The role of hypoxia in oral cancer and potentially malignant disorders: a review

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Cancers of the oral cavity and oropharynx are ranked among the most common cancers worldwide, with an estimated 442 760 incident cases and 241 458 deaths during 2012 1. Oral cancer is ranked the first most common cancer in India in males with an estimated 85 000 new cases and 63 000 associated deaths 1. In the United States, over 30 000 new cases are diagnosed each year where nearly a third dies from the disease 2. Despite advances in diagnosis and treatment, the overall 5‐year survival rate remains around 50% 3. Tobacco and alcohol are considered the primary risk factors for oral cavity cancer, which are known to be synergistic 3. The social habit of chewing of areca nut/betel quid has been strongly linked with the high incidence of oral cancer in South Asia 3. Increasingly, high‐risk human papillomavirus (HPV) has been strongly linked to tumours originating in the oropharynx (predominantly involving the tonsils and base of tongue) 3. Other risk factors, including poor diet, sun exposure and genetic predisposition, are attributable to the pathogenesis of oral cancer 3.
Squamous cell carcinoma is the most predominant histological type of oral malignancy and is mostly preceded by oral potentially malignant disorders that are mostly diagnosed histopathologically with epithelial dysplasia 4. Oral epithelial dysplasia (OED) is a histopathological diagnosis made of clinical mucosal lesions such as leukoplakia and erythroplakia for which the rate of progression to oral squamous cell carcinoma (OSCC) reportedly ranges from 1% to 36% 5. OED has been used to indicate the likelihood of malignant transformation by assessing the presence and severity of cellular atypia and architectural changes in biopsied oral epithelium. Grading OED is a controversial matter, as it is dependent on the arbitrary assessment of histomorphological features 7.
The natural history of oral squamous cell carcinoma is still not yet fully confirmed 4. Current understanding from observational clinical and molecular laboratory studies indicates that oral carcinogenesis is a multistep, multiyear and multifactorial disease where the cumulative acquisition of genetic alterations allows the cells to exhibit multiple cancer hallmarks including invasion into proximal tissue 4. Advancement in laboratory technology has resulted in better understanding of the genetic and epigenetic changes associated with OSCC development. More importantly, determination of early mutational events in oral mucosa, which predispose to OSCC, would allow screening for identification of high‐risk individuals 8. These events would explain oral carcinogenesis which involves dysregulation of oncogenes, tumour suppressor genes, cell cycle genes, angiogenic factors, epithelial to mesenchymal transition genes and epigenetic changes in addition to alteration of genome integrity or DNA damage response genes 5.
Nonetheless, in attempt to further advance the understanding of current concepts on cancer prevention and treatment, a large international group of biochemical and medical researchers operating under the name of ‘The Halifax Project’ summarized the hallmarks of cancer and developed a conceptual framework for a new approach to cancer prevention and therapy 9. Introduced by Hanahan and Weinberg in 2000 and updated in 2011, these hallmarks describe ‘biological capabilities’ acquired by cancers and include several influenced by hypoxia and hypoxia‐inducible factor (HIF) signalling, namely sustained proliferative signalling, dysregulated metabolism and angiogenesis 9. Hypoxia plays a vital role in these hallmarks. Given the multifactorial nature of tumour angiogenesis, reducing hypoxia is one of the possible future targets that could help to control cancer 9. In this review, we aim to illustrate the role of hypoxia in oral carcinogenesis and to highlight its future implications for oral cancer prevention and therapy.
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