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Bichri K, El Ghanmi A, Kouhen F, Hamdi S, Fichtali K, El Mansouri F, El Bakkouri J, Ghazi B. The Sibylline Relationship Between Human Papillomavirus and Endometrial Cancer: Scarcity of Strong Evidence Linking Both Conditions. Viruses 2025; 17:607. [PMID: 40431619 PMCID: PMC12115647 DOI: 10.3390/v17050607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 05/29/2025] Open
Abstract
Endometrial cancer (EC) is the fourth-most frequent cancer among the female population and a leading cause of death. Multiple factors are susceptible to causing tumorigenesis, including obesity, lack of physical activity, diabetes mellitus, high concentration of estrogen during menopause, unopposed exposure to estrogen, duration of menses, nulliparity and infertility. Human papillomavirus (HPV) is a double-stranded DNA virus, with certain genotypes exclusively human. HPV plays a major role in some cancers (cervical cancer, head and neck cancer, lung cancer, and anogenital cancers). Given the intricate correlation between HPV and cervical cancer, the scientific community conjectured that HPV may be implicated in the carcinogenesis of the endometrium. In this review, we will direct our interest towards previous studies that focused on the expression of HPV on EC samples and cover how both conditions might connect to each other.
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Affiliation(s)
- Khadija Bichri
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory (3Is), Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco; (K.B.); (A.E.G.); (K.F.); (F.E.M.); (J.E.B.)
| | - Adil El Ghanmi
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory (3Is), Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco; (K.B.); (A.E.G.); (K.F.); (F.E.M.); (J.E.B.)
- Department of Gynecology and Obstetrics, Mohammed VI International University Hospital, Bouskoura 27182, Morocco
| | - Fadila Kouhen
- Laboratory of Neurosciences and Oncogenetics, Neurooncology and Oncogenetic Team, Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco;
- Department of Radiotherapy, International University Hospital Cheikh Khalifa, Casablanca 82403, Morocco
| | - Salsabil Hamdi
- Virology and Public Health Laboratory, Institut Pasteur du Maroc, Casablanca 20360, Morocco;
| | - Karima Fichtali
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory (3Is), Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco; (K.B.); (A.E.G.); (K.F.); (F.E.M.); (J.E.B.)
- Department of Gynecology and Obstetrics, Mohammed VI International University Hospital, Bouskoura 27182, Morocco
| | - Fadoua El Mansouri
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory (3Is), Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco; (K.B.); (A.E.G.); (K.F.); (F.E.M.); (J.E.B.)
| | - Jalila El Bakkouri
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory (3Is), Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco; (K.B.); (A.E.G.); (K.F.); (F.E.M.); (J.E.B.)
- Clinical Immunology, Inflammation and Allergy Laboratory (LICIA), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20250, Morocco
| | - Bouchra Ghazi
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory (3Is), Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Casablanca 82403, Morocco; (K.B.); (A.E.G.); (K.F.); (F.E.M.); (J.E.B.)
- Department of Gynecology and Obstetrics, Mohammed VI International University Hospital, Bouskoura 27182, Morocco
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Farkas SA, Qvick A, Helenius G, Lillsunde-Larsson G. Pathological variants in HPV-independent vulvar tumours. Sci Rep 2025; 15:1486. [PMID: 39789097 PMCID: PMC11718117 DOI: 10.1038/s41598-024-84688-3] [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: 07/25/2024] [Accepted: 12/26/2024] [Indexed: 01/12/2025] Open
Abstract
Vulvar cancer is a rare gynaecological disease that can be caused by infection with human papillomavirus (HPV). The mutational frequencies and landscape for HPV-associated and HPV-independent vulvar tumor development are supposedly two distinctly different pathways and more detailed knowledge on target biological mechanisms for individualized future treatments is needed. The study included formalin-fixed paraffin-embedded (FFPE) samples from 32 cancer patients (16 HPV-negative and 16 HPV-associated), treated in Örebro, Sweden from 1988 to 2008. The Oncomine™ Comprehensive Assay v3 was used to detect variants across 161 different tumor relevant genes. Data analysis included quality assessment followed by variant analysis of DNA with the Oncomine Comprehensive v3 workflow and with a custom filter using the VarSome Clinical software. The RNA-analysis was performed with the Oncomine Comprehensive v3 workflow. Totally, 94% of DNA libraries and 81% of RNA libraries were of adequate quality for further downstream analysis. With the Oncomine™ filter chain there was an increased number of variants in the HPV-negative group (2.5 variants) compared to the HPV-associated group (1.5 variants). Using custom filter and the Varsome Clinical software; additional single nucleotide variants (SNV) were detected where the vast majority were classified as likely benign/benign. HPV-negative tumors had a larger fraction of variants of unknown significance (VUS), and likely pathogenic/pathogenic compared to the HPV-associated tumours. The top 10 frequently mutated genes in HPV-indepentent tumors were TP53, POLE, PTCH1, BRCA2, CREBBP, NOTCH2, ARID1A, CDKN2A, MSH2, and NOTCH1. Three fusion genes were detected; TBL1XR1(1)::PIK3CA(2) (n = 2) and NF1(5)::PSMD11(2) (n = 1). Copy number variations (CNV) were more common in HPV-associated tumors (n = 13/16, 81%) compared to HPV-negative tumors (n = 9/14, 64%). The most frequent CNV was found in the cMYC gene, followed by CDK2 (n = 5) and CDK4 (n = 4). The main outcome of this study show that vulvar cancer harbour genetic variations of different types and specifically, HPV-independent tumours are molecularly very heterogeneous and harboured more SNVs while HPV-associated tumors more frequently presented with gene amplifications. The PI3K/AKT/mTOR1 pathway was affected in both the groups as well as the cell cycle regulation pathway. Similarly, the DNA repair gene POLE was found mutated in both vulvar cancer groups.
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Affiliation(s)
- Sanja A Farkas
- Department of Laboratory Medicine, Clinical Pathology and Genetics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
| | - Alvida Qvick
- Clinical Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | | | - Gabriella Lillsunde-Larsson
- Department of Laboratory Medicine, Clinical Pathology and Genetics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- School of Health Sciences, Örebro University, Örebro, Sweden
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Cook E, Kramer CJH, Bosse T, van Poelgeest M, Van de Vijver K, Nucci MR, Parra-Herran C. Verruciform Acanthotic Vulvar Intraepithelial Neoplasia Harbors Recurrent Genomic Alterations Found in HPV-independent Squamous Cell Carcinoma. Int J Gynecol Pathol 2025:00004347-990000000-00216. [PMID: 39868730 DOI: 10.1097/pgp.0000000000001094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
The term verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) was coined to describe HPV-independent p53-wildtype lesions with characteristic clinicopathologic characteristics and association with vulvar squamous cell carcinoma (vSCC). We aimed to expand on the molecular landscape of vaVIN using comprehensive sequencing and copy number variation profiling. vaVIN diagnosis in institutional cases was confirmed by a second review, plus negative p16 and wildtype p53 by immunohistochemistry. Multigene next-generation sequencing and shallow-whole genome sequencing were used to survey for single-nucleotide variants (SNV), copy number alterations, and structural variants. Targeted TERT promoter sequencing was also carried out. Nineteen patients with vaVIN were included; 4 had concurrent vSCC. The median patient age was 74 (range 56-90) years. Genomic aberrations were noted in 18 cases (95%) as follows: PIK3CA in 10 (53%), CDKN2A in 7 (37%), HRAS in 6 (32%), FAT1 and NOTCH1-2 in 5 each (26%), TSC2 in 2 (11%), and PTEN, ARID2, and KRAS in 1 (5%) each. TERT promoter variants were detected in 11 of 13 cases successfully tested (85%). Five vaVINs harbored a TP53 variant but showed wild-type p53 immunohistochemical expression. In one of these, the concurrent carcinoma showed abnormal p53 and biallelic TP53 mutations. Out of 15 patients with follow-up (mean: 20, range: 2-50 mo), vaVIN persistence/recurrence was seen in 8 (53%), and subsequent vSCC in 2 (13%). At the last encounter, 3 (20%) patients had persistent disease and 1 (7%) died of vSCC. vaVIN is characterized by a wider molecular spectrum, beyond known alterations in PIK3CA, HRAS, and ARID2, to include TERT promoter, CDKN2A, FAT1, and NOTCH1-2, which are characteristic of HPV-independent vSCC. vaVIN can occur with concurrent or subsequent carcinoma, sometimes with fatal outcomes. These findings support the concept of vaVIN as a neoplastic process within the family of HPV-independent vulvar neoplasia.
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Affiliation(s)
- Eleanor Cook
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | | | | | - Marisa R Nucci
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Carlos Parra-Herran
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
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Karthikeyan S, Casey PJ, Wang M. RAB4A is a master regulator of cancer cell stemness upstream of NUMB-NOTCH signaling. Cell Death Dis 2024; 15:778. [PMID: 39463384 PMCID: PMC11514220 DOI: 10.1038/s41419-024-07172-w] [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: 05/10/2024] [Revised: 10/03/2024] [Accepted: 10/18/2024] [Indexed: 10/29/2024]
Abstract
Cancer stem cells (CSCs) are a group of specially programmed tumor cells that possess the characteristics of perpetual cell renewal, increased invasiveness, and often, drug resistance. Hence, eliminating CSCs is a major challenge for cancer treatment. Understanding the cellular programs that maintain CSCs, and identifying the critical regulators for such programs, are major undertakings in both basic and translational cancer research. Recently, we have reported that RAB4A is a major regulator of epithelial-to-mesenchymal transition (EMT) and it does so mainly through regulating the activation of RAC1 GTPase. In the current study, we have delineated a new signaling circuitry through which RAB4A transmits its control of cancer stemness. Using in vitro and in vivo studies, we show that RAB4A, as the upstream regulator, relays signal stepwise to NUMB, NOTCH1, RAC1, and then SOX2 to control the self-renewal property of multiple cancer cells of diverse tissue origins. Knockdown of NUMB, or overexpression of NICD (the active fragment NOTCH1) or SOX2, rescued the in vitro sphere-forming and in vivo tumor-forming abilities that were lost upon RAB4A knockdown. Furthermore, we discovered that the chain of control is mostly through transcriptional regulation at every step of the pathway. The discovery of the novel signaling axis of RAB4A-NUMB-NOTCH-SOX2 opens the path for further expansion of the signaling chain and for the identification of new regulators and interacting proteins important for CSC functions, which can be explored to develop new and effective therapies.
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Affiliation(s)
| | - Patrick J Casey
- Program in Cancer Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
| | - Mei Wang
- Program in Cancer Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
- Department of Biochemistry, National University of Singapore, Singapore, Singapore.
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Zhao YX, Zhao HP, Zhao MY, Yu Y, Qi X, Wang JH, Lv J. Latest insights into the global epidemiological features, screening, early diagnosis and prognosis prediction of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:2638-2656. [PMID: 38855150 PMCID: PMC11154680 DOI: 10.3748/wjg.v30.i20.2638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/27/2024] Open
Abstract
As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.
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Affiliation(s)
- Yi-Xin Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Meng-Yao Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Xi Qi
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Ludwig M, Birkeland A, Smith J, Gensterblum-Miller E, Zhai JI, Kulkarni A, Jiang H, Brenner C. A Genome Wide CRISPR Pro filing Approach Identi fies Mechanisms of Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma. RESEARCH SQUARE 2024:rs.3.rs-3922565. [PMID: 38464196 PMCID: PMC10925415 DOI: 10.21203/rs.3.rs-3922565/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is a lethal disease with poor survival rates, especially for cancers arising in the oral cavity or larynx. Cisplatin is a key chemotherapeutic for HNSCC; however poor survival rates may be partially due to cisplatin resistance observed in some HNSCCs. Here, we examined the utility of genome-wide CRISPR knockout profiling for nominating pivotal mechanisms of cisplatin resistance in HNSCC models. Methods We characterized the cisplatin sensitivity of 18 HNSCC cell lines. Next, we used a genome-wide CRISPR/Cas9 library to identify genes involved in cisplatin resistance. We next performed validation assays in the UM-SCC-49 cell line model. Results Our data prioritized 207 genes as pivotal for cisplatin resistance in HNSCC, including novel genes VGLL3, CIRHA1, NCOR1, SPANXA1, MAP2K7, ULK1, and CDK16. Gene set enrichment analysis identified several NOTCH family genes comprising the top pathway driving cisplatin resistance, which we then validated using a targeted NOTCH1 knockout model. Interestingly, we noted that HNSCC models with natural NOTCH pathway alterations including single allele mutations and/or frameshift alterations had diverse responses to cisplatin treatment suggesting that complex and multi-faceted mechanisms contribute to cisplatin resistance in HNSCC. Conclusions Collectively, our study validates a genome-wide CRISPR/Cas9 approach for the discovery of resistance mechanisms in HNSCC, adds to the growing evidence that NOTCH1 status should be evaluated as a biomarker of cisplatin response and provides a framework for future work aimed at overcoming cisplatin resistance.
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Varatanovic S, Stoiber S, Haas M, Lein A, Kadletz-Wanke L, Brkic FF. In vitro antineoplastic effects of MK0752 in HPV-positive head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 2023; 149:14691-14699. [PMID: 37587308 PMCID: PMC10602957 DOI: 10.1007/s00432-023-05269-x] [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: 07/09/2023] [Accepted: 08/09/2023] [Indexed: 08/18/2023]
Abstract
PURPOSE Gamma-secretase inhibitor MK0752 has shown a high therapeutic potential in different solid malignant tumors. Up to now, its antineoplastic effects were not investigated in head and neck squamous cell carcinoma (HNSCC) and particularly in human-papillomavirus (HPV)-positive tumors. METHODS We conducted cytotoxic, migration, and clonogenic assays in two HPV-negative HNSCC cell lines (Cal27 and FaDu) and one HPV-positive cell line (SCC154). Furthermore, in order to assess the pro-apoptotic effects of MK0752, a Caspase 3/7 Glo assay was performed. RESULTS Our experiments revealed antineoplastic effects of MK0752 in all three cell lines. Strong cytotoxic and antimigratory potential was shown in all cell lines, with strongest effects observed in the HPV-positive cell line. Meanwhile, anticlonogenic effects were only shown in Cal27 and SCC154. Most importantly, MK0752 induced apoptosis solely in HPV-positive SCC154. CONCLUSIONS Our novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background.
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Affiliation(s)
- Sara Varatanovic
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Stoiber
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria
| | - Markus Haas
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Alexander Lein
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Kadletz-Wanke
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Faris F Brkic
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
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Sadeghi ES, Nematpour FS, Mohtasham N, Mohajertehran F. The oncogenic role of NOTCH1 as biomarker in oral squamous cell carcinoma and oral lichen planus. Dent Res J (Isfahan) 2023; 20:102. [PMID: 38020255 PMCID: PMC10630544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 03/19/2023] [Accepted: 07/03/2023] [Indexed: 12/01/2023] Open
Abstract
Background Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer with heterogeneous molecular pathogenesis. Oral lichen planus (OLP) is demonstrated potentially can transfer to OSCC malignant lesions. Unfortunately, there are no definitive prognostic and predictive biomarkers for the clinical management of OSCC patients. The present research is the first study that compared an oral premalignant lesion such as OLP to malignant lesions like OSCC for NOTCH1 expression levels to better understand its oncogenic or tumor suppressive role. Materials and Methods In this cross-sectional study, mRNA expression of NOTCH1 was evaluated by quantitative polymerase chain reaction in 65 tissue-embedded Paraffin-Block samples, including 32 OSCC and 33 OLP. Furthermore, we collected demographic information and pathological data, including tumor stage and grade. The association between NOTCH1 and GAPDH gene expressions was determined by Chi-squared, Spearman, and Mann-Whitney tests. A P < 0.05 was considered statistically significant for all statistical analyses. Results Comparison of OSCC and OLP groups showed a statistically significant difference between the quantitative expression of the NOTCH1 gene (P < 0.001). Qualitative gene expression was divided into low expression and high expression. Both study groups demonstrated a statistically significant gene expression difference (P < 0.001). There was a statistically significant difference between age and NOTCH1 expression in the OLP group (P = 0.036). There was no correlation between NOTCH1 expression and age, gender, tumor grade, and stage. Conclusion Since the OSCC is a malignant lesion and the OLP showed the possible nature of malignancy transformation, we can consider the NOTCH1 as a biomarker for the assessment of the tumorigenesis process with a definition of a standard threshold for potentially malignant lesions and malignant OSCC tumors.
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Affiliation(s)
| | | | - Nooshin Mohtasham
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farnaz Mohajertehran
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
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Tan Y, Wang Z, Xu M, Li B, Huang Z, Qin S, Nice EC, Tang J, Huang C. Oral squamous cell carcinomas: state of the field and emerging directions. Int J Oral Sci 2023; 15:44. [PMID: 37736748 PMCID: PMC10517027 DOI: 10.1038/s41368-023-00249-w] [Citation(s) in RCA: 208] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/25/2023] [Accepted: 09/04/2023] [Indexed: 09/23/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.
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Affiliation(s)
- Yunhan Tan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhihan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Mengtong Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Bowen Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Jing Tang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
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Czerwonka A, Kałafut J, Nees M. Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies. Cancers (Basel) 2023; 15:4563. [PMID: 37760535 PMCID: PMC10526229 DOI: 10.3390/cancers15184563] [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: 08/01/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Notch signaling is responsible for conveying messages between cells through direct contact, playing a pivotal role in tissue development and homeostasis. The modulation of Notch-related processes, such as cell growth, differentiation, viability, and cell fate, offer opportunities to better understand and prevent disease progression, including cancer. Currently, research efforts are mainly focused on attempts to inhibit Notch signaling in tumors with strong oncogenic, gain-of-function (GoF) or hyperactivation of Notch signaling. The goal is to reduce the growth and proliferation of cancer cells, interfere with neo-angiogenesis, increase chemosensitivity, potentially target cancer stem cells, tumor dormancy, and invasion, and induce apoptosis. Attempts to pharmacologically enhance or restore disturbed Notch signaling for anticancer therapies are less frequent. However, in some cancer types, such as squamous cell carcinomas, preferentially, loss-of-function (LoF) mutations have been confirmed, and restoring but not blocking Notch functions may be beneficial for therapy. The modulation of Notch signaling can be performed at several key levels related to NOTCH receptor expression, translation, posttranslational (proteolytic) processing, glycosylation, transport, and activation. This further includes blocking the interaction with Notch-related nuclear DNA transcription. Examples of small-molecular chemical compounds, that modulate individual elements of Notch signaling at the mentioned levels, have been described in the recent literature.
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Affiliation(s)
- Arkadiusz Czerwonka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (J.K.); (M.N.)
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Kleszcz R. Advantages of the Combinatorial Molecular Targeted Therapy of Head and Neck Cancer-A Step before Anakoinosis-Based Personalized Treatment. Cancers (Basel) 2023; 15:4247. [PMID: 37686523 PMCID: PMC10486994 DOI: 10.3390/cancers15174247] [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: 07/16/2023] [Revised: 08/13/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The molecular initiators of Head and Heck Squamous Cell Carcinoma (HNSCC) are complex. Human Papillomavirus (HPV) infection is linked to an increasing number of HNSCC cases, but HPV-positive tumors generally have a good prognosis. External factors that promote the development of HPV-negative HNSCC include tobacco use, excessive alcohol consumption, and proinflammatory poor oral hygiene. On a molecular level, several events, including the well-known overexpression of epidermal growth factor receptors (EGFR) and related downstream signaling pathways, contribute to the development of HNSCC. Conventional chemotherapy is insufficient for many patients. Thus, molecular-based therapy for HNSCC offers patients a better chance at a cure. The first molecular target for therapy of HNSCC was EGFR, inhibited by monoclonal antibody cetuximab, but its use in monotherapy is insufficient and induces resistance. This article describes attempts at combinatorial molecular targeted therapy of HNSCC based on several molecular targets and exemplary drugs/drug candidates. The new concept of anakoinosis-based therapy, which means treatment that targets the intercellular and intracellular communication of cancer cells, is thought to be the way to improve the clinical outcome for HNSCC patients. The identification of a link between molecular targeted therapy and anakoinosis raises the potential for further progress in HPV-negative HNSCC therapy.
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Affiliation(s)
- Robert Kleszcz
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcickiego Str., 60-781 Poznan, Poland
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Xue Y, Jiang X, Wang J, Zong Y, Yuan Z, Miao S, Mao X. Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma. Biomark Res 2023; 11:2. [PMID: 36600313 PMCID: PMC9814270 DOI: 10.1186/s40364-022-00433-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/08/2022] [Indexed: 01/06/2023] Open
Abstract
Head and neck cancer is a malignant tumour with a high mortality rate characterized by late diagnosis, high recurrence and metastasis rates, and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer. Various factors are involved in the occurrence and development of HNSCC, including external inflammatory stimuli and oncogenic viral infections. In recent years, studies on the regulation of cell death have provided new insights into the biology and therapeutic response of HNSCC, such as apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and recently the newly discovered cuproptosis. We explored how various cell deaths act as a unique defence mechanism against cancer emergence and how they can be exploited to inhibit tumorigenesis and progression, thus introducing regulatory cell death (RCD) as a novel strategy for tumour therapy. In contrast to accidental cell death, RCD is controlled by specific signal transduction pathways, including TP53 signalling, KRAS signalling, NOTCH signalling, hypoxia signalling, and metabolic reprogramming. In this review, we describe the molecular mechanisms of nonapoptotic RCD and its relationship to HNSCC and discuss the crosstalk between relevant signalling pathways in HNSCC cells. We also highlight novel approaches to tumour elimination through RCD.
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Affiliation(s)
- Yuting Xue
- grid.412651.50000 0004 1808 3502Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xuejiao Jiang
- grid.24696.3f0000 0004 0369 153XBeijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Junrong Wang
- grid.412651.50000 0004 1808 3502Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuxuan Zong
- Department of Breast Surgery, The First of hospital of Qiqihar, Qiqihar, China
| | - Zhennan Yuan
- grid.412651.50000 0004 1808 3502Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Susheng Miao
- grid.412651.50000 0004 1808 3502Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xionghui Mao
- grid.412651.50000 0004 1808 3502Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
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Romero-Masters JC, Lambert PF, Munger K. Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease. Viruses 2022; 14:2138. [PMID: 36298698 PMCID: PMC9611894 DOI: 10.3390/v14102138] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and neck cancer, and non-melanoma skin cancer. Our ability to model HPV-induced malignant disease has been impeded by species specific barriers and pre-clinical animal models have been challenging to develop. The recent discovery of a murine papillomavirus, MmuPV1, that infects laboratory mice and causes the same range of malignancies caused by HPVs provides the papillomavirus field the opportunity to test mechanistic hypotheses in a genetically manipulatable laboratory animal species in the context of natural infections. The E6 and E7 proteins encoded by high-risk HPVs, which are the HPV genotypes associated with human cancers, are multifunctional proteins that contribute to HPV-induced cancers in multiple ways. In this review, we describe the known activities of the MmuPV1-encoded E6 and E7 proteins and how those activities relate to the activities of HPV E6 and E7 oncoproteins encoded by mucosal and cutaneous high-risk HPV genotypes.
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Affiliation(s)
- James C. Romero-Masters
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Karl Munger
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
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14
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Small DNA tumor viruses and human cancer: Preclinical models of virus infection and disease. Tumour Virus Res 2022; 14:200239. [PMID: 35636683 PMCID: PMC9194455 DOI: 10.1016/j.tvr.2022.200239] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 05/05/2022] [Accepted: 05/25/2022] [Indexed: 01/13/2023] Open
Abstract
Human tumor viruses cause various human cancers that account for at least 15% of the global cancer burden. Among the currently identified human tumor viruses, two are small DNA tumor viruses: human papillomaviruses (HPVs) and Merkel cell polyomavirus (MCPyV). The study of small DNA tumor viruses (adenoviruses, polyomaviruses, and papillomaviruses) has facilitated several significant biological discoveries and established some of the first animal models of virus-associated cancers. The development and use of preclinical in vivo models to study HPVs and MCPyV and their role in human cancer is the focus of this review. Important considerations in the design of animal models of small DNA tumor virus infection and disease, including host range, cell tropism, choice of virus isolates, and the ability to recapitulate human disease, are presented. The types of infection-based and transgenic model strategies that are used to study HPVs and MCPyV, including their strengths and limitations, are also discussed. An overview of the current models that exist to study HPV and MCPyV infection and neoplastic disease are highlighted. These comparative models provide valuable platforms to study various aspects of virus-associated human disease and will continue to expand knowledge of human tumor viruses and their relationship with their hosts.
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King RE, Ward-Shaw ET, Hu R, Lambert PF, Thibeault SL. Expanded Basal Compartment and Disrupted Barrier in Vocal Fold Epithelium Infected with Mouse Papillomavirus MmuPV1. Viruses 2022; 14:v14051059. [PMID: 35632798 PMCID: PMC9146965 DOI: 10.3390/v14051059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/07/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
Laryngeal infection with low-risk human papillomaviruses can cause recurrent respiratory papillomatosis (RRP), a disease with severe effects on vocal fold epithelium resulting in impaired voice function and communication. RRP research has been stymied by limited preclinical models. We recently reported a murine model of laryngeal MmuPV1 infection and disease in immunodeficient mice. In the current study, we compare quantitative and qualitative measures of epithelial proliferation, apoptosis, differentiation, and barrier between mice with MmuPV1-induced disease of the larynx and surrounding tissues and equal numbers of uninfected controls. Findings supported our hypothesis that laryngeal MmuPV1 infection recapitulates many features of RRP. Like RRP, MmuPV1 increased proliferation in infected vocal fold epithelium, expanded the basal compartment of cells, decreased differentiated cells, and altered cell–cell junctions and basement membrane. Effects of MmuPV1 on apoptosis were equivocal, as with RRP. Barrier markers resembled human neoplastic disease in severe MmuPV1-induced disease. We conclude that MmuPV1 infection of the mouse larynx provides a useful, if imperfect, preclinical model for RRP that will facilitate further study and treatment development for this intractable and devastating disease.
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Affiliation(s)
- Renee E. King
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (R.E.K.); (E.T.W.-S.); (P.F.L.)
- Department of Surgery, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Ella T. Ward-Shaw
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (R.E.K.); (E.T.W.-S.); (P.F.L.)
| | - Rong Hu
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (R.E.K.); (E.T.W.-S.); (P.F.L.)
| | - Susan L. Thibeault
- Department of Surgery, University of Wisconsin-Madison, Madison, WI 53705, USA
- Correspondence:
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FAS receptor regulates NOTCH activity through ERK-JAG1 axis activation and controls oral cancer stemness ability and pulmonary metastasis. Cell Death Dis 2022; 8:101. [PMID: 35249111 PMCID: PMC8898312 DOI: 10.1038/s41420-022-00899-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 11/08/2022]
Abstract
AbstractPulmonary metastasis occurring via the colonization of circulating cancer stem cells is a major cause of oral squamous cell carcinoma (OSCC)-related death. Thus, understanding the mechanism of OSCC pulmonary metastasis may provide a new opportunity for OSCC treatment. FAS, a well-known apoptosis-inducing death receptor, has multiple nonapoptotic, protumorigenic functions. Previously, we found that SAS OSCC cells with FAS receptor knockout did not affect orthotopic tumor growth or cervical lymph node metastasis. However, FAS knockout cells could not colonize in distant organs to form metastases upon intravenous injection, which hinted at the cancer stemness function of the FAS receptor. Immunohistochemistry staining indicated that the FAS receptor serves as a poor prognosis marker in OSCC patients. FAS knockout inhibited in vitro cancer spheroid formation, migration and invasion, and prevented mesenchymal transition in OSCC cells and inhibited OSCC pulmonary metastasis in vivo. To determine the regulatory mechanism by which the FAS receptor exerts its oncogenic function, we utilized cDNA microarrays and phosphoprotein arrays to discover key candidate genes and signaling pathway regulators. JAG1 expression and NOTCH pathway activation were controlled by the FAS receptor through ERK phosphorylation. Both JAG1 and NOTCH1 silencing decreased in vitro cancer spheroid formation. In OSCC cells, FAS ligand or JAG1 protein treatment increased NOTCH pathway activity, which could be abolished by FAS receptor knockout. In FAS knockout cells, restoring the NOTCH1 intracellular domain stimulated cancer spheroid formation. Both JAG1 and NOTCH1 silencing decreased in vivo OSCC growth. In conclusion, we found a novel FAS-ERK-JAG1-NOTCH1 axis that may contribute to OSCC stemness and pulmonary metastasis.
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Michmerhuizen NL, Heenan C, Wang J, Leonard E, Bellile E, Loganathan SK, Wong SY, Lei YL, Brenner JC. Combined Pik3ca-H1047R and loss-of-function Notch1 alleles decrease survival time in a 4-nitroquinoline N-oxide-driven head and neck squamous cell carcinoma model. Oral Oncol 2022; 126:105770. [DOI: 10.1016/j.oraloncology.2022.105770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 02/07/2022] [Indexed: 11/27/2022]
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Salama AM, Momeni-Boroujeni A, Vanderbilt C, Ladanyi M, Soslow R. Molecular landscape of vulvovaginal squamous cell carcinoma: new insights into molecular mechanisms of HPV-associated and HPV-independent squamous cell carcinoma. Mod Pathol 2022; 35:274-282. [PMID: 34650187 PMCID: PMC9450957 DOI: 10.1038/s41379-021-00942-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/17/2021] [Accepted: 09/27/2021] [Indexed: 02/03/2023]
Abstract
Squamous cell carcinomas of the lower female genital tract may be human papillomavirus-associated or independent. We studied the HPV status, mutational repertoire, histology, and clinical data of 28 samples from 26 patients, 65% with a vulvar primary and 35% with a vaginal primary. These represented invasive vulvovaginal squamous cell carcinomas that underwent clinical tumor-normal targeted massively parallel sequencing analysis. HPV status was determined using the HPV high-risk RNA ISH assay and/or by MSK-IMPACT. Eleven patients had HPV-associated squamous cell carcinoma (four vulvar and seven vaginal) and 15 patients had HPV-independent SqCC (13 vulvar and 2 vaginal). Well-differentiated squamous cell carcinomas were always HPV-independent. HPV-independent moderately and poorly differentiated carcinomas frequently had alterations in the NOTCH signaling pathway (6/7), which were also associated with increased tumor budding (P: 0.002). HPV-associated vulvovaginal squamous cell carcinoma had PIK3CA activating mutations (7/11, 64%) as the most common genomic event, while TERT gene alterations, mainly TERT promoter mutations (14/15 cases, 93%) featured significantly in HPV-independent carcinomas. Other common abnormalities in HPV-independent tumors were TP53 mutations (13/15, 87%), CDKN2A alterations (10/15, 67%), and NOTCH1 and FAT1 mutations (7/15, 47% each). A subset of both HPV-associated and -independent tumors had NOTCH pathway alterations (6/11, 55% and 10/15, 67% respectively), but different genes in this pathway were altered in these tumors. In summary, TERT, TP53, CDKN2A, and NOTCH1 gene alterations strongly point away from an HPV-driven process (odds ratios: 0.01, 0.07, 0, and 0, respectively with p values < 0.02 for all four genes), while PIK3CA activating mutations without the other mutations strongly favors an HPV-driven tumor (odds ratio: 10.12, p value: 0.016). HPV-independent carcinomas are more likely to be moderately-poorly differentiated with intermediate to high tumor cell budding. Cancer cell fraction analysis of HPV-independent squamous carcinomas suggests that TERT and/or NOTCH1 alterations along with TP53 alterations can be the initiating event in these tumors.
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Affiliation(s)
- Abeer M. Salama
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Chad Vanderbilt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Robert Soslow
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol 2022; 19:306-327. [PMID: 35105976 PMCID: PMC8805140 DOI: 10.1038/s41571-022-00603-7] [Citation(s) in RCA: 467] [Impact Index Per Article: 155.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2022] [Indexed: 12/13/2022]
Abstract
Human papillomavirus (HPV)-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV+ OPSCC from its HPV-negative (HPV−) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV+ OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV+ OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes. The incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in most developed countries. In this Review, the authors provide an overview of the epidemiology, molecular biology and treatment of HPV-positive OPSCC, including discussions of the role of treatment de-escalation and emerging novel therapies.
The incidence of human papillomavirus-associated oropharyngeal cancer (HPV+ OPSCC) is expected to continue to rise over the coming decades until the benefits of gender-neutral prophylactic HPV vaccination begin to become manifest. The incidence of HPV+ OPSCC appears to be highest in high-income countries, although more epidemiological data are needed from low- and middle-income countries, in which HPV vaccination coverage remains low. The substantially better prognosis of patients with HPV+ OPSCC compared to those with HPV– OPSCC has been recognized in the American Joint Committee on Cancer TNM8 staging guidelines, which recommend stratification by HPV status to improve staging. The molecular biology and genomic features of HPV+ OPSCC are similar to those of other HPV-associated malignancies, with HPV oncogenes (E6 and E7) acting as key drivers of pathogenesis. Treatment de-intensification is being pursued in clinical trials, although identifying the ~15% of patients with HPV+ OPSCC who have recurrent disease, and who therefore require more intensive treatment, remains a key challenge.
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Foote AG, Lungova V, Thibeault SL. Piezo1-expressing vocal fold epithelia modulate remodeling via effects on self-renewal and cytokeratin differentiation. Cell Mol Life Sci 2022; 79:591. [PMID: 36376494 PMCID: PMC9663367 DOI: 10.1007/s00018-022-04622-6] [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: 06/15/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022]
Abstract
Mechanoreceptors are implicated as functional afferents within mucosa of the airways and the recent discovery of mechanosensitive channels Piezo1 and Piezo2 has proved essential for cells of various mechanically sensitive tissues. However, the role for Piezo1/2 in vocal fold (VF) mucosal epithelia, a cell that withstands excessive biomechanical insult, remains unknown. The purpose of this study was to test the hypothesis that Piezo1 is required for VF mucosal repair pathways of epithelial cell injury. Utilizing a sonic hedgehog (shh) Cre line for epithelial-specific ablation of Piezo1/2 mechanoreceptors, we investigated 6wk adult VF mucosa following naphthalene exposure for repair strategies at 1, 3, 7 and 14 days post-injury (dpi). PIEZO1 localized to differentiated apical epithelia and was paramount for epithelial remodeling events. Injury to wildtype epithelium was most appreciated at 3 dpi. Shhcre/+; Piezo1loxP/loxP, Piezo2 loxP/+ mutant epithelium exhibited severe cell/nuclear defects compared to injured controls. Conditional ablation of Piezo1 and/or Piezo2 to uninjured VF epithelium did not result in abnormal phenotypes across P0, P15 and 6wk postnatal stages compared to heterozygote and control tissue. Results demonstrate a role for Piezo1-expressing VF epithelia in regulating self-renewal via effects on p63 transcription and YAP subcellular translocation-altering cytokeratin differentiation.
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Affiliation(s)
- Alexander G. Foote
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, USA
| | - Vlasta Lungova
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, USA
| | - Susan L. Thibeault
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, USA
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21
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Cells to Surgery Quiz: January 2022. J Invest Dermatol 2022. [DOI: 10.1016/j.jid.2021.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Kałafut J, Czerwonka A, Anameriç A, Przybyszewska-Podstawka A, Misiorek JO, Rivero-Müller A, Nees M. Shooting at Moving and Hidden Targets-Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas. Cancers (Basel) 2021; 13:6219. [PMID: 34944837 PMCID: PMC8699303 DOI: 10.3390/cancers13246219] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022] Open
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is often aggressive, with poor response to current therapies in approximately 40-50% of the patients. Current therapies are restricted to operation and irradiation, often combined with a small number of standard-of-care chemotherapeutic drugs, preferentially for advanced tumour patients. Only very recently, newer targeted therapies have entered the clinics, including Cetuximab, which targets the EGF receptor (EGFR), and several immune checkpoint inhibitors targeting the immune receptor PD-1 and its ligand PD-L1. HNSCC tumour tissues are characterized by a high degree of intra-tumour heterogeneity (ITH), and non-genetic alterations that may affect both non-transformed cells, such as cancer-associated fibroblasts (CAFs), and transformed carcinoma cells. This very high degree of heterogeneity likely contributes to acquired drug resistance, tumour dormancy, relapse, and distant or lymph node metastasis. ITH, in turn, is likely promoted by pronounced tumour cell plasticity, which manifests in highly dynamic and reversible phenomena such as of partial or hybrid forms of epithelial-to-mesenchymal transition (EMT), and enhanced tumour stemness. Stemness and tumour cell plasticity are strongly promoted by Notch signalling, which remains poorly understood especially in HNSCC. Here, we aim to elucidate how Notch signal may act both as a tumour suppressor and proto-oncogenic, probably during different stages of tumour cell initiation and progression. Notch signalling also interacts with numerous other signalling pathways, that may also have a decisive impact on tumour cell plasticity, acquired radio/chemoresistance, and metastatic progression of HNSCC. We outline the current stage of research related to Notch signalling, and how this pathway may be intricately interconnected with other, druggable targets and signalling mechanisms in HNSCC.
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Affiliation(s)
- Joanna Kałafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
| | - Arkadiusz Czerwonka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
| | - Alinda Anameriç
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
| | - Alicja Przybyszewska-Podstawka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
| | - Julia O. Misiorek
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry Polish Academy of Sciences, ul. Noskowskiego 12/14, 61-704 Poznan, Poland;
| | - Adolfo Rivero-Müller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
| | - Matthias Nees
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
- Western Finland Cancer Centre (FICAN West), Institute of Biomedicine, University of Turku, 20101 Turku, Finland
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The Balance between Differentiation and Terminal Differentiation Maintains Oral Epithelial Homeostasis. Cancers (Basel) 2021; 13:cancers13205123. [PMID: 34680271 PMCID: PMC8534139 DOI: 10.3390/cancers13205123] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Oral cancer affecting the oral cavity represents the most common cancer of the head and neck region. Oral cancer develops in a multistep process in which normal cells gradually accumulate genetic and epigenetic modifications to evolve into a malignant disease. Mortality for oral cancer patients is high and morbidity has a significant long-term impact on the health and wellbeing of affected individuals, typically resulting in facial disfigurement and a loss of the ability to speak, chew, taste, and swallow. The limited scope to which current treatments are able to control oral cancer underlines the need for novel therapeutic strategies. This review highlights the molecular differences between oral cell proliferation, differentiation and terminal differentiation, defines terminal differentiation as an important tumour suppressive mechanism and establishes a rationale for clinical investigation of differentiation-paired therapies that may improve outcomes in oral cancer. Abstract The oral epithelium is one of the fastest repairing and continuously renewing tissues. Stem cell activation within the basal layer of the oral epithelium fuels the rapid proliferation of multipotent progenitors. Stem cells first undergo asymmetric cell division that requires tightly controlled and orchestrated differentiation networks to maintain the pool of stem cells while producing progenitors fated for differentiation. Rapidly expanding progenitors subsequently commit to advanced differentiation programs towards terminal differentiation, a process that regulates the structural integrity and homeostasis of the oral epithelium. Therefore, the balance between differentiation and terminal differentiation of stem cells and their progeny ensures progenitors commitment to terminal differentiation and prevents epithelial transformation and oral squamous cell carcinoma (OSCC). A recent comprehensive molecular characterization of OSCC revealed that a disruption of terminal differentiation factors is indeed a common OSCC event and is superior to oncogenic activation. Here, we discuss the role of differentiation and terminal differentiation in maintaining oral epithelial homeostasis and define terminal differentiation as a critical tumour suppressive mechanism. We further highlight factors with crucial terminal differentiation functions and detail the underlying consequences of their loss. Switching on terminal differentiation in differentiated progenitors is likely to represent an extremely promising novel avenue that may improve therapeutic interventions against OSCC.
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Wei H, Ge Q, Zhang LY, Xie J, Gan RH, Lu YG, Zheng DL. EGCG inhibits growth of tumoral lesions on lip and tongue of K-Ras transgenic mice through the Notch pathway. J Nutr Biochem 2021; 99:108843. [PMID: 34407449 DOI: 10.1016/j.jnutbio.2021.108843] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 05/11/2021] [Accepted: 07/06/2021] [Indexed: 01/29/2023]
Abstract
Epigallocatechin-3-gallate (EGCG), the main active ingredient of green tea, exhibits low toxic side effect and versatile bioactivities, and its anti-cancer effect has been extensively studied. Most of the studies used cancer cell lines and xenograft models. However, whether EGCG can prevent tumor onset after cancer-associated mutations occur is still controversial. In the present study, Krt14-cre/ERT-Kras transgenic mice were developed and the expression of K-RasG12D was induced by tamoxifen. Two weeks after induction, the K-Ras mutant mice developed exophytic tumoral lesions on the lips and tongues, with significant activation of Notch signaling pathway. Administration of EGCG effectively delayed the time of appearance, decreased the size and weight of tumoral lesions, relieved heterotypic hyperplasia of tumoral lesions, and prolonged the life of the mice. The Notch signaling pathway was significantly inhibited by EGCG in the tumoral lesions. Furthermore, EGCG significantly induced cell apoptosis and inhibited the proliferation of tongue cancer cells by blocking the activation of Notch signaling pathway. Taken together, these results indicate EGCG as an effective chemotherapeutic agent for tongue cancer by targeting Notch pathway.
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Affiliation(s)
- Hua Wei
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, China; Department of Pediatric Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Qi Ge
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, China; Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Ling-Yu Zhang
- School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Jing Xie
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, China; Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Rui-Huan Gan
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, China; Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - You-Guang Lu
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, China; Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
| | - Da-Li Zheng
- Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, China.
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25
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Bhat GR, Hyole RG, Li J. Head and neck cancer: Current challenges and future perspectives. Adv Cancer Res 2021; 152:67-102. [PMID: 34353444 DOI: 10.1016/bs.acr.2021.05.002] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Head and neck cancers are a heterogeneous, aggressive and genetically complex collection of malignancies of the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses and salivary glands, which are difficult to treat. About 90% of all head and neck cancers are squamous cell carcinomas (HNSCC). Larynx and Oral cavity carcinomas are generally related with tobacco consumption, alcohol abuse (or both), but pharynx carcinomas are generally associated with infection of human papillomavirus (HPV), especially HPV-16 subtype. Thus, usually HNSCC can be separated into HPV-negative and HPV-positive categories. Despite substantial efforts invested into therapeutic development of HNSCC, the 5-year survival rate of patients with HNSCC still remains dismal. The primary reason being late diagnosis, recurrent metastasis, relapse and resistance to therapies. Currently surgery and radiotherapy represent the baseline treatment options for most initial stage HNSCC patients, but these treatments are associated with significant morbidity and poor prognosis. Moreover, the issue of resistance to both radiotherapy/chemotherapy and recurrent relapse are common in HNSCC. Elucidation of the genetic landscape, tumor microenvironment and aberrant signaling pathways have generated new insights into the molecular pathogenesis of this disease. Thus, the scientific research has therefore been focused on the understanding of HNSCC biology and immunobiology to identification of predictive/prognostic biomarkers, which will be key to develop more effective targeted therapies with less toxicity and high specificity.
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Affiliation(s)
- Gh Rasool Bhat
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
| | - Rosalie G Hyole
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
| | - Jiong Li
- Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Richmond, VA, United States; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, VA, United States.
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26
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Vats A, Trejo-Cerro O, Thomas M, Banks L. Human papillomavirus E6 and E7: What remains? Tumour Virus Res 2021; 11:200213. [PMID: 33716206 PMCID: PMC7972986 DOI: 10.1016/j.tvr.2021.200213] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Decades of research on the human papillomavirus oncogenes, E6 and E7, have given us huge amounts of data on their expression, functions and structures. We know much about the very many cellular proteins and pathways that they influence in one way or another. However, much of this information is quite discrete, referring to one activity examined under one condition. It is now time to join the dots to try to understand a larger picture: how, where and when do all these interactions occur... and why? Examining these questions will also show how many of the yet obscure cellular processes work together for cellular and tissue homeostasis in health and disease.
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Affiliation(s)
- Arushi Vats
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
| | - Oscar Trejo-Cerro
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
| | - Miranda Thomas
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy.
| | - Lawrence Banks
- Tumour Virology Group, ICGEB, AREA Science Park, Trieste, 34149, Italy
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27
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Khelil M, Griffin H, Bleeker MCG, Steenbergen RDM, Zheng K, Saunders-Wood T, Samuels S, Rotman J, Vos W, van den Akker BE, de Menezes RX, Kenter GG, Doorbar J, Jordanova ES. Delta-Like Ligand-Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis. Cancer Res 2021; 81:1909-1921. [PMID: 33500246 DOI: 10.1158/0008-5472.can-20-1996] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 11/25/2020] [Accepted: 01/20/2021] [Indexed: 11/16/2022]
Abstract
Human papillomavirus (HPV) drives high-grade intraepithelial neoplasia and cancer; for unknown reasons, this occurs most often in the cervical transformation zone. Either mutation or HPV E6-driven inhibition of Notch1 can drive neoplastic development in stratified squamous epithelia. However, the contribution of Notch1 and its Delta-like ligands (DLL) to site susceptibility remains poorly understood. Here, we map DLL1/DLL4 expression in cell populations present in normal cervical biopsies by immunofluorescence. In vitro keratinocyte 2D monolayer models, growth assays, and organotypic raft cultures were used to assess the functional role of DLL-Notch signaling in uninfected cells and its modulation by HPV16 in neoplasia. An RNA sequencing-based gene signature was used to suggest the cell of origin of 279 HPV-positive cervical carcinomas from The Cancer Genome Atlas and to relate this to disease prognosis. Finally, the prognostic impact of DLL4 expression was investigated in three independent cervical cancer patient cohorts. Three molecular cervical carcinoma subtypes were identified, with reserve cell tumors the most common and linked to relatively good prognosis. Reserve cells were characterized as DLL1-/DLL4+, a proliferative phenotype that is temporarily observed during squamous metaplasia and wound healing but appears to be sustained by HPV16 E6 in raft models of low-grade and, more prominently, high-grade neoplasia. High expression of DLL4 was associated with an increased likelihood of cervical cancer-associated death and recurrence. Taken together, DLL4-Notch1 signaling reflects a proliferative cellular state transiently present during physiologic processes but inherent to cervical reserve cells, making them strongly resemble neoplastic tissue even before HPV infection has occurred. SIGNIFICANCE: This study investigates cervical cancer cell-of-origin populations and describes a DLL-Notch1 phenotype that is associated with disease prognosis and that might help identify cells that are susceptible to HPV-induced carcinogenesis.
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Affiliation(s)
- Maryam Khelil
- Centre for Gynaecological Oncology Amsterdam (CGOA): Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, the Netherlands
| | - Heather Griffin
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Maaike C G Bleeker
- Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam (CCA), Amsterdam, the Netherlands
| | - Renske D M Steenbergen
- Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam (CCA), Amsterdam, the Netherlands
| | - Ke Zheng
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | | | - Sanne Samuels
- Centre for Gynaecological Oncology Amsterdam (CGOA): Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, the Netherlands
| | - Jossie Rotman
- Centre for Gynaecological Oncology Amsterdam (CGOA): Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, the Netherlands
| | - Wim Vos
- Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam (CCA), Amsterdam, the Netherlands
| | | | - Renée X de Menezes
- Amsterdam UMC, Vrije Universiteit Amsterdam, Epidemiology and Biostatistics, Amsterdam, the Netherlands
| | - Gemma G Kenter
- Centre for Gynaecological Oncology Amsterdam (CGOA): Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, the Netherlands
| | - John Doorbar
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Ekaterina S Jordanova
- Centre for Gynaecological Oncology Amsterdam (CGOA): Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, the Netherlands.
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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28
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Notch Signaling and Human Papillomavirus-Associated Oral Tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1287:105-122. [PMID: 33034029 DOI: 10.1007/978-3-030-55031-8_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.
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29
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Li Y, Li Y, Chen X. NOTCH and Esophageal Squamous Cell Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1287:59-68. [PMID: 33034026 PMCID: PMC7895477 DOI: 10.1007/978-3-030-55031-8_5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.
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Affiliation(s)
- Yong Li
- Department of Thoracic Surgery, National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA
| | - Yahui Li
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA
| | - Xiaoxin Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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30
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Grilli G, Hermida-Prado F, Álvarez-Fernández M, Allonca E, Álvarez-González M, Astudillo A, Moreno-Bueno G, Cano A, García-Pedrero JM, Rodrigo JP. Impact of notch signaling on the prognosis of patients with head and neck squamous cell carcinoma. Oral Oncol 2020; 110:105003. [PMID: 32932170 DOI: 10.1016/j.oraloncology.2020.105003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 09/04/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The function of NOTCH signaling (oncogenic or oncosuppressive) remains controversial in head and neck squamous cell carcinomas (HNSCC). The purpose of this work is to investigate the role of NOTCH pathway in HNSCC prognosis. METHODS Immunohistochemical NOTCH1 and HES1 expression was jointly evaluated and correlated with other NOTCH1 targets, p21 (WAF1/Cip1) and Cyclin D1, using an unbiased cohort of 372 surgically treated HPV-negative HNSCC patients. RESULTS Membranous NOTCH1 expression was detected in 197 (61%) out of 324 evaluable tumor samples, and nuclear NOTCH1 expression in 91 samples (28%). Nuclear HES1 expression was found in 224 (67%) cases. Membranous and nuclear NOTCH1 expression were consistently and significantly correlated with nuclear HES1 (P < 0.001) and p21 (P = 0.03) expression, but not with Cyclin D1. NOTCH1 expression was significantly associated to early stages (I-II), non-recurrent disease, and better disease-specific (DSS) and overall survival (OS) rates (P < 0.001). Moreover, triple-positive cases (NOTCH1+/HES1+/p21+) exhibited significantly improved DSS (P < 0.001) and OS (P = 0.004), thus reinforcing the association of NOTCH pathway activation with a better prognosis in HNSCC. Multivariate analysis further revealed membranous NOTCH1 expression as a robust independent predictor of better DSS (HR = 0.554; 95% IC 0.412-0.745; P < 0.001) and better OS (HR = 0.640; 95% CI 0.491-0.835; P = 0.001). CONCLUSION These findings show the association of NOTCH pathway activation with a better prognosis in HNSCC patients, also revealing membranous NOTCH1 expression as a robust independent predictor of improved survival. Accordingly, these results suggest a tumor suppressive rather than an oncogenic role for NOTCH pathway in HNSCC.
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Affiliation(s)
- Gianluigi Grilli
- Department of Otolaryngology, Ospedali Riuniti and Università degli Studi di Foggia, Foggia, Italy
| | - Francisco Hermida-Prado
- Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Mónica Álvarez-Fernández
- Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain
| | - Eva Allonca
- Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Miguel Álvarez-González
- Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain
| | - Aurora Astudillo
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain; Departamento de Patología, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Gema Moreno-Bueno
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPAZ, Madrid, Spain; Fundación MD Anderson Internacional Madrid, Spain
| | - Amparo Cano
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPAZ, Madrid, Spain
| | - Juana M García-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
| | - Juan P Rodrigo
- Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
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31
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Facompre ND, Rajagopalan P, Sahu V, Pearson AT, Montone KT, James CD, Gleber-Netto FO, Weinstein GS, Jalaly J, Lin A, Rustgi AK, Nakagawa H, Califano JA, Pickering CR, White EA, Windle BE, Morgan IM, Cohen RB, Gimotty PA, Basu D. Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models. Int J Cancer 2020; 147:3236-3249. [PMID: 32478869 DOI: 10.1002/ijc.33125] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 04/25/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023]
Abstract
Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development.
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Affiliation(s)
- Nicole D Facompre
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Pavithra Rajagopalan
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Varun Sahu
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Kathleen T Montone
- Department of Pathology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Claire D James
- School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Gregory S Weinstein
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jalal Jalaly
- Department of Pathology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alexander Lin
- Department of Radiation Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Anil K Rustgi
- Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hiroshi Nakagawa
- Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joseph A Califano
- Department of Surgery, University of California San Diego, San Diego, California, USA
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The MD Anderson Cancer Center, Houston, Texas, USA
| | - Elizabeth A White
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Bradford E Windle
- School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Iain M Morgan
- School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Roger B Cohen
- Department of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Phyllis A Gimotty
- Department of Biostatistics, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Devraj Basu
- Department of Otorhinolaryngology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.,The Wistar Institute, Philadelphia, Pennsylvania, USA
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32
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Wei T, Lambert PF. A highway to carcinogenesis: the role of IQGAP1, a signaling scaffolding protein, in head and neck cancer development. Oncoscience 2020; 7:49-51. [PMID: 32923516 PMCID: PMC7458336 DOI: 10.18632/oncoscience.511] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 04/30/2020] [Indexed: 12/17/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide. One of the most critical signaling pathways in HNSCC is the Epidermal Growth Factor Receptor/ Phosphatidylinositol 3-Kinase (EGFR/PI3K) pathway. IQ motif-containing GTPase- activating protein 1 (IQGAP1), a protein upregulated in multiple types of cancer, acts as a scaffold for this pathway and others implicated in cancer. IQGAP1 is overexpressed in HNSCCs, and its overexpression correlates with poorer prognosis in HNSCC patients, indicating that IQGAP1 might be important in HNSCC development. Here, we summarized our recent demonstrating a role of IQGAP1 in promoting HNSCC, at least in part, by scaffolding the EGFR/PI3K signaling pathway.
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Affiliation(s)
- Tao Wei
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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33
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de Carvalho AC, Perdomo S, Dos Santos W, Fernandes GC, de Jesus LM, Carvalho RS, Scapulatempo-Neto C, de Almeida GC, Sorroche BP, Arantes LMRB, Melendez ME, De Marchi P, Hayes N, Reis RM, Carvalho AL. Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma. Sci Rep 2020; 10:9970. [PMID: 32561788 PMCID: PMC7305218 DOI: 10.1038/s41598-020-66741-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.
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Affiliation(s)
| | - Sandra Perdomo
- Institute of Nutrition, Genetics and Metabolism Research, Faculty of Medicine, Universidad El Bosque, Bogotá, Colombia
- International Agency of Research on Cancer, Lyon, France
| | | | | | | | | | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Pathology and Molecular Diagnostics Service, Diagnósticos da América-DASA, São Paulo, SP, Brazil
| | | | | | | | - Matias Eliseo Melendez
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Pelé Little Prince Research Institute, Curitiba, PR, Brazil
- Little Prince College, Curitiba, PR, Brazil
| | - Pedro De Marchi
- Department of Medical Oncology, Barretos Cancer Hospital, Barretos, SP, Brazil
- Oncoclinicas, Rio de Janeiro, RJ, Brazil
| | - Neil Hayes
- Department of Medicine, Division of Oncology, UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - André Lopes Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.
- International Agency of Research on Cancer, Lyon, France.
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Abstract
Human papillomavirus (HPV) is the most common sexually transmitted pathogen, and high-risk HPVs contribute to 5% of human cancers, including 25% of head and neck squamous cell carcinomas (HNSCCs). Despite the significant role played by HPVs in HNSCC, there is currently no available in vivo system to model the process from papillomavirus infection to virus-induced HNSCC. In this paper, we describe an infection-based HNSCC model, utilizing a mouse papillomavirus (MmuPV1), which naturally infects laboratory mice. Infections of the tongue epithelium of two immunodeficient strains with MmuPV1 caused high-grade squamous dysplasia with early signs of invasive carcinoma over the course of 4 months. When combined with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO), MmuPV1 caused invasive squamous cell carcinoma (SCC) on the tongue of both immunodeficient and immunocompetent mice. These tumors expressed markers of papillomavirus infection and HPV-associated carcinogenesis. This novel preclinical model provides a valuable new means to study how natural papillomavirus infections contribute to HNSCC.IMPORTANCE The species specificity of papillomavirus has limited the development of an infection-based animal model to study HPV-associated head and neck carcinogenesis. Our study presents a novel in vivo model using the mouse papillomavirus MmuPV1 to study papillomavirus-associated head and neck cancer. In our model, MmuPV1 infects and causes lesions in both immunodeficient and genetically immunocompetent strains of mice. These virally induced lesions carry features associated with both HPV infections and HPV-associated carcinogenesis. Combined with previously identified cancer cofactors, MmuPV1 causes invasive squamous cell carcinomas in mice. This model provides opportunities for basic and translational studies of papillomavirus infection-based head and neck disease.
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A Mouse Model of Oropharyngeal Papillomavirus-Induced Neoplasia Using Novel Tools for Infection and Nasal Anesthesia. Viruses 2020; 12:v12040450. [PMID: 32316091 PMCID: PMC7232375 DOI: 10.3390/v12040450] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/03/2020] [Accepted: 04/11/2020] [Indexed: 12/11/2022] Open
Abstract
Human head and neck cancers that develop from the squamous cells of the oropharynx (Oropharyngeal Squamous Cell Carcinomas or OPSCC) are commonly associated with the papillomavirus infection. A papillomavirus infection-based mouse model of oropharyngeal tumorigenesis would be valuable for studying the development and treatment of these tumors. We have developed an efficient system using the mouse papillomavirus (MmuPV1) to generate dysplastic oropharyngeal lesions, including tumors, in the soft palate and the base of the tongue of two immune-deficient strains of mice. To maximize efficiency and safety during infection and endoscopy, we have designed a nose cone for isoflurane-induced anesthesia that takes advantage of a mouse’s need to breathe nasally and has a large window for oral manipulations. To reach and infect the oropharynx efficiently, we have repurposed the Greer Pick allergy testing device as a virus delivery tool. We show that the Pick can be used to infect the epithelium of the soft palate and the base of the tongue of mice directly, without prior scarification. The ability to induce and track oropharyngeal papillomavirus-induced tumors in the mouse, easily and robustly, will facilitate the study of oropharyngeal tumorigenesis and potential treatments.
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Spurgeon ME, Lambert PF. Mus musculus Papillomavirus 1: a New Frontier in Animal Models of Papillomavirus Pathogenesis. J Virol 2020; 94:e00002-20. [PMID: 32051276 PMCID: PMC7163119 DOI: 10.1128/jvi.00002-20] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 02/04/2020] [Indexed: 01/06/2023] Open
Abstract
Animal models of viral pathogenesis are essential tools in human disease research. Human papillomaviruses (HPVs) are a significant public health issue due to their widespread sexual transmission and oncogenic potential. Infection-based models of papillomavirus pathogenesis have been complicated by their strict species and tissue specificity. In this Gem, we discuss the discovery of a murine papillomavirus, Mus musculus papillomavirus 1 (MmuPV1), and how its experimental use represents a major advancement in models of papillomavirus-induced pathogenesis/carcinogenesis, and their transmission.
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Affiliation(s)
- Megan E Spurgeon
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Paul F Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons. Cells 2020; 9:cells9030644. [PMID: 32155948 PMCID: PMC7140461 DOI: 10.3390/cells9030644] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 12/19/2022] Open
Abstract
Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions.
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Niu K, Guo C, Teng S, Zhou D, Yu S, Yin W, Wang P, Zhu W, Duan M. Pepsin promotes laryngopharyngeal neoplasia by modulating signaling pathways to induce cell proliferation. PLoS One 2020; 15:e0227408. [PMID: 31940393 PMCID: PMC6961942 DOI: 10.1371/journal.pone.0227408] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 12/18/2019] [Indexed: 01/12/2023] Open
Abstract
Pepsin plays an important role in laryngopharyngeal reflux (LPR), a risk factor for the development of hypopharyngeal squamous cell carcinomas (HPSCC). However, the role of pepsin in HPSCC is not clear. We show by immunohistochemistry that pepsin positivity occurs in a significant proportion of human primary HPSCC specimens, and in many cases matched adjacent uninvolved epithelia are negative for pepsin. Pepsin positivity is associated with nodal involvement, suggesting that pepsin may have a role in metastasis. Treatment of FaDu cancer cells with pepsin increased cell proliferation, possibly by inducing G1/S transition. We also observed significant changes in expression of genes involved in NF-kappaB, TRAIL and Notch signaling. Our data suggest that pepsin plays an important role in HPSCC and that targeting pepsin could have potential therapeutic benefits.
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Affiliation(s)
- Kai Niu
- Department of Otolaryngology Head and Neck Surgery, the First Hospital of Jilin University, Changchun, PR China
| | - Chunjie Guo
- Department of Radiology, the First Hospital of Jilin University, Changchun, PR China
| | - Shiyong Teng
- Department of Anesthesiology, the First Hospital of Jilin University, Changchun, PR China
| | - Dandan Zhou
- Department of Radiology, the First Hospital of Jilin University, Changchun, PR China
| | - Shuyuan Yu
- Department of Otolaryngology Head and Neck Surgery, the First Hospital of Jilin University, Changchun, PR China
| | - Wanzhong Yin
- Department of Otolaryngology Head and Neck Surgery, the First Hospital of Jilin University, Changchun, PR China
| | - Ping Wang
- Department of Otolaryngology Head and Neck Surgery, the First Hospital of Jilin University, Changchun, PR China
| | - Wei Zhu
- Department of Otolaryngology Head and Neck Surgery, the First Hospital of Jilin University, Changchun, PR China
| | - Maoli Duan
- Department of Clinical Science, Intervention and Technology, Department of Otolaryngology Head and Neck Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
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Choonoo G, Blucher AS, Higgins S, Boardman M, Jeng S, Zheng C, Jacobs J, Anderson A, Chamberlin S, Evans N, Vigoda M, Cordier B, Tyner JW, Kulesz-Martin M, McWeeney SK, Laderas T. Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma. PLoS One 2019; 14:e0223639. [PMID: 31596908 PMCID: PMC6785123 DOI: 10.1371/journal.pone.0223639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/25/2019] [Indexed: 11/18/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either “light” or “dark” to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35–38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.
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Affiliation(s)
- Gabrielle Choonoo
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Aurora S. Blucher
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- * E-mail:
| | - Samuel Higgins
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Mitzi Boardman
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Sophia Jeng
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Christina Zheng
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - James Jacobs
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
- Pediatric Hematology and Oncology, OHSU Doernbecher Children’s Hospital, Portland, Oregon, United States of America
| | - Ashley Anderson
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Steven Chamberlin
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Nathaniel Evans
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Myles Vigoda
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Benjamin Cordier
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Jeffrey W. Tyner
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Molly Kulesz-Martin
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Shannon K. McWeeney
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
- Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Ted Laderas
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America
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40
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Wei T, Choi S, Buehler D, Anderson RA, Lambert PF. A PI3K/AKT Scaffolding Protein, IQ Motif-Containing GTPase Associating Protein 1 (IQGAP1), Promotes Head and Neck Carcinogenesis. Clin Cancer Res 2019; 26:301-311. [PMID: 31597661 DOI: 10.1158/1078-0432.ccr-19-1063] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 08/15/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Head and neck cancer (HNC) is the sixth most common cancer worldwide with a 5-year survival rate of less than 50%. The PI3K/AKT/mTOR signaling pathway is frequently implicated in HNC. Recently, IQ motif-containing GTPase-activating protein 1 (IQGAP1) was discovered to scaffold the PI3K/AKT signaling pathway. IQGAP1 gene expression is increased in HNC, raising the hypothesis that IQGAP1 contributes to HNC. EXPERIMENTAL DESIGN We performed a combination of in vitro studies using human cancer cell lines treated with a cell-permeable peptide that interferes with IQGAP1's ability to bind to PI3K, and in vivo studies utilizing mice genetically knocked out for the Iqgap1 (Iqgap1 -/-). In vivo EGF stimulation assays were used to evaluate PI3K signaling. To study the role of IQGAP1 in HNC, we used a well-validated mouse model that drives HNC via a synthetic oral carcinogen, 4-nitroquinoline 1-oxide (4NQO). RESULTS IQGAP1 is necessary for efficient PI3K signaling in vitro and in vivo. Disruption of IQGAP1-scaffolded PI3K/AKT signaling reduced HNC cell survival. Iqgap1 -/- mice had significantly lower cancer incidences, lesser disease severity, and fewer cancer foci. IQGAP1 protein levels were increased in HNC arising in Iqgap1+/+ mice. The level of PI3K signaling in 4NQO-induced HNC arising in Iqgap1 -/- mice was significantly reduced, consistent with the hypothesis that IQGAP1 contributes to HNC at least partly through PI3K signaling. High IQGAP1 expression correlated with reduced survival, and high pS6 levels correlated with high IQGAP1 levels in patients with HNC. CONCLUSIONS These data demonstrate that IQGAP1 contributes to head and neck carcinogenesis.
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Affiliation(s)
- Tao Wei
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Suyong Choi
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin
| | - Darya Buehler
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Richard A Anderson
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin
| | - Paul F Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. .,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
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41
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Gan RH, Lin LS, Xie J, Huang L, Ding LC, Su BH, Peng XE, Zheng DL, Lu YG. FLI-06 Intercepts Notch Signaling And Suppresses The Proliferation And Self-renewal Of Tongue Cancer Cells. Onco Targets Ther 2019; 12:7663-7674. [PMID: 31571917 PMCID: PMC6756372 DOI: 10.2147/ott.s221231] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 08/29/2019] [Indexed: 01/18/2023] Open
Abstract
Purpose The Notch signaling pathway plays an oncogenic role in tongue squamous cell carcinoma. The aim of this study was to inhibit the proliferation and self-renewal of tongue cancer cells by applying Notch signaling pathway inhibitor FLI-06 (Selleck, USA) and to lay a foundation for the clinically targeted treatment of tongue cancer for the future. Methods The mRNA expression level of Notch1 and the overall survival rate of patients with tongue cancer were examined by analyzing the TCGA database. Tongue cancer cells were treated with FLI-06. Cell proliferation, apoptosis, and stem cell self-renewal ability were tested in appropriate ways. A xenograft mouse model was established to observe tumor growth. Results From the TCGA data, we demonstrated that patients with high expression of Notch1 had a poor prognosis. We observed that the Notch signaling pathway inhibitor FLI-06 can restrain the activation of the Notch signaling pathway, decrease cell proliferation and induce cell apoptosis in vitro. The xenograft experiment indicated that intraperitoneal injection of FLI-06 inhibited tumor growth and increased cell apoptosis. FLI-06 suppressed both the mRNA and protein expression of Notch receptor and Notch targeted genes. We also observed that FLI-06 suppressed the proliferation of tongue cancer stem cells. Conclusion FLI-06 can block the proliferation and self-renewal of tongue cancer cells. It is inferred that this compound, which inhibits the Notch signaling pathway, may serve as a potential targeted drug for the treatment of tongue cancer in the clinic.
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Affiliation(s)
- Rui-Huan Gan
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, People's Republic of China
| | - Li-Song Lin
- Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Jing Xie
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350000, People's Republic of China.,Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350004, People's Republic of China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350122, People's Republic of China
| | - Li Huang
- Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou 350005, People's Republic of China.,Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350004, People's Republic of China
| | - Lin-Can Ding
- Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Bo-Hua Su
- Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou 350005, People's Republic of China
| | - Xian-E Peng
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, People's Republic of China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350122, People's Republic of China
| | - Da-Li Zheng
- Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350004, People's Republic of China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350122, People's Republic of China
| | - You-Guang Lu
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, People's Republic of China.,Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350000, People's Republic of China
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42
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Alsahafi E, Begg K, Amelio I, Raulf N, Lucarelli P, Sauter T, Tavassoli M. Clinical update on head and neck cancer: molecular biology and ongoing challenges. Cell Death Dis 2019; 10:540. [PMID: 31308358 PMCID: PMC6629629 DOI: 10.1038/s41419-019-1769-9] [Citation(s) in RCA: 343] [Impact Index Per Article: 57.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/23/2019] [Accepted: 05/28/2019] [Indexed: 12/15/2022]
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.
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Affiliation(s)
- Elham Alsahafi
- Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London, SE1 1UL, UK
| | - Katheryn Begg
- Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London, SE1 1UL, UK
| | - Ivano Amelio
- Medical Research Council, Toxicology Unit, Leicester University, Leicester, LE1 9HN, UK
| | - Nina Raulf
- Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London, SE1 1UL, UK
| | - Philippe Lucarelli
- Faculté des Sciences, de La Technologie et de La Communication, University of Luxembourg, 6, Avenue Du Swing, Belvaux, 4367, Luxembourg
| | - Thomas Sauter
- Faculté des Sciences, de La Technologie et de La Communication, University of Luxembourg, 6, Avenue Du Swing, Belvaux, 4367, Luxembourg
| | - Mahvash Tavassoli
- Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London, SE1 1UL, UK.
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43
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Dogan S, Xu B, Middha S, Vanderbilt CM, Bowman AS, Migliacci J, Morris LGT, Seshan VE, Ganly I. Identification of prognostic molecular biomarkers in 157 HPV-positive and HPV-negative squamous cell carcinomas of the oropharynx. Int J Cancer 2019; 145:3152-3162. [PMID: 31093971 DOI: 10.1002/ijc.32412] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 04/23/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing due to high-risk HPV infection. We explored the significance of genetic alterations in HPV-positive (HPV-P) and HPV-negative (HPV-N) OPSCC patients on long-term outcome. A total of 157 cases of primary resected OPSCC diagnosed from 1978 to 2005 were subjected to a targeted exome sequencing by MSK-IMPACT™ interrogating somatic mutations in 410 cancer-related genes. Mutational profiles were correlated to recurrence and survival outcomes. OPSCC included 47% HPV-positive (HPV-P) and 53% HPV-negative (HPV-N) tumors arising in the base of tongue (BOT, 43%), palatine tonsil (30%) and soft palate (SP, 27%). HPV negative status, SP location and smoking were associated with poorer outcome. Poorer overall survival was found in NOTCH1-mutated HPV-P (p = 0.039), and in SOX2-amplified HPV-N cases (p = 0.036). Chromosomal arm gains in 8p and 8q, and 16q loss were more common in HPV-P (p = 0.005, 0.04 and 0.01, respectively), while 9p, 18q and 21q losses were more frequent in HPV-N OPSCC (p = 0.006, 0.002 and 0.01, respectively). Novel, potentially functional JAK3, MYC and EP300 intragenic deletions were found in HPV-P, and FOXP1, CDKN2A, CCND1 and RUNX1 intragenic deletions and one FGFR3 inversion were detected in HPV-N tumors. HPV-N/TP53-wild-type OPSCC harbored recurrent mutations in NOTCH1/3/4 (39%), PIK3CA, FAT1 and TERT. In comparison to their oral and laryngeal counterparts, HPV-N OPSCC were genetically distinct. In OPSCC, HPV status, tumor subsite and smoking determine outcome. Risk-stratification can be further refined based on the mutational signature, namely, NOTCH1 and SOX2 mutation status.
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Affiliation(s)
- Snjezana Dogan
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bin Xu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sumit Middha
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chad M Vanderbilt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anita S Bowman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jocelyn Migliacci
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Luc G T Morris
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.,Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Venkatraman E Seshan
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ian Ganly
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.,Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Mitsiadis TA. Emerging Trends and Promises in Orofacial Cancers. Front Physiol 2019; 10:679. [PMID: 31191362 PMCID: PMC6549536 DOI: 10.3389/fphys.2019.00679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 05/13/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Thimios A Mitsiadis
- Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Zurich, Switzerland
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