The multi-faceted effects of ethanol exposure on oral dysplastic and cancer cells.
Citation:
O'Grady, Isabel Lucy, The multi-faceted effects of ethanol exposure on oral dysplastic and cancer cells., Trinity College Dublin, School of Dental Sciences, Dental Science, 2024Download Item:
Abstract:
Oral cancers (OC) are cancers that arise in several regions within the oral cavity such as the lips, gums, tongue, lining of the cheeks, and the floor or roof of the mouth. Approximately 400,000 cases were diagnosed worldwide in 2020, with almost 50% of these resulting in the death of the patient. Despite efforts to improve diagnostic and therapeutic methods available, most OC is detected at a late stage and the mortality rate remains high. The five-year survival rate for individuals diagnosed with OC is 68.5%, according to data from 2013-2019 from the National Cancer Institute. OC can be preceded by premalignant disorders of the oral cavity, including oral leukoplakia, which is categorised by the degree of dysplasia and transformation rates. Epithelial dysplasia can be indicative of an early neoplastic process, with severe or high-grade dysplasia having a higher chance of malignant transformation and worse overall prognosis. Due to the late diagnosis of most OC and the dense lymphatic network found in the oral cavity, metastasis is very common. Cervical lymph node metastasis is the prognostic factor most associated with morbidity and poor patient outcomes for OC.
The most important aetiological factors in the development of OC are alcohol and tobacco consumption, and more recently there has been increasing interest in the oral microbiome and its role in OC development. The exact mechanisms by which alcohol consumption influences oral carcinogenesis remain unclear, but it has been postulated to act via multiple pathways including direct DNA damage, inflammation, carcinogenic metabolites, acting as a co-carcinogen, altering hormone regulation and metabolic reprogramming of oral cells and tumours. When alcohol enters the body, it is metabolised by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes. The ALDH enzymes have important roles as cancer stem cell (CSC) markers in several types of cancers, including OC, as well as contributing to tumour growth, metastasis, and therapeutic resistance. Additionally, there is evidence in other cancers of bacteria having a direct causal relationship with carcinogenesis. However, no distinct relationship between the oral microbiome and OC has been defined. Exogenous factors, such as alcohol consumption, can alter the composition of the microbiome, increase host susceptibility to oral dysbiosis, as well as affect immune responses of the oral cavity. Therefore, the overall aim of this research was to investigate the multiple pathways by which alcohol consumption promotes malignant transformation and progression of OC, using oral cell lines, in vitro ethanol exposure and commensal oral microbiota as a model of these processes.
In this study, three oral cell lines (dysplastic oral mucosa DOK, gingival squamous cell carcinoma Ca9.22, and buccal squamous cell carcinoma TR146 cells) were characterised as models of alcohol consumption in OC progression and metastasis, via ethanol exposure in vitro. The unique ADH and ALDH expression profiles found in these cell lines affected their responses to ethanol and its first metabolite acetaldehyde in vitro. A novel finding of this thesis was that chronic ethanol exposure, i.e., representative of heavy or long-term alcohol consumption, overall promoted malignant transformation of dysplastic DOK cells and metastatic processes in cancerous Ca9.22 cells. Chronic ethanol exposure also modulated ALDH enzyme expression and activity in a cell line and isoform dependent manner. While ALDH1A1 was shown to have key roles in cellular pathways such as proliferation and metabolism, the use of siRNA concluded that changes to ALDH expression were a secondary feature to ethanol-induced OC progression.
The data in this thesis demonstrates that ethanol acts via multiple indirect mechanisms, such as augmenting metabolic pathways, or influencing inflammatory signalling. Ethanol was also shown to act synergistically with common oral microbe species, Candida albicans, which was heat-inactivated, to promote metastasis of Ca9.22 cells. In combination with the ability of ethanol to affect acetaldehyde production both in vitro and in vivo, and data suggesting indirect metabolic reprogramming of Ca9.22 and DOK cells, the data presented here provides compelling evidence that acetaldehyde exposure following alcohol consumption may be the driving factor in transformation and metastasis of OC.
Future work will aim to further investigate the fate of acetaldehyde in OC cells and the oral cavity, as well as compare the effect of ethanol exposure on normal oral cells to dysplasia and established OC, as investigated here. The data presented here provides novel insights into the mechanisms behind ethanol-induced oral carcinogenesis and strengthens the argument for the potential use of microbiome sequencing and selective genetic screening for OC prevention. Changes to policy and practice may help improve earlier diagnosis of OC as well as having potentially significant clinical implications for treatment and overall survival of patients. This thesis also provides a framework for further research questions about the effects of ethanol in oral carcinogenesis.
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Author: O'Grady, Isabel Lucy
Advisor:
O'Sullivan, JeffreyPublisher:
Trinity College Dublin. School of Dental Sciences. Discipline of Dental ScienceType of material:
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