Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Medical Biology".

Deadline for manuscript submissions: 15 July 2024 | Viewed by 14768

Special Issue Editor


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Guest Editor
Melbourne Dental School, University of Melbourne, Parkville 3010, Australia
Interests: oral carcinogenesis; autoimmune blistering diseases; cell adhesion
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Special Issue Information

Dear Colleagues,

I cordially invite you to share your expertise in the field of oral autoimmune diseases and oral cancer by contributing with an original or review article to Biology.

The peculiar morpho-functional characteristics of the oral cavity make it a unique anatomical district. Similarly, the diseases presenting or manifesting in the oral cavity often show distinct pathophysiological features compared to diseases manifesting in other body districts, including a range of autoimmune and neoplastic conditions. Despite the obvious differences, these classes of disease share several mechanistic processes, such as common molecular and functional pathways as well as biomarkers. For example, the tumour microenvironment is a key driver of cancer progression and, similarly, the development of autoimmune diseases involves an intricate network of cytokines and immune cells of the microenvironment. In both pathological processes, the pivotal role of the oral microbiota is being increasingly recognised. In another example, cell adhesion molecules are key to the pathophysiology of oral squamous cell carcinoma but are also the main targets of several oral autoimmune blistering diseases. From a systems biology perspective, we have used oral cancer and oral autoimmune diseases as models of internal and external perturbation of the system, respectively.

The purpose of this Special Issue is to elucidate the pathophysiology of these chronic, life-threatening conditions. An integrated view of the mechanisms maintaining health and disease of the oral cavity will highlight the importance of the molecular determinants of oral health and can provide new models that lay the foundations for translational research.

Prof. Dr. Nicola Cirillo
Guest Editor

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Keywords

  • oral cancer
  • blistering diseases
  • autoimmunity
  • cell-adhesion
  • microenvironment

Published Papers (6 papers)

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Research

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10 pages, 1432 KiB  
Article
A Novel In Vivo Active Pemphigus Model Targeting Desmoglein1 and Desmoglein3: A Tool Representing All Pemphigus Variants
by Roberta Lotti, Claudio Giacinto Atene, Emma Dorotea Zanfi, Matteo Bertesi, Carlo Pincelli and Tommaso Zanocco-Marani
Biology 2023, 12(5), 702; https://0-doi-org.brum.beds.ac.uk/10.3390/biology12050702 - 11 May 2023
Cited by 1 | Viewed by 1274
Abstract
Background: Pemphigus is a life-threatening blistering autoimmune disease. Several forms, characterized by the presence of autoantibodies against different autoantigens, have been described. In Pemphigus Vulgaris (PV), autoantibodies target the cadherin Desmoglein 3 (DSG3), while in Pemphigus foliaceous (PF) autoantibodies target the cadherin Desmoglein [...] Read more.
Background: Pemphigus is a life-threatening blistering autoimmune disease. Several forms, characterized by the presence of autoantibodies against different autoantigens, have been described. In Pemphigus Vulgaris (PV), autoantibodies target the cadherin Desmoglein 3 (DSG3), while in Pemphigus foliaceous (PF) autoantibodies target the cadherin Desmoglein 1 (DSG1). Another variant, mucocutaneous Pemphigus, is characterized by the presence of IgG against both DSG1 and DSG3. Moreover, other forms of Pemphigus characterized by the presence of autoantibodies against other autoantigens have been described. With regard to animal models, one can distinguish between passive models, where pathological IgG are transferred into neonatal mice, and active models, where B cells deriving from animals immunized against a specific autoantigen are transferred into immunodeficient mice that develop the disease. Active models recreate PV and a form of Pemphigus characterized by the presence of IgG against the cadherin Desmocollin 3 (DSC3). Further approaches allow to collect sera or B/T cells from mice immunized against a specific antigen to evaluate the mechanisms underlying the onset of the disease. Objective: To develop and characterize a new active model of Pemphigus where mice express auto antibodies against either DSG1 alone, or DSG1 and DSG3, thereby recapitulating PF and mucocutaneous Pemphigus, respectively. In addition to the existing models, with the active models reported in this work, it will be possible to recapitulate and mimic the main forms of pemphigus in adult mice, thus allowing a better understanding of the disease in the long term, including the benefit/risk ratio of new therapies. Results: The new DSG1 and the DSG1/DSG3 mixed models were developed as proposed. Immunized animals, and subsequently, animals that received splenocytes from the immunized donors produce a high concentration of circulating antibodies against the specific antigens. The severity of the disease was assessed by evaluating the PV score, evidencing that the DSG1/DSG3 mixed model exhibits the most severe symptoms among those analyzed. Alopecia, erosions, and blistering were observed in the skin of DSG1, DSG3 and DSG1/DSG3 models, while lesions in the mucosa were observed only in DSG3 and DSG1/DSG3 animals. The effectiveness of the corticosteroid Methyl-Prednisolone was evaluated in the DSG1 and DSG1/DSG3 models, that showed only partial responsiveness. Full article
(This article belongs to the Special Issue Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer)
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21 pages, 44852 KiB  
Article
Commonly Prescribed Anticoagulants Exert Anticancer Effects in Oral Squamous Cell Carcinoma Cells In Vitro
by Li-Qiao R. Ling, Zichen Lin, Rita Paolini, Camile S. Farah, Michael McCullough, Mathew A. W. T. Lim and Antonio Celentano
Biology 2022, 11(4), 596; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11040596 - 14 Apr 2022
Cited by 4 | Viewed by 3003
Abstract
Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. With anticoagulant usage on the rise, it is important to elucidate their potential effects on tumour biology and interactions with chemotherapeutics. The aim of the present study was to investigate [...] Read more.
Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. With anticoagulant usage on the rise, it is important to elucidate their potential effects on tumour biology and interactions with chemotherapeutics. The aim of the present study was to investigate the effects of anticoagulants on OSCC cell lines and their interactions with the drug 5-fluorouracil (5-FU). Cell proliferation was assessed using an MTS in vitro assay in two human OSCC cell lines (H357/H400) and in normal oral keratinocytes (OKF6) treated with the 5-FU (0.2/1/5/10 μg/mL), conventional anticoagulants warfarin (1/5/10/20 μM) and heparin (5/20/80 U), as well as four new oral anticoagulants, dabigatran (5/10/20 μM), rivaroxaban (5/10/20 μM), apixaban (0.1/1/5 μg/mL), and edoxaban (5/10/20 μM). Cell migration was assessed at 3 h intervals up to18 h using a wound healing assay. Our results clearly demonstrate, for the first time, that commonly prescribed anticoagulants exert in vitro antiproliferative effects on OSCC cells. Furthermore, treatment with some anticoagulants reduced the migration of OSCC cell lines. Nevertheless, most of the anticoagulants tested reduced the effectiveness of the chemotherapeutic agent tested, 5-FU, highlighting potential flaws in the current pharmacological management of these patients. Our findings showed the need for the immediate translation of this research to preclinical animal models. Full article
(This article belongs to the Special Issue Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer)
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Review

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10 pages, 282 KiB  
Review
The Role of Non-Neuronal Acetylcholine in the Autoimmune Blistering Disease Pemphigus Vulgaris
by Delila Pouldar Foulad, Nicola Cirillo and Sergei A. Grando
Biology 2023, 12(3), 354; https://0-doi-org.brum.beds.ac.uk/10.3390/biology12030354 - 23 Feb 2023
Cited by 2 | Viewed by 1449
Abstract
The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters [...] Read more.
The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies. Herein, we describe the role of autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, as well as the annexin-like molecule pemphaxin that also binds ACh, in the immunopathogenesis of PV. The identification of targets in this disease is important, as they may lead to novel diagnostic and therapeutic options in the future for this potentially deadly disease. Full article
(This article belongs to the Special Issue Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer)
19 pages, 1148 KiB  
Review
Escape from Cellular Senescence Is Associated with Chromosomal Instability in Oral Pre-Malignancy
by Stephen S. Prime, Nicola Cirillo and E. Kenneth Parkinson
Biology 2023, 12(1), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/biology12010103 - 10 Jan 2023
Cited by 2 | Viewed by 2337
Abstract
An escape from cellular senescence through the development of unlimited growth potential is one of the hallmarks of cancer, which is thought to be an early event in carcinogenesis. In this review, we propose that the molecular effectors of senescence, particularly the inactivation [...] Read more.
An escape from cellular senescence through the development of unlimited growth potential is one of the hallmarks of cancer, which is thought to be an early event in carcinogenesis. In this review, we propose that the molecular effectors of senescence, particularly the inactivation of TP53 and CDKN2A, together with telomere attrition and telomerase activation, all lead to aneuploidy in the keratinocytes from oral potentially malignant disorders (OPMD). Premalignant keratinocytes, therefore, not only become immortal but also develop genotypic and phenotypic cellular diversity. As a result of these changes, certain clonal cell populations likely gain the capacity to invade the underlying connective tissue. We review the clinical implications of these changes and highlight a new PCR-based assay to identify aneuploid cell in fluids such as saliva, a technique that is extremely sensitive and could facilitate the regular monitoring of OPMD without the need for surgical biopsies and may avoid potential biopsy sampling errors. We also draw attention to recent studies designed to eliminate aneuploid tumour cell populations that, potentially, is a new therapeutic approach to prevent malignant transformations in OPMD. Full article
(This article belongs to the Special Issue Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer)
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Other

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18 pages, 1477 KiB  
Systematic Review
Overexpression of E-Cadherin Is a Favorable Prognostic Biomarker in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
by Alejandro I. Lorenzo-Pouso, Fábio França-Vieira e Silva, Alba Pérez-Jardón, Cintia M. Chamorro-Petronacci, Mônica G. Oliveira-Alves, Óscar Álvarez-Calderón-Iglesias, Vito Carlo Alberto Caponio, Morena Pinti, Vittoria Perrotti and Mario Pérez-Sayáns
Biology 2023, 12(2), 239; https://0-doi-org.brum.beds.ac.uk/10.3390/biology12020239 - 02 Feb 2023
Cited by 6 | Viewed by 2117
Abstract
Oral squamous cell carcinoma (OSCC) is characterized by poor survival, mostly due to local invasion, loco-regional recurrence, and metastasis. Given that the weakening of cell-to-cell adhesion is a feature associated with the migration and invasion of cancer cells, different studies have explored the [...] Read more.
Oral squamous cell carcinoma (OSCC) is characterized by poor survival, mostly due to local invasion, loco-regional recurrence, and metastasis. Given that the weakening of cell-to-cell adhesion is a feature associated with the migration and invasion of cancer cells, different studies have explored the prognostic utility of cell adhesion molecules such as E-cadherin (E-cad). This study aims to summarize current evidence in a meta-analysis, focusing on the prognostic role of E-cad in OSCC. To find studies meeting inclusion criteria, Scopus, Web of Science, EMBASE, Medline, and OpenGrey databases were systematically assessed and screened. The selection process led to 25 studies, which were considered eligible for inclusion in the meta-analysis, representing a sample of 2553 patients. E-cad overexpression was strongly associated with longer overall survival (OS) with Hazard Ratio (HR)  = 0.41 95% confidence interval (95% CI) (0.32–0.54); p < 0.001 and disease-free survival with HR 0.47 95% CI (0.37–0.61); p < 0.001. In terms of OS, patients with tongue cancer experienced better survivability when expressing E-cad with HR 0.28 95% CI (0.19–0.43); p < 0.001. Globally, our findings indicate the prognostic role of the immunohistochemical assessment of E-cad in OSCC and its expression might acquire a different role based on the oral cavity subsites. Full article
(This article belongs to the Special Issue Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer)
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12 pages, 677 KiB  
Systematic Review
Caspase Inhibition as a Possible Therapeutic Strategy for Pemphigus Vulgaris: A Systematic Review of Current Evidence
by Sanna Huda, Bethany Chau, Chuanqi Chen, Herman Somal, Neiloy Chowdhury and Nicola Cirillo
Biology 2022, 11(2), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11020314 - 16 Feb 2022
Viewed by 2949
Abstract
Background: Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell–cell detachment (acantholysis) resulting in mucocutaneous blistering. The exact pathogenesis of blister formation is unknown and this has hampered the development of non-steroidal, mechanism-based treatments for this autoimmune disease. This systematic [...] Read more.
Background: Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell–cell detachment (acantholysis) resulting in mucocutaneous blistering. The exact pathogenesis of blister formation is unknown and this has hampered the development of non-steroidal, mechanism-based treatments for this autoimmune disease. This systematic review aims to investigate the role of caspases in the pathogenesis of PV to inform the choice of more targeted therapeutic agents. Methods: A systematic search of MEDLINE/PubMed and Scopus databases was conducted to identify eligible studies. Multiple phases of inclusion and exclusion of the primary articles were conducted in pairs, and studies were recorded and analysed according to the latest version of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Risk of bias assessment was conducted for extracted in vivo animal intervention studies using SYRCLE’s risk of bias tool. Results: Eight articles from a total of 2338 in vitro, in vivo, and human studies met the inclusion criteria, with a high degree of inter-rater reliability. By and large, the results show that caspase activation was pathogenic in experimental PV because pan-caspase inhibitors could block or reduce PV acantholysis and blistering in vitro and in vivo, respectively. The pathogenic pathways identified involved caspase-1 and caspase-3. One study failed to show any improvement in the PV model with a caspase inhibitor. The majority of animal studies had high or unclear risk of bias. Conclusion: There are consistent data pointing towards a pathogenic role of caspase activation in PV acantholysis. However, high-quality evidence to confirm that caspase inhibition can prevent PV-induced blistering in vivo is limited. Therefore, further research is required to test the preclinical efficacy of caspase inhibitors in PV. Full article
(This article belongs to the Special Issue Patho-Mechanisms Associated with Oral Autoimmune Disease and Cancer)
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