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1
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Awuah WA, Ben-Jaafar A, Karkhanis S, Nkrumah-Boateng PA, Kong JSH, Mannan KM, Shet V, Imran S, Bone M, Boye ANA, Ranganathan S, Shah MH, Abdul-Rahman T, Atallah O. Cancer stem cells in meningiomas: novel insights and therapeutic implications. Clin Transl Oncol 2025; 27:1438-1459. [PMID: 39316249 PMCID: PMC12000263 DOI: 10.1007/s12094-024-03728-6] [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: 08/21/2024] [Accepted: 09/09/2024] [Indexed: 09/25/2024]
Abstract
Meningiomas (MGs), which arise from meningothelial cells of the dura mater, represent a significant proportion of primary tumours of the central nervous system (CNS). Despite advances in treatment, the management of malignant meningioma (MMG) remains challenging due to diagnostic, surgical, and resection limitations. Cancer stem cells (CSCs), a subpopulation within tumours capable of self-renewal and differentiation, are highlighted as key markers of tumour growth, metastasis, and treatment resistance. Identifying additional CSC-related markers enhances the precision of malignancy evaluations, enabling advancements in personalised medicine. The review discusses key CSC biomarkers that are associated with high levels of expression, aggressive tumour behaviour, and poor outcomes. Recent molecular research has identified CSC-related biomarkers, including Oct-4, Sox2, NANOG, and CD133, which help maintain cellular renewal, proliferation, and drug resistance in MGs. This study highlights new therapeutic strategies that could improve patient prognosis with more durable tumour regression. The use of combination therapies, such as hydroxyurea alongside diltiazem, suggests more efficient and effective MG management compared to monotherapy. Signalling pathways such as NOTCH and hedgehog also offer additional avenues for therapeutic development. CRISPR/Cas9 technology has also been employed to create meningioma models, uncovering pathways related to cell growth and proliferation. Since the efficacy of traditional therapies is limited in most cases due to resistance mechanisms in CSCs, further studies on the biology of CSCs are warranted to develop therapeutic interventions that are likely to be effective in MG. Consequently, improved diagnostic approaches may lead to personalised treatment plans tailored to the specific needs of each patient.
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Affiliation(s)
| | - Adam Ben-Jaafar
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | | | | | - Jonathan Sing Huk Kong
- School of Medicine, College of Medical & Veterinary Life Sciences, University of Glasgow, Glasgow, UK
| | - Krishitha Meenu Mannan
- School of Medicine, Queen's University Belfast, Dentistry & Biomedical Sciences, Belfast, UK
| | - Vallabh Shet
- University of Connecticut New Britain Program, New Britain, Connecticut, USA
| | - Shahzeb Imran
- School of Medicine, Queen's University Belfast, Dentistry & Biomedical Sciences, Belfast, UK
| | - Matan Bone
- Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
| | | | | | | | | | - Oday Atallah
- Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
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2
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Chen L, Fang R, Cai Z, Huang B, Zhang J, Li Y, Chen Y, Xu Z, Lei W, Zhang M. CD271 high cancer stem cells regulate macrophage polarization in head and neck squamous cell carcinoma. Oral Oncol 2025; 162:107181. [PMID: 39854870 DOI: 10.1016/j.oraloncology.2025.107181] [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: 11/04/2024] [Revised: 12/23/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025]
Abstract
PURPOSE Cancer stem cells (CSCs) are considered key drivers of progression in head and neck squamous cell carcinoma (HNSCC). Our single-cell RNA sequencing (scRNA-seq) analysis revealed predominant expression of CD271 in CSCs, however, its role as a CSC marker in HNSCC requires further elucidation. We investigated the stemness characteristics of CD271high HNSCC cells and their interactions with the tumor immune microenvironment. METHODS scRNA-seq data from hypopharyngeal squamous cell carcinoma (HPSCC) tissues were analyzed to identify expression profile of CSCs. Overall survival was compared between CD271high and CD271low patients based on immunostaining of HPSCC samples. The stemness of CD271high HNSCC cells was evaluated via an in vivo limiting dilution assay. In a C57BL/6 mice model, the percentage of immune cells and macrophage subtypes were analyzed by flow cytometry. The role of CD271 in macrophage polarization was further examined by in vitro coculture of CD271high cells with CD14+ monocytes. Gene expressions were analyzed by qPCR. RESULTS CD271 is predominantly expressed in CSCs identified by scRNA-seq analysis. CD271 enhances HNSCC cell proliferation and is negatively correlated with patient prognosis in HPSCC. CD271 knockdown suppressed HNSCC tumor growth and regulated macrophage polarization within the TME. CD271high cells exhibited stemness features and enhanced tumor growth in vivo. CONCLUSIONS CD271high HNSCC cells exhibit CSC characteristics and regulate macrophage polarization. Targeting CD271 may improve the immunosuppressive TME to inhibit tumor growth. Combining CD271-targeting agents with other therapies presents a promising strategy that may enhance therapeutic efficacy and prognosis in HNSCC.
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Affiliation(s)
- Lifan Chen
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Ruihua Fang
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Zhimou Cai
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Bixue Huang
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Jinhong Zhang
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Yun Li
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Yi Chen
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Zhenglin Xu
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China
| | - Wenbin Lei
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China.
| | - Minjuan Zhang
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, PR China.
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3
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Vangala V, Chen YC, Dinavahi SS, Gowda K, Lone NA, Herlyn M, Drabick J, Helm K, Zhu J, Neves RI, Sharma AK, Berg A, Archetti M, Amin S, Schell TD, Robertson GP. Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations. ACS Pharmacol Transl Sci 2024; 7:3573-3584. [PMID: 39539277 PMCID: PMC11555517 DOI: 10.1021/acsptsci.4c00453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/26/2024] [Accepted: 10/02/2024] [Indexed: 11/16/2024]
Abstract
The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDHhigh and ALDHlow subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development.
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Affiliation(s)
- Venugopal Vangala
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Yu-Chi Chen
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Saketh S. Dinavahi
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Krishne Gowda
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Nazir A. Lone
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Meenhard Herlyn
- Molecular
and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Joseph Drabick
- Department
of Medicine, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Klaus Helm
- Department
of Dermatology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Jiyue Zhu
- Department
of Pharmaceutical Sciences, Washington State
University College of Pharmacy and Pharmaceutical Sciences, Spokane, Washington 99202, United States
| | - Rogerio I. Neves
- Department
of Surgery, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Arun K. Sharma
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Arthur Berg
- Department
of Public Health Sciences, Pennsylvania
State University College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Marco Archetti
- Department
of Biology, Pennsylvania State University, State College, Pennsylvania 16802, United States
| | - Shantu Amin
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Todd D. Schell
- Department
of Microbiology and Immunology, Pennsylvania
State University College of Medicine, Hershey, Pennsylvania 17033, United States
| | - Gavin P. Robertson
- Department
of Pharmacology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
- Department
of Dermatology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
- Department
of Pathology, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
- Department
of Surgery, Pennsylvania State University
College of Medicine, Hershey, Pennsylvania 17033, United States
- Foreman
Foundation for Melanoma Research, Pennsylvania
State University College of Medicine, Hershey, Pennsylvania 17033, United States
- Melanoma
Center, Pennsylvania State University College
of Medicine, Hershey, Pennsylvania 17033, United States
- Melanoma
Therapeutics Program, Pennsylvania State
University College of Medicine, Hershey, Pennsylvania 17033, United States
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Acharya SK, Shai S, Choon YF, Gunardi I, Hartanto FK, Kadir K, Roychoudhury A, Amtha R, Vincent-Chong VK. Cancer Stem Cells in Oral Squamous Cell Carcinoma: A Narrative Review on Experimental Characteristics and Methodological Challenges. Biomedicines 2024; 12:2111. [PMID: 39335624 PMCID: PMC11429394 DOI: 10.3390/biomedicines12092111] [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: 07/14/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation of cancer cells that are believed to initiate and drive cancer progression. In animal models, xenotransplanted CSCs have demonstrated the ability to produce tumors. Since their initial isolation in blood cancers, CSCs have been identified in various solid human cancers, including oral squamous cell carcinoma (OSCC). In addition to their tumorigenic properties, dysregulated stem-cell-related signaling pathways-Wnt family member (Wnt), neurogenic locus notch homolog protein (Notch), and hedgehog-have been shown to endow CSCs with characteristics like self-renewal, phenotypic plasticity, and chemoresistance, contributing to recurrence and treatment failure. Consequently, CSCs have become targets for new therapeutic agents, with some currently in different phases of clinical trials. Notably, small molecule inhibitors of the hedgehog signaling pathway, such as vismodegib and glasdegib, have been approved for the treatment of basal cell carcinoma and acute myeloid leukemia, respectively. Other strategies for eradicating CSCs include natural compounds, nano-drug delivery systems, targeting mitochondria and the CSC microenvironment, autophagy, hyperthermia, and immunotherapy. Despite the extensive documentation of CSCs in OSCC since its first demonstration in head and neck (HN) SCC in 2007, none of these novel pharmacological approaches have yet entered clinical trials for OSCC patients. This narrative review summarizes the in vivo and in vitro evidence of CSCs and CSC-related signaling pathways in OSCC, highlighting their role in promoting chemoresistance and immunotherapy resistance. Additionally, it addresses methodological challenges and discusses future research directions to improve experimental systems and advance CSC studies.
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Affiliation(s)
- Surendra Kumar Acharya
- Department of Oral Medicine, Radiology and Surgery, Faculty of Dentistry, Lincoln University College, Petaling Jaya 47301, Selangor, Malaysia
| | - Saptarsi Shai
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030, USA;
| | - Yee Fan Choon
- Department of Oral and Maxillofacial Surgical Sciences, Faculty of Dentistry, MAHSA University, Jenjarom 42610, Selangor, Malaysia;
| | - Indrayadi Gunardi
- Oral Medicine Department, Faculty of Dentistry, Universitas Trisakti, Jakarta 11440, Indonesia; (I.G.); (F.K.H.)
| | - Firstine Kelsi Hartanto
- Oral Medicine Department, Faculty of Dentistry, Universitas Trisakti, Jakarta 11440, Indonesia; (I.G.); (F.K.H.)
| | - Kathreena Kadir
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Ajoy Roychoudhury
- Department of Oral and Maxillofacial Surgery, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Rahmi Amtha
- Oral Medicine Department, Faculty of Dentistry, Universitas Trisakti, Jakarta 11440, Indonesia; (I.G.); (F.K.H.)
| | - Vui King Vincent-Chong
- Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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5
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Yumnam G, Devi RS, Singh CI. Mapping the landscape of oral cancer research trends: a systematic scientometric review of global efforts. Oral Maxillofac Surg 2024; 28:1077-1093. [PMID: 38664290 DOI: 10.1007/s10006-024-01253-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: 01/13/2024] [Accepted: 04/20/2024] [Indexed: 08/18/2024]
Abstract
PURPOSE The primary goal of this study was to assess the growth, most influential articles, countries, journals, authors, and papers published in the field of global oral cancer. Research articles on oral cancer, published between 1989 and 2022, were identified through the Web of Science database to achieve this. METHODS A comprehensive dataset comprising 7,178 documents was meticulously extracted from the Web of Science, forming the basis for scientometric analysis. A refined subset of 4,901 documents was judiciously selected following a rigorous screening process for meticulous, in-depth analysis. RESULTS The field has witnessed a remarkable publication surge, with the United States taking the lead in productivity. The journal Oral Oncology has become the foremost publication, renowned for its prolific output and widespread citation. This trend highlights the growing importance and interest in this domain, with researchers and experts worldwide contributing to the expanding body of knowledge. The United States' dominance in productivity suggests its strong commitment to advancing research in the field, while Oral Oncology's recognition underscores its influential role in disseminating cutting-edge findings and fostering scientific progress. CONCLUSION This scientometric analysis is a valuable resource for researchers, funding agencies, industry, and institutions, offering guidance and insights. CLINICAL TRIAL NUMBER Not Applicable.
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Affiliation(s)
- Gyanajeet Yumnam
- Department of Library and Information Science, Manipur University, Imphal, India
| | - Rajkumari Sofia Devi
- Department of Library and Information Science, Manipur University, Imphal, India
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6
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Kumar P, Lakhera R, Aggarwal S, Gupta S. Unlocking the Therapeutic Potential of Oral Cancer Stem Cell-Derived Exosomes. Biomedicines 2024; 12:1809. [PMID: 39200273 PMCID: PMC11351673 DOI: 10.3390/biomedicines12081809] [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: 07/18/2024] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Oral cancer (OC) presents a significant global health burden with rising incidence rates. Despite advancements in diagnosis and treatments, the survival rate for OC patients, particularly those with advanced or recurrent disease, remains low at approximately 20%. This poor prognosis is often due to a small population of cancer stem cells (CSCs) that are capable of self-renewal and immune evasion, playing pivotal roles in proliferation, tumor initiation, progression, metastasis, and therapy resistance. Exosomes, which are nano-sized extracellular vesicles (EVs), have emerged as crucial mediators of cell-to-cell communication within the tumor microenvironment (TME). These vesicles carry diverse molecules such as DNA, RNA, proteins, lipids, and metabolites, influencing various cellular processes. Emerging evidence suggests that CSC-derived EVs significantly promote tumor progression and metastasis and maintain the balance between CSCs and non-CSCs, which is vital for intracellular communication within the TME of oral cancer. Recent reports indicate that oral cancer stem cell-derived EVs (OCSC-EVs) influence stemness, immune evasion, metastasis, angiogenesis, tumor reoccurrence, and drug resistance. Understanding OCSC-EVs could significantly improve oral cancer diagnosis, prognosis, and therapy. In this mini-review, we explore OCSC-derived exosomes in oral cancer, examining their potential as diagnostic and prognostic biomarkers that reflect CSC characteristics, and delve into their therapeutic implications, emphasizing their roles in tumor progression and therapy resistance. However, despite their promising potential, several challenges remain, including the need to standardize isolation and characterization methods and to elucidate exosome-mediated mechanisms. Thus, a comprehensive understanding of OCSC-EVs could pave the way for innovative therapeutic strategies that have the potential to improve clinical outcomes for OC patients.
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Affiliation(s)
- 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
| | - Rishabh Lakhera
- Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida 201313, India
| | - Sadhna Aggarwal
- Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - 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
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7
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Liang KY, Su NY, Yang HP, Hsieh PL, Fang CY, Tsai LL, Liao YW, Liu CM, Yu CC. Gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC) promotes oral cancer stemness by acting as a molecular sponge of miR331-3p. J Dent Sci 2024; 19:1389-1395. [PMID: 39035323 PMCID: PMC11259681 DOI: 10.1016/j.jds.2024.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 04/29/2024] [Indexed: 07/23/2024] Open
Abstract
Background/purpose Accumulating evidence has suggested that treatment failure of cancer therapy can be attributed to cancer stem cells (CSCs). Among numerous regulators of cancer stemness, non-coding RNAs (ncRNAs) have gained significant attention recently. In this study, we examined the role of gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC) in oral CSCs (OCSCs). Materials and methods RNA Sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the expression of GAPLINC. Flow cytometry and sphere-forming assay were exploited to isolate OCSCs. Measurement of aldehyde dehydrogenase 1 (ALDH1) activity, CD44 expressing cells, and various phenotypic assays, such as self-renewal, migration, invasion, and colony-forming abilities, were conducted in CSCs of two types of oral cancer cells (SAS and GNM) following the knockdown of GAPLINC. A luciferase reporter was also carried out to validate the direct interaction between GAPLINC and microRNA (miR)-331-3p. Results Our results showed that GAPLINC was overexpressed in OCSCs from patient-derived and oral cancer cell lines. We demonstrated that silencing of GAPLINC in OCSCs downregulated various CSC hallmarks, such as ALDH1 activity, percentage of CD44-expressing cells, self-renewal capacity, and colony-forming ability. Moreover, our results revealed that the effect of GAPLINC on cancer stemness was mediated by direct repression of miR-331-3p. Conclusion These data have potential clinical implications in that we unraveled the aberrant upregulation of GAPLINC and demonstrated that suppression of GAPLINC may reduce cancer stemness via sequestering miR-331-3p.
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Affiliation(s)
- Kuang-Yuan Liang
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Kaohsiung Armed Forces General Hospital Gangshan Branch, Kaohsiung, Taiwan
| | - Ni-Yu Su
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsiu-Pin Yang
- Department of Dentistry, Kaohsiung Armed Forces General Hospital Gangshan Branch, Kaohsiung, Taiwan
| | - Pei-Ling Hsieh
- Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chih-Yuan Fang
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Lo-Lin Tsai
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Research and Education, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Yi-Wen Liao
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chia-Ming Liu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
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8
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Freund MM, Harrison MM, Torres-Zelada EF. Exploring the reciprocity between pioneer factors and development. Development 2024; 151:dev201921. [PMID: 38958075 PMCID: PMC11266817 DOI: 10.1242/dev.201921] [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] [Indexed: 07/04/2024]
Abstract
Development is regulated by coordinated changes in gene expression. Control of these changes in expression is largely governed by the binding of transcription factors to specific regulatory elements. However, the packaging of DNA into chromatin prevents the binding of many transcription factors. Pioneer factors overcome this barrier owing to unique properties that enable them to bind closed chromatin, promote accessibility and, in so doing, mediate binding of additional factors that activate gene expression. Because of these properties, pioneer factors act at the top of gene-regulatory networks and drive developmental transitions. Despite the ability to bind target motifs in closed chromatin, pioneer factors have cell type-specific chromatin occupancy and activity. Thus, developmental context clearly shapes pioneer-factor function. Here, we discuss this reciprocal interplay between pioneer factors and development: how pioneer factors control changes in cell fate and how cellular environment influences pioneer-factor binding and activity.
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Affiliation(s)
- Meghan M. Freund
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 52706, USA
| | - Melissa M. Harrison
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 52706, USA
| | - Eliana F. Torres-Zelada
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 52706, USA
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9
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Chakrabarti D, Qayoom S, Srivastava K, Resu AV, Kukreja D, Goel MM, Singh US, Akhtar N, Rajan S, Verma M, Gupta R, Bhatt MLB. Cancer stem cell biomarkers SOX2 and Oct4 in cervical cancer patients undergoing chemoradiotherapy. Asia Pac J Clin Oncol 2024; 20:407-415. [PMID: 38403883 DOI: 10.1111/ajco.14049] [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: 09/29/2022] [Revised: 01/21/2024] [Accepted: 02/02/2024] [Indexed: 02/27/2024]
Abstract
BACKGROUND Cancer stem cell biomarkers SRY (sex-determining region Y)-box 2 (SOX2) and octamer-binding transcription factor 4 (Oct4) account for radioresistance in cervical squamous cell cancers (CSCCs). Their clinical implications are limited and contradictory. METHODS In this prospective cohort study, we recruited patients with FIGO IB2-IVA CSCC treated with primary chemoradiotherapy on regular follow-up. Tissue biopsy specimens were evaluated for SOX2 and Oct4 expression by immunohistochemistry, quantified by a product of proportion and intensity scores. RESULTS A total of 59 patients were included. Most had a moderately differentiated (81%), keratinizing (59%) CSCC, and ≥FIGO stage IIB disease (95%). SOX2 expression (high:low 21:38 patients) and Oct4 expression (high:low 4:55 patients) had a significant interrelation (p = 0.005, odds ratio (95% CI) - 1.23 (1.004-1.520)). At a median follow-up of 36 months, the 3-year overall survival (OS) was 60% and 53% for low and high SOX2 expression (p = 0.856), and 54% and 100% for low and high Oct4 expression (p = 0.114). The 3-year disease-frese survival (DFS) was 65% and 50% in the low and high SOX2 expression (p = 0.259), and 59% and 75% for low and high Oct4 expression (p = 0.598). SOX2 expression was the only variable significantly associated with a lower OS and DFS on regression analysis. CONCLUSION Our study demonstrated a trend toward improved OS and DFS with low SOX2 and high Oct4 expression in CSCC patients undergoing chemoradiotherapy.
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Affiliation(s)
- Deep Chakrabarti
- Department of Radiotherapy, King George's Medical University, Lucknow, India
- The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Sumaira Qayoom
- Department of Pathology, King George's Medical University, Lucknow, India
| | - Kirti Srivastava
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Abigail Veravolu Resu
- Department of Radiotherapy, King George's Medical University, Lucknow, India
- Department of Radiation Oncology, Super Speciality Cancer Institute & Hospital, Lucknow, India
| | - Divya Kukreja
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Madhu Mati Goel
- Department of Pathology, King George's Medical University, Lucknow, India
- Laboratory Medicine, Medanta Hospital, Lucknow, India
| | - U S Singh
- Department of Pathology, King George's Medical University, Lucknow, India
| | - Naseem Akhtar
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Shiv Rajan
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Mranalini Verma
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Rajeev Gupta
- Department of Radiotherapy, King George's Medical University, Lucknow, India
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10
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Saravanan M. Comment on "Prognostic biomarkers in oral squamous cell carcinoma: A systematic review". Oral Oncol 2024; 153:106805. [PMID: 38653000 DOI: 10.1016/j.oraloncology.2024.106805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 04/10/2024] [Indexed: 04/25/2024]
Affiliation(s)
- Muthupandian Saravanan
- AMR & Nanotherapeutics Lab, Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai 600 077, India.
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11
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Ferreon JC, Ta HM, Yun H, Choi KJ, Quan MD, Tsoi PS, Kim C, Lee CW, Ferreon ACM. Stereospecific NANOG PEST Stabilization by Pin1. Biochemistry 2024; 63:1067-1074. [PMID: 38619104 PMCID: PMC12022813 DOI: 10.1021/acs.biochem.4c00056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
NANOG protein levels correlate with stem cell pluripotency. NANOG concentrations fluctuate constantly with low NANOG levels leading to spontaneous cell differentiation. Previous literature implicated Pin1, a phosphorylation-dependent prolyl isomerase, as a key player in NANOG stabilization. Here, using NMR spectroscopy, we investigate the molecular interactions of Pin1 with the NANOG unstructured N-terminal domain that contains a PEST sequence with two phosphorylation sites. Phosphorylation of NANOG PEST peptides increases affinity to Pin1. By systematically increasing the amount of cis PEST conformers, we show that the peptides bind tighter to the prolyl isomerase domain (PPIase) of Pin1. Phosphorylation and cis Pro enhancement at both PEST sites lead to a 5-10-fold increase in NANOG binding to the Pin1 WW domain and PPIase domain, respectively. The cis-populated NANOG PEST peptides can be potential inhibitors for disrupting Pin1-dependent NANOG stabilization in cancer stem cells.
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Affiliation(s)
- Josephine C. Ferreon
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Hai Minh Ta
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Hyosuk Yun
- Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Kyoung-Jae Choi
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - My Diem Quan
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Phoebe S. Tsoi
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Choel Kim
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Chul Won Lee
- Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Allan Chris M. Ferreon
- Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States
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Chiang YF, Huang KC, Chen HY, Hamdy NM, Huang TC, Chang HY, Shieh TM, Huang YJ, Hsia SM. Hinokitiol Inhibits Breast Cancer Cells In Vitro Stemness-Progression and Self-Renewal with Apoptosis and Autophagy Modulation via the CD44/Nanog/SOX2/Oct4 Pathway. Int J Mol Sci 2024; 25:3904. [PMID: 38612715 PMCID: PMC11011552 DOI: 10.3390/ijms25073904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/11/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (β-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol's potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.
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Affiliation(s)
- Yi-Fen Chiang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan; (Y.-F.C.); (K.-C.H.); (H.-Y.C.)
| | - Ko-Chieh Huang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan; (Y.-F.C.); (K.-C.H.); (H.-Y.C.)
| | - Hsin-Yuan Chen
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan; (Y.-F.C.); (K.-C.H.); (H.-Y.C.)
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt;
| | - Tsui-Chin Huang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110301, Taiwan;
| | - Hsin-Yi Chang
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Tzong-Ming Shieh
- School of Dentistry, College of Dentistry, China Medical University, Taichung 40402, Taiwan
| | - Yun-Ju Huang
- Department of Biotechnology and Food Technology, Southern Taiwan University of Science and Technology, Tainan City 710301, Taiwan;
| | - Shih-Min Hsia
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan; (Y.-F.C.); (K.-C.H.); (H.-Y.C.)
- School of Food and Safety, Taipei Medical University, Taipei 110301, Taiwan
- Nutrition Research Center, Taipei Medical University Hospital, Taipei 110301, Taiwan
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110301, Taiwan
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13
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Kaur K, Jewett A. Role of Natural Killer Cells as Cell-Based Immunotherapy in Oral Tumor Eradication and Differentiation Both In Vivo and In Vitro. Crit Rev Immunol 2024; 44:87-98. [PMID: 38618731 DOI: 10.1615/critrevimmunol.2024052389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Despite advancements in the field of cancer therapeutics, the five-year survival rate remains low in oral cancer patients. Therefore, the effective therapeutics are needed against oral cancer. Also, several studies including ours, have shown severely suppressed function and number of NK cells in oral cancer patients. In this review, we discuss the approach to inhibit the tumor growth and metastasis by direct killing or NK cell-mediated tumor differentiation. This review also provides an overview on supercharging NK cells using osteoclasts and probiotic bacteria, and their efficacy as cancer immunotherapeutic in humanized-BLT mice.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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14
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Vastrad SJ, Ritesh G, V SS, Saraswathy GR, Augustine D, Alzahrani KJ, Alzahrani FM, Halawani IF, Ashi H, Alshahrani M, Hassan RN, Baeshen HA, Saravanan KS, Satish KS, Vutukuru P, Patil S. Panoramic view of key cross-talks underpinning the oral squamous cell carcinoma stemness - unearthing the future opportunities. Front Oncol 2023; 13:1247399. [PMID: 38170015 PMCID: PMC10759990 DOI: 10.3389/fonc.2023.1247399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/09/2023] [Indexed: 01/05/2024] Open
Abstract
The clinical management of oral cancer is often frequented with challenges that arise from relapse, recurrence, invasion and resistance towards the cornerstone chemo and radiation therapies. The recent conceptual advancement in oncology has substantiated the role of cancer stem cells (CSC) as a predominant player of these intricacies. CSC are a sub-group of tumor population with inherent adroitness to self-renew with high plasticity. During tumor evolution, the structural and functional reprogramming persuades the cancer cells to acquire stem-cell like properties, thus presenting them with higher survival abilities and treatment resistance. An appraisal on key features that govern the stemness is of prime importance to confront the current challenges encountered in oral cancer. The nurturing niche of CSC for maintaining its stemness characteristics is thought to be modulated by complex multi-layered components encompassing neoplastic cells, extracellular matrix, acellular components, circulatory vessels, various cascading signaling molecules and stromal cells. This review focuses on recapitulating both intrinsic and extrinsic mechanisms that impart the stemness. There are contemplating evidences that demonstrate the role of transcription factors (TF) in sustaining the neoplastic stem cell's pluripotency and plasticity alongside the miRNA in regulation of crucial genes involved in the transformation of normal oral mucosa to malignancy. This review illustrates the interplay between miRNA and various known TF of oral cancer such as c-Myc, SOX, STAT, NANOG and OCT in orchestrating the stemness and resistance features. Further, the cross-talks involved in tumor micro-environment inclusive of cytokines, macrophages, extra cellular matrix, angiogenesis leading pathways and influential factors of hypoxia on tumorigenesis and CSC survival have been elucidated. Finally, external factorial influence of oral microbiome gained due to the dysbiosis is also emphasized. There are growing confirmations of the possible roles of microbiomes in the progression of oral cancer. Given this, an attempt has been made to explore the potential links including EMT and signaling pathways towards resistance and stemness. This review provides a spectrum of understanding on stemness and progression of oral cancers at various regulatory levels along with their current therapeutic knowledge. These mechanisms could be exploited for future research to expand potential treatment strategies.
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Affiliation(s)
- Soujanya J. Vastrad
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Giri Ritesh
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Sowmya S. V
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, India
| | | | - Dominic Augustine
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, India
| | - Khalid J. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Fuad M. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ibrahim F. Halawani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
- Haematology and Immunology Department, Faculty of Medicine, Umm Al-Qura University, AI Abdeyah, Makkah, Saudi Arabia
| | - Heba Ashi
- Department of Dental Public Health, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Alshahrani
- Department of Endodontic, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Reem Nabil Hassan
- Department of Biological Sciences (Genome), Faculty of Sciences, King Abdul-Aziz University, Jeddah, Saudi Arabia
| | - Hosam Ali Baeshen
- Department of Orthodontics Faculty of Dentistry, King Abdulaziz University, Bengaluru, India
| | - Kamatchi Sundara Saravanan
- Department of Pharmacognosy, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Kshreeraja S. Satish
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Pravallika Vutukuru
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Shankargouda Patil
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT, United States
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15
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Singh D, Biswas D, Tewari M, Kar AG, Ansari MA, Singh S, Narayan G. Clinical Significance of Overexpression of Oct4 in Advanced Stage Gallbladder Carcinoma. J Gastrointest Cancer 2023; 54:1231-1239. [PMID: 36705780 DOI: 10.1007/s12029-023-00913-8] [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] [Accepted: 01/22/2023] [Indexed: 01/28/2023]
Abstract
BACKGROUND Oct4 has critical role in maintaining pluripotency, proliferative potential, and self-renewal capacity in embryonic stem and germ cells. Although Oct4 has been shown to be upregulated in many cancers, its clinical significance in gallbladder carcinoma is poorly understood. METHODS We studied the expression profile of Oct4 in 61 GBC and 30 chronic cholecystitis (as control) using real time RT-PCR, western blotting, and immunohistochemistry. The expression data was correlated with clinico-pathological parameters. The diagnostic utility was assessed through ROC curve, and prognostic value was analyzed by Kaplan-Meier method. RESULTS Oct4 was significantly upregulated at mRNA as well as protein levels. The higher mRNA expression shows significant association with late stage, late T stage, and higher grade of tumor. A significant positive correlation was also observed with stage, T stage, and tumor grade. Sum score analysis of protein expression shows positive correlation with stage and the presence or absence of gallstone in tumor samples. The ROC curve analysis revealed the moderate diagnostic potential of Oct4. Kaplan-Meier analysis showed that patients having higher expression of Oct4 were having low mean survival compared with the patients with lower Oct4 expression. CONCLUSION In conclusion, our data suggests that higher expression of Oct4 may serve as potential biological indicator for tumor aggressiveness and poor prognosis of GBC.
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Affiliation(s)
- Deepika Singh
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
- Department of Radiation Oncology, The Ohio State University, Columbus, 43210, USA
| | - Dipanjan Biswas
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
- Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Amrita Ghosh Kar
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Mumtaz Ahmad Ansari
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Sunita Singh
- Department of Zoology, Banaras Hindu University, Mahila Mahavidyalaya, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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16
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Olmedo I, Martínez D, Carrasco-Rojas J, Jara JA. Mitochondria in oral cancer stem cells: Unraveling the potential drug targets for new and old drugs. Life Sci 2023; 331:122065. [PMID: 37659591 DOI: 10.1016/j.lfs.2023.122065] [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: 06/15/2023] [Revised: 08/21/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
Head and neck cancer is a major health problem worldwide, with most cases arising in the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, accounting for over 90% of all cases. Compared to other types of cancer, OSCC, has the worse prognosis, with a 5-year survival rate of 50%. Additionally, OSCC is characterized by a high rate of resistance to chemotherapy treatment, which may be partly explained by the presence of cancer stem cells (CSC) subpopulation. CSC can adapt to harmful environmental condition and are highly resistant to both chemotherapy and radiotherapy treatments, thus contributing to tumor relapse. The aim of this review is to highlight the role of mitochondria in oral CSC as a potential target for oral cancer treatment. For this purpose, we reviewed some fundamental aspects of the most validated protein markers of stemness, autophagy, the mitochondrial function and energy metabolism in oral CSC. Moreover, a discussion will be made on why energy metabolism, especially oxidative phosphorylation in CSC, may offer such a diverse source of original pharmacological target for new drugs. Finally, we will describe some drugs able to disturb mitochondrial function, with emphasis on those aimed to interrupt the electron transport chain function, as novel therapeutic strategies in multidrug-resistant oral CSC. The reutilization of old drugs approved for clinical use as new antineoplastics, in cancer treatment, is also matter of revision.
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Affiliation(s)
- Ivonne Olmedo
- Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Daniela Martínez
- Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Javiera Carrasco-Rojas
- Center for Regenerative Medicine, School of Medicine, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile
| | - José A Jara
- Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago, Chile; Department of Toxicological and Pharmacological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
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17
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Zisis V, Andreadis D, Anastasiadou PA, Akrivou M, Vizirianakis IS, Anagnostou L, Malamos D, Paraskevopoulos K, Poulopoulos A. Expression of the Embryonic Cancer Stem Cells' Biomarkers SOX2 and OCT3/4 in Oral Leukoplakias and Squamous Cell Carcinomas: A Preliminary Study. Cureus 2023; 15:e45482. [PMID: 37859926 PMCID: PMC10584277 DOI: 10.7759/cureus.45482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
INTRODUCTION Cancer stem cells (CSCs) are incriminated for initiating the process of carcinogenesis either de novo or through the transformation of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinoma (OSCC). The aim of this study was to detect the expression of embryonic-type CSC markers OCT3/4 and SOX2 in OSCCs and oral leukoplakias (OLs), the most common of OPMDs. 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 experiment was conducted in the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece. This study focuses on the semiquantitative immunohistochemical (IHC) pattern of expression of CSCs protein-biomarkers SOX2 and OCT3/4, in paraffin embedded samples of 21 OSCCs of different grades of differentiation and 30 cases of OLs with different grades of dysplasia, compared to five cases of normal oral mucosa in both terms of cells' stain positivity and intensity. Statistical analysis was performed through SPSS 2017 Pearson Chi-square and the significance level was set at 0.05 (p=0.05). The expression of the respective genes of SOX2 and OCT3/4 was studied through quantitative polymerase chain reaction (qPCR), in paraffin-embedded samples of 12 cases of OLs with mild/non dysplasia and 19 cases moderately/poorly differentiated OSCCs(n=19) and five normal mucosa using the Independent Paired T-test. RESULTS The genes SOX2 and Oct3/4 were expressed in all examined cases although no statistically significant correlations among normal, OL and OSCC, were established. A nuclear/membrane staining of OCT3/4 was noticed only in three out of 21 OSCCs but in none of OLs or normal cases (without statistical significance). A characteristic nuclear staining of SOX2 was noticed in the majority of the samples, mostly in the basal and parabasal layers of the epithelium. SOX2 was significantly detected in the OSCCs group (strong positivity in 17/21) than in the OL group (30 cases, mostly mildly stained) (p-value=0.007), and the normal oral epithelium (mild stained, p=0.065). Furthermore, SOX2 was overexpressed in well differentiated OSCCs group (5/OSCCs, strongly stained) rather than in mildly dysplastic and non-dysplastic OLs samples (14/OLs, mildly stained) (p-value =0.035). CONCLUSION The characteristic expression of SOX2 but not of OCT3/4 in OLs' and OSCCs' lesions suggests the presence of neoplastic cells with certain CSC characteristics whose implication in the early stages of oral tumorigenesis could be further evaluated. The clinical use of SOX2, as prognostic factor, requires further experimental evaluation in larger number of samples.
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Affiliation(s)
- Vasileios Zisis
- Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Dimitrios Andreadis
- Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Pinelopi A Anastasiadou
- Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Meni Akrivou
- Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Ioannis S Vizirianakis
- Health Sciences, University of Nicosia, Nicosia, CYP
- Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Lefteris Anagnostou
- Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Dimitrios Malamos
- Oral Medicine, National and Kapodistrian University of Athens, Athens, GRC
| | | | - Athanasios Poulopoulos
- Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, GRC
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18
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Zisis V, Andreadis D, Anastasiadou P, Vahtsevanos K, Akrivou M, Vizirianakis IS, Poulopoulos A. Preliminary Study of the Cancer Stem Cells' Biomarker CD147 in Leukoplakia: Dysplasia and Squamous Cell Carcinoma of Oral Epithelial Origin. Cureus 2023; 15:e38807. [PMID: 37303447 PMCID: PMC10256256 DOI: 10.7759/cureus.38807] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2023] [Indexed: 06/13/2023] Open
Abstract
Objectives Cancer stem cells (CSCs) are responsible for initiating the process of carcinogenesis de novo, as well as through the transformation of oral potential malignant disorders (OPMDs) to oral squamous cell carcinoma (OSCC). The aim of our study was to detect the expression of stemness-type CSC marker CD147 in oral leukoplakias (OLs), the most common OPMD, and OSCCs as well. Materials and methods This study focuses on the semiquantitative immunohistochemical pattern of the expression of the CSC protein biomarker CD147 in paraffin-embedded samples of 20 OSCCs of different grades of differentiation and 30 cases of OLs without or with different grades of dysplasia, compared to the normal oral epithelium in terms of cells' stain positivity. Statistical analysis was performed through Statistical Package for Social Sciences (SPSS) version 25.0 (IBM SPSS Statistics, Armonk, NY) with Pearson chi-square test, and the significance level was set at 0.05 (p=0.05). In addition, the study clarified the expression of the respective gene of CD147 through quantitative polymerase chain (qPCR), in paraffin-embedded samples of the two extreme graduations: OLs of mildly dysplastic or non-dysplastic cases (n=10 cases) and OSCCs of moderately/poorly differentiated cases (n=17). Statistical analysis was then performed through SPSS version 25.0 with an independent paired t-test, and the significance level was set at 0.05 (p=0.05). Results The gene CD147 was expressed in all cases, although no statistically significant correlations were established. Regarding its protein products, the characteristic membranous staining of CD147 was noticed in the majority of the samples, mostly in the basal and parabasal layers of the epithelium. CD147 was upregulated significantly in the moderately and severely dysplastic OLs than in the mildly dysplastic and non-dysplastic OLs (p=0.008). Also, CD147 was upregulated significantly in the mildly dysplastic and non-dysplastic OLs than in the normal oral epithelium (p=0.012). Discussion The characteristic expression of CD147 in OLs and OSCCs' lesions suggests the presence of stemlike cancer cells, illustrating an underlying effect on the early stages of oral dysplasia, in the OL stage. The clinical application of CD147 as prognostic factor requires the experimental evaluation in larger number of samples. Conclusion Stem cells play an important role in the process of carcinogenesis. A major goal in cancer research is the identification of specific biomarkers for the detection of cancer stem cells. CD147 is considered as an innovative stem cell marker. Our findings in oral mucosal potentially malignant disorders showed that CD147 is expressed more intensely in parallel with the progression of the grade of dysplasia in OL. On the other hand, in oral squamous cell carcinoma, CD147 expression remains stable regardless of the degree of differentiation.
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Affiliation(s)
- Vasileios Zisis
- Oral Medicine/Pathology, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | - Dimitrios Andreadis
- Oral Medicine/Pathology, Aristotle University of Thessaloniki, Thessaloniki, GRC
| | | | | | - Meni Akrivou
- Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, GRC
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Chaudhury S, Panda S, Mohanty N, Panda S, Mohapatra D, Nagaraja R, Sahoo A, Gopinath D, Lewkowicz N, Lapinska B. Can Immunoexpression of Cancer Stem Cell Markers Prognosticate Tongue Squamous Cell Carcinoma? A Systematic Review and Meta-Analysis. J Clin Med 2023; 12:jcm12082753. [PMID: 37109090 PMCID: PMC10144949 DOI: 10.3390/jcm12082753] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/31/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
The objective was to evaluate the association of the immunoexpression of cancer stem cell (CSC) markers with clinicopathological and survival outcomes in tongue squamous cell carcinoma (TSCC) patients. This systematic review and meta-analysis [PROSPERO (CRD42021226791)] included observational studies that compared the association of clinicopathological and survival outcomes with CSC immunoexpression in TSCC patients. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were used as outcome measures. Six studies identified the association with three surface markers (c-MET, STAT3, CD44) and four transcription markers (NANOG, OCT4, BMI, SOX2). The odds of early-stage presentation were 41% (OR = 0.59, 95% CI 0.42-0.83) and 75% (OR = 0.25; 95% CI 0.14-0.45) lower in CSC and SOX2 immuno-positive cases than immuno-negative cases, respectively. The odds of well-differentiated tumors in transcription marker immuno-positive cases were 45% lower compared to immuno-negative cases (OR = 0.55, 95% CI 0.32-0.96). The odds of positive lymph nodes were 2.01 times higher in CSC immuno-positive cases compared to immuno-negative cases (OR = 2.01, 95% CI 1.11-3.65). Mortality in immuno-positive cases was 121% higher than that in immuno-negative cases (HR = 2.21; 95% CI 1.16-4.21). Advanced tumor staging and grading, lymph node metastasis, and mortality were significantly associated with positive immunoexpression of CSC markers.
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Affiliation(s)
- Sayantanee Chaudhury
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha 'O' Anusandhan, Deemed to be University, Bhubaneswar 751003, India
| | - Swagatika Panda
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha 'O' Anusandhan, Deemed to be University, Bhubaneswar 751003, India
| | - Neeta Mohanty
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha 'O' Anusandhan, Deemed to be University, Bhubaneswar 751003, India
| | - Saurav Panda
- Department of Periodontics and Implantology, Institute of Dental Sciences, Siksha 'O' Anusandhan, Deemed to be University, Bhubaneswar 751003, India
| | - Diksha Mohapatra
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha 'O' Anusandhan, Deemed to be University, Bhubaneswar 751003, India
| | - Ravishankar Nagaraja
- Department of Biostatistics, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110021, India
| | - Alkananda Sahoo
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha 'O' Anusandhan, Deemed to be University, Bhubaneswar 751003, India
| | - Divya Gopinath
- Basic Medical and Dental Sciences Department, Ajman University, Ajman P.O. Box 346, United Arab Emirates
- Centre for Transdisciplinary Research, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai 600077, India
| | - Natalia Lewkowicz
- Department of Periodontology and Oral Diseases, Medical University of Lodz, 251 Pomorska St, 92-213 Lodz, Poland
| | - Barbara Lapinska
- Department of General Dentistry, Medical University of Lodz, 251 Pomorska St, 92-213 Lodz, Poland
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IFIT2 Depletion Promotes Cancer Stem Cell-like Phenotypes in Oral Cancer. Biomedicines 2023; 11:biomedicines11030896. [PMID: 36979874 PMCID: PMC10045464 DOI: 10.3390/biomedicines11030896] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/05/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023] Open
Abstract
(1) Background: Cancer stem cells (CSCs) are a small cell population associated with chemoresistance, metastasis and increased mortality rate in oral cancer. Interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) depletion results in epithelial to mesenchymal transition, invasion, metastasis, and chemoresistance in oral cancer. To date, no study has demonstrated the effect of IFIT2 depletion on the CSC-like phenotype in oral cancer cells. (2) Methods: Q-PCR, sphere formation, Hoechst 33,342 dye exclusion, immunofluorescence staining, and flow cytometry assays were performed to evaluate the expression of the CSC markers in IFIT2-depleted cells. A tumorigenicity assay was adopted to assess the tumor formation ability. Immunohistochemical staining was used to examine the protein levels of IFIT2 and CD24 in oral cancer patients. (3) Results: The cultured IFIT2 knockdown cells exhibited an overexpression of ABCG2 and CD44 and a downregulation of CD24 and gave rise to CSC-like phenotypes. Clinically, there was a positive correlation between IFIT2 and CD24 in the patients. IFIT2high/CD24high/CD44low expression profiles predicted a better prognosis in HNC, including oral cancer. The TNF-α blockade abolished the IFIT2 depletion-induced sphere formation, indicating that TNF-α may be involved in the CSC-like phenotypes in oral cancer. (4) Conclusions: The present study demonstrates that IFIT2 depletion promotes CSC-like phenotypes in oral cancer.
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Herzog AE, Somayaji R, Nör JE. Bmi-1: A master regulator of head and neck cancer stemness. FRONTIERS IN ORAL HEALTH 2023; 4:1080255. [PMID: 36726797 PMCID: PMC9884974 DOI: 10.3389/froh.2023.1080255] [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] [Received: 10/26/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Head and neck cancers are composed of a diverse group of malignancies, many of which exhibit an unacceptably low patient survival, high morbidity and poor treatment outcomes. The cancer stem cell (CSC) hypothesis provides an explanation for the substantial patient morbidity associated with treatment resistance and the high frequency of tumor recurrence/metastasis. Stem cells are a unique population of cells capable of recapitulating a heterogenous organ from a single cell, due to their capacity to self-renew and differentiate into progenitor cells. CSCs share these attributes, in addition to playing a pivotal role in cancer initiation and progression by means of their high tumorigenic potential. CSCs constitute only a small fraction of tumor cells but play a major role in tumor initiation and therapeutic evasion. The shift towards stem-like phenotype fuels many malignant features of a cancer cell and mediates resistance to conventional chemotherapy. Bmi-1 is a master regulator of stem cell self-renewal as part of the polycomb repressive complex 1 (PRC1) and has emerged as a prominent player in cancer stem cell biology. Bmi-1 expression is upregulated in CSCs, which is augmented by tumor-promoting factors and various conventional chemotherapies. Bmi-1+ CSCs mediate chemoresistance and metastasis. On the other hand, inhibiting Bmi-1 rescinds CSC function and re-sensitizes cancer cells to chemotherapy. Therefore, elucidating the functional role of Bmi-1 in CSC-mediated cancer progression may unveil an attractive target for mechanism-based, developmental therapeutics. In this review, we discuss the parallels in the role of Bmi-1 in stem cell biology of health and disease and explore how this can be leveraged to advance clinical treatment strategies for head and neck cancer.
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Affiliation(s)
- Alexandra E. Herzog
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Ritu Somayaji
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Jacques E. Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States,Department of Otolaryngology – Head and Neck Surgery, University of Michigan Medical School; Ann Arbor, MI, United States,Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, United States,Universityof Michigan Rogel Cancer Center, Ann Arbor, MI, United States
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22
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Shao S, Scholtz LU, Gendreizig S, Martínez-Ruiz L, Florido J, Escames G, Schürmann M, Hain C, Hose L, Mentz A, Schmidt P, Wang M, Goon P, Wehmeier M, Brasch F, Kalinowski J, Oppel F, Sudhoff H. Primary head and neck cancer cell cultures are susceptible to proliferation of Epstein-Barr virus infected lymphocytes. BMC Cancer 2023; 23:47. [PMID: 36639629 PMCID: PMC9840248 DOI: 10.1186/s12885-022-10481-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 12/23/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND New concepts for a more effective anti-cancer therapy are urgently needed. Experimental flaws represent a major counter player of this development and lead to inaccurate and unreproducible data as well as unsuccessful translation of research approaches into clinics. In a previous study we have created epithelial cell cultures from head and neck squamous cell carcinoma (HNSCC) tissue. METHODS We characterize primary cell populations isolated from human papillomavirus positive HNSCC tissue for their marker expression by RT-qPCR, flow cytometry, and immunofluorescence staining. Their sensitivity to MDM2-inhibition was measured using cell viability assays. RESULTS Primary HNSCC cell cultures showed the delayed formation of spheroids at higher passages. These spheroids mimicked the morphology and growth characteristics of other established HNSCC spheroid models. However, expression of epithelial and mesenchymal markers could not be detected in these cells despite the presence of the HNSCC stem cell marker aldehyde dehydrogenase 1 family member A1. Instead, strong expression of B- and T-lymphocytes markers was observed. Flow cytometry analysis revealed a heterogeneous mixture of CD3 + /CD25 + T-lymphocytes and CD19 + B-lymphocytes at a ratio of 4:1 at passage 5 and transformed lymphocytes at late passages (≥ passage 12) with CD45 + CD19 + CD20 + , of which around 10 to 20% were CD3 + CD25 + CD56 + . Interestingly, the whole population was FOXP3-positive indicative of regulatory B-cells (Bregs). Expression of transcripts specific for the Epstein-Barr-virus (EBV) was detected to increase in these spheroid cells along late passages, and this population was vulnerable to MDM2 inhibition. HPV + HNSCC cells but not EBV + lymphocytes were detected to engraft into immunodeficient mice. CONCLUSIONS In this study we present a primary cell culture of EBV-infected tumor-infiltrating B-lymphocytes, which could be used to study the role of these cells in tumor biology in future research projects. Moreover, by describing the detailed characteristics of these cells, we aim to caution other researchers in the HNSCC field to test for EBV-infected lymphocyte contaminations in primary cell cultures ahead of further experiments. Especially researchers who are interested in TIL-based adopted immunotherapy should exclude these cells in their primary tumor models, e.g. by MDM2-inhibitor treatment. BI-12-derived xenograft tumors represent a suitable model for in vivo targeting studies.
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Affiliation(s)
- Senyao Shao
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Lars Uwe Scholtz
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Sarah Gendreizig
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Laura Martínez-Ruiz
- grid.4489.10000000121678994Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain ,grid.4489.10000000121678994Department of Physiology, Faculty of Medicine, University of Granada, 18016 Granada, Spain ,grid.459499.cCIBERFES, Ibs. Granada, San Cecilio University Hospital, 18016 Granada, Spain
| | - Javier Florido
- grid.4489.10000000121678994Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain ,grid.4489.10000000121678994Department of Physiology, Faculty of Medicine, University of Granada, 18016 Granada, Spain ,grid.459499.cCIBERFES, Ibs. Granada, San Cecilio University Hospital, 18016 Granada, Spain
| | - Germaine Escames
- grid.4489.10000000121678994Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain ,grid.4489.10000000121678994Department of Physiology, Faculty of Medicine, University of Granada, 18016 Granada, Spain ,grid.459499.cCIBERFES, Ibs. Granada, San Cecilio University Hospital, 18016 Granada, Spain
| | - Matthias Schürmann
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Carsten Hain
- grid.7491.b0000 0001 0944 9128Center for Biotechnology (CeBiTec), Universität Bielefeld, Bielefeld, Germany
| | - Leonie Hose
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany ,Department of Pathology, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Almut Mentz
- Department of Pathology, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Pascal Schmidt
- grid.7491.b0000 0001 0944 9128Center for Biotechnology (CeBiTec), Universität Bielefeld, Bielefeld, Germany
| | - Menghang Wang
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany ,grid.11135.370000 0001 2256 9319Department of Otolaryngology Head and Neck Surgery, Peking University International Hospital, Peking University, Beijing, 102206 China
| | - Peter Goon
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Michael Wehmeier
- Department of Laboratory Medicine, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Frank Brasch
- Department of Pathology, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Jörn Kalinowski
- grid.7491.b0000 0001 0944 9128Center for Biotechnology (CeBiTec), Universität Bielefeld, Bielefeld, Germany
| | - Felix Oppel
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
| | - Holger Sudhoff
- grid.7491.b0000 0001 0944 9128Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany
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Seok HJ, Choi JY, Yi JM, Bae IH. Targeting miR-5088-5p attenuates radioresistance by suppressing Slug. Noncoding RNA Res 2023; 8:164-173. [PMID: 36632615 PMCID: PMC9827365 DOI: 10.1016/j.ncrna.2022.12.005] [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] [Received: 10/31/2022] [Revised: 12/23/2022] [Accepted: 12/30/2022] [Indexed: 01/04/2023] Open
Abstract
Radiotherapy is widely used for cancer treatment, but paradoxically, it has been reported that surviving cancer cells can acquire resistance, leading to recurrence or metastasis. Efforts to reduce radioresistance are required to increase the effectiveness of radiotherapy. miRNAs are advantageous as therapeutic agents because it can simultaneously inhibit the expression of several target mRNAs. Therefore, this study discovered miRNA that regulated radioresistance and elucidated its signaling mechanism. Our previous study confirmed that miR-5088-5p was associated with malignancy and metastasis in breast cancer. As a study to clarify the relationship between radiation and miR-5088-5p identified as onco-miRNA, it was confirmed that radiation induced hypomethylation of the promoter of miR-5088-5p and its expression increased. On the other hand, miR-5088-5p inhibitors were confirmed to reduce radiation-induced epithelial-mesenchymal transition, stemness, and metastasis by reducing Slug. Therefore, this study showed the potential of miR-5088-5p inhibitors as therapeutic agents to suppress radioresistance.
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Key Words
- Ang, angiopoietin
- CSC, cancer stem-like cell
- DBC2, deleted in breast cancer 2
- DNMT, DNA methyl transferases
- EMT, epithelial-mesenchymal transition
- H&E, hematoxylin and eosin
- IR, ionizing radiation
- MSP, methylation-specific PCR
- MTT, methylthiazole tetrazolium
- Promoter methylation
- Radioresistance
- Resistance
- Slug
- VEGF, vascular endothelial growth factor
- miR-5088-5p inhibitor
- miRNA, microRNA
- siRNA, small-interfering RNA
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Affiliation(s)
- Hyun Jeong Seok
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Jae Yeon Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, Republic of Korea
| | - In Hwa Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea,Corresponding author. Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea.
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Prognostic implications of FGFR3high/Ki-67high in oral squamous cell carcinoma. JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY, MEDICINE, AND PATHOLOGY 2023. [DOI: 10.1016/j.ajoms.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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25
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Liang KY, Chun-Yu Ho D, Yang HP, Hsieh PL, Fang CY, Tsai LL, Chao SC, Liu CM, Yu CC. LINC01296 promotes cancer stemness traits in oral carcinomas by sponging miR-143. J Dent Sci 2023; 18:814-821. [PMID: 37021272 PMCID: PMC10068493 DOI: 10.1016/j.jds.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/08/2023] [Indexed: 01/25/2023] Open
Abstract
Background/purpose Emerging evidence has shown that various failures in cancer therapy, such as drug resistance, metastasis, and cancer relapse are attributed to cancer stem cells (CSCs). Also, growing attention has been paid to the regulation of non-coding RNAs in cancer stemness. Here, we aimed to investigate the contribution of LINC01296 in the modulation of oral CSCs. Materials and methods The phenotypic assays including migration, invasion, and colony-forming abilities were carried out in CSCs of two types of oral cancer cells (SAS and GNM) following the knockdown of LINC01296. In addition, the percentage of cells expressing stemness marker, ALDH1, and drug resistance marker, ABCG2, was examined as well as the self-renewal capacity after silencing of LINC01296. Moreover, a luciferase reporter was used to validate the direct interaction between LINC01296 and miR-143. Results Our results showed that LINC01296 was significantly overexpressed in oral cancer tissues and positively correlated with stemness markers. The phenotypic and flow cytometry assays demonstrated that suppression of LINC01296 reduced the aggressiveness, cancer stemness features, and colony-forming and self-renewal abilities in oral CSCs. Furthermore, we demonstrated that LINC01296 may enhance cancer stemness features through suppression of the effect of miR-143. Conclusion Silencing of LINC01296 may be a promising direction for oral cancer therapy by reducing cancer stemness via regulation of miR-143.
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Affiliation(s)
- Kuang-Yuan Liang
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Kaohsiung Armed Forces General Hospital Gangshan Branch, Kaohsiung, Taiwan
- Department of Dentistry, Taichung Armed Forces General Hospital, Taichung, Taiwan
| | - Dennis Chun-Yu Ho
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsiu-Pin Yang
- Department of Dentistry, Kaohsiung Armed Forces General Hospital Gangshan Branch, Kaohsiung, Taiwan
| | - Pei-Ling Hsieh
- Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chih-Yuan Fang
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Lo-Lin Tsai
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Research and Education, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Shih-Chi Chao
- Department of Medical Research and Education, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Ming Liu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
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Kaur K, Jewett A. Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers. Crit Rev Immunol 2023; 43:13-25. [PMID: 37938193 DOI: 10.1615/critrevimmunol.2023050618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
In this paper, we review a number of in vitro and in vivo studies regarding the efficacy of supercharged NK (sNK) cell therapy in elimination or treatment of cancer. We have performed studies using six different types of cancer models of oral, pancreatic, glioblastoma, melanoma, hepatic and ovarian cancers using hu-BLT mice. Our in vitro studies demonstrated that primary NK cells preferentially target cancer stem-like cells (CSCs)/poorly differentiated tumors whereas sNK cells target both CSCs/poorly-differentiated and well-differentiated tumors significantly higher than primary activated NK cells. Our in vivo studies in humanized-BLT mice showed that sNK cells alone or in combination with other cancer therapeutics prevented tumor growth and metastasis. In addition, sNK cells were able to increase IFN-γ secretion and cytotoxic function by the immune cells in bone marrow, spleen, gingiva, pancreas and peripheral blood. Furthermore, sNK cells were able to increase the expansion and function of CD8+ T cells both in in vitro and in vivo studies. Overall, our studies demonstrated that sNK cells alone or in combination with other cancer therapeutics were not only effective against eliminating aggressive cancers, but were also able to increase the expansion and function of CD8+ T cells to further target cancer cells, providing a successful approach to eradicate and cure cancer.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations. Bull Math Biol 2022; 85:8. [PMID: 36562835 DOI: 10.1007/s11538-022-01113-4] [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: 05/20/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022]
Abstract
Evolutionary dynamics allows us to understand many changes happening in a broad variety of biological systems, ranging from individuals to complete ecosystems. It is also behind a number of remarkable organizational changes that happen during the natural history of cancers. These reflect tumour heterogeneity, which is present at all cellular levels, including the genome, proteome and phenome, shaping its development and interrelation with its environment. An intriguing observation in different cohorts of oncological patients is that tumours exhibit an increased proliferation as the disease progresses, while the timescales involved are apparently too short for the fixation of sufficient driver mutations to promote explosive growth. Here, we discuss how phenotypic plasticity, emerging from a single genotype, may play a key role and provide a ground for a continuous acceleration of the proliferation rate of clonal populations with time. We address this question by combining the analysis of real-time growth of non-small-cell lung carcinoma cells (N-H460) together with stochastic and deterministic mathematical models that capture proliferation trait heterogeneity in clonal populations to elucidate the contribution of phenotypic transitions on tumour growth dynamics.
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Kuthala N, Shanmugam M, Yao CL, Chiang CS, Hwang KC. One step synthesis of 10B-enriched 10BPO4 nanoparticles for effective boron neutron capture therapeutic treatment of recurrent head-and-neck tumor. Biomaterials 2022; 290:121861. [DOI: 10.1016/j.biomaterials.2022.121861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 10/08/2022] [Accepted: 10/13/2022] [Indexed: 11/15/2022]
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Pisani S, Bertino G, Prina-Mello A, Locati LD, Mauramati S, Genta I, Dorati R, Conti B, Benazzo M. Electroporation in Head-and-Neck Cancer: An Innovative Approach with Immunotherapy and Nanotechnology Combination. Cancers (Basel) 2022; 14:5363. [PMID: 36358782 PMCID: PMC9658293 DOI: 10.3390/cancers14215363] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Squamous cell carcinoma is the most common malignancy that arises in the head-and-neck district. Traditional treatment could be insufficient in case of recurrent and/or metastatic cancers; for this reason, more selective and enhanced treatments are in evaluation in preclinical and clinical trials to increase in situ concentration of chemotherapy drugs promoting a selectively antineoplastic activity. Among all cancer treatment types (i.e., surgery, chemotherapy, radiotherapy), electroporation (EP) has emerged as a safe, less invasive, and effective approach for cancer treatment. Reversible EP, using an intensive electric stimulus (i.e., 1000 V/cm) applied for a short time (i.e., 100 μs), determines a localized electric field that temporarily permealizes the tumor cell membranes while maintaining high cell viability, promoting cytoplasm cell uptake of antineoplastic agents such as bleomycin and cisplatin (electrochemotherapy), calcium (Ca2+ electroporation), siRNA and plasmid DNA (gene electroporation). The higher intracellular concentration of antineoplastic agents enhances the antineoplastic activity and promotes controlled tumor cell death (apoptosis). As secondary effects, localized EP (i) reduces the capillary blood flow in tumor tissue ("vascular lock"), lowering drug washout, and (ii) stimulates the immune system acting against cancer cells. After years of preclinical development, electrochemotherapy (ECT), in combination with bleomycin or cisplatin, is currently one of the most effective treatments used for cutaneous metastases and primary skin and mucosal cancers that are not amenable to surgery. To reach this clinical evidence, in vitro and in vivo models were preclinically developed for evaluating the efficacy and safety of ECT on different tumor cell lines and animal models to optimize dose and administration routes of drugs, duration, and intensity of the electric field. Improvements in reversible EP efficacy are under evaluation for HNSCC treatment, where the focus is on the development of a combination treatment between EP-enhanced nanotechnology and immunotherapy strategies.
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Affiliation(s)
- Silvia Pisani
- Department of Otorhinolaryngology, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi, 19, 27100 Pavia, Italy
| | - Giulia Bertino
- Department of Otorhinolaryngology, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi, 19, 27100 Pavia, Italy
| | - Adriele Prina-Mello
- LBCAM, Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin 8, Ireland
- Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, DO2 W085 Dublin, Ireland
| | - Laura Deborah Locati
- Translational Oncology, IRCCS ICS Maugeri, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Simone Mauramati
- Department of Otorhinolaryngology, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi, 19, 27100 Pavia, Italy
| | - Ida Genta
- Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
| | - Rossella Dorati
- Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
| | - Bice Conti
- Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
| | - Marco Benazzo
- Department of Otorhinolaryngology, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi, 19, 27100 Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
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Marles H, Biddle A. Cancer stem cell plasticity and its implications in the development of new clinical approaches for oral squamous cell carcinoma. Biochem Pharmacol 2022; 204:115212. [PMID: 35985402 DOI: 10.1016/j.bcp.2022.115212] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 11/25/2022]
Abstract
Oral squamous cell carcinoma (SCC) represents a major worldwide disease burden, with high rates of recurrence and metastatic spread following existing treatment methods. Populations of treatment resistant cancer stem cells (CSCs) are well characterised in oral SCC. These populations of CSCs engage the cellular programme known as epithelial mesenchymal transition (EMT) to enhance metastatic spread and therapeutic resistance. EMT is characterised by specific morphological changes and the expression of certain cell surface markers that represent a transition from an epithelial phenotype to a mesenchymal phenotype. This process is regulated by several cellular pathways that interact both horizontally and hierarchically. The cellular changes in EMT occur along a spectrum, with sub-populations of cells displaying both epithelial and mesenchymal features. The unique features of these CSCs in terms of their EMT state, cell surface markers and metabolism may offer new druggable targets. In addition, these features could be used to identify more aggressive disease states and the opportunity to personalise therapy depending on the presence of certain CSC sub-populations.
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Affiliation(s)
- Henry Marles
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Adrian Biddle
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.
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Xie W, Yu J, Yin Y, Zhang X, Zheng X, Wang X. OCT4 induces EMT and promotes ovarian cancer progression by regulating the PI3K/AKT/mTOR pathway. Front Oncol 2022; 12:876257. [PMID: 36033461 PMCID: PMC9399417 DOI: 10.3389/fonc.2022.876257] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022] Open
Abstract
Background Octamer-binding transcription factor 4 (OCT4) is a key stem cell transcription factor involved in the development of various cancers. The role of OCT4 in ovarian cancer (OC) progression and its molecular mechanism are not fully understood. Methods First, immunohistochemistry (IHC) assays of ovarian benign cyst tissues, OC tissues, and omental metastatic tissues were performed to reveal OCT4 expression profiles. We knocked down OCT4 in two OC cell lines (SKOV3 and A2780) using a lentiviral vector and performed in vitro and in vivo experiments. OCT4 was knocked down to assess the proliferation, migration, and invasion of OC cells using CCK-8, colony formation, wound healing, and Transwell assays. In addition, the nude tumor mouse model was used for in vivo study. Mechanistically, we demonstrated that OCT4 influenced protein expression in the phosphoinositol 3-kinase (PI3K)/AKT/mTOR pathway and epithelial-mesenchymal transition (EMT)-related proteins by Western blotting and immunofluorescence (IF) assays. The interaction between OCT4 and p-AKT was further confirmed by coimmunoprecipitation (CoIP) assays. Importantly, AKT activation by its activator SC79 reversed the biological functions of OCT4 knockdown. Results OCT4 expression was significantly upregulated in OC samples and metastatic tissues. OCT4 knockdown notably inhibited the proliferation, migration, and invasion of OC cells in vitro and in vivo. Moreover, the expression of p-PI3K, p-AKT, and p-mTOR was downregulated after OCT4 knockdown. An AKT agonist reversed the effect of OCT4 knockdown on OC cells. EMT in OC samples was enhanced by OCT4. Conclusions Our study shows that OCT4 promotes the proliferation, migration, and invasion of OC cells by participating in the PI3K/AKT/mTOR signaling axis, suggesting that it could serve as a potential therapeutic target for OC patients.
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Butylidenephthalide Abrogates the Snail-Induced Cancer Stemness in Oral Carcinomas. Int J Mol Sci 2022; 23:ijms23116157. [PMID: 35682836 PMCID: PMC9180956 DOI: 10.3390/ijms23116157] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/26/2022] [Accepted: 05/26/2022] [Indexed: 02/06/2023] Open
Abstract
Oral cancer is one of the most common cancers worldwide, especially in South Central Asia. It has been suggested that cancer stem cells (CSC) play crucial roles in tumor relapse and metastasis, and approaches to target CSC may lead to promising results. Here, aldehyde dehydrogenase 1 (ALDH1) and CD44 were utilized to isolate CSCs of oral cancer. Butylidenephthalide, a bioactive phthalide compound from Angelica sinensis, was tested for its anti-CSC effects. MTT assay showed that a lower concentration of butylidenephthalide was sufficient to inhibit the proliferation of patient-derived ALDH1+/CD44+ cells without affecting normal cells. Administration of butylidenephthalide not only reduced ALDH1 activity and CD44 expression, it also suppressed the migration, invasion, and colony formation abilities of ALDH1+/CD44+ cells using a transwell system and clonogenic assay. A patient-derived xenograft mouse model supported our in vitro findings that butylidenephthalide possessed the capacity to retard tumor development. We found that butylidenephthalide dose-dependently downregulated the gene and protein expression of Sox2 and Snail. Our results demonstrated that overexpression of Snail in ALDH1-/CD44- (non-CSCs) cells induced the CSC phenotypes, whereas butylidenephthalide treatment successfully diminished the enhanced self-renewal and propagating properties. In summary, this study showed that butylidenephthalide may serve as an adjunctive for oral cancer therapy.
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Morsczeck C. Mechanisms during Osteogenic Differentiation in Human Dental Follicle Cells. Int J Mol Sci 2022; 23:5945. [PMID: 35682637 PMCID: PMC9180518 DOI: 10.3390/ijms23115945] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 12/22/2022] Open
Abstract
Human dental follicle cells (DFCs) as periodontal progenitor cells are used for studies and research in regenerative medicine and not only in dentistry. Even if innovative regenerative therapies in medicine are often considered the main research area for dental stem cells, these cells are also very useful in basic research and here, for example, for the elucidation of molecular processes in the differentiation into mineralizing cells. This article summarizes the molecular mechanisms driving osteogenic differentiation of DFCs. The positive feedback loop of bone morphogenetic protein (BMP) 2 and homeobox protein DLX3 and a signaling pathway associated with protein kinase B (AKT) and protein kinase C (PKC) are presented and further insights related to other signaling pathways such as the WNT signaling pathway are explained. Subsequently, some works are presented that have investigated epigenetic modifications and non-coding ncRNAs and their connection with the osteogenic differentiation of DFCs. In addition, studies are presented that have shown the influence of extracellular matrix molecules or fundamental biological processes such as cellular senescence on osteogenic differentiation. The putative role of factors associated with inflammatory processes, such as interleukin 8, in osteogenic differentiation is also briefly discussed. This article summarizes the most important insights into the mechanisms of osteogenic differentiation in DFCs and is intended to be a small help in the direction of new research projects in this area.
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Affiliation(s)
- Christian Morsczeck
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
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Najafzadeh B, Motafakkerazad R, Najafi S, Amini M, Alemohammad H, Vasefifar P, Baradaran B. Nanog suppression enhanced the chemosensitivity of Human Non-Small-Cell Lung Cancer cells to Cisplatin and inhibited cell migration. Pathol Res Pract 2022; 233:153869. [DOI: 10.1016/j.prp.2022.153869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 03/21/2022] [Accepted: 03/30/2022] [Indexed: 11/25/2022]
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Lu MY, Fang CY, Hsieh PL, Liao YW, Tsai LL, Yu CC. miR-509 inhibits cancer stemness properties in oral carcinomas via directly targeting PlK1. J Dent Sci 2022; 17:653-658. [PMID: 35756764 PMCID: PMC9201550 DOI: 10.1016/j.jds.2021.09.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 09/25/2021] [Indexed: 11/02/2022] Open
Abstract
Background/purpose Oral cancer is one of the common cancers worldwide. Emerging evidence has indicated that microRNAs (non-coding RNA molecules of approximately 22 nucleotides in length) are implicated in the regulation of cancer stemness. However, the functional role of microRNA-509 (miR-509) in the characteristics of oral cancer stem cells (CSCs) has not been unraveled. Materials and methods The expression level of miR-509 in ALDH1+ and sphere oral CSCs was examined by qRT-PCR. The aldehyde dehydrogenase 1 (ALDH1) activity and CD44 expression were assessed using flow cytometry. Self-renewal, transwell migration, and colony formation assays were conducted to measure the CSC phenotypes. Besides, a luciferase reporter assay was used to confirm the direct interaction between miR-509 and its target polo-like kinase 1 (plk1). Results We showed the expression of miR-509 was downregulated in the CSCs derived from oral cancer cells (SAS), and upregulation of miR-509 diminished the several CSCs features, including ALDH1 activity, self-renewal capacity, CD44 expression, migration, and colony-forming abilities. Moreover, the result from the luciferase reporter assay validated the direct binding of miR-509 to plk1. Conclusion Our results suggest that the miR-509/plk1 axis may mediate the cancer stemness in oral cancer, and targeting this axis may attenuate the progression of oral cancer.
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Affiliation(s)
- Ming-Yi Lu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Yuan Fang
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei, Taiwan.,School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pei-Ling Hsieh
- Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan
| | - Yi-Wen Liao
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Lo-Lin Tsai
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei, Taiwan.,School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Education and Research, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
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Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3983637. [PMID: 35310040 PMCID: PMC8926538 DOI: 10.1155/2022/3983637] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 12/09/2021] [Accepted: 02/02/2022] [Indexed: 12/22/2022]
Abstract
Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents. Apigenin (4′,5,7-trihydroxyflavone) is one of the most researched phenolic compounds that exhibits antitumor effects in several cancers. The aim of the current study was to investigate the effect and underlying mechanisms of apigenin on OS. To address this, OS cells (SOSP-9607) were treated with different concentrations of apigenin. The proliferation, migration, invasion, stem-like properties, and Warburg effect of apigenin-treated OS cells were evaluated. Apigenin was found to suppress the proliferation of SOSP-9607 cells and inhibit epithelial-mesenchymal transition, as indicated by decreased number of migrated and invaded cells, decreased protein expression of vimentin, and increased protein expression of E-cadherin. Additionally, apigenin suppressed tumorsphere formation and reduced the proportion of SOSP-9607 cells with positive expression of the stem cell-related markers Nanog and OCT-4. Apigenin inhibited the Warburg effect in SOSP-9607 cells, as demonstrated by decreased glucose and lactic acid levels, increased citrate and ATP levels, and downregulation of GLUT1, HK1, and LDHA, which are metabolism-related enzymes related to the Warburg effect. Moreover, apigenin inhibited the phosphorylation of PI3K, Akt, and mTOR in SOSP-9607 cells. Collectively, these results indicate that apigenin suppresses the Warburg effect and stem-like properties in SOSP-9607 cells, which may be mediated by PI3K/Akt/mTOR signaling, thus, providing a novel strategy for OS treatment.
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Dubey P, Gupta R, Mishra A, Kumar V, Bhadauria S, Bhatt MLB. Evaluation of correlation between CD44, radiotherapy response, and survival rate in patients with advanced stage of head and neck squamous cell carcinoma (HNSCC). Cancer Med 2022; 11:1937-1947. [PMID: 35274800 PMCID: PMC9089225 DOI: 10.1002/cam4.4497] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 11/13/2021] [Accepted: 11/26/2021] [Indexed: 02/06/2023] Open
Abstract
Purpose Cancer stem cells (CSCs) constitute a distinctive subpopulation of cancer cells that are competent in tumor initiation, invasion, recurrence, and resistance to chemoradiotherapy. CD44, a hyaluronic acid (HA) receptor has been considered as a potential CSC marker in head and neck cancer. The purpose of this study is to evaluate the correlation between CD44 and clinicopathological parameters, treatment response, survival, and recurrence. Methods The CD44 expression was examined by immunohistochemistry (IHC) in 90 samples of head and neck squamous cell carcinoma (HNSCC) confirmed patients. The expression of CD44 and its association with clinicopathological parameters, treatment response, and survival was determined. Results In all HNSCC patient samples, CD44 was expressed consistently at different intensities. Tumor size (p < 0.001), stage (p < 0.001), and treatment response (p < 0.001) showed statistically significant association with CD44 expression. Alcohol and CD44 were observed as independent predictors of response to radiotherapy using multivariate ordinal logistic regression analysis. Analysis of 2‐year overall survival (OS) showed that CD44 expression (p = 0.02), tumor size (p = 0.001), lymph node status (p < 0.001), stage (p < 0.001), and grade (p = 0.007) were significantly associated with OS. Using Cox regression analysis, lymph node status (p = 0.001), grade (p < 0.001), recurrence (p < 0.001), and CD44 expression (p = 0.003) were found to be potential independent predictors of OS. Conclusion Our findings suggest that CD44 contributes to resistance to radiotherapy and poor OS. The results also suggest that except for CD44 there could be other factors such as lymph node metastasis, grade, and alcohol which should be investigated as potential targets for therapy.
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Affiliation(s)
- Parul Dubey
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Rajeev Gupta
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Anupam Mishra
- Department of Otorhinolaryngology & Head Neck Surgery, King George's Medical University, Lucknow, India
| | - Vijay Kumar
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Smrati Bhadauria
- Division of Toxicology & Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, India
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FAS receptor regulates NOTCH activity through ERK-JAG1 axis activation and controls oral cancer stemness ability and pulmonary metastasis. Cell Death Dis 2022; 8:101. [PMID: 35249111 PMCID: PMC8898312 DOI: 10.1038/s41420-022-00899-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 11/08/2022]
Abstract
AbstractPulmonary metastasis occurring via the colonization of circulating cancer stem cells is a major cause of oral squamous cell carcinoma (OSCC)-related death. Thus, understanding the mechanism of OSCC pulmonary metastasis may provide a new opportunity for OSCC treatment. FAS, a well-known apoptosis-inducing death receptor, has multiple nonapoptotic, protumorigenic functions. Previously, we found that SAS OSCC cells with FAS receptor knockout did not affect orthotopic tumor growth or cervical lymph node metastasis. However, FAS knockout cells could not colonize in distant organs to form metastases upon intravenous injection, which hinted at the cancer stemness function of the FAS receptor. Immunohistochemistry staining indicated that the FAS receptor serves as a poor prognosis marker in OSCC patients. FAS knockout inhibited in vitro cancer spheroid formation, migration and invasion, and prevented mesenchymal transition in OSCC cells and inhibited OSCC pulmonary metastasis in vivo. To determine the regulatory mechanism by which the FAS receptor exerts its oncogenic function, we utilized cDNA microarrays and phosphoprotein arrays to discover key candidate genes and signaling pathway regulators. JAG1 expression and NOTCH pathway activation were controlled by the FAS receptor through ERK phosphorylation. Both JAG1 and NOTCH1 silencing decreased in vitro cancer spheroid formation. In OSCC cells, FAS ligand or JAG1 protein treatment increased NOTCH pathway activity, which could be abolished by FAS receptor knockout. In FAS knockout cells, restoring the NOTCH1 intracellular domain stimulated cancer spheroid formation. Both JAG1 and NOTCH1 silencing decreased in vivo OSCC growth. In conclusion, we found a novel FAS-ERK-JAG1-NOTCH1 axis that may contribute to OSCC stemness and pulmonary metastasis.
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Routila J, Qiao X, Weltner J, Rantala JK, Carpén T, Hagström J, Mäkitie A, Leivo I, Ruuskanen M, Söderlund J, Rintala M, Hietanen S, Irjala H, Minn H, Westermarck J, Ventelä S. Cisplatin overcomes radiotherapy resistance in OCT4-expressing head and neck squamous cell carcinoma. Oral Oncol 2022; 127:105772. [PMID: 35245886 DOI: 10.1016/j.oraloncology.2022.105772] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Cisplatin is combined with radiotherapy for advanced head and neck squamous cell carcinoma (HNSCC). While providing a beneficial effect on survival, it also causes side effects and thus is an important target when considering treatment de-escalation. Currently, there are no biomarkers to predict its patient-selective therapeutic utility. In this study, we examined the role of the stem cell factor OCT4 as a potential biomarker to help clinicians stratify HNSCC patients between radiotherapy and chemoradiotherapy. MATERIALS AND METHODS OCT4 immunohistochemical staining of a population-validated tissue microarray (PV-TMA) (n = 166) representative of a standard HNSCC patients was carried out, and 5-year survival was analyzed. The results were validated using ex vivo drug sensitivity analysis of HNSCC tumor samples, and further cross-validated in independent oropharyngeal (n = 118), nasopharyngeal (n = 170), and vulvar carcinoma (n = 95) clinical datasets. In vitro, genetically modified, patient-derived HNSCC cells were used. RESULTS OCT4 expression in HNSCC tumors was associated with radioresistance. However, combination therapy with cisplatin was found to overcome thisradioresistance in OCT4-expressing HNSCC tumors. The results were validated by using several independent patient cohorts. Furthermore, CRISPRa-based OCT4 overexpression in the HNSCC cell line resulted in apoptosis resistance, and cisplatin was found to downregulate OCT4 protein expression in vitro. Ex vivo drug sensitivity analysis of HNSCC tumors confirmed the association between OCT4 expression and cisplatin sensitivity. CONCLUSION This study introduces OCT4 immunohistochemistry as a simple and cost-effective diagnostic approach for clinical practice to identify HNSCC patients benefitting from radiosensitization by cisplatin using either full or reduced dosing.
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Affiliation(s)
- Johannes Routila
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Xi Qiao
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Jere Weltner
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-14186 Stockholm, Sweden and Division of Obstetrics and Gynecology, Karolinska Universitetssjukhuset, SE-14186 Stockholm, Sweden
| | - Juha K Rantala
- MISVIK Biology Ltd, Karjakatu 35 B, 20520 Turku, Finland
| | - Timo Carpén
- Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland
| | - Jaana Hagström
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Antti Mäkitie
- Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland
| | - Ilmo Leivo
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland; Institute of Biomedicine, Pathology, University of Turku, Kiinamyllynkatu 10 D, 20520 Turku, Finland
| | - Miia Ruuskanen
- Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Jenni Söderlund
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
| | - Marjut Rintala
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
| | - Sakari Hietanen
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku, Finland
| | - Heikki Irjala
- Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Heikki Minn
- FICAN West Cancer Centre, Turku, Finland; Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Turku, Finland
| | - Jukka Westermarck
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Biomedical Institute, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; FICAN West Cancer Centre, Turku, Finland
| | - Sami Ventelä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland; FICAN West Cancer Centre, Turku, Finland.
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Ponomarev A, Gilazieva Z, Solovyeva V, Allegrucci C, Rizvanov A. Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression. Cancers (Basel) 2022; 14:970. [PMID: 35205716 PMCID: PMC8869813 DOI: 10.3390/cancers14040970] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients' tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies.
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Affiliation(s)
- Alexey Ponomarev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Zarema Gilazieva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Valeriya Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Cinzia Allegrucci
- School of Veterinary Medicine and Science (SVMS) and Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK;
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
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IGF2BP2 maybe a novel prognostic biomarker in oral squamous cell carcinoma. Biosci Rep 2022; 42:230746. [PMID: 35129592 PMCID: PMC8859425 DOI: 10.1042/bsr20212119] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 11/25/2022] Open
Abstract
Aim: The main of the present study was to investigate the role of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in oral squamous cell carcinoma (OSCC) with the overarching of providing new biomarkers or potential therapeutic targets for OSCC. Methods: We combined datasets downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and samples collected from the clinic to evaluate the expression of IGF2BP2 in OSCC. IGF2BP2 survival analysis was respectively performed based on TCGA, GEO, and clinical samples. Correlations between IGF2BP2 expression and clinicopathological parameters were then analyzed, and signaling pathways associated with IGF2BP2 expression were identified using gene set enrichment analysis (GSEA 4.1.0). Moreover, an IGF2BP2 co-expressed gene network was constructed, followed by gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on IGF2BP2 co-expressed genes. Finally, TIMER and CIBERSORT were used to analyze the correlations among IGF2BP2, IGF2BP2-coexpressed genes, and tumor-infiltrating immune cells (TICs). Results: IGF2BP2 was highly expressed in OSCC and significantly correlated with overall survival of OSCC patients (P<0.01). High IGF2BP2 expression correlated with poor overall survival. The GSEA results showed that cell apoptosis-, tumor-, and immune-related pathways were significantly enriched in samples with high IGF2BP2 expression. Furthermore, GO and KEGG enrichment analyses results of IGF2BP2 co-expressed genes indicated that these genes are mainly associated with immunity/inflammation and tumorigenesis. In addition, IGF2BP2 and its co-expressed genes are associated with TICs (P<0.01). Conclusion: IGF2BP2 may be a potential prognostic biomarker in OSCC and correlates with immune infiltrates.
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Shahoumi LA. Oral Cancer Stem Cells: Therapeutic Implications and Challenges. FRONTIERS IN ORAL HEALTH 2022; 2:685236. [PMID: 35048028 PMCID: PMC8757826 DOI: 10.3389/froh.2021.685236] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is currently one of the 10 most common malignancies worldwide, characterized by a biologically highly diverse group of tumors with non-specific biomarkers and poor prognosis. The incidence rate of HNSCC varies widely throughout the world, with an evident prevalence in developing countries such as those in Southeast Asia and Southern Africa. Tumor relapse and metastasis following traditional treatment remain major clinical problems in oral cancer management. Current evidence suggests that therapeutic resistance and metastasis of cancer are mainly driven by a unique subpopulation of tumor cells, termed cancer stem cells (CSCs), or cancer-initiating cells (CICs), which are characterized by their capacity for self-renewal, maintenance of stemness and increased tumorigenicity. Thus, more understanding of the molecular mechanisms of CSCs and their behavior may help in developing effective therapeutic interventions that inhibit tumor growth and progression. This review provides an overview of the main signaling cascades in CSCs that drive tumor repropagation and metastasis in oral cancer, with a focus on squamous cell carcinoma. Other oral non-SCC tumors, including melanoma and malignant salivary gland tumors, will also be considered. In addition, this review discusses some of the CSC-targeted therapeutic strategies that have been employed to combat disease progression, and the challenges of targeting CSCs, with the aim of improving the clinical outcomes for patients with oral malignancies. Targeting of CSCs in head and neck cancer (HNC) represents a promising approach to improve disease outcome. Some CSC-targeted therapies have already been proven to be successful in pre-clinical studies and they are now being tested in clinical trials, mainly in combination with conventional treatment regimens. However, some studies revealed that CSCs may not be the only players that control disease relapse and progression of HNC. Further, clinical research studying a combination of therapies targeted against head and neck CSCs may provide significant advances.
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Affiliation(s)
- Linah A Shahoumi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
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Patil S, Al-Brakati A, Abidi NH, Almasri MA, Almeslet AS, Patil VR, Raj AT, Bhandi S. CD44-positive cancer stem cells from oral squamous cell carcinoma exhibit reduced proliferation and stemness gene expression upon adipogenic induction. Med Oncol 2022; 39:23. [PMID: 34982245 DOI: 10.1007/s12032-021-01617-4] [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: 10/21/2021] [Accepted: 11/19/2021] [Indexed: 10/19/2022]
Abstract
We proposed to assess adipogenic differentiation and its effect on the proliferation and stemness markers in CD44 + OSCC CSCs. D44 + CSCs were sorted by magnetic sorting from the single-cell suspension of the OSCC tumor. Adipogenic differentiation was induced by an adipogenic induction medium. Lipid droplet formation was confirmed by oil red O staining. The expression of the cell surface marker was analyzed by flow cytometry. Real-time qPCR was performed to examine the gene expression activity. CD44 + OSCC CSCs can differentiate into adipocytes and adipogenesis in these cells decrease their proliferation and stemness gene expression. Adipogenic induction can make the cancer stem cells from OSCC tumors lose their stemness potential. Oral cancer, especially OSCC, is a huge burden worldwide. Similar to other stem cells, cancer stem cells can differentiate into other lineage cells. Our study shows that the proliferation and stemness gene expression in the CSCs from OSCC tumors can be thwarted by inducing them to differentiate into adipocytes, which could be advantageous to find out new clinical approaches in the treatment of cancers, like OSCC.
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Affiliation(s)
- Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, 45412, Saudi Arabia.
| | - Ashraf Al-Brakati
- Department of Human Anatomy, College of Medicine, Taif University, Taif, 21944, Saudi Arabia
| | - Nazim H Abidi
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Jazan University, Jazan, 45412, Saudi Arabia
| | - Mazen A Almasri
- Department of Oral and Maxillofacial Surgery, King Abdulaziz University, Jeddah city, Saudi Arabia
| | - Asma Saleh Almeslet
- Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Riyadh Elm University, Riyadh, 12611, Saudi Arabia
| | | | - A Thirumal Raj
- Department of Oral Pathology and Microbiology, Sri Venkateswara Dental College and Hospital, Chennai, 600130, India
| | - Shilpa Bhandi
- Department of Restorative Dental Science, Division of Operative Dentistry, College of Dentistry, Jazan University, Jazan, 45142, Saudi Arabia
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Wilczyński JR. Cancer Stem Cells: An Ever-Hiding Foe. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:219-251. [PMID: 35165866 DOI: 10.1007/978-3-030-91311-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cancer stem cells are a population of cells enable to reproduce the original phenotype of the tumor and capable to self-renewal, which is crucial for tumor proliferation, differentiation, recurrence, and metastasis, as well as chemoresistance. Therefore, the cancer stem cells (CSCs) have become one of the main targets for anticancer therapy and many ongoing clinical trials test anti-CSCs efficacy of plenty of drugs. This chapter describes CSCs starting from general description of this cell population, through CSCs markers, signaling pathways, genetic and epigenetic regulation, role of epithelial-mesenchymal transition (EMT) transition and autophagy, cooperation with microenvironment (CSCs niche), and finally role of CSCs in escaping host immunosurveillance against cancer.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
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den bossche VV, Zaryouh H, Vara-Messler M, Vignau J, Machiels JP, Wouters A, Schmitz S, Corbet C. Microenvironment-driven intratumoral heterogeneity in head and neck cancers: clinical challenges and opportunities for precision medicine. Drug Resist Updat 2022; 60:100806. [DOI: 10.1016/j.drup.2022.100806] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023]
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Joshi J, Patel H, Bhavnagari H, Tarapara B, Pandit A, Shah F. Eliminating Cancer Stem-Like Cells in Oral Cancer by Targeting Elementary Signaling Pathways. Crit Rev Oncog 2022; 27:65-82. [PMID: 37199303 DOI: 10.1615/critrevoncog.2022047207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Oral cancer is a heterogeneous, aggressive, and complex entity. Current major treatment options for the disease are surgery, chemo, and/or radiotherapy either alone or in combination with each other. Each treatment method has its own limitations such as a significant journey with deformities and a protracted rehabilitation process leading to loss of self-esteem, loss of tolerance, and therapeutic side effects. Conventional therapies are frequently experienced with regimen resistance and recurrence attributed to the cancer stem cells (CSCs). Given that CSCs exert their tumorigenesis by affecting several cellular and molecular targets and pathways an improved understanding of CSCs' actions is required. Hence, more research is recommended to fully understand the fundamental mechanisms driving CSC-mediated treatment resistance. Despite the difficulties and disagreements surrounding the removal of CSCs from solid tumors, a great amount of knowledge has been derived from the characterization of CSCs. Various efforts have been made to identify the CSCs using several cell surface markers. In the current review, we will discuss numerous cell surface markers such as CD44, ALDH1, EPCAM, CD24, CD133, CD271, CD90, and Cripto-1 for identifying and isolating CSCs from primary oral squamous cell carcinoma (OSCC). Further, a spectrum of embryonic signaling pathways has been thought to be the main culprit of CSCs' active state in cancers, resulting in conventional therapeutic resistance. Hence, we discuss the functional and molecular bases of several signaling pathways such as the Wnt/beta;-catenin, Notch, Hedgehog, and Hippo pathways and their associations with disease aggressiveness. Moreover, numerous inhibitors targeting the above mentioned signaling pathways have already been identified and some of them are already undergoing clinical trials. Hence, the present review encapsulates the characterization and effectiveness of the prospective potential targeted therapies for eradicating CSCs in oral cancers.
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Affiliation(s)
- Jigna Joshi
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Hitarth Patel
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Hunayna Bhavnagari
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Bhoomi Tarapara
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Apexa Pandit
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Franky Shah
- Molecular Diagnostic and Research Lab-III, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
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Maurya M, Gupta V, Agarwal P, Kumar M, Sagar M, Raghuvanshi S, Gupta S. Expression of aldehyde dehydrogenase 1A1 in oral squamous cell carcinoma and its correlation with clinicopathological parameters. Natl J Maxillofac Surg 2022; 13:208-215. [PMID: 36051794 PMCID: PMC9426695 DOI: 10.4103/njms.njms_402_21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 12/30/2021] [Accepted: 01/15/2022] [Indexed: 11/04/2022] Open
Abstract
Background: Materials and Methods: Results: Conclusion:
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MicroRNA 630 Represses NANOG Expression through Transcriptional and Post-Transcriptional Regulation in Human Embryonal Carcinoma Cells. Int J Mol Sci 2021; 23:ijms23010046. [PMID: 35008480 PMCID: PMC8744645 DOI: 10.3390/ijms23010046] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/17/2021] [Accepted: 12/17/2021] [Indexed: 12/25/2022] Open
Abstract
The pluripotent transcription factor NANOG is essential for maintaining embryonic stem cells and driving tumorigenesis. We previously showed that PKC activity is involved in the regulation of NANOG expression. To explore the possible involvement of microRNAs in regulating the expression of key pluripotency factors, we performed a genome-wide analysis of microRNA expression in the embryonal carcinoma cell line NT2/D1 in the presence of the PKC activator, PMA. We found that MIR630 was significantly upregulated in PMA-treated cells. Experimentally, we showed that transfection of MIR630 mimic into embryonal carcinoma cell lines directly targeted the 3′UTR of OCT4, SOX2, and NANOG and markedly suppressed their expression. RNAhybrid and RNA22 algorithms were used to predict miRNA target sites in the NANOG 3′UTR, four possible target sites of MIR630 were identified. To examine the functional interaction between MIR630 and NANOG mRNA, the predicted MIR630 target sites in the NANOG 3′UTR were deleted and the activity of the reporters were compared. After targeted mutation of the predicted MIR630 target sites, the MIR630 mimic inhibited NANOG significantly less than the wild-type reporters. It is worth noting that mutation of a single putative binding site in the 3′UTR of NANOG did not completely abolish MIR630-mediated suppression, suggesting that MIR630 in the NANOG 3′UTR may have multiple binding sites and act together to maximally repress NANOG expression. Interestingly, MIR630 mimics significantly downregulated NANOG gene transcription. Exogenous expression of OCT4, SOX2, and NANOG lacking the 3′UTR almost completely rescued the reduced transcriptional activity of MIR630. MIR630 mediated the expression of differentiation markers in NT2/D1 cells, suggesting that MIR630 leads to the differentiation of NT2/D1 cell. Our findings show that MIR630 represses NANOG through transcriptional and post-transcriptional regulation, suggesting a direct link between core pluripotency factors and MIR630.
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Phiboonchaiyanan PP, Puthongking P, Chawjarean V, Harikarnpakdee S, Sukprasansap M, Chanvorachote P, Priprem A, Govitrapong P. Melatonin and its derivative disrupt cancer stem-like phenotypes of lung cancer cells via AKT downregulation. Clin Exp Pharmacol Physiol 2021; 48:1712-1723. [PMID: 34396568 DOI: 10.1111/1440-1681.13572] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 07/28/2021] [Accepted: 08/11/2021] [Indexed: 12/27/2022]
Abstract
Cancer stem cells (CSCs), a small subpopulation of tumour cells, have properties of self-renewal and multipotency, which drive cancer progression and resistance to current treatments. Compounds potentially targeting CSCs have been recently developed. This study shows how melatonin, an endogenous hormone synthesised by the pineal gland, and its derivative suppress CSC-like phenotypes of human non-small cell lung cancer (NSCLC) cell lines, H460, H23, and A549. The effects of MLT and its derivative, acetyl melatonin (ACT), on CSC-like phenotypes were investigated using assays for anchorage-independent growth, three-dimensional spheroid formation, scratch wound healing ability, and CSC marker and upstream protein signalling expression. Enriched CSC spheroids were used to confirm the effect of both compounds on lung cancer cells. MLT and ACT inhibited CSC-like behaviours by suppression of colony and spheroid formation in NSCLC cell lines. Their effects on spheroid formation were confirmed in CSC-enriched H460 cells. CSC markers, CD133 and ALDH1A1, were depleted by both compounds. The behaviour and factors associated to epithelial-mesenchymal transition, as indicated by cell migration and the protein vimentin, were also decreased by MLT and ACT. Mechanistically, MLT and ACT decreased the expression of stemness proteins Oct-4, Nanog, and β-catenin by reducing active AKT (phosphorylated AKT). Suppression of the AKT pathway was not mediated through melatonin receptors. This study demonstrates a novel role, and its underlying mechanism, for MLT and its derivative ACT in suppression of CSC-like phenotypes in NSCLC cells, indicating that they are potential candidates for lung cancer treatment.
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Affiliation(s)
- Preeyaporn Plaimee Phiboonchaiyanan
- College of Pharmacy, Rangsit University, Pathumthani, Thailand
- Cosmeceutical Research, Development and Testing Center, College of Pharmacy, Rangsit University, Pathum Thani, Thailand
| | - Ploenthip Puthongking
- Melatonin Research Group, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Verisa Chawjarean
- College of Pharmacy, Rangsit University, Pathumthani, Thailand
- Cosmeceutical Research, Development and Testing Center, College of Pharmacy, Rangsit University, Pathum Thani, Thailand
| | - Saraporn Harikarnpakdee
- College of Pharmacy, Rangsit University, Pathumthani, Thailand
- Cosmeceutical Research, Development and Testing Center, College of Pharmacy, Rangsit University, Pathum Thani, Thailand
| | - Monruedee Sukprasansap
- Food Toxicology Unit, Institute of Nutrition, Mahidol University, Nakhon Pathom, Thailand
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Aroonsri Priprem
- Faculty of Pharmacy, Mahasarakham University, Maha Sarakham, Thailand
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Kusena JWT, Shariatzadeh M, Thomas RJ, Wilson SL. Understanding cell culture dynamics: a tool for defining protocol parameters for improved processes and efficient manufacturing using human embryonic stem cells. Bioengineered 2021; 12:979-996. [PMID: 33757391 PMCID: PMC8806349 DOI: 10.1080/21655979.2021.1902696] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/09/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022] Open
Abstract
Standardization is crucial when culturing cells including human embryonic stem cells (hESCs) which are valuable for therapy development and disease modeling. Inherent issues regarding reproducibility of protocols are problematic as they hinder translation to good manufacturing practice (GMP), thus reducing clinical efficacy and uptake. Pluripotent cultures require standardization to ensure that input material is consistent prior to differentiation, as inconsistency of input cells creates end-product variation. To improve protocols, developers first must understand the cells they are working with and their related culture dynamics. This innovative work highlights key conditions required for optimized and cost-effective bioprocesses compared to generic protocols typically implemented. This entailed investigating conditions affecting growth, metabolism, and phenotype dynamics to ensure cell quality is appropriate for use. Results revealed critical process parameters (CPPs) including feeding regime and seeding density impact critical quality attributes (CQAs) including specific metabolic rate (SMR) and specific growth rate (SGR). This implied that process understanding, and control is essential to maintain key cell characteristics, reduce process variation and retain CQAs. Examination of cell dynamics and CPPs permitted the formation of a defined protocol for culturing H9 hESCs. The authors recommend that H9 seeding densities of 20,000 cells/cm2, four-day cultures or three-day cultures following a recovery passage from cryopreservation and 100% medium exchange after 48 hours are optimal. These parameters gave ~SGR of 0.018 hour-1 ± 1.5x10-3 over three days and cell viabilities ≥95%±0.4, while producing cells which highly expressed pluripotent and proliferation markers, Oct3/4 (>99% positive) and Ki-67 (>99% positive).
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Affiliation(s)
- J W T Kusena
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Epinal Way, Loughborough University, Loughborough, Leicestershire, UK
| | - M Shariatzadeh
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Epinal Way, Loughborough University, Loughborough, Leicestershire, UK
| | - R J Thomas
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Epinal Way, Loughborough University, Loughborough, Leicestershire, UK
| | - S L Wilson
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Epinal Way, Loughborough University, Loughborough, Leicestershire, UK
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