RESUMO
We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.
Assuntos
Carcinoma de Células Escamosas , Anemia de Fanconi , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Neoplasias Bucais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , DNARESUMO
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.
RESUMO
Oral submucous fibrosis (OSF) is a potentially malignant condition of the oral cavity characterized by progressive fibrosis of the submucosal tissues. OSF is typically associated with the use of betel quid (BQ), a chewing package made of natural products (e.g., areca nut, betel leaves), with or without smokeless tobacco. BQ ingredients contain pro-carcinogenic bioactive compounds, but also potentially protective biomolecules, and we have shown recently that the chemical properties of different BQ recipes vary, which may explain the unequal prevalence of OSF and oral cancer in BQ users in different geographical regions. Hence, this scoping review was aimed at evaluating the existing literature regarding different BQ compounds and their association with OSF. The repository of the National Library of Medicine (MEDLINE/PubMed), medRxiv databases, Google scholar, Baidu scholar, CNKI, and EBSCO were used to search for publications that investigated the association between BQ chewing and OSF up to November 2021. The search terminology was constructed using the keywords "betel quid" and "oral submucous fibrosis", and their associated terms, with the use of Boolean operators. The search was conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, together with clear inclusion and exclusion criteria. The review showed that the risk of developing OSF varied between different BQ recipes, and that chewing BQ mixtures containing betel inflorescence (BI) significantly increased the risk of OSF, as did the addition of tobacco. Conversely, the use of betel leaf in the mixture was likely to be protective, which may be due to the presence of polyphenols. Although further research is needed to determine the effect of individual BQ ingredients in the development of OSF, our pilot results provide the scope and rationale for informing future chemopreventive strategies for OSF and oral cancer in BQ chewers.
Assuntos
Neoplasias Bucais , Fibrose Oral Submucosa , Areca/efeitos adversos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/epidemiologia , Fibrose Oral Submucosa/induzido quimicamente , Fibrose Oral Submucosa/epidemiologia , Prevalência , Nicotiana , Estados UnidosRESUMO
Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids-arecoline, arecaidine, guvacoline and guvacine-together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and/or treat potentially malignant oral disorders and oral cancer in BQ users.
Assuntos
Areca/química , Carcinoma de Células Escamosas/induzido quimicamente , Neoplasias Bucais/induzido quimicamente , Fibrose Oral Submucosa/induzido quimicamente , Extratos Vegetais/efeitos adversos , Arecolina/efeitos adversos , Arecolina/análogos & derivados , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Humanos , Neoplasias Bucais/patologia , Ácidos Nicotínicos/efeitos adversos , Fibrose Oral Submucosa/patologiaRESUMO
The discovery of a small subset of cancer cells with self-renewal properties that can give rise to phenotypically diverse tumour populations has shifted our understanding of cancer biology. Targeting cancer stem cells (CSCs) is becoming a promising therapeutic strategy in various malignancies, including head and neck squamous cell carcinoma (HNSCC). Diverse sub-populations of head and neck cancer stem cells (HNCSCs) have been identified previously using CSC specific markers, the most common being CD44, Aldehyde Dehydrogenase 1 (ALDH1), and CD133, or by side population assays. Interestingly, distinct HNCSC subsets play different roles in the generation and progression of tumours. This article aims to review the evidence for a role of specific CSCs in HNSCC tumorigenesis, invasion, and metastasis, together with resistance to treatment.
Assuntos
Antineoplásicos/uso terapêutico , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacosRESUMO
Pemphigus and pemphigoid diseases are potentially life-threatening autoimmune blistering disorders that are characterized by intraepithelial and subepithelial blister formation, respectively. In both disease groups, skin and/or mucosal blistering develop as a result of a disruption of intercellular adhesion (pemphigus) and cell-extracellular matrix (ECM) adhesion (pemphigoid). Given that metalloproteinases can target cell adhesion molecules, the purpose of the present study was to investigate the role of these enzymes in the pathogenesis of these bullous dermatoses. Studies examining MMPs (matrix metalloproteinases) and the ADAM (a disintegrin and metalloproteinase) family of proteases in pemphigus and pemphigoid were selected from articles published in the repository of the National Library of Medicine (MEDLINE/PubMed) and bioRxiv. Multiple phases of screening were conducted, and relevant data were extracted and tabulated, with 29 articles included in the final qualitative analysis. The majority of the literature investigated the role of specific components of the MMP family primarily in bullous pemphigoid (BP) whereas studies that focused on pemphigus were rarer. The most commonly studied metalloproteinase was MMP-9 followed by MMP-2; other MMPs included MMP-1, MMP-3, MMP-8, MMP-12 and MMP-13. Molecules related to MMPs were also included, namely, ADAM5, 8, 10, 15, 17, together with TIMP-1 and TIMP-3. The results demonstrated that ADAM10 and MMP-9 activity is necessary for blister formation in experimental models of pemphigus vulgaris (PV) and BP, respectively. The data linking MMPs to the pathogenesis of experimental BP were relatively strong but the evidence for involvement of metalloproteinases in PV was more tentative. These molecules represent potential candidates for the development of mechanism-based treatments of these blistering diseases.
Assuntos
Proteína ADAM10/genética , Metaloproteinase 9 da Matriz/genética , Penfigoide Bolhoso/genética , Pênfigo/genética , Proteínas ADAM/classificação , Proteínas ADAM/genética , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Adesão Celular/genética , Matriz Extracelular/genética , Humanos , Metaloproteinases da Matriz/classificação , Metaloproteinases da Matriz/genética , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/patologia , Pênfigo/imunologia , Pênfigo/patologiaRESUMO
The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-ß1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-ß1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-ß signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-ß1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , MicroRNAs/metabolismo , Neoplasias Bucais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Humanos , Miofibroblastos/metabolismo , Fenótipo , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
BACKGROUND: Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers. METHODS: The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11ß-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11ß-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues. RESULTS: We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11ß-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11ß-HSDs demonstrated that 11ß-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11ß-HSD2 activity by 18ß-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11ß-HSD2 was significantly reduced in human SCCs of the skin. CONCLUSIONS: The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Carcinoma de Células Escamosas/enzimologia , Células Epiteliais/enzimologia , Hidrocortisona/metabolismo , Melanoma/enzimologia , Neoplasias Cutâneas/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/análise , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Hormônio Adrenocorticotrópico/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/química , Adesão Celular , Proliferação de Células/efeitos dos fármacos , Cortisona/farmacologia , Meios de Cultivo Condicionados/farmacologia , Regulação para Baixo , Inativação Gênica , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Células HT29 , Humanos , Hidrocortisona/imunologia , Hidrocortisona/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Células MCF-7 , Melanoma/química , Comunicação Parácrina , Receptores de Glucocorticoides/imunologia , Receptores de Glucocorticoides/metabolismo , Neoplasias Cutâneas/químicaRESUMO
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-ß signaling. Similar to TGF-ß1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
Assuntos
Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Fibroblastos/patologia , Miofibroblastos/patologia , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Humanos , Camundongos , Miofibroblastos/metabolismo , Neoplasias/metabolismo , Fenótipo , Prognóstico , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Senescência Celular/fisiologia , Ciclo-Oxigenase 2/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais/fisiologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Celecoxib/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Técnicas de Cocultura , Dinoprostona/metabolismo , Humanos , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
Oral cancers are predominantly oral squamous cell carcinomas (OSCCs) derived from keratinocytes, and there is now very detailed knowledge of the genetics and molecular biology of the epithelial tumourigenic component of these cancers, including the identification of cancer stem or tumour-initiating cells. Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus. There is also evidence that OSCCs arise from a 'field' of altered cells and that malignant conversion takes place pre-dominantly at the microscopic level. However, in the last decade, it has been realised that tumour development and progression are influenced by the cells of the microenvironment with cross-talk between the epithelial (tumour) and mesenchymal components. OSCCs, especially those that have bypassed cellular senescence, produce an array of proteins and metabolites that induce cellular senescence in the normal surrounding cells; indeed, senescence is a common property of cancer-associated fibroblasts (CAFs). Cellular senescence is defined as an irreversible cell cycle arrest and is associated with the release of molecules known as the senescence-associated secretory phenotype that can selectively promote the growth of pre-neoplastic keratinocytes (osteopontin) and cancer invasion (transforming growth factor ß, matrix metalloproteinases, interleukin 6 and lactate). In addition, both old and new work has shown that keratinocytes harbouring NOTCH loss-of-function mutations that lead to defective keratinocyte differentiation and loss of squamous epithelial barrier function may act as a tumour-promoting stimulus for initiated cells harbouring RAS pathway mutations by activating a wound response in the tumour mesenchyme. Thus, not all keratinocytes in the tumour tissue may be tumourigenic and may instead act as promoters of tumour growth and progression analogous to the much-studied CAFs which co-evolve with the genetically altered tumourigenic cells. This new data is discussed in relation to attempts to develop novel non-invasive diagnostics and therapeutics for oral cancer.
Assuntos
Senescência Celular/fisiologia , Neoplasias Bucais/etiologia , Animais , Carcinoma de Células Escamosas/etiologia , Senescência Celular/genética , Fibroblastos/patologia , Fibroblastos/fisiologia , Instabilidade Genômica , Humanos , Queratinócitos/patologia , Queratinócitos/fisiologia , Metaboloma , Modelos Biológicos , Papillomaviridae/patogenicidade , Receptor Notch1/genética , Receptor Notch1/fisiologia , Homeostase do Telômero , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologiaRESUMO
BACKGROUND: Burning mouth syndrome (BMS) is an idiopathic disease characterized by the feeling of burning in the oral cavity. Ten per cent of patients presenting to oral medicine clinics have BMS. Anxiety and depression are common co-morbidities in BMS, but it is not known if they are associated with specific BMS symptoms. OBJECTIVE: In an exploratory analysis, this study examined the association of generalized anxiety and depression with individual BMS symptoms. METHODS: Forty-one patients were recruited from a dental outpatient clinic (30 with BMS and 11 with other oral conditions), evaluating specific BMS symptoms and their intensity. Anxiety and depression symptoms were assessed using a standardized measure (Clinical Interview Schedule-Revised). RESULTS: Taste change (p = 0.007), fear of serious illness (p = 0.011), metallic taste (p = 0.018) and sensation of a film on the gums (p = 0.047) were associated with an excess of psychiatric symptoms. More specifically, metallic taste (coefficient = 0.497, 95% CI = 0.149-0.845; p = 0.006) and sensation of film on gums (coefficient = 0.625, 95% CI = 0.148-1.103; p = 0.012) were associated significantly with higher scores for depressive symptoms; taste change (coefficient = 0.269, 95% CI = 0.077-0.461; p = 0.007), bad breath (coefficient = 0.273, 95% CI = 0.065-0.482; p = 0.012) and fear of serious illness (coefficient = 0.242, 95% CI = 0.036-0.448; p = 0.023) were associated with higher anxiety scores. CONCLUSION: Specific BMS symptoms are associated differentially with generalized anxiety and depression. Dental practitioners should ascertain which BMS symptoms are predominant and be mindful of the association of certain symptoms with anxiety or depression and, where necessary, consider medical consultation.
Assuntos
Ansiedade/psicologia , Síndrome da Ardência Bucal/psicologia , Depressão/psicologia , Transtornos de Ansiedade/psicologia , Atitude Frente a Saúde , Bruxismo/psicologia , Transtorno Depressivo/psicologia , Medo/psicologia , Feminino , Doenças da Gengiva/psicologia , Halitose/psicologia , Humanos , Hipestesia/psicologia , Masculino , Pessoa de Meia-Idade , Parestesia/psicologia , Distúrbios do Paladar/psicologia , Hábitos Linguais/psicologia , Xerostomia/psicologiaRESUMO
Biomedical higher education has been acquiring increasing importance worldwide, including the Kingdom of Saudi Arabia, and effective strategies to improve outcomes and competitiveness are key for academic success. The plan presented here is divided into two major phases. Phase 1 (Communication, Research governance, Education planning, Accreditation) deals mainly with adopting a systematic approach to academic activities according to the current international standards. In other words, the aim is to re-organise what is already in place, taking into account current guidelines and strategies that help improve quality of education and research. It is suggested that this is not necessarily to be achieved by major investments but, rather, by a more imaginative and structured work plan. In Phase 2 (Translational practice, Implementation, Networking, Growth), higher education institutions are expected to invest in new strategic resources, to establish strong reciprocal links with international academic partners and industry, and to shift their attention to the hot topics and current academic challenges, leading the way in translational education models and pioneering cutting-edge research.
RESUMO
Cellular senescence can modulate various pathologies and is associated with irreparable DNA double-strand breaks (IrrDSBs). Extracellular senescence metabolomes (ESMs) were generated from fibroblasts rendered senescent by proliferative exhaustion (PEsen) or 20 Gy of γ rays (IrrDSBsen) and compared with those of young proliferating cells, confluent cells, quiescent cells, and cells exposed to repairable levels of DNA damage to identify novel noninvasive markers of senescent cells. ESMs of PEsen and IrrDSBsen overlapped and showed increased levels of citrate, molecules involved in oxidative stress, a sterol, monohydroxylipids, tryptophan metabolism, phospholipid, and nucleotide catabolism, as well as reduced levels of dipeptides containing branched chain amino acids. The ESM overlaps with the aging and disease body fluid metabolomes, supporting their utility in the noninvasive detection of human senescent cells in vivo and by implication the detection of a variety of human pathologies. Intracellular metabolites of senescent cells showed a relative increase in glycolysis, gluconeogenesis, the pentose-phosphate pathway, and, consistent with this, pyruvate dehydrogenase kinase transcripts. In contrast, tricarboxylic acid cycle enzyme transcript levels were unchanged and their metabolites were depleted. These results are surprising because glycolysis antagonizes senescence entry but are consistent with established senescent cells entering a state of low oxidative stress.
Assuntos
Senescência Celular/fisiologia , Fibroblastos/fisiologia , Glicólise/fisiologia , Homeostase/fisiologia , Metaboloma/genética , Modelos Biológicos , Envelhecimento/fisiologia , Técnicas de Cultura de Células , Dano ao DNA/fisiologia , Fibroblastos/efeitos da radiação , Raios gama , Gluconeogênese/fisiologia , Humanos , Espectrometria de Massas , Oxirredução , Estresse Oxidativo/fisiologia , Reação em Cadeia da Polimerase , Estatísticas não ParamétricasRESUMO
OBJECTIVES: It is well recognized that oral squamous cell carcinoma (OSCC) cases from Asia that are associated with betel quid chewing are phenotypically distinct to those from Western countries that are predominantly caused by smoking/drinking, but the molecular basis of these differences are largely unknown. The aim of this study is to examine gene expression, related carcinogenic pathways and molecular processes that might be responsible for the phenotypic heterogeneity of OSCC between UK and Sri Lankan population groups. METHODS: We have compared the gene expression profiles of OSCCs and normal oral mucosal tissues from both Sri Lankan and UK individuals using Affymetrix gene expression arrays. The generated data was interrogated using significance analysis of microarrays and Ingenuity Pathway Analysis (IPA). RESULTS: The gene expression profiles of UK and Sri Lankan OSCC are similar in many respects to other oral cancer expression profiles reported in the literature and were mainly similar to each other. However, genes involved in tumor invasion, metastasis and recurrence were more obviously associated with UK tumors as opposed to those from Sri Lanka. CONCLUSION: The development of OSCCs in both UK and Sri Lankan populations appears largely mediated by similar biological pathways despite the differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. However, IPA revealed a highly activated "Cell-mediated Immune Response" in Sri Lankan normal and tumor samples relative to UK cohorts. It seems likely, therefore, that any future attempts to personalize treatment for OSCC patients will need to be different in Western and Asian countries to reflect differences in gene expression and the immune status of the patients.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/epidemiologia , Areca , Carcinoma de Células Escamosas/etnologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Mastigação , Pessoa de Meia-Idade , Neoplasias Bucais/etnologia , Fatores de Risco , Fumar/epidemiologia , Sri Lanka/etnologia , Reino Unido/etnologiaRESUMO
Virtually all patients receiving radio- and chemotherapy for cancer develop oral mucositis, a severe and highly debilitating condition. The onset of mucositis is thought to involve the production of reactive oxygen species (ROS) in the submucosa. Here we investigated a possible protective effect of a commercial formulation of hyaluronic acid (HA) enriched with amino acids (Mucosamin(®)) against the damage induced by oxidative stress both in vitro and in vivo. Transient exposure of normal human oral fibroblasts to hydrogen peroxide (H(2)O(2)) led to irreversible senescence, as demonstrated by sustained increase in the levels of p16(INK4A) and SA-ßGal. Conditioned media from senescent fibroblasts induced detrimental effects on keratinocytes, as shown by reduced metabolic activity and migration capability. Pre-treatment with Mucosamin(®) prevented H(2)O(2) -induced, but not TGF-ß-induced, fibroblast senescence with a concomitant reduction of fibroblast-induced loss of keratinocyte vitality and functional activity. Finally, data from a case-series of patients undergoing radio/chemotherapy strongly suggested that prophylactic use of the hyaluronic acid-based compound in the form of a spray may be effective in preventing the onset of oral mucositis.
Assuntos
Antineoplásicos/efeitos adversos , Quimiorradioterapia/efeitos adversos , Fibroblastos/efeitos dos fármacos , Ácido Hialurônico/análogos & derivados , Radioterapia/efeitos adversos , Estomatite/prevenção & controle , Idoso , Movimento Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Queratinócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/radioterapia , Estresse Oxidativo , Estomatite/etiologia , Fatores de TempoRESUMO
The cell adhesion molecule plakophilin 3 (Pkp3) plays an essential role in the maintenance of skin integrity and is targeted in certain autoimmune conditions. In one example, we have shown that Pkp3 is instrumental in mediating the discohesive effects of sera from patients with pemphigus vulgaris (PV), a life-threatening autoimmune disease that targets intercellular adhesion in the epidermis. In the present study, we determine the effect of PV autoimmune globulin (PV IgG) on Pkp3 in an in-vitro model of PV. We demonstrate that Pkp3 becomes tyrosine phosphorylated as early as 30 min upon binding of PV IgG to keratinocyte surface and eventually detaches from its binding partner desmoglein 3 (Dsg3). In parallel, Pkp3 is depleted from the membrane (Triton X-soluble) fraction and accumulates in the cytoplasm within 240 min of incubation with PV IgG. Inhibition of Pkp3 phosphorylation by a Src inhibitor attenuates the discohesive effects of PV IgG. Taken together, the data demonstrate that activation of Src-kinase signalling is crucial for PV acantholysis and acts, at least in part, via phosphorylation of the adaptor protein Pkp3.
Assuntos
Autoanticorpos/farmacologia , Desmogleína 3/imunologia , Imunoglobulina G/farmacologia , Queratinócitos/efeitos dos fármacos , Pênfigo/imunologia , Placofilinas/imunologia , Quinases da Família src/imunologia , Adesão Celular/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Desmogleína 3/genética , Epiderme/imunologia , Epiderme/patologia , Regulação da Expressão Gênica , Humanos , Queratinócitos/imunologia , Queratinócitos/patologia , Pênfigo/genética , Pênfigo/patologia , Fosforilação , Placofilinas/genética , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Transporte Proteico , Transdução de Sinais , Tirosina/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/genéticaRESUMO
OBJECTIVES: The frequency of common oncogenic mutations and TP53 was determined in Asian oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The OncoCarta(™) panel v1.0 assay was used to characterize oncogenic mutations. In addition, exons 4-11 of the TP53 gene were sequenced. Statistical analyses were conducted to identify associations between mutations and selected clinico-pathological characteristics and risk habits. RESULTS: Oncogenic mutations were detected in PIK3CA (5.7%) and HRAS (2.4%). Mutations in TP53 were observed in 27.7% (31/112) of the OSCC specimens. Oncogenic mutations were found more frequently in non-smokers (p = 0.049) and TP53 truncating mutations were more common in patients with no risk habits (p = 0.019). Patients with mutations had worse overall survival compared to those with absence of mutations; and patients who harbored DNA binding domain (DBD) and L2/L3/LSH mutations showed a worse survival probability compared to those patients with wild type TP53. The majority of the oncogenic and TP53 mutations were G:C > A:T and A:T > G:C base transitions, regardless of the different risk habits. CONCLUSION: Hotspot oncogenic mutations which are frequently present in common solid tumors are exceedingly rare in OSCC. Despite differences in risk habit exposure, the mutation frequency of PIK3CA and HRAS in Asian OSCC were similar to that reported in OSCC among Caucasians, whereas TP53 mutations rates were significantly lower. The lack of actionable hotspot mutations argue strongly for the need to comprehensively characterize gene mutations associated with OSCC for the development of new diagnostic and therapeutic tools.