presence of a small subpopulation of tumor-initiating tongue cancer stem cells (TCSCs) that are intrinsically resistant to conventional chemoradio-therapies enabling cancer to relapse. Therefore, targeting TCSCs may provide efficient therapeutic strategy for relapse-free survival of TSCC patients. Indeed, the development of new TCSC targeting therapeutic approaches for the successful elimination of HPV+ve/-ve TCSCs could be achieved either by targeting the self-renewal pathways, epithelial mesenchymal transition, vascular niche, nanoparticles-based therapy, induction of differentiation, chemoradio-sensitization of TCSCs or TCSC-derived exosome-based drug delivery and inhibition of HPV oncogenes or by regulating epigenetic pathways. In this review, we have discussed all these potential approaches and highlighted several important signaling pathways/networks involved in the formation and maintenance of TCSCs, which are targetable as novel therapeutic targets to sensitize/eliminate TCSCs and to improve survival of TSCC patients.
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Affiliation(s)
- Shilpi Gupta
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India; National Institute of Cancer Prevention and Research (NICPR), I-7, Sector-39, Noida 201301, India
| | - Prabhat Kumar
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India
| | - Bhudev C Das
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India.
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Varun BR, Jayanthi P, Ramani P. Cancer stem cells: A comprehensive review on identification and therapeutic implications. J Oral Maxillofac Pathol 2020; 24:190. [PMID: 32508482 PMCID: PMC7269290 DOI: 10.4103/jomfp.jomfp_336_19] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 12/15/2019] [Indexed: 12/17/2022] Open
Abstract
Cancer stem cells (CSCs) are distinct subpopulations of tumor cells that possess the ability for perpetual self-renewal and proliferation. They produce downstream progenitor cells and cancer cells that drive tumor growth. Studies of many cancer types including oral squamous cell carcinoma (OSCC) have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple CSC subtypes within OSCC, making investigation reliant on the use of multiple markers. This review paper focuses on the current knowledge in CSC markers including OCT4, SOX2, NANOG, aldehyde dehydrogenase 1, CD44, CD24, CD133 and Musashi-1, highlighting their use and validity in OSCC CSC research.
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Affiliation(s)
- B R Varun
- Department of Oral and Maxillofacial Pathology, PMS College of Dental Sciences and Research, Thiruvananthapuram, Tamil Nadu, India
| | - P Jayanthi
- Department of Oral and Maxillofacial Pathology, Azeezia College of Dental Sciences and Research, Kollam, Kerala, India
| | - Pratibha Ramani
- Department of Oral and Maxillofacial Pathology, Saveetha Dental College, Chennai, Tamil Nadu, India
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The current markers of cancer stem cell in oral cancers. Life Sci 2020; 249:117483. [PMID: 32135187 DOI: 10.1016/j.lfs.2020.117483] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/19/2020] [Accepted: 03/01/2020] [Indexed: 12/18/2022]
Abstract
Head and neck cancer (HNC) constitute 5% of all reported cancers. Among all, the oral cavity cancer is the most frequent type of HNC which accounts for over half of HNC cases. Mouth cancer ranks the sixth leading cause of cancer-related mortality. Generally, conventional chemotherapy has shown success at decreasing relapse and metastasis rates and improves the overall prognosis. Recently, target therapy and targeted drug delivery systems have been introduced as promising treatments. The elimination of efficiency of current therapeutic strategies due to the spared cancer stem cells that cause chemotherapy resistance, relapse and metastasis. Inefficiency methodologies in the elimination of all cancer cells in the body are a major problem that remained to be resolved before to confront the new cancer therapies. Many studies imply to cancer stem cell markers as important agents for targeted anti-cancer as well as improving chemotherapy efficiencies. The potentials of targeted cancer therapy led us to search for novel markers in the mouth cancer stem cells especially in rare cancers. The aimed of this research was, first a comprehensive critical review of the previous studies on the markers of cancer stem cells in oral cancers including oral squamous cell carcinoma, salivary gland cancers, and to highlight the most common cancer stem cell markers which have potential to be exploited as indicators for the preneoplastic lesion malignancy, oral cancer progression, and/or treatment prognosis.
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Rao RS, Raju K L, Augustine D, Patil S. Prognostic Significance of ALDH1, Bmi1, and OCT4 Expression in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma. Cancer Control 2020; 27:1073274820904959. [PMID: 32951453 PMCID: PMC7791458 DOI: 10.1177/1073274820904959] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/18/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Increasing evidence suggests the involvement of cancer stem cells (CSCs) in both oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Among the various CSC markers, aldehyde dehydrogenase (ALDH) 1, B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1), and octamer-binding protein 4 (OCT4) have been noted to increase in OSCC. The aim of the study was to analyze ALDH1, Bmi1, and OCT4 expression in OED and OSCC with clinicopathologic correlation and survival analysis. METHODS A total of 40 cases each of OED and OSCC were retrieved from departmental archives. Expression of ALDH1, Bmi1, and OCT4 was analyzed using immunohistochemistry and was correlated with clinicopathological parameters. A follow-up ranging from 6 to 52 months was considered for Kaplan-Meier survival analysis. The log-rank test was performed to analyze significant difference in survival rates. RESULTS The expression levels of ALDH1, Bmi1, and OCT4 increased significantly from OED through OSCC (P < .05). The expression of ALDH1 and OCT4 showed a significant correlation with lymph node metastasis. Positive cases of ALDH1 showed a significantly reduced survival rate compared to cases showing negative expression. Kaplan-Meier survival analysis showed a significant reduction of survival rate (P = .00) in patients showing a positive expression for all the 3 markers. CONCLUSION ALDH1 and OCT4 could be used as individual prognostic markers for assessing prognosis. ALDH1, Bmi1, and OCT4 could be used as a collective panel of markers to enable surgeons in predicting the prognosis of patients and thereby carry out prompt follow-up for such cases.
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Affiliation(s)
- Roopa S. Rao
- Department of Oral Pathology and Microbiology, Faculty of Dental
Sciences, M.S. Ramaiah University of Applied
Sciences, India
| | - Lizbeth Raju K
- Department of Oral Pathology and Microbiology, Faculty of Dental
Sciences, M.S. Ramaiah University of Applied
Sciences, India
| | - Dominic Augustine
- Department of Oral Pathology and Microbiology, Faculty of Dental
Sciences, M.S. Ramaiah University of Applied
Sciences, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, College
of Dentistry, Jazan University, Saudi Arabia
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14
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Xie X, Urabe G, Marcho L, Stratton M, Guo LW, Kent CK. ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation. iScience 2019; 19:872-882. [PMID: 31513972 PMCID: PMC6739626 DOI: 10.1016/j.isci.2019.08.044] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/09/2019] [Accepted: 08/21/2019] [Indexed: 01/24/2023] Open
Abstract
Vascular smooth muscle cell (VSMC) proliferation promotes intimal hyperplasia (IH) in occluding vascular diseases. Here we identified a positive role of ALDH1A3 (an aldehyde dehydrogenase) in this pro-IH process. The expression of ALDH1A3, but not that of 18 other isoforms of the ALDH family, was substantially increased in cytokine-stimulated VSMCs. PDGF(BB) stimulated VSMC total ALDH activity and proliferation, whereas ALDH1A3 silencing abolished this effect. ALDH1A3 silencing also diminished the expression of two matricellular proteins (TNC1 and ESM1), revealing a previously unrecognized ALDH1A3 function. Loss-of-function experiments demonstrated that TNC1 and ESM1 mediated ALDH1A3's pro-proliferative function via activation of AKT/mTOR and/or MEK/ERK pathways. Furthermore, ALDH inhibition with disulfiram blocked VSMC proliferation/migration in vitro and decreased TNC1 and ESM1 and IH in angioplasty-injured rat carotid arteries. Thus, ALDH1A3 promotes VSMC proliferation at least partially through TNC1/ESM1 upregulation; dampening excessive ALDH1A3 activity represents a potential approach to IH mitigation.
The ALDH1A3 isoform promotes vascular smooth muscle cell proliferation ALDH1A3's function is mediated by its upregulation of TNC1 and ESM1 The pan-ALDH inhibitor drug disulfiram mitigates intimal hyperplasia
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Affiliation(s)
- Xiujie Xie
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Go Urabe
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Lynn Marcho
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Matthew Stratton
- Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Lian-Wang Guo
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
| | - Craig K Kent
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
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15
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Koshkin V, Kochmann S, Sorupanathan A, Peng C, Ailles LE, Liu G, Krylov SN. Cytometry of Reaction Rate Constant: Measuring Reaction Rate Constant in Individual Cells To Facilitate Robust and Accurate Analysis of Cell-Population Heterogeneity. Anal Chem 2019; 91:4186-4194. [PMID: 30829484 DOI: 10.1021/acs.analchem.9b00388] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Robust and accurate analysis of cell-population heterogeneity is challenging but required in many areas of biology and medicine. In particular, it is pivotal to the development of reliable cancer biomarkers. Here, we prove that cytometry of reaction rate constant (CRRC) can facilitate such analysis when the kinetic mechanism of a reaction associated with the heterogeneity is known. In CRRC, the cells are loaded with a reaction substrate, and its conversion into a product is followed by time-lapse fluorescence microscopy at the single-cell level. A reaction rate constant is determined for every cell, and a kinetic histogram "number of cells versus the rate constant" is used to determine quantitative parameters of reaction-based cell-population heterogeneity. Such parameters include, for example, the number and sizes of subpopulations. In this work, we applied CRRC to a reaction of substrate extrusion from cells by ATP-binding cassette (ABC) transporters. This reaction is viewed as a potential basis for predictive biomarkers of chemoresistance in cancer. CRRC proved to be robust (insensitive to variations in experimental settings) and accurate for finding quantitative parameters of cell-population heterogeneity. In contrast, a typical nonkinetic analysis, performed on the same data sets, proved to be both nonrobust and inaccurate. Our results suggest that CRRC can potentially facilitate the development of reliable cancer biomarkers on the basis of quantitative parameters of cell-population heterogeneity. A plausible implementation scenario of CRRC-based development, validation, and clinical use of a predictor of ovarian cancer chemoresistance to its frontline therapy is presented.
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Affiliation(s)
| | | | | | | | - Laurie E Ailles
- Department of Medical Biophysics , University of Toronto , Toronto , Ontario N5G 1L7 , Canada
| | - Geoffrey Liu
- Department of Medicine, Medical Oncology , Princess Margaret Cancer Centre , Toronto , Ontario M5G 2M9 , Canada
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16
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Schaal CM, Bora-Singhal N, Kumar DM, Chellappan SP. Regulation of Sox2 and stemness by nicotine and electronic-cigarettes in non-small cell lung cancer. Mol Cancer 2018; 17:149. [PMID: 30322398 PMCID: PMC6190543 DOI: 10.1186/s12943-018-0901-2] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 09/28/2018] [Indexed: 01/03/2023] Open
Abstract
Background Lung cancer is the leading cause of cancer related deaths and its incidence is highly correlated with cigarette smoking. Nicotine, the addictive component of tobacco smoke, cannot initiate tumors, but can promote proliferation, migration, and invasion of cells in vitro and promote tumor growth and metastasis in vivo. This nicotine-mediated tumor promotion is facilitated through the activation of nicotinic acetylcholine receptors (nAChRs), specifically the α7 subunit. More recently, nicotine has been implicated in promoting self-renewal of stem-like side-population cells from lung cancers. This subpopulation of cancer stem-like cells has been implicated in tumor initiation, generation of the heterogeneous tumor population, metastasis, dormancy, and drug resistance. Here we describe the molecular events driving nicotine and e-cigarette extract mediated stimulation of self-renewal of stem-like cells from non-small cell lung cancer. Methods Experiments were conducted using A549 and H1650 non-small cell lung cancer cell lines and human mesenchymal stem cells according to protocols described in this paper. 2 μM nicotine or e-cigarette extracts was used in all relevant experiments. Biochemical analysis using western blotting, transient transfections, RT-PCR and cell biological analysis using double immunofluorescence and confocal microscopy, as well as proximity ligation assays were conducted. Results Here we demonstrate that nicotine can induce the expression of embryonic stem cell factor Sox2, which is indispensable for self-renewal and maintenance of stem cell properties in non-small cell lung adenocarcinoma (NSCLC) cells. We further demonstrate that this occurs through a nAChR-Yap1-E2F1 signaling axis downstream of Src and Yes kinases. Our data suggests Oct4 may also play a role in this process. Over the past few years, electronic cigarettes (e-cigarettes) have been promoted as healthier alternatives to traditional cigarette smoking as they do not contain tobacco; however, they do still contain nicotine. Hence we have investigated whether e-cigarette extracts can enhance tumor promoting properties similar to nicotine; we find that they can induce expression of Sox2 as well as mesenchymal markers and enhance migration and stemness of NSCLC cells. Conclusions Our findings shed light on novel molecular mechanisms underlying the pathophysiology of smoking-related lung cancer in the context of cancer stem cell populations, and reveal new pathways involved that could potentially be exploited therapeutically. Electronic supplementary material The online version of this article (10.1186/s12943-018-0901-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Courtney M Schaal
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.,The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
| | - Namrata Bora-Singhal
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Durairaj Mohan Kumar
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Srikumar P Chellappan
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.
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17
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Yalcin EB, Tong M, Gallucci G, de la Monte SM. Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities. Drug Metab Lett 2018; 12:117-124. [PMID: 29886839 PMCID: PMC9964543 DOI: 10.2174/1872312812666180611115418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 01/30/2023]
Abstract
BACKGROUND The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco-specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism. OBJECTIVE We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both. METHODS 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks. Ethanol-fed rats were binge-administered ethanol (2 g/kg; on Mondays, Wednesdays, and Fridays) by intraperitoneal (i.p.) injection, while control group administered saline in weeks 7 and 8 (n=12/group). Six rats from each group were administered i.p. injections of NNK (2 mg/kg) or saline on Tuesdays, Thursdays, and Saturdays of weeks 3 through 8. Alcohol dehydrogenase, catalase, and aldehyde dehydrogenase activities were measured using commercial assays. Cytochrome P450 mRNA levels (17 isoforms) were measured by quantitative reverse transcription-polymerase chain reaction. Malondialdehyde immunoreactivity was measured by enzyme-linked immunosorbent assay. RESULTS Dual exposures to ethanol and NNK significantly increased frontal lobe ADH activity relative to control (P=0.01) and ethanol only (P=0.04) treatments, and ALDH relative to control (P=0.02). In contrast, malondialdehyde-protein expression was not significantly altered by ethanol+NNK. Ethanol decreased CYP1A1 mRNA expression relative to control (P=0.02), and combined ethanol+NNK exposures decreased the expression of CYP1A1 (P=0.01) and CYP2C6 (P=0.03). CONCLUSION Dual exposures to ethanol and NNK increase brain ethanol metabolism and inhibit the expression of CYP450s that regulate xenobiotic metabolism.
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Affiliation(s)
- Emine B. Yalcin
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
| | - Ming Tong
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
| | - Gina Gallucci
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
| | - Suzanne M. de la Monte
- Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI;,Departments of Neurology, Neurosurgery, and Pathology, Rhode Island Hospital and the Alpert Medical School of Brown University, USA,Address correspondence to this author at the Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903. Tel: 401-444-7364; Fax: 401-444-2939;
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18
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Sampling from single-cell observations to predict tumor cell growth in-vitro and in-vivo. Oncotarget 2017; 8:111176-111189. [PMID: 29340046 PMCID: PMC5762314 DOI: 10.18632/oncotarget.22693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/16/2017] [Indexed: 01/06/2023] Open
Abstract
Cancer stem-like cells (CSCs) are a topic of increasing importance in cancer research, but are difficult to study due to their rarity and ability to rapidly divide to produce non-self-cells. We developed a simple model to describe transitions between aldehyde dehydrogenase (ALDH) positive CSCs and ALDH(-) bulk ovarian cancer cells. Microfluidics device-isolated single cell experiments demonstrated that ALDH+ cells were more proliferative than ALDH(-) cells. Based on our model we used ALDH+ and ALDH(-) cell division and proliferation properties to develop an empiric sampling algorithm and predict growth rate and CSC proportion for both ovarian cancer cell line and primary ovarian cancer cells, in-vitro and in-vivo. In both cell line and primary ovarian cancer cells, the algorithm predictions demonstrated a high correlation with observed ovarian cancer cell proliferation and CSC proportion. High correlation was maintained even in the presence of the EGF-like domain multiple 6 (EGFL6), a growth factor which changes ALDH+ cell asymmetric division rates and thereby tumor growth rates. Thus, based on sampling from the heterogeneity of in-vitro cell growth and division characteristics of a few hundred single cells, the simple algorithm described here provides rapid and inexpensive means to generate predictions that correlate with in-vivo tumor growth.
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Abstract
Cancer stem cells (CSCs) have been identified in oral cavity squamous cell carcinoma (OCSCC). CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells and cancer cells that drive tumor growth. Studies of many cancer types including OCSCC have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple CSC subtypes within OCSCC, making investigation reliant on the use of multiple markers. This review examines the current knowledge in CSC markers OCT4, SOX2, NANOG, ALDH1, phosphorylated STAT3, CD44, CD24, CD133, and Musashi-1, specifically focusing on their use and validity in OCSCC CSC research and how they may be organized into the CSC hierarchy. OCSCC CSCs also express components of the renin–angiotensin system (RAS), which suggests CSCs may be novel therapeutic targets by modulation of the RAS using existing medications.
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Affiliation(s)
- Ranui Baillie
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Swee T Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand.,Wellington Regional Plastic, Maxillofacial and Burns Unit, Hutt Hospital, Wellington, New Zealand
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20
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Kamate W, Baad R, Vibhute N, Belgaumi U, Kadashetti V, Gugwad S. Trending Speculations of Tumor-Initiating Cells in Squamous Cell Cancers of Head and Neck. Int J Stem Cells 2017; 10:21-27. [PMID: 28446006 PMCID: PMC5488773 DOI: 10.15283/ijsc16065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2017] [Indexed: 12/27/2022] Open
Abstract
Tumor-initiating cells are a diminutive subpopulation of stem cells that have ability of long term self-renewal and generation of varied traits of tumor cell population. Understanding the concept of tumor-initiating cells may have a great implicative intimation for our comprehension of cancer pathobiology and for the delineation of new therapies directed towards these stem cells. The present review is an endeavor to conceptualize the role of tumor-initiating cells in the Squamous Cell Cancers (SCC) of head and neck, their role in tumorigenesis and the possible supplementary approach in the latest treatment modalities.
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Affiliation(s)
- Wasim Kamate
- Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University (KIMSDU), Karad, India
| | - Rajendra Baad
- Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University (KIMSDU), Karad, India
| | - Nupura Vibhute
- Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University (KIMSDU), Karad, India
| | - Uzma Belgaumi
- Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University (KIMSDU), Karad, India
| | - Vidya Kadashetti
- Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University (KIMSDU), Karad, India
| | - Sushma Gugwad
- Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University (KIMSDU), Karad, India
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21
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Mansourian A, Shanbehzadeh N, Kia SJ, Moosavi MS. Increased salivary aldehyde dehydrogenase 1 in non-reticular oral lichen planus. An Bras Dermatol 2017; 92:168-171. [PMID: 28538873 PMCID: PMC5429099 DOI: 10.1590/abd1806-4841.20174964] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 03/27/2016] [Indexed: 11/27/2022] Open
Abstract
Background Oral lichen planus is a potentially malignant disorder. One of the malignant
transformation markers is cancer stem cells. One of the proposed marker for
the detection of cancer stem cells's in head and neck cancer is aldehyde
dehydrogenase. Recently it is shown that aldehyde dehydrogenase 1 expression
in tissue samples is associated with oral lichen planus malignant
transformation. Objective This study evaluates salivary aldehyde dehydrogenase 1 in oral lichen
planus. Method Thirty patients and 30 age and sex-matched healthy volunteers were recruited.
Oral lichen planus was diagnosed based on the modified World Health
Organization criteria. Subjects in the case group were divided into
reticular and non-reticular forms. Unstimulated salivary samples were
collected at 10-12 AM. Saliva concentrations of aldehyde dehydrogenase 1
were measured by ELISA. Results The differences between aldehyde dehydrogenase levels in the oral lichen
planus group compared with the control group were not significant but
aldehyde dehydrogenase in non-reticular oral lichen planus was significantly
higher than that of the reticular form. Limitations of the study This is a cross-sectional study, thus longitudinal studies in oral lichen
planus may present similar or different results. Conclusions The mechanism of malignant transformation in oral lichen planus is not
defined. Previous analyses revealed that the aldehyde dehydrogenase 1
expression is significantly correlated with increased risk of
transformation. This finding is consistent with our results because in the
erosive and ulcerative forms of oral lichen planus, which have an increased
risk of transformation, salivary aldehyde dehydrogenase 1 was overexpressed.
A higher salivary aldehyde dehydrogenase level in non-reticular oral lichen
planus can be a defensive mechanism against higher oxidative stress in these
groups. Aldehyde dehydrogenase may be one of the malignant transformation
markers in oral lichen planus. Further studies are needed for introducing
aldehyde dehydrogenase as a prognostic indicator in certain lesions.
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Affiliation(s)
- Arash Mansourian
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences - Tehran, Iran
| | - Najmeh Shanbehzadeh
- Department of Oral Medicine, School of Dentistry, Hormozgan University of Medical Sciences - Bandar Abbas, Iran
| | - Seyed Javad Kia
- Department of Oral Medicine, Guilan University of Medical Sciences, Dental School - Rasht, Iran
| | - Mahdieh-Sadat Moosavi
- Dental Research Center, Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences - Tehran, Iran
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22
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Bae WJ, Lee SH, Rho YS, Koo BS, Lim YC. Transforming growth factor β1 enhances stemness of head and neck squamous cell carcinoma cells through activation of Wnt signaling. Oncol Lett 2016; 12:5315-5320. [PMID: 28105240 DOI: 10.3892/ol.2016.5336] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Accepted: 09/22/2016] [Indexed: 01/02/2023] Open
Abstract
Transforming growth factor β (TGFβ) ligands, including TGFβ1, are multifunctional cytokines known as key regulators of cell growth, differentiation and inflammation. Dysregulated TGFβ signaling is common in numerous solid tumors, including head and neck squamous cell carcinoma (HNSCC). Previously, TGFβ ligands were also reported to be associated with an enhancement of stemness in glioma stem-like cells. However, their role in HNSCC cancer stem cells (CSCs) has not been explored. The present study demonstrated that TGFβ1 enriches the properties of HNSCC CSCs. TGFβ1 promoted sphere formation and increased stemness-associated gene expression (Oct4 and Sox2) of primary HNSCC CSCs. Additionally, the population of aldehyde dehydrogenase (ALDH)-positive cells was increased subsequent to exogenous treatment of cells with TGFβ1. In addition, following stimulation with TGFβ1, the cells exhibited more resistance to cisplatin and elevated expression of Twist, Snail and Slug. Mechanistically, TGFβ1 acts as an upstream stimulator of Wnt/β-catenin signaling. Collectively, the present findings provide insights toward the development of TGFβ1 signaling inhibition strategies for treating HNSCC CSCs.
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Affiliation(s)
- Woo-Jin Bae
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 142-702, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul 03181, Republic of Korea
| | - Young-Soo Rho
- Department of Otorhinolaryngology-Head and Neck Surgery, Ilsong Memorial Institute of Head and Neck Cancer, Hallym University, College of Medicine, Seoul 05355, Republic of Korea
| | - Bon-Seok Koo
- Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea
| | - Young-Chang Lim
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 142-702, Republic of Korea
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Lei F, Sun C, Xu S, Wang Q, OuYang Y, Chen C, Xia H, Wang L, Zheng P, Zhu W. Design, synthesis, biological evaluation and docking studies of novel 2-substituted-4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as dual PI3Kα/mTOR inhibitors. Eur J Med Chem 2016; 116:27-35. [PMID: 27043268 DOI: 10.1016/j.ejmech.2016.03.033] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 03/11/2016] [Accepted: 03/13/2016] [Indexed: 11/16/2022]
Abstract
Four series of 2-substituted-4-morpholino- 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives (9-28) were designed, synthesized and their structures were confirmed by (1)H NMR, (13)C NMR and MS spectrum. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). And four selected compounds (10, 11, 24, 27) were further evaluated for the IC50 values against PI3Kα and mTOR kinases. Seven of the target compounds exhibited moderate to excellent antitumor activities against these three cancer cell lines. The most promising compound 11 showed good antitumor potency for A549, PC-3 and MCF-7 cell lines with IC50 values of 0.52 ± 0.10 μM, 1.41 ± 0.10 μM, 4.82 ± 0.24 μM and moderate antitumor activities against PI3Kα/mTOR with IC50 values of 6.72 ± 0.30 μM and 0.94 ± 0.10 μM. Structure-activity relationships (SARs) and docking studies indicated that aryl urea scaffolds had a significant impact on the antitumor activities, and aryl pyridine urea scaffolds produced the best potency. Variations in substitutions of the aryl group had a significant impact on the activity and 3-Cl-4-F or 3-CF3-4-Cl substitution was more preferred.
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Affiliation(s)
- Fei Lei
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Chengyu Sun
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Shan Xu
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Qinqin Wang
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Yiqiang OuYang
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Chen Chen
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Hui Xia
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Linxiao Wang
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China
| | - Pengwu Zheng
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
| | - Wufu Zhu
- School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China; Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
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CD44 high CD24 low molecular signature determines the Cancer Stem Cell and EMT phenotype in Oral Squamous Cell Carcinoma. Stem Cell Res 2016; 16:405-17. [DOI: 10.1016/j.scr.2016.02.028] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 01/14/2016] [Accepted: 02/11/2016] [Indexed: 12/22/2022] Open
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SOD2 is a C-myc target gene that promotes the migration and invasion of tongue squamous cell carcinoma involving cancer stem-like cells. Int J Biochem Cell Biol 2015; 60:139-46. [PMID: 25578561 DOI: 10.1016/j.biocel.2014.12.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 11/15/2014] [Accepted: 12/28/2014] [Indexed: 01/06/2023]
Abstract
Our previous studies revealed that manganese superoxide dismutase (SOD2) contributes to the migration and invasion of tongue squamous cell carcinoma (TSCC). The purpose of the current study was to further clarify the mechanisms of SOD2 in the migration and invasion of TSCC. Side population (SP) cells were used as cancer stem-like cells and further assessed by sphere and colony formation assays, and the expression of stem cell markers (Bmi1, Nanog and ABCG2). We found that UM1 cells (TSCC cells with increased SOD2 expression, migration and invasion abilities) possessed a higher proportion of SP cells, sphere and colony formation, and expressed a higher level of stem cell markers compared to UM2 cells (reduced SOD2 expression, migration and invasion abilities). SOD2 expression as well as migration and invasion abilities were enhanced in SP cells compared to non-SP cells. Knockdown of SOD2 in UM1 cells or SP cells inhibited the migration and invasion abilities, reduced sphere and colony formation, and the expression of stem cell markers. Direct binding of the C-myc protein to the SOD2 promoter was demonstrated by chromatin immunoprecipitation and luciferase assays. Knockdown of C-myc in UM1 cells inhibited SOD2 expression as well as migration and invasion abilities. Our results indicate that cancer stem-like cells play an important role in the migration and invasion of TSCC. SOD2 is a direct target gene of C-myc and C-myc-SOD2-mediated migration and invasion of TSCC involve cancer stem-like cells.
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He Q, Liu Z, Zhao T, Zhao L, Zhou X, Wang A. Bmi1 drives stem-like properties and is associated with migration, invasion, and poor prognosis in tongue squamous cell carcinoma. Int J Biol Sci 2015; 11:1-10. [PMID: 25552924 PMCID: PMC4278249 DOI: 10.7150/ijbs.10405] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 10/17/2014] [Indexed: 11/05/2022] Open
Abstract
Bmi1 (B-cell-specific Moloney murine leukemia virus insertion site 1) had been found to involve in self -renewal of stem cells and tumorigenesis in various malignancies. The purpose of this study is to evaluate the role of Bmi1 in the development of tongue squamous cell carcinoma (TSCC) and its functional effect on the migration and invasion of TSCC. Initially, immunohistochemistry revealed that Bmi1 overexpression was a common event in premalignant dysplasia, primary TSCC, and lymph node metastases and was associated with a poor prognosis. A significant correlation between Bmi1 and SOD2 (manganese superoxide dismutase) expression was observed. Side population (SP) cells were used as cancer stem-like cells and further assessed by sphere and colony formation assays, and the expression of stem cell markers. TSCC cells with higher migration and invasion ability (UM1 cell lines) showed a higher proportion of SP cells and Bmi1 expression than TSCC cells with lower migration and invasion ability (UM2 cell lines). Knockdown of Bmi1 in UM1 or SP cells inhibited migration and invasion and decreased the sphere and colony formation, and the expression of stem cell markers and SOD2. Direct binding of C-myc to the Bmi1 promoter was demonstrated by chromatin immunoprecipitation and luciferase assays. Moreover, C-myc knockdown in SP cells inhibited their migration and invasion and decreased the expression of Bmi1 and SOD2. Our results indicate that the deregulation of Bmi1 expression is a frequent event during the progression of TSCC and may have a prognostic value for patients with this disease. The Bmi1-mediated migration and invasion of TSCC is related to cancer stem-like cells and involves the C-myc-Bmi1-SOD2 pathway.
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Affiliation(s)
- Qianting He
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhonghua Liu
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Tingting Zhao
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Luodan Zhao
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaofeng Zhou
- 2. Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612-7213, USA. ; 3. Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612-7213, USA
| | - Anxun Wang
- 1. Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
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Vollbrecht C, König K, Heukamp L, Büttner R, Odenthal M. [Molecular pathology of the lungs. New perspectives by next generation sequencing]. DER PATHOLOGE 2013; 34:16-24. [PMID: 23389825 DOI: 10.1007/s00292-012-1704-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Lung cancer is one of the most frequent malignancies in the western world. Its frequent association with a wide spectrum of mutations in genes encoding various signal transducers that are often linked to therapy response, emphasizes the obvious need for improved, fast and highly efficient approaches in molecular pathology. Comprehensive analyses of the mutation status of progression and therapy relevant genes can be performed by the novel sequencing forms named next generation sequencing (NGS) providing extremely high capacities for ultra-deep sequence analyses. The 454 pyrosequencing method, the sequencing by synthesis and the semiconductor sequencing platform are now available for parallel sequencing approaches of multitudinous target genes linked to multiple tumor DNA applications. The "one molecule, one clone, one read" principle by the NGS approaches supplies not only information on allele frequencies and mutation rates but also has the advantage of a very sensitive detection of low frequency variants.
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Affiliation(s)
- C Vollbrecht
- Institut für Pathologie, Universitätsklinik zu Köln, Kerpener Str. 62, 50924, Köln, Deutschland
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Fujiwara D, Kato K, Nohara S, Iwanuma Y, Kajiyama Y. The usefulness of three-dimensional cell culture in induction of cancer stem cells from esophageal squamous cell carcinoma cell lines. Biochem Biophys Res Commun 2013; 434:773-8. [PMID: 23602898 DOI: 10.1016/j.bbrc.2013.04.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 04/07/2013] [Indexed: 01/16/2023]
Abstract
In recent years, research on resistance to chemotherapy and radiotherapy in cancer treatment has come under the spotlight, and researchers have also begun investigating the relationship between resistance and cancer stem cells. Cancer stem cells are assumed to be present in esophageal cancer, but experimental methods for identification and culture of these cells have not yet been established. To solve this problem, we created spheroids using a NanoCulture® Plate (NCP) for 3-dimensional (3-D) cell culture, which was designed as a means for experimentally reproducing the 3-D structures found in the body. We investigated the potential for induction of cancer stem cells from esophageal cancer cells. Using flow cytometry we analyzed the expression of surface antigen markers CD44, CD133, CD338 (ABCG2), CD318 (CDCP1), and CD326 (EpCAM), which are known cancer stem cell markers. None of these surface antigen markers showed enhanced expression in 3-D cultured cells. We then analyzed aldehyde dehydrogenase (ALDH) enzymatic activity using the ALDEFLUOR reagent, which can identify immature cells such as stem cells and precursor cells. 3-D-cultured cells were strongly positive for ALDH enzyme activity. We also analyzed the expression of the stem cell-related genes Sox-2, Nanog, Oct3/4, and Lin28 using RT-PCR. Expression of Sox-2, Nanog, and Lin28 was enhanced. Analysis of expression of the hypoxic surface antigen marker carbonic anhydrase-9 (CA-9), which is an indicator of cancer stem cell induction and maintenance, revealed that CA-9 expression was enhanced, suggesting that hypoxia had been induced. Comparison of cancer drug resistance using cisplatin and doxorubicin in 3-D-cultured esophageal cancer cells showed that cancer drug resistance had increased. These results indicate that 3-D culture of esophageal squamous cell carcinoma lines is a useful method for inducing cancer stem cells.
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Affiliation(s)
- Daisuke Fujiwara
- Department of Esophageal & Gastroenterological Surgery, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan
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Chong ZZ, Shang YC, Wang S, Maiese K. A Critical Kinase Cascade in Neurological Disorders: PI 3-K, Akt, and mTOR. FUTURE NEUROLOGY 2012; 7:733-748. [PMID: 23144589 DOI: 10.2217/fnl.12.72] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neurodegenerative disorders lead to disability and death in a significant proportion of the world's population. However, many disorders of the nervous system remain with limited effective treatments. Kinase pathways in the nervous system that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR) offer exciting prospects for the understanding of neurodegenerative pathways and the development of new avenues of treatment. PI 3-K, Akt, and mTOR pathways are vital cellular components that determine cell fate during acute and chronic disorders, such as Huntington's disease, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and trauma. Yet, the elaborate relationship among these kinases and the variable control of apoptosis and autophagy can lead to unanticipated biological and clinical outcomes. Crucial for the successful translation of PI 3-K, Akt, and mTOR into robust and safe clinical strategies will be the further elucidation of the complex roles that these kinase pathways hold in the nervous system.
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Affiliation(s)
- Zhao Zhong Chong
- Laboratory of Cellular and Molecular Signaling, Newark, New Jersey 07101 ; New Jersey Health Sciences University, Newark, New Jersey 07101
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