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1
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Tugizov S. HIV-1 Tat-induced disruption of epithelial junctions and epithelial-mesenchymal transition of oral and genital epithelial cells lead to increased invasiveness of neoplastic cells and the spread of herpes simplex virus and cytomegalovirus. Front Immunol 2025; 16:1541532. [PMID: 40018040 PMCID: PMC11866325 DOI: 10.3389/fimmu.2025.1541532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/28/2025] [Indexed: 03/01/2025] Open
Abstract
Human immunodeficiency virus (HIV-1) transactivator Tat is a unique multi-functional viral protein secreted by infected cells. Although its primary function is to promote HIV-1 transcription, secreted Tat interacts with neighboring cells and induces numerous disease-associated pathological changes. Despite the substantial reduction of viral load and disease burden, Tat expression and secretion persist in people living with HIV who are undergoing treatment with highly effective combination antiretroviral therapy (cART). Tat interacts with both oral and genital epithelial cells and impairs their mucosal barrier functions, which facilitates the entry of other pathogenic viruses. Tat-mediated interactions with both human papillomavirus (HPV) -infected and HPV-negative neoplastic epithelial cells lead to epithelial-mesenchymal transition and increased invasiveness of malignant cells. Likewise, Tat-induced disruption of oral epithelial cell junctions leads to herpes simplex virus-1 (HSV-1) infection and spread via exposure of its receptor, nectin-1. HIV-1 Tat facilitates infection and spread of human cytomegalovirus (HCMV) by activating mitogen-activated protein kinases (MAPK) and promoting NF-κB signaling, both critical for the replication and production of progeny virions. HIV extracellular Tat also plays a critical role in human herpesvirus 8 (HHV8) -caused Kaposi sarcoma (KS) pathogenesis by synergizing with HHV-8 lytic proteins and promoting the proliferation, angiogenesis, and migration of endothelial cells. Collectively, these findings emphasize the critical impact of HIV-1 Tat on HIV/AIDS pathogenesis during the cART era and highlight the need for further research on the molecular mechanisms underlying Tat-mediated interactions with oral and genital mucosal epithelial cells.
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Affiliation(s)
- Sharof Tugizov
- Department of Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
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2
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Radaic A, Kamarajan P, Cho A, Wang S, Hung G, Najarzadegan F, Wong DT, Ton‐That H, Wang C, Kapila YL. Biological biomarkers of oral cancer. Periodontol 2000 2024; 96:250-280. [PMID: 38073011 PMCID: PMC11163022 DOI: 10.1111/prd.12542] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/09/2023] [Indexed: 06/12/2024]
Abstract
The oral squamous cell carcinoma (OSCC) 5 year survival rate of 41% has marginally improved in the last few years, with less than a 1% improvement per year from 2005 to 2017, with higher survival rates when detected at early stages. Based on histopathological grading of oral dysplasia, it is estimated that severe dysplasia has a malignant transformation rate of 7%-50%. Despite these numbers, oral dysplasia grading does not reliably predict its clinical behavior. Thus, more accurate markers predicting oral dysplasia progression to cancer would enable better targeting of these lesions for closer follow-up, especially in the early stages of the disease. In this context, molecular biomarkers derived from genetics, proteins, and metabolites play key roles in clinical oncology. These molecular signatures can help predict the likelihood of OSCC development and/or progression and have the potential to detect the disease at an early stage and, support treatment decision-making and predict treatment responsiveness. Also, identifying reliable biomarkers for OSCC detection that can be obtained non-invasively would enhance management of OSCC. This review will discuss biomarkers for OSCC that have emerged from different biological areas, including genomics, transcriptomics, proteomics, metabolomics, immunomics, and microbiomics.
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Affiliation(s)
- Allan Radaic
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Pachiyappan Kamarajan
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Alex Cho
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Sandy Wang
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Guo‐Chin Hung
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | | | - David T. Wong
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Hung Ton‐That
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Cun‐Yu Wang
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
| | - Yvonne L. Kapila
- School of DentistryUniversity of California, Los Angeles (UCLA)Los AngelesCaliforniaUSA
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3
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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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4
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Chiappara G, Di Vincenzo S, Cascio C, Pace E. Stem cells, Notch-1 signaling, and oxidative stress: a hellish trio in cancer development and progression within the airways. Is there a role for natural compounds? Carcinogenesis 2024; 45:621-629. [PMID: 39046986 DOI: 10.1093/carcin/bgae049] [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: 04/23/2024] [Revised: 06/22/2024] [Accepted: 07/20/2024] [Indexed: 07/27/2024] Open
Abstract
Notch-1 signaling plays a crucial role in stem cell maintenance and in repair mechanisms in various mucosal surfaces, including airway mucosa. Persistent injury can induce an aberrant activation of Notch-1 signaling in stem cells leading to an increased risk of cancer initiation and progression. Chronic inflammatory respiratory disorders, including chronic obstructive pulmonary disease (COPD) is associated with both overactivation of Notch-1 signaling and increased lung cancer risk. Increased oxidative stress, also due to cigarette smoke, can further contribute to promote cancer initiation and progression by amplifying inflammatory responses, by activating the Notch-1 signaling, and by blocking regulatory mechanisms that inhibit the growth capacity of stem cells. This review offers a comprehensive overview of the effects of aberrant Notch-1 signaling activation in stem cells and of increased oxidative stress in lung cancer. The putative role of natural compounds with antioxidant properties is also described.
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Affiliation(s)
- Giuseppina Chiappara
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
| | - Serena Di Vincenzo
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
| | - Caterina Cascio
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
| | - Elisabetta Pace
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
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5
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Gisina A, Yarygin K, Lupatov A. The Impact of Glycosylation on the Functional Activity of CD133 and the Accuracy of Its Immunodetection. BIOLOGY 2024; 13:449. [PMID: 38927329 PMCID: PMC11200695 DOI: 10.3390/biology13060449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 06/01/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Abstract
The membrane glycoprotein CD133 (prominin-1) is widely regarded as the main molecular marker of cancer stem cells, which are the most malignant cell subpopulation within the tumor, responsible for tumor growth and metastasis. For this reason, CD133 is considered a promising prognostic biomarker and molecular target for antitumor therapy. Under normal conditions, CD133 is present on the cell membrane in glycosylated form. However, in malignancies, altered glycosylation apparently leads to changes in the functional activity of CD133 and the availability of some of its epitopes for antibodies. This review focuses on CD133's glycosylation in human cells and its impact on the function of this glycoprotein. The association of CD133 with proliferation, differentiation, apoptosis, autophagy, epithelial-mesenchymal transition, the organization of plasma membrane protrusions and extracellular trafficking is discussed. In this review, particular attention is paid to the influence of CD133's glycosylation on its immunodetection. A list of commercially available and custom antibodies with their characteristics is provided. The available data indicate that the development of CD133-based biomedical technologies should include an assessment of CD133's glycosylation in each tumor type.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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6
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Ortiz RC, Amôr NG, Saito LM, Santesso MR, Lopes NM, Buzo RF, Fonseca AC, Amaral-Silva GK, Moyses RA, Rodini CO. CSC highE-cadherin low immunohistochemistry panel predicts poor prognosis in oral squamous cell carcinoma. Sci Rep 2024; 14:10583. [PMID: 38719848 PMCID: PMC11078993 DOI: 10.1038/s41598-024-55594-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 02/26/2024] [Indexed: 05/12/2024] Open
Abstract
Identifying marker combinations for robust prognostic validation in primary tumour compartments remains challenging. We aimed to assess the prognostic significance of CSC markers (ALDH1, CD44, p75NTR, BMI-1) and E-cadherin biomarkers in OSCC. We analysed 94 primary OSCC and 67 metastatic lymph node samples, including central and invasive tumour fronts (ITF), along with clinicopathological data. We observed an increase in ALDH1+/CD44+/BMI-1- tumour cells in metastatic lesions compared to primary tumours. Multivariate analysis highlighted that elevated p75NTR levels (at ITF) and reduced E-cadherin expression (at the tumour centre) independently predicted metastasis, whilst ALDH1high exhibited independent predictive lower survival at the ITF, surpassing the efficacy of traditional tumour staging. Then, specifically at the ITF, profiles characterized by CSChighE-cadherinlow (ALDH1highp75NTRhighE-cadherinlow) and CSCintermediateE-cadherinlow (ALDH1 or p75NTRhighE-cadherinlow) were significantly associated with worsened overall survival and increased likelihood of metastasis in OSCC patients. In summary, our study revealed diverse tumour cell profiles in OSCC tissues, with varying CSC and E-cadherin marker patterns across primary tumours and metastatic sites. Given the pivotal role of reduced survival rates as an indicator of unfavourable prognosis, the immunohistochemistry profile identified as CSChighE-cadherinlow at the ITF of primary tumours, emerges as a preferred prognostic marker closely linked to adverse outcomes in OSCC.
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Affiliation(s)
- Rafael Carneiro Ortiz
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil.
- Post-Graduation Program in Rehabilitation Sciences, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRAC/USP), Av. Octavio Pinheiro Brisolla, 9-75, Jardim Brasil, São Paulo, Brazil.
| | - Nádia Ghinelli Amôr
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Luciana Mieli Saito
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Mariana Rodrigues Santesso
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, 18618-687, Brazil
| | - Nathália Martins Lopes
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Rodrigo Fonseca Buzo
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Angélica Cristina Fonseca
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | | | - Raquel Ajub Moyses
- Department of Head and Neck Surgery, LIM28, Clinical Hospital HCFMUSP, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Camila Oliveira Rodini
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil.
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7
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Ruszkowska-Ciastek B, Kwiatkowska K, Marques-da-Silva D, Lagoa R. Cancer Stem Cells from Definition to Detection and Targeted Drugs. Int J Mol Sci 2024; 25:3903. [PMID: 38612718 PMCID: PMC11011379 DOI: 10.3390/ijms25073903] [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: 02/26/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Cancers remain the second leading cause of mortality in the world. Preclinical and clinical studies point an important role of cancer/leukaemia stem cells (CSCs/LSCs) in the colonisation at secondary organ sites upon metastatic spreading, although the precise mechanisms for specific actions are still not fully understood. Reviewing the present knowledge on the crucial role of CSCs/LSCs, their plasticity, and population heterogeneity in treatment failures in cancer patients is timely. Standard chemotherapy, which acts mainly on rapidly dividing cells, is unable to adequately affect CSCs with a low proliferation rate. One of the proposed mechanisms of CSC resistance to anticancer agents is the fact that these cells can easily shift between different phases of the cell cycle in response to typical cell stimuli induced by anticancer drugs. In this work, we reviewed the recent studies on CSC/LSC alterations associated with disease recurrence, and we systematised the functional assays, markers, and novel methods for CSCs screening. This review emphasises CSCs' involvement in cancer progression and metastasis, as well as CSC/LSC targeting by synthetic and natural compounds aiming at their elimination or modulation of stemness properties.
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Affiliation(s)
- Barbara Ruszkowska-Ciastek
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum, 85-094 Bydgoszcz, Poland
| | - Katarzyna Kwiatkowska
- Department of Laboratory Diagnostics, Jan Biziel University Hospital No. 2, 85-168 Bydgoszcz, Poland;
| | - Dorinda Marques-da-Silva
- Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials (LSRE-LCM), Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal; (D.M.-d.-S.); (R.L.)
- Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Ricardo Lagoa
- Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials (LSRE-LCM), Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal; (D.M.-d.-S.); (R.L.)
- Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
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8
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Zhang S, Yang R, Ouyang Y, Shen Y, Hu L, Xu C. Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0333. [PMID: 38164743 PMCID: PMC10845928 DOI: 10.20892/j.issn.2095-3941.2023.0333] [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: 09/04/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.
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Affiliation(s)
- Shuo Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Rui Yang
- Department of Ultrasound in Medicine, Chengdu Wenjiang District People’s Hospital, Chengdu 611130, China
| | - Yujie Ouyang
- Acupuncture and Massage College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Shen
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- School of Pharmacy, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lanlin Hu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
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Vukovic Đerfi K, Vasiljevic T, Matijevic Glavan T. Recent Advances in the Targeting of Head and Neck Cancer Stem Cells. APPLIED SCIENCES 2023; 13:13293. [DOI: 10.3390/app132413293] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous cancer with a poor overall response to therapy. One of the reasons for this therapy resistance could be cancer stem cells (CSCs), a small population of cancer cells with self-renewal and tumor-initiating abilities. Tumor cell heterogeneity represents hurdles for therapeutic elimination of CSCs. Different signaling pathway activations, such as Wnt, Notch, and Sonic-Hedgehog (SHh) pathways, lead to the expression of several cancer stem factors that enable the maintenance of CSC features. Identification and isolation of CSCs are based either on markers (CD133, CD44, and aldehyde dehydrogenase (ALDH)), side populations, or their sphere-forming ability. A key challenge in cancer therapy targeting CSCs is overcoming chemotherapy and radiotherapy resistance. However, in novel therapies, various approaches are being employed to address this hurdle such as targeting cell surface markers, other stem cell markers, and different signaling or metabolic pathways, but also, introducing checkpoint inhibitors and natural compounds into the therapy can be beneficial.
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Affiliation(s)
- Kristina Vukovic Đerfi
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tea Vasiljevic
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tanja Matijevic Glavan
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
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10
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Gisina A, Kim Y, Yarygin K, Lupatov A. Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons. Int J Mol Sci 2023; 24:17398. [PMID: 38139228 PMCID: PMC10744290 DOI: 10.3390/ijms242417398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The CD133 cell membrane glycoprotein, also termed prominin-1, is expressed on some of the tumor cells of both solid and blood malignancies. The CD133-positive tumor cells were shown to exhibit higher proliferative activity, greater chemo- and radioresistance, and enhanced tumorigenicity compared to their CD133-negative counterparts. For this reason, CD133 is regarded as a potential prognostic biomarker in oncology. The CD133-positive cells are related to the cancer stem cell subpopulation in many types of cancer. Recent studies demonstrated the involvement of CD133 in the regulation of proliferation, autophagy, and apoptosis in cancer cells. There is also evidence of its participation in the epithelial-mesenchymal transition associated with tumor progression. For a number of malignant tumor types, high CD133 expression is associated with poor prognosis, and the prognostic significance of CD133 has been confirmed in a number of meta-analyses. However, some published papers suggest that CD133 has no prognostic significance or even demonstrate a certain correlation between high CD133 levels and a positive prognosis. This review summarizes and discusses the existing evidence for and against the prognostic significance of CD133 in cancer. We also consider possible reasons for conflicting findings from the studies of the clinical significance of CD133.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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11
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Dai Y, Wu Z, Chen Y, Ye X, Wang C, Zhu H. OCT4's role and mechanism underlying oral squamous cell carcinoma. J Zhejiang Univ Sci B 2023; 24:796-806. [PMID: 37701956 PMCID: PMC10500100 DOI: 10.1631/jzus.b2200602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 04/06/2023] [Indexed: 09/14/2023]
Abstract
Oral squamous cell carcinoma (OSCC), a common malignancy of the head and neck, ranks sixth worldwide in terms of cancers with the most negative impact, owing to tumor relapse rates, cervical lymphnode metastasis, and the lack of an efficacious systemic therapy. Its prognosis is poor, and its mortality rate is high. Octamer-binding transcription factor 4 (OCT4) is a member of the Pit-Oct-Unc (POU) family and is a key reprogramming factor that produces a marked effect in preserving the pluripotency and self-renewal state of embryonic stem cells (ESCs). According to recent studies, OCT4 participates in retaining the survival of OSCC cancer stem cells (CSCs), which has far-reaching implications for the occurrence, recurrence, metastasis, and prognosis of oral carcinogenesis. Therefore, we summarize the structure, subtypes, and function of OCT4 as well as its role in the occurrence, progression, and prognosis of OSCC.
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Affiliation(s)
- Yuwei Dai
- Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Ziqiong Wu
- School of Stomatology, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yitong Chen
- School of Stomatology, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xinjian Ye
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Disease of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China
| | - Chaowei Wang
- Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Huiyong Zhu
- Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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12
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Cierpikowski P, Leszczyszyn A, Bar J. The Role of Hedgehog Signaling Pathway in Head and Neck Squamous Cell Carcinoma. Cells 2023; 12:2083. [PMID: 37626893 PMCID: PMC10453169 DOI: 10.3390/cells12162083] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/12/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading malignancy worldwide, with a poor prognosis and limited treatment options. Molecularly targeted therapies for HNSCC are still lacking. However, recent reports provide novel insights about many molecular alterations in HNSCC that may be useful in future therapies. Therefore, it is necessary to identify new biomarkers that may provide a better prediction of the disease and promising targets for personalized therapy. The poor response of HNSCC to therapy is attributed to a small population of tumor cells called cancer stem cells (CSCs). Growing evidence indicates that the Hedgehog (HH) signaling pathway plays a crucial role in the development and maintenance of head and neck tissues. The HH pathway is normally involved in embryogenesis, stem cell renewal, and tissue regeneration. However, abnormal activation of the HH pathway is also associated with carcinogenesis and CSC regulation. Overactivation of the HH pathway was observed in several tumors, including basal cell carcinoma, that are successfully treated with HH inhibitors. However, clinical studies about HH pathways in HNSCC are still rare. In this review, we summarize the current knowledge and recent advances regarding the HH pathway in HNSCC and discuss its possible implications for prognosis and future therapy.
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Affiliation(s)
- Piotr Cierpikowski
- Department of Maxillofacial Surgery, The Ludwik Rydygier Specialist Hospital, Osiedle Zlotej Jesieni 1, 31-826 Krakow, Poland
| | - Anna Leszczyszyn
- Dental Surgery Outpatient Clinic, 4th Military Clinical Hospital, Weigla 5, 53-114 Wroclaw, Poland;
| | - Julia Bar
- Department of Immunopathology and Molecular Biology, Wroclaw Medical University, Bujwida 44, 50-345 Wroclaw, Poland
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Joshi P, Waghmare S. Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges. World J Stem Cells 2023; 15:438-452. [PMID: 37342225 PMCID: PMC10277967 DOI: 10.4252/wjsc.v15.i5.438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
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Affiliation(s)
- Priyanka Joshi
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjeev Waghmare
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
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Lu Y, Kou Y, Gao Y, Yang P, Liu S, Zhang F, Li M. Eldecalcitol inhibits the progression of oral cancer by suppressing the expression of GPx-1. Oral Dis 2023; 29:615-627. [PMID: 34431176 DOI: 10.1111/odi.14010] [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: 06/13/2021] [Revised: 08/04/2021] [Accepted: 08/22/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVES This study aimed to investigate the role of eldecalcitol in the progression of oral squamous cell carcinoma and to explore the related mechanism. MATERIALS AND METHODS The effects of eldecalcitol on the proliferation, cell cycle, apoptosis, and migration of oral cancer cells (SCC-15 and CAL-27) were evaluated with cell counting kit-8, flow cytometry, quantitative real-time polymerase chain reaction, western blotting, and scratch assay. Mouse xenograft tumor model was established to further confirm the role of eldecalcitol in the progression of oral cancer. Immunohistochemistry, quantitative real-time polymerase chain reaction, and western blotting were used to detect glutathione peroxidase-1 expression in oral cancer tissue and cells treated with eldecalcitol. RESULTS Eldecalcitol was found to inhibit the proliferation and migration of SCC-15 and CAL-27 cells significantly, block the cell cycle in the G0/G1 phase, and enhance the apoptosis. In addition, glutathione peroxidase-1 was downregulated by eldecalcitol and acted as an important medium of eldecalcitol in inhibiting the proliferation and migration of SCC-15 and CAL-27 cells, as well as promoting their apoptosis. CONCLUSIONS Eldecalcitol may inhibit the progression of oral cancer by suppressing the expression of glutathione peroxidase-1, which may provide new insight into the application of eldecalcitol as a potential anti-cancer drug.
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Affiliation(s)
- Yupu Lu
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Yuying Kou
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Yuan Gao
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Panpan Yang
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shanshan Liu
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Fan Zhang
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Minqi Li
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.,Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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Siqueira JM, Heguedusch D, Rodini CO, Nunes FD, Rodrigues MFSD. Mechanisms involved in cancer stem cell resistance in head and neck squamous cell carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:116-137. [PMID: 37065869 PMCID: PMC10099599 DOI: 10.20517/cdr.2022.107] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/04/2023] [Accepted: 02/08/2023] [Indexed: 04/18/2023]
Abstract
Despite scientific advances in the Oncology field, cancer remains a leading cause of death worldwide. Molecular and cellular heterogeneity of head and neck squamous cell carcinoma (HNSCC) is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment. Cancer stem cells (CSCs) are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis, leading to poor prognosis in different types of cancer. CSCs exhibit a high level of plasticity, quickly adapting to the tumor microenvironment changes, and are intrinsically resistant to current chemo and radiotherapies. The mechanisms of CSC-mediated therapy resistance are not fully understood. However, they include different strategies used by CSCs to overcome challenges imposed by treatment, such as activation of DNA repair system, anti-apoptotic mechanisms, acquisition of quiescent state and Epithelial-mesenchymal transition, increased drug efflux capacity, hypoxic environment, protection by the CSC niche, overexpression of stemness related genes, and immune surveillance. Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients. This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC, supporting the use of possible strategies to overcome therapy failure.
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Affiliation(s)
- Juliana Mota Siqueira
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Daniele Heguedusch
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Camila Oliveira Rodini
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo 17012-230, Brazil
| | - Fabio Daumas Nunes
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Maria Fernanda Setúbal Destro Rodrigues
- Biophotonics Applied to Health Sciences, Nove de Julho University, UNINOVE, São Paulo 01504-001, Brazil
- Correspondence to: PhD. Maria Fernanda Setúbal Destro Rodrigues. Biophotonics Applied to Health Sciences, Nove de Julho University, UNINOVE, Rua Vergueiro, 235/249 - Liberdade, São Paulo 01504-001, Brazil. E-mail:
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Abstract
Tissue factor (TF), an initiator of extrinsic coagulation pathway, is positively correlated with venous thromboembolism (VTE) of tumor patients. Beyond thrombosis, TF plays a vital role in tumor progression. TF is highly expressed in cancer tissues and circulating tumor cell (CTC), and activates factor VIIa (FVIIa), which increases tumor cells proliferation, angiogenesis, epithelial-mesenchymal transition (EMT) and cancer stem cells(CSCs) activity. Furthermore, TF and TF-positive microvesicles (TF+MVs) activate the coagulation system to promote the clots formation with non-tumor cell components (e.g., platelets, leukocytes, fibrin), which makes tumor cells adhere to clots to form CTC clusters. Then, tumor cells utilize clots to cause its reducing fluid shear stress (FSS), anoikis resistance, immune escape, adhesion, extravasation and colonization. Herein, we review in detail that how TF signaling promotes tumor metastasis, and how TF-targeted therapeutic strategies are being in the preclinical and clinical trials.
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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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Characterization of Cancer Stem Cell Characteristics and Development of a Prognostic Stemness Index Cell-Related Signature in Oral Squamous Cell Carcinoma. DISEASE MARKERS 2021; 2021:1571421. [PMID: 34840626 PMCID: PMC8617564 DOI: 10.1155/2021/1571421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 10/06/2021] [Indexed: 01/27/2023]
Abstract
Objective Cancer stem cells (CSCs) with self-renewal and plasticity contribute to tumor initiation and progression. This study developed an mRNA expression-based stemness index- (mRNAsi-) associated signature and validated biological functions of stem cell-related genes in oral squamous cell carcinoma (OSCC). Methods Here, mRNAsi was measured for OSCC samples from TCGA cohort, and prognosis and tumor microenvironment (stromal/immune scores, tumor purity) in high- and low-mRNAsi samples were evaluated with survival analyses and ESTIMATE algorithm. Based on prognostic mRNAsi-related genes, a risk score model was constructed by the LASSO method. The predictive accuracy was evaluated by uni- and multivariate Cox analyses and ROC curves. Among the genes in the model, the functions of H2AFZ on proliferation, apoptosis, invasion, and EMT were investigated in OSCC cells. Results High mRNAsi was distinctly associated with undesirable prognosis, increased stromal and immune scores, and lowered tumor purity. The mRNAsi-associated signature containing 11 genes was developed, and high-risk score was distinctly related to poor survival outcomes. Moreover, this signature was an independent and robust risk factor. H2AFZ upregulation significantly enhanced proliferative and invasive capacities and facilitated EMT as well as lowered apoptotic levels in Cal-27 and HSC-3 cells. Conclusion Our study characterized cancer stem cell characteristics that were closely related to tumor microenvironment and developed a stemness index cell-related signature that could assist prognosis prediction and risk stratification for OSCC. H2AFZ could become a potential therapeutic target against OSCC.
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Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells. Mar Drugs 2021; 19:md19050261. [PMID: 34063628 PMCID: PMC8147647 DOI: 10.3390/md19050261] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/30/2022] Open
Abstract
It has been recognized that cancer stem-like cells (CSCs) in tumor tissue crucially contribute to therapeutic failure, resulting in a high mortality rate in lung cancer patients. Due to their stem-like features of self-renewal and tumor formation, CSCs can lead to drug resistance and tumor recurrence. Herein, the suppressive effect of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from Thai blue sponge Xestospongia sp., on cancer spheroid initiation and self-renewal in the CSCs of human lung cancer cells is revealed. The depletion of stemness transcription factors, including Nanog, Oct-4, and Sox2 in the lung CSC-enriched population treated with jorunnamycin A (0.5 μM), resulted from the activation of GSK-3β and the consequent downregulation of β-catenin. Interestingly, pretreatment with jorunnamycin A at 0.5 μM for 24 h considerably sensitized lung CSCs to cisplatin-induced apoptosis, as evidenced by upregulated p53 and decreased Bcl-2 in jorunnamycin A-pretreated CSC-enriched spheroids. Moreover, the combination treatment of jorunnamycin A (0.5 μM) and cisplatin (25 μM) also diminished CD133-overexpresssing cells presented in CSC-enriched spheroids. Thus, evidence on the regulatory functions of jorunnamycin A may facilitate the development of this marine-derived compound as a novel chemotherapy agent that targets CSCs in lung cancer treatment.
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Yu T, Tang Q, Chen X, Fan W, Zhou Z, Huang W, Liang F. TGF-β1 and IL-17A comediate the protumor phenotype of neutrophils to regulate the epithelial-mesenchymal transition in oral squamous cell carcinoma. J Oral Pathol Med 2021; 50:353-361. [PMID: 33164231 DOI: 10.1111/jop.13122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/08/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND The role of neutrophils in cancer has been the subject of intense research in recent years. One major theme that has emerged is that not all neutrophils are equal in the field of cancer. However, it remains unclear what induces the protumorigenic or antitumorigenic phenotype predominate in tumor. Therefore, this study aimed to investigate what factors induce which of these two phenotypes of neutrophil predominate in OSCC and to explore the role of neutrophil polarization on tumor. METHODS Immunofluorescence and immunohistochemistry staining were used to observe neutrophil infiltration and the expression of TGF-β1 and IL-17A in OSCC tissues. Recombinant human TGF-β1 and IL-17A were used to modulate neutrophil polarization. OSCC cell (SCC9 and SAS cell lines) migration, proliferation, invasion, stemness, and EMT were analyzed after treatment with conditioned medium from TGF-β1/IL-17A-activated neutrophils. The levels of neutrophil-associated markers in OSCC tissues and peripheral blood were examined by immunofluorescence staining and quantitative PCR. RESULTS Our data showed neutrophil infiltration and elevated expression of TGF-β1 and IL-17A in OSCC tissues. The cooperative effect of TGF-β1 and IL-17A promoted neutrophils to take on a protumor phenotype in vitro. TGF-β1/IL-17A-activated neutrophils remarkably induced cell migration, proliferation, invasion, stemness, and EMT in OSCC cells. Additionally, OSCC patients showed increased expression of MMP9 and decreased expression of CCL3 in circulating neutrophils. CONCLUSION TGF-β1 and IL-17A cooperated to augment the protumor functions of neutrophils, thereby promoting the progression of OSCC cells. In addition, the combination of neutrophil-associated markers may serve as a predictive method to screen for patients with OSCC.
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Affiliation(s)
- Tao Yu
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, China.,Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
| | - Qinchao Tang
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, China.,Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
| | - Xueru Chen
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, China.,Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
| | - Wan Fan
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, China.,Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
| | - Zhuoqian Zhou
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, China.,Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
| | - Wanqian Huang
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China
| | - Feixin Liang
- Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, China.,Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
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