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Mohammad S, Ullah I, Ali A, Jan Z, Aleem B, Khan M, Naseem W. Role of circulating tumor DNA and cell-free DNA biomarkers in diagnosis and prognosis of oral cancer - a systematic review. BMC Oral Health 2025; 25:522. [PMID: 40217229 PMCID: PMC11987223 DOI: 10.1186/s12903-025-05898-3] [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: 02/01/2025] [Accepted: 03/27/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Oral squamous cell carcinoma is the most common malignant neoplasm of the oral cavity, contributing significantly to cancer-related mortality worldwide. Circulating tumor DNA could be a promising biomarker for the early diagnosis and prognosis of oral cancer. OBJECTIVE The aim of this systematic review was to consolidate the existing literature on the role of circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) in the diagnosis and prognosis of oral cancer. METHODOLOGY The review protocol followed PRISMA guidelines. A systematic search was conducted across PubMed, Web of Science, Google Scholar and SCOPUS. Only English-language studies were included, while narrative reviews, HPV-positive OSCC, systematic reviews, meta-analyses, abstracts, and letters to the editor were excluded. Data were extracted on study design, country, sample size, participant characteristics, assessment methods, type of oral cancer and measured outcomes. Risk of bias was evaluated using Newcastle-Ottawa Scale (NOS). RESULTS A total of 3,155 records were identified, out of which 17 studies met the inclusion criteria. These comprised eleven cohort studies, one was a case series, two were descriptive studies, and three were case-control studies. The studies primarily addressed oral squamous cell carcinoma (OSCC) and head and neck squamous cell carcinoma (HNSCC). Findings revealed that elevated cfDNA levels are associated with poor prognosis, lymph node metastasis, larger tumor size and advanced disease stages. ctDNA acts as a predictive tool for monitoring cancer progression, treatment response, recurrence risk, and overall survival. Among 12 studies evaluated using NOS, 8 were of good quality, while 4 were fair quality. CONCLUSION ctDNA and cfDNA exhibit promising prognostic and diagnostic potential for OSCC and HNSCC. Elevated cfDNA levels correlate with poor prognosis, while ctDNA shows potential for monitoring cancer progression and treatment response.
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Affiliation(s)
- Samrina Mohammad
- Department of Oral Pathology, Khyber College of Dentistry, Peshawar, Pakistan
| | - Ihsan Ullah
- IPDM, Khyber Medical University, Peshawar, Pakistan.
| | - Asif Ali
- IPDM, Khyber Medical University, Peshawar, Pakistan
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Zainab Jan
- Institute of Radiation and Nuclear Medicine IRNUM Hospital, Peshawar, Pakistan
| | - Benish Aleem
- IPDM, Khyber Medical University, Peshawar, Pakistan
| | - Muslim Khan
- Maxillofacial Surgery, Khyber College of Dentistry, Peshawar, Pakistan
| | - Waqas Naseem
- Department of Health Sciences, University of Debrecen, Debrecen, Hungary.
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2
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Amano Y, Hasegawa M, Kihara A, Matsubara D, Fukushima N, Nishino H, Mori Y, Inamura K, Niki T. Clinicopathological and prognostic significance of stromal p16 and p53 expression in oral squamous cell carcinoma. Ann Diagn Pathol 2025; 75:152439. [PMID: 39837151 DOI: 10.1016/j.anndiagpath.2025.152439] [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: 11/05/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/23/2025]
Abstract
The tumor microenvironment is highly heterogeneous and consists of neoplastic cells and diverse stromal components, including fibroblasts, endothelial cells, pericytes, immune cells, local and bone marrow-derived stromal stem and progenitor cells, and the surrounding extracellular matrix. Although the significance of p16 and p53 has been reported in various tumor types, their involvement in the stromal cells of oral squamous cell carcinoma (OSCC) remains unclear. We performed immunohistochemical analyses of p16 and p53 expression in OSCC samples, Of the 116 samples, 74 showed p16-positive stromal cells, and 33 showed p53-positive stromal cells. Both p16 and p53 positivity were associated with an increased histological grade, lymphovascular invasion, an immature stromal pattern with abundant amorphous extracellular matrix material, infiltrative invasion patterns (Yamamoto Kohama classification-4C and 4D), and poor prognosis. Multivariate analyses identified p16 and p53 positivity in the stroma as independent prognostic factors for overall survival (P = 0.032 and P = 0.020, respectively); moreover, stromal p16 positivity correlated with stromal p53 positivity. These findings indicated that p16 and p53 stroma positivity may regulate OSCC tumor aggressiveness.
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Affiliation(s)
- Yusuke Amano
- Division of Tumor Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan.
| | - Masayo Hasegawa
- Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Department of Otolaryngology-Head and Neck Surgery, Jichi Medical University Saitama Medical Center, 1-847, Amanumacho, Omiya-ku, Saitama, Japan
| | - Atsushi Kihara
- Division of Tumor Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan
| | - Daisuke Matsubara
- Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Department of Pathology, Faculty of medicine, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, Ibaraki, Japan
| | - Noriyoshi Fukushima
- Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan
| | - Hiroshi Nishino
- Department of Otolaryngology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan
| | - Yoshiyuki Mori
- Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University Saitama Medical Center, 1-847, Amanumacho, Omiya, Saitama, Saitama, Japan
| | - Kentaro Inamura
- Division of Tumor Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan; Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, Japan
| | - Toshiro Niki
- Department of Pathology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, Japan
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Wu NC, Quevedo R, Nurse M, Hezaveh K, Liu H, Sun F, Muffat J, Sun Y, Simmons CA, McGaha TL, Prinos P, Arrowsmith CH, Ailles L, D'Arcangelo E, McGuigan AP. The use of a multi-metric readout screen to identify EHMT2/G9a-inhibition as a modulator of cancer-associated fibroblast activation state. Biomaterials 2025; 314:122879. [PMID: 39395244 DOI: 10.1016/j.biomaterials.2024.122879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 09/20/2024] [Accepted: 10/04/2024] [Indexed: 10/14/2024]
Abstract
Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression, including mediating tumour cell invasion via their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM). Given that reduced CAF abundance in tumours correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in regions of tumour-stromal mixing with the goal of reducing tumour aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, we performed an image-based, phenotypic screen that enabled us to identify modulators of CAF abundance and the capacity of CAFs to induce tumour cell invasion. We identified EHMT2 (also known as G9a), an enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as a potent modulator of CAF abundance and CAF-mediated tumour cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed EHMT2 participated in driving CAFs towards a pro-invasive phenotype and mediated CAF hyperproliferation, a feature typically associated with activated fibroblasts in tumours. Our study suggests that EHMT2 regulates CAF state within the tumour microenvironment by impacting CAF activation, as well as by magnifying the pro-invasive effects of these activated CAFs on tumour cell invasion through promoting CAF hyperproliferation.
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Affiliation(s)
- Nila C Wu
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Rene Quevedo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Michelle Nurse
- Department of Chemical Engineering & Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Kebria Hezaveh
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Haijiao Liu
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada
| | - Fumao Sun
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada
| | - Julien Muffat
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada
| | - Yu Sun
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada
| | - Craig A Simmons
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada
| | - Tracy L McGaha
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Panagiotis Prinos
- Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada
| | - Cheryl H Arrowsmith
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Laurie Ailles
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Elisa D'Arcangelo
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
| | - Alison P McGuigan
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Chemical Engineering & Applied Chemistry, University of Toronto, Toronto, ON, Canada.
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Cui D, Kong N, Yang W, Yan F. Recent advances in nanoarchitectonics of two-dimensional nanomaterials for dental biosensing and drug delivery. Adv Colloid Interface Sci 2025; 337:103388. [PMID: 39754906 DOI: 10.1016/j.cis.2024.103388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/06/2025]
Abstract
Two-dimensional (2D) nanoarchitectonics involve the creation of functional material assemblies and structures at the nanoscopic level by combining and organizing nanoscale components through various strategies, such as chemical and physical reforming, atomic and molecular manipulation, and self-assembly. Significant advancements have been made in the field, with the goal of producing functional materials from these nanoscale components. 2D nanomaterials, in particular, have gained substantial attention due to their large surface areas which are ideal for numerous surface-active applications. In this review article, nanoarchitectonics of 2D nanomaterials based biomedical applications are discussed. We aim to provide a concise overview of how nanoarchitectonics using 2D nanomaterials can be applied to dental healthcare, with an emphasis on biosensing and drug delivery. By offering a deeper understanding of nanoarchitectonics with programmable structures and predictable properties, we hope to inspire new innovations in the dental bioapplications of 2D nanomaterials.
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Affiliation(s)
- Di Cui
- Department of Periodontology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210008, China; School of Life and Environmental Sciences, Centre for Sustainable Bioproducts, Deakin University Waurn Ponds, Victoria, 3216, Australia
| | - Na Kong
- School of Life and Environmental Sciences, Centre for Sustainable Bioproducts, Deakin University Waurn Ponds, Victoria, 3216, Australia
| | - Wenrong Yang
- School of Life and Environmental Sciences, Centre for Sustainable Bioproducts, Deakin University Waurn Ponds, Victoria, 3216, Australia.
| | - Fuhua Yan
- Department of Periodontology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210008, China.
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Søland TM, Lipka A, Ruus AK, Molværsmyr AK, Galtung HK, Haug TM. Extracellular vesicles from cancer cell lines of different origins drive the phenotype of normal oral fibroblasts in a CAF-like direction. Front Oncol 2024; 14:1456346. [PMID: 39381039 PMCID: PMC11458688 DOI: 10.3389/fonc.2024.1456346] [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: 07/03/2024] [Accepted: 09/06/2024] [Indexed: 10/10/2024] Open
Abstract
Introduction Normal oral fibroblasts (NOFs) are located in the connective tissue of the oral mucosa. The NOFs play an important role in wound healing, tumor progression, and metastasis. They are subjected to influence by external and internal stimuli, among them extracellular vesicles (EVs), that are considered as important players in cell to cell communication, especially in carcinogenesis and metastatic processes. During tumorigenesis, stromal NOFs may undergo activation into cancer-associated fibroblasts (CAFs) that modify their phenotype to provide pro-oncogenic signals that in turn facilitate tumor initiation, progression, and metastasis. The aim of the study was to reveal the effect of EVs derived from local (oral squamous cell carcinoma - OSCC) and distant (pancreatic adenocarcinoma - PDAC; malignant melanoma brain metastasis - MBM) cancer origin on NOFs and their possible change into a CAF-like direction. Methods The effect of each of the cancer EV types on NOFs proliferation, viability, and migration was tested. Also, changes in gene expression of the well-established CAF biomarkers ACTA2, FAP, PDGFR, and two putative CAF biomarkers, the Ca2+- activated ion channels ANO1 and KCNMA, were studied. Results Obtained results indicate that NOFs receive and process signals transmitted by EVs originating from both OSCC, PDAC, and MBM. The fibroblast response was dependent on EV origin and concentration, and duration of EV exposure. Conclusion The present results indicate that the molecular cargo of the EVs direct NOFs towards a pro-tumorigenic phenotype.
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6
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Liu Y, Lu X, Sun S, Yu H, Li H. The therapeutic use of exosomes in children with adenoid hypertrophy accompanied by otitis media with effusion (AHOME): a protocol study. BMC Pediatr 2024; 24:521. [PMID: 39134977 PMCID: PMC11318249 DOI: 10.1186/s12887-024-04999-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 08/08/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND The adenoids act as a reservoir of bacterial pathogens and immune molecules, and they are significantly involved in children with otitis media with effusion (OME). As an essential carrier of intercellular substance transfer and signal transduction, exosomes with different biological functions can be secreted by various types of cells. There remains significant uncertainty regarding the clinical relevance of exosomes to OME, especially in its pathophysiologic development. In this study, we will seek to determine the biological functions of exosomes in children with adenoid hypertrophy accompanied by OME (AHOME). METHODS The diagnostic criteria for OME in children aged 4-10 years include a disease duration of at least 3 months, type B or C acoustic immittance, and varying degrees of conductive hearing loss. Adenoidal hypertrophy is diagnosed when nasal endoscopy shows at least 60% adenoidal occlusion in the nostrils or when nasopharyngeal lateral X-ray shows A/N > 0.6. Children who meet the indications for adenoidectomy surgery undergo adenoidectomy. Peripheral blood, nasopharyngeal swab, and adenoid tissue will be collected from patients, and the exosomes will be isolated from the samples. Following the initial collection, patients will undergo adenoidectomy and peripheral blood and nasopharyngeal swabs will be collected again after 3 months. EXPECTED RESULTS This study aims to identify differences in exosomes from preoperative adenoid tissue and peripheral blood samples between children with AHOME and those with adenoid hypertrophy alone. Additionally, it seeks to determine changes in microbial diversity in adenoid tissue between these groups. CONCLUSIONS The findings are expected to provide new insights into the diagnosis and treatment of OME, to identify novel biomarkers, and to enhance our understanding of the pathophysiology of OME, potentially leading to the development of innovative diagnostic and therapeutic approaches.
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Affiliation(s)
- Yixuan Liu
- Department of ENT Institute and Otorhinolaryngology, NHC Key Laboratory of Hearing Medicine Research, Demin Han's Academician Workstation, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200032, People's Republic of China
| | - Xiaoling Lu
- Department of ENT Institute and Otorhinolaryngology, NHC Key Laboratory of Hearing Medicine Research, Demin Han's Academician Workstation, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200032, People's Republic of China
| | - Shan Sun
- Department of ENT Institute and Otorhinolaryngology, NHC Key Laboratory of Hearing Medicine Research, Demin Han's Academician Workstation, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200032, People's Republic of China.
| | - Huiqian Yu
- Department of ENT Institute and Otorhinolaryngology, NHC Key Laboratory of Hearing Medicine Research, Demin Han's Academician Workstation, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200032, People's Republic of China.
| | - Huawei Li
- Department of ENT Institute and Otorhinolaryngology, NHC Key Laboratory of Hearing Medicine Research, Demin Han's Academician Workstation, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200032, People's Republic of China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
- The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
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Hadzi-Petrushev N, Stojchevski R, Jakimovska A, Stamenkovska M, Josifovska S, Stamatoski A, Sazdova I, Sopi R, Kamkin A, Gagov H, Mladenov M, Avtanski D. GLUT5-overexpression-related tumorigenic implications. Mol Med 2024; 30:114. [PMID: 39107723 PMCID: PMC11304774 DOI: 10.1186/s10020-024-00879-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 07/17/2024] [Indexed: 08/10/2024] Open
Abstract
Glucose transporter 5 (GLUT5) overexpression has gained increasing attention due to its profound implications for tumorigenesis. This manuscript provides a comprehensive overview of the key findings and implications associated with GLUT5 overexpression in cancer. GLUT5 has been found to be upregulated in various cancer types, leading to alterations in fructose metabolism and enhanced glycolysis, even in the presence of oxygen, a hallmark of cancer cells. This metabolic shift provides cancer cells with an alternative energy source and contributes to their uncontrolled growth and survival. Beyond its metabolic roles, recent research has unveiled additional aspects of GLUT5 in cancer biology. GLUT5 overexpression appears to play a critical role in immune evasion mechanisms, which further worsens tumor progression and complicates therapeutic interventions. This dual role of GLUT5 in both metabolic reprogramming and immune modulation highlights its significance as a potential diagnostic marker and therapeutic target. Understanding the molecular mechanisms driving GLUT5 overexpression is crucial for developing targeted therapeutic strategies that can disrupt the unique vulnerabilities of GLUT5-overexpressing cancer cells. This review emphasizes the complexities surrounding GLUT5's involvement in cancer and underscores the pressing need for continued research to unlock its potential as a diagnostic biomarker and therapeutic target, ultimately improving cancer management and patient outcomes.
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Affiliation(s)
- Nikola Hadzi-Petrushev
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, Skopje, 1000, North Macedonia
| | - Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY, 10022, USA
- Feinstein Institutes for Medical Research, Manhasset, NY, 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Anastasija Jakimovska
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, Skopje, 1000, North Macedonia
| | - Mimoza Stamenkovska
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, Skopje, 1000, North Macedonia
| | - Slavica Josifovska
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, Skopje, 1000, North Macedonia
| | - Aleksandar Stamatoski
- Faculty of Dental Medicine, University Clinic for Maxillofacial Surgery in Skopje, Ss. Cyril and Methodius University, Skopje, 1000, North Macedonia
| | - Iliyana Sazdova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University 'St. Kliment Ohridski', Sofia, 1504, Bulgaria
| | - Ramadan Sopi
- Faculty of Medicine, University of Prishtina, Prishtina, 10 000, Kosovo
| | - Andre Kamkin
- Institute of Physiology of the Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" Ministry of Health, Moscow, Russian Federation
| | - Hristo Gagov
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University 'St. Kliment Ohridski', Sofia, 1504, Bulgaria
| | - Mitko Mladenov
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, Skopje, 1000, North Macedonia
- Institute of Physiology of the Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" Ministry of Health, Moscow, Russian Federation
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY, 10022, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, 11030, USA.
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA.
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Srivastava P, Rai A, Kumar M. Expression profile of diagnostic genes in oral submucous fibrosis. Pathol Res Pract 2024; 260:155416. [PMID: 38944023 DOI: 10.1016/j.prp.2024.155416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 06/09/2024] [Accepted: 06/19/2024] [Indexed: 07/01/2024]
Abstract
Oral Submucous Fibrosis (OSMF) is a chronic precancerous disorder of the oral mucosa caused by chewing of areca nut and its other variants. Chewing of areca nuts leads to dysregulated expression of specific genes, leading to various premalignant or malignant disorders. This study aimed to determine the differential expression of the diagnostic genes (MYH6, TNNT3, MYL1, and TPM2) in healthy controls and OSMF patients using saliva and tissue samples, determining the histopathological grade of the clinical samples. A total of 20 patients were included in the study and were divided into two groups: Group I consisted of 10 healthy patients (control group) and Group II consisted of 10 OSMF patients. Unstimulated whole saliva samples were collected from both groups, and the tissue samples were divided into two parts: one for RT-qPCR analysis and the other for histopathological assay. The expression profile of genes concerning OSMF saliva and tissue samples was significantly upregulated compared to the healthy control, and all the clinical samples of the study were categorized into histopathological grade 1. The findings of this study concluded that these genes can be referred to as diagnostic genes for OSMF in early and very early clinical samples, and saliva can be used as a promising diagnostic tool for early OSMF studies.
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Affiliation(s)
- Prerna Srivastava
- Department of Bioengineering and Biotechnology, Birla Institute of Technology, Mesra, Ranchi, India
| | - Arpita Rai
- Dental Institute, Rajendra Institute of Medical Sciences, Ranchi 834009, India
| | - Manish Kumar
- Department of Bioengineering and Biotechnology, Birla Institute of Technology, Mesra, Ranchi, India.
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9
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Suzuki S, Nagakawa Y, Miyamoto R, Osakabe H, Kiya Y, Yamaguchi H, Nagao T, Einama T, Ao T, Shimoda M. Prognostic factors based on histological categorization of desmoplastic reactions in pancreatic cancer. World J Surg 2024; 48:1973-1980. [PMID: 38943046 DOI: 10.1002/wjs.12269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/16/2024] [Indexed: 06/30/2024]
Abstract
BACKGROUND/PURPOSE In colorectal cancer, the morphological categorization of fibrotic cancer stroma in the invasive frontal zone of the primary tumor is well reflected in the prognosis. Conversely, the histological characteristics of pancreatic cancer (PC) reveal fibrotic hyperplasia of stroma known as desmoplasia; however, its characterization is unknown. Therefore, this study aimed to evaluate the prognostic factors according to the histological categorization of desmoplastic reactions in PC. METHODS We retrospectively enrolled 167 patients who underwent curative resection for PC. The desmoplastic pattern was histologically classified as mature, intermediate, or immature. Clinicopathological features were evaluated, and disease-free and overall survival (OS) were analyzed in the three groups. Prognostic factors were assessed using univariate and multivariate analyses. RESULTS In total, 19 mature, 87 intermediate, and 61 immature desmoplastic patterns were evaluated. Jaundice decompression, white blood cell count, and platelet/lymphocyte ratio were significantly different among the groups. The mature group had a better disease-free survival (DFS) prognosis than the other two groups; however, OS did not differ between the groups. Desmoplastic patterns showed significant differences between the three groups for DFS. CONCLUSIONS Desmoplastic patterns are a prognostic factor of DFS for PC, with mature desmoplastic reactions associated with good prognosis. Thus, they may aid in individualized therapeutic approaches in patients with PC.
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Affiliation(s)
- Shuji Suzuki
- Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, Inashikigun, Ibaraki, Japan
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Ryoichi Miyamoto
- Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, Inashikigun, Ibaraki, Japan
| | - Hiroaki Osakabe
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Yoshitaka Kiya
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Hiroshi Yamaguchi
- Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan
| | - Toshitaka Nagao
- Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Tadakazu Ao
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Mitsugi Shimoda
- Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, Inashikigun, Ibaraki, Japan
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10
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Togni L, Furlani M, Belloni A, Riberti N, Giuliani A, Notarstefano V, Santoni C, Giorgini E, Rubini C, Santarelli A, Mascitti M. Biomolecular alterations temporally anticipate microarchitectural modifications of collagen in oral tongue squamous cell carcinoma. iScience 2024; 27:110303. [PMID: 39040062 PMCID: PMC11261445 DOI: 10.1016/j.isci.2024.110303] [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: 11/30/2023] [Revised: 04/03/2024] [Accepted: 06/16/2024] [Indexed: 07/24/2024] Open
Abstract
High resolution analysis of collagen bundles could provide information on tumor onset and evolution. This study was focused on the microarchitecture and biomolecular organization of collagen bundles in oral tongue squamous cell carcinoma (OTSCC). Thirty-five OTSCC biopsy samples were analyzed by synchrotron-based phase-contrast microcomputed tomography and Fourier transform infrared imaging (FTIRI) spectroscopy. PhC-microCT evidenced the presence of reduced and disorganized collagen in the tumor area compared to the extratumoral (ExtraT) one. FTIRI also revealed a reduction of folded secondary structures in the tumor area, and highlighted differences in the peritumoral (PeriT) areas in relation with the OTSCC stage, whereby a significantly lower amount of collagen with less organized fibers was found in the PeriT stroma of advanced-OTSCC stages. Interestingly, no significant morphometrical mismatches were detected in the same region by PhC-microCT analysis. These results suggest that biomolecular alterations in the OTSCC stroma temporally anticipate structural modifications of collagen bundle microarchitecture.
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Affiliation(s)
- Lucrezia Togni
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, via Tronto 10, 60126 Ancona, Italy
| | - Michele Furlani
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, via Tronto 10, 60126 Ancona, Italy
| | - Alessia Belloni
- Department of Life and Environmental Science, Marche Polytechnic University, via Brecce Bianche, Ancona, Italy
| | - Nicole Riberti
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, via dei Vestini 31, 66013 Chieti, Italy
| | - Alessandra Giuliani
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, via Tronto 10, 60126 Ancona, Italy
| | - Valentina Notarstefano
- Department of Life and Environmental Science, Marche Polytechnic University, via Brecce Bianche, Ancona, Italy
| | - Chiara Santoni
- Department of Life and Environmental Science, Marche Polytechnic University, via Brecce Bianche, Ancona, Italy
| | - Elisabetta Giorgini
- Department of Life and Environmental Science, Marche Polytechnic University, via Brecce Bianche, Ancona, Italy
| | - Corrado Rubini
- Department of Biomedical Sciences and Public Health, Marche Polytechnic University, via Tronto 10, Ancona, Italy
| | - Andrea Santarelli
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, via Tronto 10, 60126 Ancona, Italy
- Dentistry Clinic, National Institute of Health and Science of Aging, IRCCS INRCA, via Tronto 10, 60126 Ancona, Italy
| | - Marco Mascitti
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, via Tronto 10, 60126 Ancona, Italy
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11
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Dirheimer L, Pons T, François A, Lamy L, Cortese S, Marchal F, Bezdetnaya L. Targeting of 3D oral cancer spheroids by αVβ6 integrin using near-infrared peptide-conjugated IRDye 680. Cancer Cell Int 2024; 24:228. [PMID: 38951897 PMCID: PMC11218202 DOI: 10.1186/s12935-024-03417-y] [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: 03/21/2024] [Accepted: 06/22/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND In the treatment of oral cavity cancer, margin status is one of the most critical prognostic factors. Positive margins are associated with higher local recurrence and lower survival rates. Therefore, the universal goal of oral surgical oncology is to achieve microscopically clear margins. Near-infrared fluorescence guided surgery (FGS) could improve surgical resection using fluorescent probes. αVβ6 integrin has shown great potential for cancer targeting due to its overexpression in oral cancers. Red fluorescent contrast agent IRDye 680 coupled with anti-αVβ6 peptide (IRDye-A20) represents an asset to improve FGS of oral cancer. This study investigates the potential of IRDye-A20 as a selective imaging agent in 3D three-dimensional tongue cancer cells. METHODS αVβ6 integrin expression was evaluated by RT-qPCR and Western Blotting in 2D HSC-3 human tongue cancer cells and MRC-5 human fibroblasts. Targeting ability of IRDye-A20 was studied in both cell lines by flow cytometry technique. 3D tumor spheroid models, homotypic (HSC-3) and stroma-enriched heterotypic (HSC-3/MRC-5) spheroids were produced by liquid overlay procedure and further characterized using (immuno)histological and fluorescence-based techniques. IRDye-A20 selectivity was evaluated in each type of spheroids and each cell population. RESULTS αVβ6 integrin was overexpressed in 2D HSC-3 cancer cells but not in MRC-5 fibroblasts and consistently, only HSC-3 were labelled with IRDye-A20. Round shaped spheroids with an average diameter of 400 μm were produced with a final ratio of 55%/45% between HSC-3 and MRC-5 cells, respectively. Immunofluorescence experiments demonstrated an uniform expression of αVβ6 integrin in homotypic spheroid, while its expression was restricted to cancer cells only in heterotypic spheroid. In stroma-enriched 3D model, Cytokeratin 19 and E-cadherin were expressed only by cancer cells while vimentin and fibronectin were expressed by fibroblasts. Using flow cytometry, we demonstrated that IRDye-A20 labeled the whole homotypic spheroid, while in the heterotypic model all cancer cells were highly fluorescent, with a negligible fluorescence in fibroblasts. CONCLUSIONS The present study demonstrated an efficient selective targeting of A20FMDV2-conjugated IRDye 680 in 3D tongue cancer cells stroma-enriched spheroids. Thus, IRDye-A20 could be a promising candidate for the future development of the fluorescence-guided surgery of oral cancers.
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Affiliation(s)
- L Dirheimer
- Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique, UMR 7039, Université de Lorraine, Vandoeuvre-lès-Nancy, France
| | - T Pons
- ESPCI Paris, LPEM UMR 8213, PSL University, CNRS, Sorbonne University, Paris, France
| | - A François
- Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique, UMR 7039, Université de Lorraine, Vandoeuvre-lès-Nancy, France
- Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, Vandoeuvre-lès-Nancy, 54519, France
| | - L Lamy
- Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique, UMR 7039, Université de Lorraine, Vandoeuvre-lès-Nancy, France
- Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, Vandoeuvre-lès-Nancy, 54519, France
| | - S Cortese
- Surgical Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, Vandoeuvre-lès-Nancy, 54519, France
| | - F Marchal
- Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique, UMR 7039, Université de Lorraine, Vandoeuvre-lès-Nancy, France
- Surgical Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, Vandoeuvre-lès-Nancy, 54519, France
| | - L Bezdetnaya
- Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique, UMR 7039, Université de Lorraine, Vandoeuvre-lès-Nancy, France.
- Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, Vandoeuvre-lès-Nancy, 54519, France.
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12
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Hendawi NY, Crane HL, Mehanna H, Bolt R, Lambert DW, Hunter KD. Fibroblasts from HPV-negative oropharynx squamous cell carcinomas stimulate the release of osteopontin from cancer cells via the release of IL-6. FRONTIERS IN ORAL HEALTH 2024; 5:1390081. [PMID: 38803348 PMCID: PMC11128591 DOI: 10.3389/froh.2024.1390081] [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: 02/22/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) shows distinct biological and clinical behaviour when compared to HPV-negative OPSCC. The overall role of the tumour microenvironment (TME) in head and neck cancer progression and metastasis has been studied intensively, but differences in HPV-negative and HPV-positive OPSCCs are less understood. Objective To investigate the role of cancer-associated fibroblasts (CAFs) and the functional interactions of normal tonsil fibroblasts (NTFs) and OP CAFs with HPV+ and HPV- OPSCC cells and explore novel candidates in tumour-fibroblast crosstalk. Materials and methods A retrospective cohort of 143 primary OPSCCs was characterised using HPV16/18 RNAScope assay, p16 IHC and ɑ-SMA. Four OPSCC, three NTF and 2 new OPSCC CAF cultures were used to assess the cytokine-based interactions using cytokine arrays on conditioned media (CM), followed by co-culture approaches to identify the role of individual cell types and the role of OPN (SPP1) and IL-6 in SCC/fibroblast communication. Results HPV status was associated with better overall survival. Although ɑ-SMA expression was observed in both OPSCC subtypes, it provided survival stratification only in the HPV-positive group (Log-Rank p = 0.02). Three normal tonsillar fibroblast cultures (NTFs) were characterised by induction of myofibroblastic and senescent phenotypes with similar reactivity to our published NOF phenotype. The OPSCC-derived CAF cultures were characterised and their baseline myofibroblastic and senescence phenotypes varied. Cytokine array analysis of CM to identify novel candidates in the crosstalk between OPSCC tumour cells and NTFs/CAFs identified differences in the cytokine profiles on comparison of HPV+ and HPV- OPSCC cells. Osteopontin (OPN/SPP1) was identified, particularly in HPV-negative OPSCC cell analyses. We have demonstrated that OPN was produced by the OPSCC cells and revealed an associated upregulation of IL-6 in fibroblasts. Treatment of NTFs with rOPN showed alteration in phenotype, including increased contraction and IL-6 production. Antibody-mediated inhibition of CD44v6 attenuated the production of IL-6 by OPN in NTFs. Conclusion This investigation with OPSCC fibroblasts provides novel insights into the role of CAFs in OPSCC mediated by IL-6 stimulated release of OPN from HPV negative OPSCC cells. The details of HPV-positive SCC cell/fibroblast cytokine crosstalk remain elusive.
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Affiliation(s)
- Naeima Yahia Hendawi
- Academic Unit of Oral Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
- Faculty of Dentistry, University of Benghazi, Benghazi, Libya
| | - Hannah L. Crane
- Academic Unit of Oral Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
| | - Hisham Mehanna
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Robert Bolt
- Academic Unit of Oral Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
| | - Daniel W. Lambert
- Academic Unit of Oral Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
| | - Keith D. Hunter
- Academic Unit of Oral Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
- Liverpool Head and Neck Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
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Mukherjee P, Zhou X, Galli S, Davidson B, Zhang L, Ahn J, Aljuhani R, Benicky J, Ailles L, Pomin VH, Olsen M, Goldman R. Aspartate β-Hydroxylase Is Upregulated in Head and Neck Squamous Cell Carcinoma and Regulates Invasiveness in Cancer Cell Models. Int J Mol Sci 2024; 25:4998. [PMID: 38732216 PMCID: PMC11084744 DOI: 10.3390/ijms25094998] [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: 04/11/2024] [Revised: 04/23/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Aspartate β-hydroxylase (ASPH) is a protein associated with malignancy in a wide range of tumors. We hypothesize that inhibition of ASPH activity could have anti-tumor properties in patients with head and neck cancer. In this study, we screened tumor tissues of 155 head and neck squamous cell carcinoma (HNSCC) patients for the expression of ASPH using immunohistochemistry. We used an ASPH inhibitor, MO-I-1151, known to inhibit the catalytic activity of ASPH in the endoplasmic reticulum, to show its inhibitory effect on the migration of SCC35 head and neck cancer cells in cell monolayers and in matrix-embedded spheroid co-cultures with primary cancer-associated fibroblast (CAF) CAF 61137 of head and neck origin. We also studied a combined effect of MO-I-1151 and HfFucCS, an inhibitor of invasion-blocking heparan 6-O-endosulfatase activity. We found ASPH was upregulated in HNSCC tumors compared to the adjacent normal tissues. ASPH was uniformly high in expression, irrespective of tumor stage. High expression of ASPH in tumors led us to consider it as a therapeutic target in cell line models. ASPH inhibitor MO-I-1151 had significant effects on reducing migration and invasion of head and neck cancer cells, both in monolayers and matrix-embedded spheroids. The combination of the two enzyme inhibitors showed an additive effect on restricting invasion in the HNSCC cell monolayers and in the CAF-containing co-culture spheroids. We identify ASPH as an abundant protein in HNSCC tumors. Targeting ASPH with inhibitor MO-I-1151 effectively reduces CAF-mediated cellular invasion in cancer cell models. We propose that the additive effect of MO-I-1151 with HfFucCS, an inhibitor of heparan 6-O-endosulfatases, on HNSCC cells could improve interventions and needs to be further explored.
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Affiliation(s)
- Pritha Mukherjee
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
| | - Xin Zhou
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
- Biotechnology Program, Northern Virginia Community College, Manassas, VA 20109, USA
| | - Susana Galli
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057, USA
| | - Bruce Davidson
- Department of Otolaryngology-Head and Neck Surgery, MedStar Georgetown University Hospital, Washington, DC 20057, USA
| | - Lihua Zhang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC 20057, USA
| | - Reem Aljuhani
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057, USA
| | - Julius Benicky
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
| | - Laurie Ailles
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Vitor H. Pomin
- Department of BioMolecular Sciences, University of Mississippi, Oxford, MS 38677, USA;
- Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Mark Olsen
- Department of Pharmaceutical Sciences, College of Pharmacy Glendale Campus, Midwestern University, Glendale, AZ 85308, USA
- Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, IL 60515, USA
| | - Radoslav Goldman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057, USA
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Zhao D, Wu T, Tan Z, Xu J, Lu Z. Role of non-coding RNAs mediated pyroptosis on cancer therapy: a review. Expert Rev Anticancer Ther 2024; 24:239-251. [PMID: 38594965 DOI: 10.1080/14737140.2024.2341737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 04/08/2024] [Indexed: 04/11/2024]
Abstract
INTRODUCTION Non-coding RNAs (ncRNAs), which are incapable of encoding proteins, are involved in the progression of numerous tumors by altering transcriptional and post-transcriptional processing. Recent studies have revealed prominent features of ncRNAs in pyroptosis, a type of non-apoptotic programmed cellular destruction linked to an inflammatory reaction. Drug resistance has arisen gradually as a result of anti-apoptotic proteins, therefore strategies based on pyroptotic cell death have attracted increasing attention. We have observed that ncRNAs may exert significant influence on cancer therapy, chemotherapy, radio- therapy, targeted therapy and immunotherapy, by regulating pyroptosis. AREAS COVERED Literatures were searched (December 2023) for studies on cancer therapy for ncRNAs-mediated pyroptotic cell death. EXPERT OPINION The most universal mechanical strategy for ncRNAs to regulate target genes is competitive endogenous RNAs (ceRNA). Besides, certain ncRNAs could directly interact with proteins and modulate downstream genes to induce pyroptosis, resulting in tumor growth or inhibition. In this review, we aim to display that ncRNAs, predominantly long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), could function as potential biomarkers for diagnosis and prognosis and produce new insights into anti-cancer strategies modulated by pyroptosis for clinical applications.
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Affiliation(s)
- Dan Zhao
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tangwei Wu
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheqiong Tan
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Xu
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhongxin Lu
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Cancer Research Institute of Wuhan, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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15
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Jank BJ, Schnoell J, Kladnik K, Sparr C, Haas M, Gurnhofer E, Lein AL, Brunner M, Kenner L, Kadletz-Wanke L, Heiduschka G. Targeting TGF beta receptor 1 in head and neck squamous cell carcinoma. Oral Dis 2024; 30:1114-1127. [PMID: 37154295 DOI: 10.1111/odi.14594] [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: 01/16/2023] [Revised: 03/17/2023] [Accepted: 04/13/2023] [Indexed: 05/10/2023]
Abstract
OBJECTIVES The transforming growth factor-Beta (TGF-ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF-ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro. MATERIALS AND METHODS TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient-derived cancer-associated fibroblasts was applied to mimic the tumor microenvironment. RESULTS Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1+ tumor and OS was observed for the subgroup with TGFBR1-stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects. CONCLUSION Our results indicate a high risk of death in tumorTGFBR1+|stromaTGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.
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Affiliation(s)
- Bernhard J Jank
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Julia Schnoell
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Katharina Kladnik
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Carmen Sparr
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Markus Haas
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Gurnhofer
- Department of Experimental Pathology and Laboratory Animal Pathology Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Alexander L Lein
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Markus Brunner
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Department of Experimental Pathology and Laboratory Animal Pathology Department of Pathology, Medical University of Vienna, Vienna, Austria
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria
- Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria
- CBmed GmbH - Center for Biomarker Research in Medicine, Graz, Austria
| | - Lorenz Kadletz-Wanke
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Heiduschka
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
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Shoaee S, Masinaei M, Saeedi Moghaddam S, Sofi-Mahmudi A, Hessari H, Shamsoddin E, Heydari MH, Larijani B, Fakhrzadeh H, Farzadfar F. National and Subnational Trend of Dental Caries of Permanent Teeth in Iran, 1990-2017. Int Dent J 2024; 74:129-137. [PMID: 37574408 PMCID: PMC10829359 DOI: 10.1016/j.identj.2023.07.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/14/2023] [Accepted: 07/22/2023] [Indexed: 08/15/2023] Open
Abstract
OBJECTIVE There are currently no integrated data on the trend of dental caries amongst distinct age groups in Iran. We aimed to assess the national and subnational trend of dental caries of permanent teeth in Iran from 1990 to 2017. METHODS A literature search about dental caries and the decayed-missing-filled teeth index (DMFT) was performed in PubMed, Web of Science, Scopus, and 3 national databases (in Persian). All eligible national oral health surveys in these 28 years were included. We categorised and aggregated the DMFT values and their components based on age (5-year-based groups from 5 to 9 to 60+ years), sex, year, and province. The data for missing spots were estimated using the spatiotemporal Bayesian hierarchical model. We used the bootstrap method in multilevel models to predict the uncertainty interval (UI) of the modelled results. RESULTS Nationally, the all-ages mean DMFT increased by nearly 58.0% (6.8 [95% UI, 4.1-10.5] in 1990 to 10.8 [95% UI, 7.5-14.5] in 2017). Decayed teeth (DT) and missing teeth (MT) rose by 84.5% and 31.6% during this period, respectively. Filled teeth (FT) showed almost a 2.6-fold increase in the same period from 0.6 (95% UI, 0.01-1.6) in 1990 to 1.7 (95% UI, 0.6-2.8) in 2017. The proportion of DT and FT continuously increased in both sexes. In 2017, the highest DT, MT, and FT were estimated in the 25-29 (4.9 [95% UI, 2.5-7.2]), 60+ (21.5 [95% UI, 17.5-25.4]), and 35-39 (2.6 [95% UI, 1.3-4.0]) year age groups. CONCLUSIONS Caries of permanent dentition levies a growing burden on the Iranian population. Considering the continuous increase in caries during the 1990-2017 period, Iranian policymakers should pay heed to these findings and react more proactively to mitigate this perpetuating issue. Implementing nationwide interventions such as sugar consumption management should be encouraged to achieve sustainable outcomes in this regards.
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Affiliation(s)
- Shervan Shoaee
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Kerman Oral and Dental Diseases Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Masoud Masinaei
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sahar Saeedi Moghaddam
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Sofi-Mahmudi
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Cochrane Iran Associate Centre, National Institute for Medical Research Development (NIMAD), Tehran, Iran
| | - Hossein Hessari
- Research Center for Caries Prevention, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Shamsoddin
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Cochrane Iran Associate Centre, National Institute for Medical Research Development (NIMAD), Tehran, Iran
| | - Mohammad-Hossein Heydari
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Fakhrzadeh
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshad Farzadfar
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Arebro J, Lee CM, Bennewith KL, Garnis C. Cancer-Associated Fibroblast Heterogeneity in Malignancy with Focus on Oral Squamous Cell Carcinoma. Int J Mol Sci 2024; 25:1300. [PMID: 38279300 PMCID: PMC10816981 DOI: 10.3390/ijms25021300] [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: 12/01/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 01/28/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) remains an understudied and significant global cancer killer and dismal survival rates have not changed in decades. A better understanding of the molecular basis of OSCC progression and metastasis is needed to develop new approaches for treating this disease. The supportive network surrounding cancer tumor cells known as the tumor microenvironment (TME) has gained increasing interest lately since it performs essential protumorigenic functions. Cancer-associated fibroblasts (CAFs) are one of the main cell types in the TME and are known to play a key role in influencing the biological behavior of tumors. CAFs present a heterogeneity both in phenotype as well as functions, leading to the suggestion of different CAF subtypes in several cancer forms. The task to subtype CAFs in OSCC has, however, just begun, and there is today no united way of subtyping CAFs in this disease. This review aims to define the features of CAFs and to summarize CAF subtype research in malignancy with focus on OSCC including aspects as disease prognosis and therapeutic opportunities.
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Affiliation(s)
- Julia Arebro
- Department of Interdisciplinary Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (C.-M.L.); (K.L.B.); (C.G.)
- Division of ENT Diseases, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14186 Stockholm, Sweden
- Department of ENT Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden
| | - Che-Min Lee
- Department of Interdisciplinary Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (C.-M.L.); (K.L.B.); (C.G.)
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
| | - Kevin L. Bennewith
- Department of Interdisciplinary Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (C.-M.L.); (K.L.B.); (C.G.)
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
- Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada
| | - Cathie Garnis
- Department of Interdisciplinary Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (C.-M.L.); (K.L.B.); (C.G.)
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
- Division of Otolaryngology, Department of Surgery, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
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18
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Ibrahim MMA. Role of myofibroblasts in oral plasma cell granuloma: Immunohistochemical evaluation of α-SMA and ALK in a retrospective study of 30 cases. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2023; 124:101595. [PMID: 37573967 DOI: 10.1016/j.jormas.2023.101595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION Oral plasma cell granuloma (OPCG) is a rare reactive lesion with generally benign yet occasionally aggressive behavior. Myofibroblasts are important in many physiologic, and pathologic conditions. The role of myofibroblasts in the clinical behavior of OPCG was assessed as well as its usefulness in differentiating this lesion from the inflammatory myofibroblastic tumor mimicking plasma cell granuloma. MATERIAL AND METHODS This retrospective study included 30 paraffin blocks of OPCG. Immunohistochemical evaluation of alpha-smooth muscle actin (α-SMA) and Anaplastic lymphoma kinase (ALK) antibodies was performed. The mean area of positive expression was calculated and scored semiquantitatively with clinicopathologic correlations. RESULTS Most of the cases were clinically non-aggressive. Alveolar bone resorption was observed in nine cases, two of them showed severe resorption and stromal fibrosis. Negative α-SMA was observed in 70% of cases showing a predominance of plasma cells in the stroma. All cases of stromal fibrosis revealed positive α-SMA of a weak percentage. A statistically significant difference was observed between α-SMA expression and the clinicopathologic variables. Negative ALK expression was noted in all cases. DISCUSSION Myofibroblasts were infrequently found in OPCG. Remarkably, the aggressive behavior in cases with intense fibrosis was related to the existence of myofibroblasts even of non-neoplastic nature and minimal amount. The number of myofibroblasts and their nature assessed via α-SMA and ALK immunohistochemical expression respectively might be valuable in predicting the biological behavior of OPCG and may hold diagnostic significance in challenging OPCG cases that might mimic inflammatory myofibroblastic tumor.
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19
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Elahi F, Spuck N, Berger M, Kramer FJ, Heim N. Mathematical approach improves predictability of length of hospitalisation due to oral squamous cell carcinoma: a retrospective investigation of 153 patients. Br J Oral Maxillofac Surg 2023; 61:605-611. [PMID: 37852819 DOI: 10.1016/j.bjoms.2023.09.004] [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: 04/13/2023] [Revised: 07/06/2023] [Accepted: 09/18/2023] [Indexed: 10/20/2023]
Abstract
Oral squamous cell carcinoma (OSCC), a common cancer of the head and neck, is a major public health problem. The length of stay in hospital (LOS) of patients with OSCC, which can range from a few days to several months, has implications for the patient's recovery. The aim of the study was to identify and evaluate risk factors that have an impact on the prolongation of inpatient hospital stay. A four-year retrospective study reviewed hospital records of 153 inpatients with OSCC. A statistical model for discrete time-to-event data, with the LOS in hospital measured in days for which the event of interest was discharge from hospital, was applied. The model utilises a tree-building algorithm to identify relevant risk factors for a prolonged LOS. Age, type of flap, and occurrence of complications turned out to be relevant variables. Before, and on day 12, the LOS was mainly dependent on flap type and age, whereas after day 12 it was influenced by the presence of early complications. Predicting the likelihood of discharge can improve the management and resource utilisation of the healthcare system among inpatients.
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Affiliation(s)
- Franziska Elahi
- Department of Oral and Cranio-Maxillo and Facial Plastic Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
| | - Nikolai Spuck
- Institute of Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
| | - Moritz Berger
- Institute of Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
| | - Franz-Josef Kramer
- Department of Oral and Cranio-Maxillo and Facial Plastic Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
| | - Nils Heim
- Department of Oral and Cranio-Maxillo and Facial Plastic Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
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20
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Hoshimaru T, Nonoguchi N, Kosaka T, Furuse M, Kawabata S, Yagi R, Kurisu Y, Kashiwagi H, Kameda M, Takami T, Kataoka-Sasaki Y, Sasaki M, Honmou O, Hiramatsu R, Wanibuchi M. Actin Alpha 2, Smooth Muscle (ACTA2) Is Involved in the Migratory Potential of Malignant Gliomas, and Its Increased Expression at Recurrence Is a Significant Adverse Prognostic Factor. Brain Sci 2023; 13:1477. [PMID: 37891844 PMCID: PMC10605410 DOI: 10.3390/brainsci13101477] [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: 09/27/2023] [Revised: 10/17/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Malignant glioma is a highly invasive tumor, and elucidating the glioma invasion mechanism is essential for developing novel therapies. We aimed to highlight actin alpha 2, smooth muscle (ACTA2) as potential biomarkers of brain invasion and distant recurrence in malignant gliomas. Using the human malignant glioma cell line, U251MG, we generated ACTA2 knockdown (KD) cells treated with small interfering RNA, and the cell motility and proliferation of the ACTA2 KD group were analyzed. Furthermore, tumor samples from 12 glioma patients who underwent reoperation at the time of tumor recurrence were utilized to measure ACTA2 expression in the tumors before and after recurrence. Thereafter, we examined how ACTA2 expression correlates with the time to tumor recurrence and the mode of recurrence. The results showed that the ACTA2 KD group demonstrated a decline in the mean motion distance and proliferative capacity compared to the control group. In the clinical glioma samples, ACTA2 expression was remarkably increased in recurrent samples compared to the primary samples from the same patients, and the higher the change in ACTCA2 expression from the start to relapse, the shorter the progression-free survival. In conclusion, ACTA2 may be involved in distant recurrence in clinical gliomas.
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Affiliation(s)
- Takumi Hoshimaru
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Naosuke Nonoguchi
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Takuya Kosaka
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Motomasa Furuse
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Shinji Kawabata
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Ryokichi Yagi
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Yoshitaka Kurisu
- Department of Pathology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Hideki Kashiwagi
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Masahiro Kameda
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Toshihiro Takami
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Yuko Kataoka-Sasaki
- Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Hokkaido 060-8556, Japan
| | - Masanori Sasaki
- Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Hokkaido 060-8556, Japan
| | - Osamu Honmou
- Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Hokkaido 060-8556, Japan
| | - Ryo Hiramatsu
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
| | - Masahiko Wanibuchi
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan
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21
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Niklander SE, Aránguiz P, Faunes F, Martínez-Flores R. Aging and oral squamous cell carcinoma development: the role of cellular senescence. FRONTIERS IN ORAL HEALTH 2023; 4:1285276. [PMID: 37904749 PMCID: PMC10613501 DOI: 10.3389/froh.2023.1285276] [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: 08/29/2023] [Accepted: 09/29/2023] [Indexed: 11/01/2023] Open
Abstract
The gradual accumulation and inadequate renewal of senescent cells over time drive organismal aging. Senescent cells undergo altered gene expression and release inflammatory mediators collectively termed the senescence-associated secretory phenotype (SASP), which significantly contributes to a spectrum of age-related disorders, including cancer. In the context of carcinogenesis, the SASP produced by senescent cells has been implicated in the promotion of epithelial cancers, including oral squamous cell carcinoma (OSCC), the most common form of oral cancer. Senescent cells within the tumor microenvironment release factors that amplify the growth and invasiveness of neighboring cancer cells. Senotherapeutics, including senolytics and senomorphics, emerge as promising modalities to target senescent cells and their associated inflammatory factors, thereby opening novel avenues for augmenting the efficacy of cancer treatments. Here, we review the general aspects of cellular senescence, focusing on the relation between senescence-related inflammation with cancer development. We also analyze the available evidence linking cellular senescence with OSCC, highlighting possible clinical applications.
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Affiliation(s)
- Sven Eric Niklander
- Unit of Oral Pathology and Oral Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar, Chile
| | - Pablo Aránguiz
- Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Viña del Mar, Chile
| | - Fernando Faunes
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Viña del Mar, Chile
| | - René Martínez-Flores
- Unit of Oral Pathology and Oral Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar, Chile
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22
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Miyamoto S, Hirohashi Y, Morita R, Miyazaki A, Ogi K, Kanaseki T, Ide K, Shirakawa J, Tsukahara T, Murai A, Sasaya T, Koike K, Kina S, Kawano T, Goto T, Ntege EH, Shimizu Y, Torigoe T. Exploring olfactory receptor family 7 subfamily C member 1 as a novel oral cancer stem cell target for immunotherapy. Cancer Sci 2023; 114:3496-3508. [PMID: 37344992 PMCID: PMC10475777 DOI: 10.1111/cas.15873] [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: 01/19/2023] [Revised: 05/10/2023] [Accepted: 05/14/2023] [Indexed: 06/23/2023] Open
Abstract
The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self-renewal and multi-differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen-specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC-2 and HSC-3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G-protein-coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell-targeted immunotherapy, in CSC-targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen-A24-restricted OR7C1 oral CSC-specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC-targeted immunotherapy in oral cancer.
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Affiliation(s)
- Sho Miyamoto
- Department of Oral SurgerySapporo Medical University School of MedicineSapporoJapan
| | - Yoshihiko Hirohashi
- Department of PathologySapporo Medical University School of MedicineSapporoJapan
| | - Rena Morita
- Division of Fundamental Health Sciences, School of Nursing and Social ServicesHealth Sciences University of HokkaidoTobetsu‐ChoJapan
| | - Akihiro Miyazaki
- Department of Oral SurgerySapporo Medical University School of MedicineSapporoJapan
| | - Kazuhiro Ogi
- Department of Oral SurgerySapporo Medical University School of MedicineSapporoJapan
| | - Takayuki Kanaseki
- Department of PathologySapporo Medical University School of MedicineSapporoJapan
| | - Kentaro Ide
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
| | - Jumpei Shirakawa
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
| | - Tomohide Tsukahara
- Department of PathologySapporo Medical University School of MedicineSapporoJapan
| | - Aiko Murai
- Department of PathologySapporo Medical University School of MedicineSapporoJapan
| | - Takashi Sasaya
- Department of Oral SurgerySapporo Medical University School of MedicineSapporoJapan
- Department of PathologySapporo Medical University School of MedicineSapporoJapan
| | - Kazushige Koike
- Department of Oral SurgerySapporo Medical University School of MedicineSapporoJapan
| | - Shinichiro Kina
- Center for Medical EducationGunma University Graduate School of MedicineMaebashiJapan
| | - Toshihiro Kawano
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
| | - Takahiro Goto
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
| | - Edward Hosea Ntege
- Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
- Department of Plastic and Reconstructive Surgery, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
| | - Yusuke Shimizu
- Department of Plastic and Reconstructive Surgery, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
| | - Toshihiko Torigoe
- Department of PathologySapporo Medical University School of MedicineSapporoJapan
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23
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Budi HS, Farhood B. Targeting oral tumor microenvironment for effective therapy. Cancer Cell Int 2023; 23:101. [PMID: 37221555 DOI: 10.1186/s12935-023-02943-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/11/2023] [Indexed: 05/25/2023] Open
Abstract
Oral cancers are among the common head and neck malignancies. Different anticancer therapy modalities such as chemotherapy, immunotherapy, radiation therapy, and also targeted molecular therapy may be prescribed for targeting oral malignancies. Traditionally, it has been assumed that targeting malignant cells alone by anticancer modalities such as chemotherapy and radiotherapy suppresses tumor growth. In the last decade, a large number of experiments have confirmed the pivotal role of other cells and secreted molecules in the tumor microenvironment (TME) on tumor progression. Extracellular matrix and immunosuppressive cells such as tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs) play key roles in the progression of tumors like oral cancers and resistance to therapy. On the other hand, infiltrated CD4 + and CD8 + T lymphocytes, and natural killer (NK) cells are key anti-tumor cells that suppress the proliferation of malignant cells. Modulation of extracellular matrix and immunosuppressive cells, and also stimulation of anticancer immunity have been suggested to treat oral malignancies more effectively. Furthermore, the administration of some adjuvants or combination therapy modalities may suppress oral malignancies more effectively. In this review, we discuss various interactions between oral cancer cells and TME. Furthermore, we also review the basic mechanisms within oral TME that may cause resistance to therapy. Potential targets and approaches for overcoming the resistance of oral cancers to various anticancer modalities will also be reviewed. The findings for targeting cells and potential therapeutic targets in clinical studies will also be reviewed.
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Affiliation(s)
- Hendrik Setia Budi
- Department of Oral Biology, Dental Pharmacology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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24
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Gandhi V, Mahajan A, Kansal YP. An Immunohistochemical Analysis for Evaluating the Diagnostic Role of Myofibroblasts in Oral Squamous Cell Carcinoma using α-Smooth Muscle Actin Antibody. Adv Biomed Res 2023; 12:123. [PMID: 37434928 PMCID: PMC10331533 DOI: 10.4103/abr.abr_160_21] [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: 06/10/2021] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 07/13/2023] Open
Abstract
Background One of the most common types of malignancies affecting the head and neck region is oral squamous cell carcinoma (OSCC). Little less is known about the role of myofibroblasts in the pathogenetic process of OSCC. Hence, we assessed the involvement of myofibroblasts in the invasive process of OSCC using α-SMA (α-smooth muscle actin) antibody. Materials and Methods Four study groups in total were organized as follows: 40 cases each of well-differentiated OSCC (WDOSCC), moderately differentiated OSCC (MDOSCC), poorly differentiated OSCC (PDOSCC), and controls make up Group 1, Group 2, Group 3, and Group 4, respectively. The percentage of α-SMA immunopositive cells and staining intensity (A) multiplied together to determine the final staining score (B). The final staining index was produced by multiplying staining intensity (A) by the proportion of immunopositive cells that were stained with α-SMA (B) (FSI). Score Zero was graded as Index Zero by FSI while scores One and Two received an Index Low rating, scores Three and Four an Index Moderate rating, and scores Six and Nine an Index High rating. Results Significantly higher expression of myofibroblast was observed in OSCC group in comparison with the control group. However; no significant difference in myofibroblast expression was observed while comparing different grades of OSCC. Conclusion We recommend using myofibroblasts as a stromal marker to track the severity and development of OSCC.
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Affiliation(s)
- Vaishali Gandhi
- Department of Human Anatomy, SGRD University of Health Sciences, Amritsar, Punjab, India
| | - Anupama Mahajan
- Department of Human Anatomy, SGRD Medical College and Hospital, Amritsar, Punjab, India
| | - Yash Pal Kansal
- Department of General Pathology, Dasmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India
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25
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Prieto-Fernández L, Montoro-Jiménez I, de Luxan-Delgado B, Otero-Rosales M, Rodrigo JP, Calvo F, García-Pedrero JM, Álvarez-Teijeiro S. Dissecting the functions of cancer-associated fibroblasts to therapeutically target head and neck cancer microenvironment. Biomed Pharmacother 2023; 161:114502. [PMID: 37002578 DOI: 10.1016/j.biopha.2023.114502] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/22/2023] [Accepted: 03/07/2023] [Indexed: 03/15/2023] Open
Abstract
Head and neck cancers (HNC) are a diverse group of aggressive malignancies with high morbidity and mortality, leading to almost half-million deaths annually worldwide. A better understanding of the molecular processes governing tumor formation and progression is crucial to improve current diagnostic and prognostic tools as well as to develop more personalized treatment strategies. Tumors are highly complex and heterogeneous structures in which growth and dissemination is not only governed by the cancer cells intrinsic mechanisms, but also by the surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) emerge as predominant TME components and key players in the generation of permissive conditions that ultimately impact in tumor progression and metastatic dissemination. Although CAFs were initially considered a consequence of tumor development, it is now well established that they actively contribute to numerous cancer hallmarks i.e., tumor cell growth, migration and invasion, cancer cell stemness, angiogenesis, metabolic reprograming, inflammation, and immune system modulation. In this scenario, therapeutic strategies targeting CAF functions could potentially have a major impact in cancer therapeutics, providing avenues for new treatment options or for improving efficacy in established approaches. This review is focused on thoroughly dissecting existing evidences supporting the contribution of CAFs in HNC biology with an emphasis on current knowledge of the key molecules and pathways involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effectively interfere the tumor-stroma crosstalk for HNC patients benefit. involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effec- tively interfere the tumor-stroma crosstalk for HNC patients benefit.
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Affiliation(s)
- Llara Prieto-Fernández
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Irene Montoro-Jiménez
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz de Luxan-Delgado
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
| | - María Otero-Rosales
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain
| | - Juan P Rodrigo
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Fernando Calvo
- Instituto de Biomedicina y Biotecnología de Cantabria (Consejo Superior de Investigaciones Científicas, Universidad de Cantabria), Santander, Spain
| | - Juana M García-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
| | - Saúl Álvarez-Teijeiro
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
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26
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Hu C, Zhang Y, Wu C, Huang Q. Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma: opportunities and challenges. Cell Death Discov 2023; 9:124. [PMID: 37055382 PMCID: PMC10102018 DOI: 10.1038/s41420-023-01428-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/25/2023] [Accepted: 04/03/2023] [Indexed: 04/15/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the most severe and complex malignant diseases with a high level of heterogeneity and, as a result, a wide range of therapeutic responses, regardless of clinical stage. Tumor progression depends on ongoing co-evolution and cross-talk with the tumor microenvironment (TME). In particular, cancer-associated fibroblasts (CAFs), embedded in the extracellular matrix (ECM), induce tumor growth and survival by interacting with tumor cells. Origin of CAFs is quite varied, and the activation patterns of CAFs are also heterogeneous. Crucially, the heterogeneity of CAFs appears to play a key role in ongoing tumor expansion, including facilitating proliferation, enhancing angiogenesis and invasion, and promoting therapy resistance, through the production of cytokines, chemokines, and other tumor-promotive molecules in the TME. This review describes the various origin and heterogeneous activation mechanisms of CAFs, and biological heterogeneity of CAFs in HNSCC is also included. Moreover, we have highlighted versatility of CAFs heterogeneity in HNSCC progression, and have discussed different tumor-promotive functions of CAFs respectively. In the future, it is a promising strategy for the therapy of HNSCC that specifically targeting tumor-promoting CAF subsets or the tumor-promoting functional targets of CAFs.
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Affiliation(s)
- Chen Hu
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, 100730, Beijing, China
| | - Yifan Zhang
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China
| | - Chunping Wu
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China.
| | - Qiang Huang
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China.
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Ye M, Huang X, Wu Q, Liu F. Senescent Stromal Cells in the Tumor Microenvironment: Victims or Accomplices? Cancers (Basel) 2023; 15:cancers15071927. [PMID: 37046588 PMCID: PMC10093305 DOI: 10.3390/cancers15071927] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/11/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Cellular senescence is a unique cellular state. Senescent cells enter a non-proliferative phase, and the cell cycle is arrested. However, senescence is essentially an active cellular phenotype, with senescent cells affecting themselves and neighboring cells via autocrine and paracrine patterns. A growing body of research suggests that the dysregulation of senescent stromal cells in the microenvironment is tightly associated with the development of a variety of complex cancers. The role of senescent stromal cells in impacting the cancer cell and tumor microenvironment has also attracted the attention of researchers. In this review, we summarize the generation of senescent stromal cells in the tumor microenvironment and their specific biological functions. By concluding the signaling pathways and regulatory mechanisms by which senescent stromal cells promote tumor progression, distant metastasis, immune infiltration, and therapy resistance, this paper suggests that senescent stromal cells may serve as potential targets for drug therapy, thus providing new clues for future related research.
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Affiliation(s)
- Minghan Ye
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu 610065, China
| | - Xinyi Huang
- 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 250100, China
| | - Qianju Wu
- Stomatological Hospital of Xiamen Medical College, Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment, Xiamen 361008, China
- Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Fei Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu 610065, China
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28
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Prieto-Fernandez L, Villaronga MDLA, Hermida-Prado F, Hijazi M, Montoro-Jimenez I, Pevida M, Llames S, Rodrigo JP, Cutillas P, Calvo F, Garcia-Pedrero JM, Alvarez-Teijeiro S. Driving role of head and neck cancer cell secretome on the invasion of stromal fibroblasts: Mechanistic insights by phosphoproteomics. Biomed Pharmacother 2023; 158:114176. [PMID: 36916400 DOI: 10.1016/j.biopha.2022.114176] [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: 10/26/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) are major players in tumor-stroma communication, and participate in several cancer hallmarks to drive tumor progression and metastatic dissemination. This study investigates the driving effects of tumor-secreted factors on CAF biology, with the ultimate goal of identifying effective therapeutic targets/strategies for head and neck squamous cell carcinomas (HNSCC). METHODS Functionally, conditioned media (CM) from different HNSCC-derived cell lines and normal keratinocytes (Kc) were tested on the growth and invasion of populations of primary CAFs and normal fibroblasts (NFs) using 3D invasion assays in collagen matrices. The changes in MMPs expression were evaluated by RT-qPCR and kinase enrichment was analyzed using mass spectrometry phosphoproteomics. RESULTS Our results consistently demonstrate that HNSCC-secreted factors (but not Kc CM) specifically and robustly promoted pro-invasive properties in both CAFs and NFs, thereby reflecting the plasticity of fibroblast subtypes. Concomitantly, HNSCC-secreted factors massively increased metalloproteinases levels in CAFs and NFs. By contrast, HNSCC CM and Kc CM exhibited comparable growth-promoting effects on stromal fibroblasts. Mechanistically, phosphoproteomic analysis predominantly revealed phosphorylation changes in fibroblasts upon treatment with HNSCC CM, and various promising kinases were identified: MKK7, MKK4, ASK1, RAF1, BRAF, ARAF, COT, PDK1, RSK2 and AKT1. Interestingly, pharmacologic inhibition of RAF1/BRAF using sorafenib emerged as the most effective drug to block tumor-promoted fibroblast invasion without affecting fibroblast viability CONCLUSIONS: Our findings demonstrate that HNSCC-secreted factors specifically fine tune the invasive potential of stromal fibroblasts, thereby generating tumor-driven pro-invasive niches, which in turn to ultimately facilitate cancer cell dissemination. Furthermore, the RAF/BRAF inhibitor sorafenib was identified as a promising candidate to effectively target the onset of pro-invasive clusters of stromal fibroblasts in the HNSCC microenvironment.
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Affiliation(s)
- Llara Prieto-Fernandez
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Maria de Los Angeles Villaronga
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Hermida-Prado
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Maruan Hijazi
- Cell Signalling & Proteomics Group, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
| | - Irene Montoro-Jimenez
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Pevida
- Tissue engineering unit, Centro Comunitario Sangre y Tejidos de Asturias (CCST), Oviedo, Spain; Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, Oviedo, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) ISCIII, Madrid, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Sara Llames
- Tissue engineering unit, Centro Comunitario Sangre y Tejidos de Asturias (CCST), Oviedo, Spain; Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, University of Oviedo, Oviedo, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) ISCIII, Madrid, Spain; Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Juan Pablo Rodrigo
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro Cutillas
- Cell Signalling & Proteomics Group, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
| | - Fernando Calvo
- Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom; Instituto de Biomedicina y Biotecnología de Cantabria (Consejo Superior de Investigaciones Científicas, Universidad de Cantabria), Santander, Spain
| | - Juana Maria Garcia-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
| | - Saul Alvarez-Teijeiro
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
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The Role of Extracellular Vesicles in Diseases of the Ear, Nose, and Throat. Med Sci (Basel) 2022; 11:medsci11010006. [PMID: 36649043 PMCID: PMC9844415 DOI: 10.3390/medsci11010006] [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: 11/23/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Extracellular vesicles (EVs) are membranous nanoparticles produced by most cell types into the extracellular space and play an important role in cell-to-cell communication. Historically, EVs were categorized based on their methods of biogenesis and size into three groups: exosomes, microvesicles, and apoptotic bodies. Most recently, EV nomenclature has evolved to categorize these nanoparticles based on their size, surface markers, and/or the cell type which secreted them. Many techniques have been adopted in recent years which leverage these characteristics to isolate them from cell culture media and biological fluids. EVs carry various "cargo", including DNA, RNA, proteins, and small signaling molecules. After isolation, EVs can be characterized by various methods to analyze their unique cargo profiles which define their role in cell-to-cell communication, normal physiology, and disease progression. The study of EV cargo has become more common recently as we continue to delineate their role in various human diseases. Further understanding these mechanisms may allow for the future use of EVs as novel biomarkers and therapeutic targets in diseases. Furthermore, their unique cargo delivery mechanisms may one day be exploited to selectively deliver therapeutic agents and drugs. Despite the growing research interest in EVs, limited studies have focused on the role of EVs in the diseases of the ear, nose, and throat. In this review, we will introduce EVs and their cargo, discuss methods of isolation and characterization, and summarize the most up-to-date literature thus far into the role of EVs in diseases of the ear, nose, and throat.
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Mellone M, Piotrowska K, Venturi G, James L, Bzura A, Lopez MA, James S, Wang C, Ellis MJ, Hanley CJ, Buckingham JF, Cox KL, Hughes G, Valge-Archer V, King EV, Beers SA, Jaquet V, Jones GD, Savelyeva N, Sayan E, Parsons JL, Durant S, Thomas GJ. ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance. Cancer Res 2022; 82:4571-4585. [PMID: 36353752 PMCID: PMC9755965 DOI: 10.1158/0008-5472.can-22-0435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 07/28/2022] [Accepted: 09/21/2022] [Indexed: 11/11/2022]
Abstract
Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance. SIGNIFICANCE ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors.
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Affiliation(s)
- Massimiliano Mellone
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Klaudia Piotrowska
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Giulia Venturi
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Lija James
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Aleksandra Bzura
- Department of Genetics and Genome Biology, Cancer Research Centre, University of Leicester, Leicester, United Kingdom
| | - Maria A. Lopez
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Sonya James
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Chuan Wang
- Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool, United Kingdom
| | - Matthew J. Ellis
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Christopher J. Hanley
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Josephine F. Buckingham
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Kerry L. Cox
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Gareth Hughes
- Bioscience, Oncology Innovative Medicines and Early Development (IMED) Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Viia Valge-Archer
- Bioscience, Oncology Innovative Medicines and Early Development (IMED) Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Emma V. King
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Stephen A. Beers
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Vincent Jaquet
- Department of Pathology and Immunology, Centre Médical Universitaire, Genève, Switzerland
| | - George D.D. Jones
- Department of Genetics and Genome Biology, Cancer Research Centre, University of Leicester, Leicester, United Kingdom
| | - Natalia Savelyeva
- Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool, United Kingdom
| | - Emre Sayan
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Jason L. Parsons
- Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool, United Kingdom
| | - Stephen Durant
- Bioscience, Oncology Innovative Medicines and Early Development (IMED) Biotech Unit, AstraZeneca, Cambridge, United Kingdom
| | - Gareth J. Thomas
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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Gadbail AR, Sarode SC, Chaudhary MS, Gondivkar SM, Tekade SA, Yuwanati M, Sarode GS, Hande A, Patil S. Ki-67, CD105, and α-smooth muscle actin expression in oral squamous cell carcinoma corresponds with different forms of tobacco consumption habits. J Cancer Res Ther 2022; 18:S197-S204. [PMID: 36510964 DOI: 10.4103/jcrt.jcrt_1307_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Association with variety of etiological agents is one of the characteristic features of oral squamous cell carcinoma (OSCC). We hypothesized the existence of tobacco consumption habit-based heterogeneity in the immunohistochemical expression of carcinogenesis relevant molecular markers in OSCC. Hence, the present study was conducted to investigate the carcinogenesis relevant three commonly expressed markers (Ki-67, CD105, and α-smooth muscle acting [SMA]) in various forms of tobacco consumption habits in OSCC patients. Materials and Methods A total of 217 patients of OSCC were included in the study, and based on the habit, they were broadly categorized into tobacco lime (TL), TL and areca nut (TLAN), and areca nut (AN). Further, categorization was done on the basis of absence or presence of additional habit of smoking. Immunohistochemistry (IHC) was performed using Ki-67, CD105, and α-SMA markers on formalin-fixed paraffin-embedded tissues. Results TLAN (62.21%) was the most common habit noted in OSCC patient followed by TL (20.73%) and AN (15.20%). The additional habit of smoking was observed in 31.11% and 25.92% of TL and TLAN habits of OSCC patients, respectively. All the three markers (Ki-67, CD105, and α-SMA) showed statistically significant differences in the habit group such as TL, TLAN, and AN (P < 0.001). Although the expression of all the three markers was increased in TL as compared with TLAN, differences were not statistically significant. When these markers were compared in with and without smoking category, only TLAN with smoking and TLAN without smoking showed statistically significant differences in the expression of all three markers. Conclusions Ki-67 CD105 and α-SMA immunohistochemical expression in OSCC corresponds with different forms of tobacco consumption habits. Habit-related unique carcinogenesis events are reflected at IHC level thus providing proof of concept for future studies.
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Affiliation(s)
- Amol Ramchandra Gadbail
- Department of Dentistry, Indira Gandhi Government Medical College and Hospital, Nagpur, Maharashtra, India
| | - Sachin C Sarode
- Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
| | - Minal S Chaudhary
- Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Shailesh M Gondivkar
- Department of Oral Medicine and Radiology, Government Dental College and Hospital, Nagpur, Maharashtra, India
| | - Satyajit Ashok Tekade
- Department of Oral Pathology and Microbiology, Modern Dental College and Research Centre, Indore, Maharashtra, India
| | - Monal Yuwanati
- Department of Oral Pathology and Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Gargi S Sarode
- Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
| | - Alka Hande
- Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
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Yang Y, Ahn J, Edwards NJ, Benicky J, Rozeboom AM, Davidson B, Karamboulas C, Nixon KCJ, Ailles L, Goldman R. Extracellular Heparan 6- O-Endosulfatases SULF1 and SULF2 in Head and Neck Squamous Cell Carcinoma and Other Malignancies. Cancers (Basel) 2022; 14:cancers14225553. [PMID: 36428645 PMCID: PMC9688903 DOI: 10.3390/cancers14225553] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Pan-cancer analysis of TCGA and CPTAC (proteomics) data shows that SULF1 and SULF2 are oncogenic in a number of human malignancies and associated with poor survival outcomes. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. These heparan sulfate editing enzymes were considered largely functional redundant but single-cell RNAseq (scRNAseq) shows that SULF1 is secreted by cancer-associated fibroblasts in contrast to the SULF2 derived from tumor cells. Our RNAScope and patient-derived xenograft (PDX) analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer even though its expression in cancer cells is low. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.
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Affiliation(s)
- Yang Yang
- Department of Biochemistry and Molecular & Cell Biology, Georgetown University, Washington, DC 20057, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC 20057, USA
| | - Nathan J. Edwards
- Department of Biochemistry and Molecular & Cell Biology, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
| | - Julius Benicky
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Aaron M. Rozeboom
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Bruce Davidson
- Department of Otolaryngology-Head and Neck Surgery, MedStar Georgetown University Hospital, Washington, DC 20057, USA
| | - Christina Karamboulas
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
| | - Kevin C. J. Nixon
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
| | - Laurie Ailles
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Radoslav Goldman
- Department of Biochemistry and Molecular & Cell Biology, Georgetown University, Washington, DC 20057, USA
- Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
- Correspondence: ; Tel.: +1-202-687-9868
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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: 7] [Impact Index Per Article: 2.3] [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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Paolini R, Moore C, Matthyssen T, Cirillo N, McCullough M, Farah CS, Botha H, Yap T, Celentano A. Transcriptional regulation of glucose transporters in human oral squamous cell carcinoma cells. J Oral Pathol Med 2022; 51:679-683. [PMID: 35920070 PMCID: PMC9542080 DOI: 10.1111/jop.13342] [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: 07/06/2022] [Accepted: 07/12/2022] [Indexed: 12/24/2022]
Abstract
The increased glucose uptake observed in cancer cells is mediated by glucose transporters (GLUTs), a class of transmembrane proteins that facilitate the transport of glucose and other substrates across the plasma membrane. Despite the important role of glucose in the pathophysiology of oral squamous cell carcinoma (OSCC), there is very limited data regarding the expression of GLUTs in normal or malignant cells from the oral mucosa. We analysed the messenger RNA (mRNA) expression of all 14 GLUTs in two OSCC (H357/H400) and one non‐malignant oral keratinocyte (OKF6) cell line using a quantitative polymerase chain reaction. GLUT expression was evaluated at baseline and after treatment with two specific GLUT inhibitors, namely, BAY876 (GLUT1) and WZB117 (GLUT1, GLUT3 and GLUT4). Here, we show that GLUT1, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT12 and GLUT13 transcripts were measurably expressed in all cell lines while GLUT2, GLUT7, GLUT9, GLUT11 and GLUT14 were not expressed. GLUT10 was only found in H357. In the presence of BAY876 and WZB117, OSCC cells exhibited significant alterations in the transcriptional profile of GLUTs. In particular, we observed distinct proliferation‐dependent changes of mRNAs to GLUT1, GLUT3, GLUT4, GLUT5 and GLUT6 in response to selective GLUT inhibitors. In summary, we documented for the first time the expression of GLUT5, GLUT6 and GLUT12 in normal and malignant oral keratinocytes. Whilst regulation of GLUT transcripts was cell line and inhibitor specific, GLUT3 was consistently upregulated in actively proliferating OSCC cell lines, but not in OKF6, regardless of the inhibitor used, suggesting that modulation of this transporter may act as one of the primary compensation mechanisms for OSCC cells upon inhibition of glucose uptake.
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Affiliation(s)
- Rita Paolini
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Caroline Moore
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Tamara Matthyssen
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Nicola Cirillo
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Michael McCullough
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Camile S Farah
- Australian Centre for Oral Oncology Research & Education, Nedlands, WA, Australia.,Oral, Maxillofacial and Dental Surgery, Fiona Stanley Hospital, Murdoch, WA, Australia.,Head and Neck Pathology, Australian Clinical Labs, Subiaco, WA, Australia
| | - Heinrich Botha
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Tami Yap
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
| | - Antonio Celentano
- Melbourne Dental School, The University of Melbourne, Carlton, VIC, Australia
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35
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Wu J, Ding Y, Wang J, Lyu F, Tang Q, Song J, Luo Z, Wan Q, Lan X, Xu Z, Chen L. Single‐cell RNA
sequencing in oral science: Current awareness and perspectives. Cell Prolif 2022; 55:e13287. [PMID: 35842899 PMCID: PMC9528768 DOI: 10.1111/cpr.13287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 05/10/2022] [Accepted: 05/29/2022] [Indexed: 11/30/2022] Open
Abstract
The emergence of single‐cell RNA sequencing enables simultaneous sequencing of thousands of cells, making the analysis of cell population heterogeneity more efficient. In recent years, single‐cell RNA sequencing has been used in the investigation of heterogeneous cell populations, cellular developmental trajectories, stochastic gene transcriptional kinetics, and gene regulatory networks, providing strong support in life science research. However, the application of single‐cell RNA sequencing in the field of oral science has not been reviewed comprehensively yet. Therefore, this paper reviews the development and application of single‐cell RNA sequencing in oral science, including fields of tissue development, teeth and jaws diseases, maxillofacial tumors, infections, etc., providing reference and prospects for using single‐cell RNA sequencing in studying the oral diseases, tissue development, and regeneration.
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Affiliation(s)
- Jie Wu
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology Sun Yat‐sen University Guangzhou China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Yumei Ding
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
| | - Jinyu Wang
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
| | - Fengyuan Lyu
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
- Center of Stomatology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
| | - Jiangyuan Song
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
| | - Zhiqiang Luo
- National Engineering Research Center for Nanomedicine College of Life Science and Technolog Huazhong University of Science and Technology Wuhan China
| | - Qian Wan
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy Huazhong University of Science and Technology Wuhan China
- Institute of Brain Research Huazhong University of Science and Technology Wuhan China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Key Laboratory of Molecular Imaging Wuhan China
| | - Zhi Xu
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- School of Stomatology, Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan China
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Gao W, Zhang ZW, Wang HY, Li XD, Peng WT, Guan HY, Liao YX, Liu A. TMED2/9/10 Serve as Biomarkers for Poor Prognosis in Head and Neck Squamous Carcinoma. Front Genet 2022; 13:895281. [PMID: 35754792 PMCID: PMC9214264 DOI: 10.3389/fgene.2022.895281] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/18/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies’ progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated. Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape to investigate the roles of TMED family members in HNSC. Results: Compared with normal tissues, the mRNA expression levels of TMED1/2/4/5/7/8/9/10 were significantly increased in the TCGA HNSC dataset. And we combined GEPIA 2 and Kaplan-Meier Plotter to select TMED2/9/10 with prognostic value. Then we detected the levels of mRNA in the GEO HNSC database and the protein expression in HPA. It was found that the mRNA and protein expression levels of TMED2/9/10 were increased in HNSC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that TMED2/9/10 and their co-expressed genes promoted the malignant behavior of tumors by participating in biological processes such as intracellular transferase complex, protein transport, focal adhesion, intracellular protein processing. Single-cell analysis and immune infiltration analysis suggested that immune responses of cancer-associated fibroblasts and endothelial cells might be associated with prognosis. Finally, the transcription factors-genes network and protein-protein functional interaction network pointed to genes such as X-box binding protein 1 (XBP1) and TMED7, which might cooperate with TMED2/9/10 to change the progression of HNSC. Conclusions: Our study implied that TMED2/9/10 and related genes mightjointly affect the prognosis of HNSC, providing specific clues for further experimental research, personalized diagnosis strategies, and targeted clinical therapy for HNSC.
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Affiliation(s)
- Wen Gao
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhe-Wen Zhang
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Hong-Yi Wang
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin-Di Li
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Wei-Ting Peng
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Hao-Yu Guan
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Yu-Xuan Liao
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - An Liu
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
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37
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Sharpe BP, Hayden A, Manousopoulou A, Cowie A, Walker RC, Harrington J, Izadi F, Breininger SP, Gibson J, Pickering O, Jaynes E, Kyle E, Saunders JH, Parsons SL, Ritchie AA, Clarke PA, Collier P, Mongan NP, Bates DO, Yacqub-Usman K, Garbis SD, Walters Z, Rose-Zerilli M, Grabowska AM, Underwood TJ. Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts. Cell Rep Med 2022; 3:100541. [PMID: 35732148 PMCID: PMC9244979 DOI: 10.1016/j.xcrm.2022.100541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/14/2021] [Accepted: 01/28/2022] [Indexed: 12/03/2022]
Abstract
The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.
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Affiliation(s)
- Benjamin P Sharpe
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Annette Hayden
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | | | - Andrew Cowie
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Robert C Walker
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Jack Harrington
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Fereshteh Izadi
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK; Centre for NanoHealth, Swansea University Medical School, Singleton Campus, Swansea SA2 8PP, UK
| | - Stella P Breininger
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Jane Gibson
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Oliver Pickering
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Eleanor Jaynes
- University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Ewan Kyle
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - John H Saunders
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
| | - Simon L Parsons
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK; Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK
| | - Alison A Ritchie
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Philip A Clarke
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Pamela Collier
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Nigel P Mongan
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA; Biodiscovery Institute, School of Veterinary Medicine and Science, University of Nottingham, Nottingham NG5 1PB, UK
| | - David O Bates
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Kiren Yacqub-Usman
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | | | - Zoë Walters
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Matthew Rose-Zerilli
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK
| | - Anna M Grabowska
- Ex Vivo Cancer Pharmacology Centre of Excellence, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Timothy J Underwood
- School of Cancer Sciences, Faculty of Medicine, Room CS B2, MP824, Somers Cancer Research Building, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK.
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Kankeu Fonkoua LA, Sirpilla O, Sakemura R, Siegler EL, Kenderian SS. CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities. Mol Ther Oncolytics 2022; 25:69-77. [PMID: 35434273 PMCID: PMC8980704 DOI: 10.1016/j.omto.2022.03.009] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable outcomes in individuals with hematological malignancies, but its success has been hindered by barriers intrinsic to the tumor microenvironment (TME), particularly for solid tumors, where it has yet to make its mark. In this article, we provide an updated review and future perspectives on features of the TME that represent barriers to CART cell therapy efficacy, including competition for metabolic fuels, physical barriers to infiltration, and immunosuppressive factors. We then discuss novel and promising strategies to overcome these obstacles that are in preclinical development or under clinical investigation.
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Affiliation(s)
- Lionel A. Kankeu Fonkoua
- T Cell Engineering Laboratory, Mayo Clinic, Rochester, MN, USA
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Olivia Sirpilla
- T Cell Engineering Laboratory, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Reona Sakemura
- T Cell Engineering Laboratory, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Elizabeth L. Siegler
- T Cell Engineering Laboratory, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Saad S. Kenderian
- T Cell Engineering Laboratory, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
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39
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Bhome R, Emaduddin M, James V, House LM, Thirdborough SM, Mellone M, Tulkens J, Primrose JN, Thomas GJ, De Wever O, Mirnezami AH, Sayan AE. Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR-200 levels in extracellular vesicles. J Extracell Vesicles 2022; 11:e12226. [PMID: 35595718 PMCID: PMC9122835 DOI: 10.1002/jev2.12226] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 02/14/2022] [Accepted: 04/26/2022] [Indexed: 12/28/2022] Open
Abstract
Colorectal cancer (CRC) with a mesenchymal gene expression signature has the greatest propensity for distant metastasis and is characterised by the accumulation of cancer‐associated fibroblasts in the stroma. We investigated whether the epithelial to mesenchymal transition status of CRC cells influences fibroblast phenotype, with a focus on the transfer of extracellular vesicles (EVs), as a controlled means of cell–cell communication. Epithelial CRC EVs suppressed TGF‐β‐driven myofibroblast differentiation, whereas mesenchymal CRC EVs did not. This was driven by miR‐200 (miR‐200a/b/c, ‐141), which was enriched in epithelial CRC EVs and transferred to recipient fibroblasts. Ectopic miR‐200 expression or ZEB1 knockdown, in fibroblasts, similarly suppressed myofibroblast differentiation. Supporting these findings, there was a strong negative correlation between miR‐200 and myofibroblastic markers in a cohort of CRC patients in the TCGA dataset. This was replicated in mice, by co‐injecting epithelial or mesenchymal CRC cells with fibroblasts and analysing stromal markers of myofibroblastic phenotype. Fibroblasts from epithelial tumours contained more miR‐200 and expressed less ACTA2 and FN1 than those from mesenchymal tumours. As such, these data provide a new mechanism for the development of fibroblast heterogeneity in CRC, through EV‐mediated transfer of miRNAs, and provide an explanation as to why CRC tumours with greater metastatic potential are CAF rich.
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Affiliation(s)
- Rahul Bhome
- Cancer Sciences Unit, University of Southampton, Southampton, UK.,University Surgery, University of Southampton, Southampton, UK
| | | | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
| | - Louise M House
- Cancer Sciences Unit, University of Southampton, Southampton, UK
| | | | | | - Joeri Tulkens
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - John N Primrose
- University Surgery, University of Southampton, Southampton, UK
| | - Gareth J Thomas
- Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Alex H Mirnezami
- Cancer Sciences Unit, University of Southampton, Southampton, UK.,University Surgery, University of Southampton, Southampton, UK
| | - A Emre Sayan
- Cancer Sciences Unit, University of Southampton, Southampton, UK
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40
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The Role of Zinc Finger Proteins in Various Oral Conditions. ScientificWorldJournal 2022; 2022:4612054. [PMID: 35463825 PMCID: PMC9033369 DOI: 10.1155/2022/4612054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 03/30/2022] [Indexed: 11/23/2022] Open
Abstract
The zinc finger proteins (ZNFs) are essential transcription factors, and the genes encoding them constitute about 3% of the entire human genome. They are involved in the development of several tissues, and any alterations in their structure may promote chronic conditions like diabetes and tumorigenesis. Lately, their role in the development, progression, and metastasis of Oral Squamous Cell Carcinoma (OSCC), Epithelial Dysplasia, Oral Lichen Planus, and Periodontitis has been found. The present review aims to describe their role in various oral conditions. Electronic databases like Medline (PubMed) and Scopus were searched for original studies related to the role of ZNFs in various oral conditions. It yielded 48 studies included in the review. It was found that the ZNFs influenced chronic conditions like Oral Cancer and Periodontitis. They act both as tumor suppressors and oncogenes and have an anti-inflammatory effect. The knowledge from the present review may be utilized in designing drugs that prevent unusual expression of specific ZNFs. Besides, they may be applied as prognostic markers due to their high expression specificity in some tumors.
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41
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Noda Y, Ishida M, Ueno Y, Fujisawa T, Iwai H, Tsuta K. Novel pathological predictive factors for extranodal extension in oral squamous cell carcinoma: a retrospective cohort study based on tumor budding, desmoplastic reaction, tumor-infiltrating lymphocytes, and depth of invasion. BMC Cancer 2022; 22:402. [PMID: 35418058 PMCID: PMC9006434 DOI: 10.1186/s12885-022-09393-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
Background Extranodal extension (ENE) is a poor prognostic factor for oral squamous cell carcinoma (OSCC). Identifying ENE by clinical and/or radiological examination is difficult, thereby leading to unnecessary neck dissections. Currently, no definitive predictors are available for ENE. Thus, we aimed to determine the histological predictors of ENE by routine histopathological examination using biopsy and surgically resected specimens. Methods This retrospective study included 186 surgically resected OSCC and 83 matched biopsy specimens. Clinical features associated with the tumor microenvironment, including desmoplastic reaction (DR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs), were evaluated using hematoxylin and eosin-stained primary OSCC and neck dissection specimens. These histological features were divided into two groups: DR-immature (DR-I) and DR-mature (DR-M); TB-high (TB-H) and TB-low (TB-L); and TILs-low (TILs-L) and TILs-high (TILs-H). Clinical depth of invasion (cDOI) and pathological DOI (pDOI) were adapted for biopsies and resections, respectively; DOI was evaluated as DOI > 10 mm and DOI ≤ 10 mm. The clinicopathological relationships between these histopathological features and ENE and the independent risk factors for ENE were analyzed. The histological predictors of ENE were evaluated. Results The histological status of DR, TILs, and TB present in biopsy and resection specimens showed high accuracy with that of ENE. DR-I, TILs-L, and TB-H were significantly associated with lymph node metastasis, cDOI, and pDOI. Bivariate and multivariate analyses revealed that TB-H and pDOI > 10 mm in resections were independent factors for the presence of ENE (ENE +). The combination of TB-H/pDOI > 10 mm in resection specimens showed high specificity (91%) and accuracy (83%) regarding ENE + . Although there proved to be no independent factors in biopsies, DR-I and TILs-L were significantly associated with ENE + (p < 0.001). The combination of DR-I/TILs-L/cDOI > 10 mm in biopsies exhibited high sensitivity and specificity with ENE + (70% and 77%, respectively, p < 0.001). These histological predictors could detect even minor ENE (< 2 mm). Conclusions The tumor microenvironment status in primary OSCC was significantly associated with that of ENE, and TB-H was an independent risk factor for ENE. The histological status of DR-I/TILs-L/cDOI > 10 mm in biopsy specimens and TB-H/pDOI > 10 mm in resection specimens is a useful predictor of ENE. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09393-8.
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Affiliation(s)
- Yuri Noda
- Department of Pathology and Laboratory Medicine, Kansai Medical University Hospital, 2-3-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan.
| | - Mitsuaki Ishida
- Department of Pathology and Laboratory Medicine, Kansai Medical University Hospital, 2-3-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan
| | - Yasuhiro Ueno
- Department of Radiology, Kansai Medical University Hospital, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan
| | - Takuo Fujisawa
- Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Hospital, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan
| | - Hiroshi Iwai
- Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Hospital, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan
| | - Koji Tsuta
- Department of Pathology and Laboratory Medicine, Kansai Medical University Hospital, 2-3-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan
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42
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Parkinson EK, Prime SS. Oral Senescence: From Molecular Biology to Clinical Research. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.822397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cellular senescence is an irreversible cell cycle arrest occurring following multiple rounds of cell division (replicative senescence) or in response to cellular stresses such as ionizing radiation, signaling imbalances and oxidative damage (stress-induced premature senescence). Even very small numbers of senescent cells can be deleterious and there is evidence that senescent cells are instrumental in a number of oral pathologies including cancer, oral sub mucous fibrosis and the side effects of cancer therapy. In addition, senescent cells are present and possibly important in periodontal disease and other chronic inflammatory conditions of the oral cavity. However, senescence is a double-edged sword because although it operates as a suppressor of malignancy in pre-malignant epithelia, senescent cells in the neoplastic environment promote tumor growth and progression. Many of the effects of senescent cells are dependent on the secretion of an array of diverse therapeutically targetable proteins known as the senescence-associated secretory phenotype. However, as senescence may have beneficial roles in wound repair, preventing fibrosis and stem cell activation the clinical exploitation of senescent cells is not straightforward. Here, we discuss biological mechanisms of senescence and we review the current approaches to target senescent cells therapeutically, including senostatics and senolytics which are entering clinical trials.
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von der Grün J, Winkelmann R, Burck I, Martin D, Rödel F, Wild PJ, Bankov K, Weigert A, Kur IM, Brandts C, Filmann N, Issing C, Thönissen P, Tanneberger AM, Rödel C, Ghanaati S, Balermpas P. Neoadjuvant Chemoradiotherapy for Oral Cavity Cancer: Predictive Factors for Response and Interim Analysis of the Prospective INVERT-Trial. Front Oncol 2022; 12:817692. [PMID: 35402268 PMCID: PMC8988145 DOI: 10.3389/fonc.2022.817692] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 03/02/2022] [Indexed: 01/10/2023] Open
Abstract
Background To study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC). Methods The INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate. Results Seventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT. Conclusion nCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs.
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Affiliation(s)
- Jens von der Grün
- Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt a. M., Goethe-University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe-University Frankfurt, Frankfurt, Germany
| | - Ria Winkelmann
- Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Iris Burck
- Department of Diagnostic and Interventional Radiology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Daniel Martin
- Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt a. M., Goethe-University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe-University Frankfurt, Frankfurt, Germany
| | - Franz Rödel
- Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt a. M., Goethe-University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe-University Frankfurt, Frankfurt, Germany
| | - Peter Johannes Wild
- Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Katrin Bankov
- Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Ivan-Maximiliano Kur
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christian Brandts
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt a. M., Goethe-University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe-University Frankfurt, Frankfurt, Germany
- Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Natalie Filmann
- Institute of Biostatistics and Mathematical Modelling, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christian Issing
- Frankfurt Cancer Institute (FCI), Goethe-University Frankfurt, Frankfurt, Germany
- Department of Otorhinolaryngology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Philipp Thönissen
- Department of Oral, Maxillofacial and Facial Plastic Surgery, Goethe-University Frankfurt, Frankfurt, Germany
| | - Anna Maria Tanneberger
- Department of Oral, Maxillofacial and Facial Plastic Surgery, Goethe-University Frankfurt, Frankfurt, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt a. M., Goethe-University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe-University Frankfurt, Frankfurt, Germany
| | - Shahram Ghanaati
- Department of Oral, Maxillofacial and Facial Plastic Surgery, Goethe-University Frankfurt, Frankfurt, Germany
| | - Panagiotis Balermpas
- Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany
- Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland
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Rajthala S, Parajuli H, Dongre HN, Ljøkjel B, Hoven KM, Kvalheim A, Lybak S, Neppelberg E, Sapkota D, Johannessen AC, Costea DE. MicroRNA-138 Abates Fibroblast Motility With Effect on Invasion of Adjacent Cancer Cells. Front Oncol 2022; 12:833582. [PMID: 35371970 PMCID: PMC8968121 DOI: 10.3389/fonc.2022.833582] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/08/2022] [Indexed: 12/21/2022] Open
Abstract
Background Recent studies have shown aberrant expression of micro-RNAs in cancer-associated fibroblasts (CAFs). This study aimed to investigate miR-138 dysregulation in CAFs in oral squamous cell carcinoma (OSCC) and its effects on their phenotype and invasion of adjacent OSCC cells. Methods Expression of miR-138 was first investigated in OSCC lesions (n = 53) and OSCC-derived CAFs (n = 15). MiR-138 mimics and inhibitors were used to functionally investigate the role of miR-138 on CAF phenotype and the resulting change in their ability to support OSCC invasion. Results Expression of miR-138 showed marked heterogeneity in both OSCC tissues and cultured fibroblasts. Ectopic miR-138 expression reduced fibroblasts’ motility and collagen contraction ability and suppressed invasion of suprajacent OSCC cells, while its inhibition resulted in the opposite outcome. Transcript and protein examination after modulation of miR-138 expression showed changes in CAF phenotype-specific molecules, focal adhesion kinase axis, and TGFβ1 signaling pathway. Conclusions Despite its heterogeneous expression, miR-138 in OSCC-derived CAFs exhibits a tumor-suppressive function.
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Affiliation(s)
- Saroj Rajthala
- The Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Himalaya Parajuli
- The Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Harsh Nitin Dongre
- The Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Borghild Ljøkjel
- Head and Neck Clinic, Haukeland University Hospital, Bergen, Norway
| | | | | | - Stein Lybak
- Head and Neck Clinic, Haukeland University Hospital, Bergen, Norway
| | - Evelyn Neppelberg
- Head and Neck Clinic, Haukeland University Hospital, Bergen, Norway
- Department of Oral Surgery, Institute of Clinical Dentistry, University of Bergen, Bergen, Norway
| | - Dipak Sapkota
- Department of Oral Biology, University of Oslo, Oslo, Norway
| | - Anne Christine Johannessen
- The Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Daniela-Elena Costea
- The Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
- *Correspondence: Daniela-Elena Costea,
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Anwar Sadat S, Shaikh MH, Tajin F, Akter R, Shuvo SA, Ahmed H. Oral submucous fibrosis associated oral squamous cell carcinoma: A case report with review of literature. ORAL AND MAXILLOFACIAL SURGERY CASES 2022. [DOI: 10.1016/j.omsc.2022.100246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Kim JY, Kim J, Bandara BMR, Tilakaratne WM, Kim D. Leaf extract of Osbeckia octandra induces apoptosis in oral squamous cell carcinoma cells. BMC Complement Med Ther 2022; 22:20. [PMID: 35078428 PMCID: PMC8787916 DOI: 10.1186/s12906-022-03505-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 12/22/2021] [Indexed: 11/10/2022] Open
Abstract
Background Osbeckia octandra is a plant endemic to Sri Lanka and is used in ethnomedicine for treating various diseases. However, the anti-cancer properties of O. octandra are yet to be fully investigated. In the present study, we evaluated the anti-cancer effects of O. octandra on oral cancer cells. Methods Human oral cancer cell lines (HSC2, YD10B, YD38, YD9, and YD32) were used in this study. BrdU incorporation, cell cycle and annexin-V/PI staining were all evaluated using flow cytometry to determine the extent to which O. octandra leaf extract inhibits cell proliferation and induces apoptosis. Cell viability and reactive oxygen species (ROS) were also measured in order to investigate the anti-cancer effects of O. octandra extracts. Western blotting was performed to detect cell cycle related protein such as cyclin d1 and cdk4, and to detect apoptosis-related proteins such as Bcl-2, Bcl-XL, Bax, Caspase-9, Cleaved caspase-3, Fas, Caspase-8, and Bid. Results Leaf extract of O. octandra reduced oral squamous cell carcinoma (OSCC) cell viability in a dose-dependent manner. Leaf extract of O. octandra has non-toxic in normal keratinocytes. Also, O. octandra extract interrupted the DNA replication via G1 phase arrests, and this effect was independent of ROS generation. In the apoptosis-related experiments, the population of annexin V-positive cells increased upon treatment with O. octandra extract. Furthermore, the expression of anti-apoptotic protein (Bcl-2 and Bcl-xL) was decreased, whereas the expression of cleaved caspase-3 protein was increased in O. octandra-treated OSCC cells. Conclusions The results suggest that a leaf extract of O. octandra inhibited the proliferation of OSCC cells through G1 phase arrest and interrupting DNA replication. The leaf extract of O. octandra could trigger the apoptotic response via caspase 3 activation in OSCC cells. These results suggest that O. octandra has the potential to be developed as an alternative medicine for treating OSCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-022-03505-4.
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Affiliation(s)
- Jue Young Kim
- Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea.,Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 06230, Republic of Korea
| | - Jin Kim
- Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - B M Ratnayake Bandara
- Department of Chemistry, Faculty of Science, University of Peradeniya, Peradeniya, 20400, Sri Lanka
| | - Wanninayake M Tilakaratne
- Department of Oral Pathology, Faculty of Dental Sciences, Center for Research in Oral Cancer, University of Peradeniya, Peradeniya, 20400, Sri Lanka.,Department of Oral Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Dokyeong Kim
- Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea. .,Precision Medicine Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
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Heft Neal ME, Brenner JC, Prince MEP, Chinn SB. Advancement in Cancer Stem Cell Biology and Precision Medicine-Review Article Head and Neck Cancer Stem Cell Plasticity and the Tumor Microenvironment. Front Cell Dev Biol 2022; 9:660210. [PMID: 35047489 PMCID: PMC8762309 DOI: 10.3389/fcell.2021.660210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 12/01/2021] [Indexed: 12/16/2022] Open
Abstract
Head and Neck cancer survival has continued to remain around 50% despite treatment advances. It is thought that cancer stem cells play a key role in promoting tumor heterogeneity, treatment resistance, metastasis, and recurrence in solid malignancies including head and neck cancer. Initial studies identified cancer stem cell markers including CD44 and ALDH in head and neck malignancies and found that these cells show aggressive features in both in vitro and in vivo studies. Recent evidence has now revealed a key role of the tumor microenvironment in maintaining a cancer stem cell niche and promoting cancer stem cell plasticity. There is an increasing focus on identifying and targeting the crosstalk between cancer stem cells and surrounding cells within the tumor microenvironment (TME) as new therapeutic potential, however understanding how CSC maintain a stem-like state is critical to understanding how to therapeutically alter their function. Here we review the current evidence for cancer stem cell plasticity and discuss how interactions with the TME promote the cancer stem cell niche, increase tumor heterogeneity, and play a role in treatment resistance.
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Affiliation(s)
- Molly E Heft Neal
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - J Chad Brenner
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Mark E P Prince
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Steven B Chinn
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
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48
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Yu B, Huang C, Xu J, Liu S, Guan Y, Li T, Zheng X, Ding J. Prediction of the degree of pathological differentiation in tongue squamous cell carcinoma based on radiomics analysis of magnetic resonance images. BMC Oral Health 2021; 21:585. [PMID: 34798867 PMCID: PMC8603498 DOI: 10.1186/s12903-021-01947-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 11/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Tongue squamous cell carcinoma (TSCC) is one of the most difficult malignancies to control. It displays particular and aggressive behaviour even at an early stage. The purpose of this paper is to explore the value of radiomics based on magnetic resonance fat-suppressed T2-weighted images in predicting the degree of pathological differentiation of TSCC. Methods Retrospective analysis of 127 patients with TSCC who were randomly divided into a primary cohort and a test cohort, including well-differentiated, moderately differentiated and poorly differentiated. The tumour regions were manually labelled in fat-suppressed T2-weighted imaging (FS-T2WI), and PyRadiomics was used to extract radiomics features. The radiomics features were then selected by the least absolute shrinkage and selection operator (LASSO) method. The model was established by the logistic regression classifier using a 5-fold cross-validation method, applied to all data and evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity. Results In total, 1132 features were extracted, and seven features were selected for modelling. The AUC in the logistic regression model for well-differentiated TSCC was 0.90 with specificity and precision values of 0.92 and 0.78, respectively, and the sensitivity for poorly differentiated TSCC was 0.74. Conclusions The MRI-based radiomics signature could discriminate between well-differentiated, moderately differentiated and poorly differentiated TSCC and might be used as a biomarker for preoperative grading.
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Affiliation(s)
- Baoting Yu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, 130021, China
| | - Chencui Huang
- Department of Research Collaboration, R&D Center, Beijing Deepwise & League of PHD Technology Co., Ltd, No. 829 of Xinmin Street, Chaoyang District, Beijing, 100080, China
| | - Jingxu Xu
- Department of Research Collaboration, R&D Center, Beijing Deepwise & League of PHD Technology Co., Ltd, No. 829 of Xinmin Street, Chaoyang District, Beijing, 100080, China
| | - Shuo Liu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, 130021, China
| | - Yuyao Guan
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, 130021, China
| | - Tong Li
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, 130021, China
| | - Xuewei Zheng
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, 130021, China
| | - Jun Ding
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, 130021, China. .,Department of Research Collaboration, R&D Center, Beijing Deepwise & League of PHD Technology Co., Ltd, No. 829 of Xinmin Street, Chaoyang District, Beijing, 100080, China.
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Loh JJ, Ma S. The Role of Cancer-Associated Fibroblast as a Dynamic Player in Mediating Cancer Stemness in the Tumor Microenvironment. Front Cell Dev Biol 2021; 9:727640. [PMID: 34760886 PMCID: PMC8573407 DOI: 10.3389/fcell.2021.727640] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/24/2021] [Indexed: 01/15/2023] Open
Abstract
The enrichment of cancer-associated fibroblast (CAFs) in a tumor microenvironment (TME) cultivates a pro-tumorigenic niche via aberrant paracrine signaling and matrix remodeling. A favorable niche is critical to the maintenance of cancer stem cells (CSCs), a population of cells that are characterized by their enhanced ability to self-renew, metastasis, and develop therapy resistance. Mounting evidence illustrates the interplay between CAF and cancer cells expedites malignant progression. Therefore, targeting the key cellular components and factors in the niche may promote a more efficacious treatment. In this study, we discuss how CAF orchestrates a niche that enhances CSC features and the potential therapeutic implication.
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Affiliation(s)
- Jia Jian Loh
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
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Profiling and Functional Analysis of microRNA Deregulation in Cancer-Associated Fibroblasts in Oral Squamous Cell Carcinoma Depicts an Anti-Invasive Role of microRNA-204 via Regulation of Their Motility. Int J Mol Sci 2021; 22:ijms222111960. [PMID: 34769388 PMCID: PMC8584862 DOI: 10.3390/ijms222111960] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/30/2021] [Accepted: 11/02/2021] [Indexed: 12/27/2022] Open
Abstract
Background: Knowledge on the role of miR changes in tumor stroma for cancer progression is limited. This study aimed to investigate the role of miR dysregulation in cancer-associated fibroblasts (CAFs) in oral squamous cell carcinoma (OSCC). Methodology: CAF and normal oral fibroblasts (NOFs) were isolated from biopsies of OSCC patients and healthy individuals after informed consent and grown in 3D collagen gels. Total RNA was extracted. Global miR expression was profiled using Illumina version 2 panels. The functional impact of altered miR-204 expression in fibroblasts on their phenotype and molecular profile was investigated using mimics and inhibitors of miR-204. Further, the impact of miR-204 expression in fibroblasts on invasion of adjacent OSCC cells was assessed in 3D-organotypic co-cultures. Results: Unsupervised hierarchical clustering for global miR expression resulted in separate clusters for CAF and NOF. SAM analysis identified differential expression of twelve miRs between CAF and NOF. Modulation of miR-204 expression did not affect fibroblast cell proliferation, but resulted in changes in the motility phenotype, expression of various motility-related molecules, and invasion of the adjacent OSCC cells. 3′ UTR miR target reporter assay showed ITGA11 to be a direct target of miR-204. Conclusions: This study identifies differentially expressed miRs in stromal fibroblasts of OSCC lesions compared with normal oral mucosa and it reveals that one of the significantly downregulated miRs in CAF, miR-204, has a tumor-suppressive function through inhibition of fibroblast migration by modulating the expression of several different molecules in addition to directly targeting ITGA11.
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