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