PI3K-Akt expression in dysplastic oral lesions and implications for recurrence and malignant transformation

There are around 12,400 new head and neck cancer cases in the UK every year, that's 34 every day (2016-2018) with 4,143 deaths each year. It is the 8th most common cancer in the UK, accounting for 3% of all new cancer cases. Between 19% and 59% of people diagnosed with head and neck cancers in England survive their disease for ten years or more (Cancer Research UK 2018). In the UK, oral cancer incidence rates have steadily risen since the 1980s. Mistry et al (2011) projected that cancers of the lip, mouth and pharynx will increase by 1% per year to 2030.

In 2010 the National Screening Committee review (NSC) stated that there is “good evidence that tobacco in all forms (both smoked and smokeless, including snuff) and betel quid are carcinogenic in the upper aerodigestive tract, which includes the mouth. There is also convincing evidence that alcoholic drinks are carcinogenic and act synergistically with tobacco” (Speight & Warnakulasuriya 2010).

The natural history of oral cancer is only partly understood, with reports of “it is clear that oral squamous cell carcinoma (OSCC) is preceded by changes in the oral mucosa, but the extent or nature of these changes is uncertain” (Speight & Warnakulasuriya 2010). However, it was also noted that “only about 5% of these lesions will progress to malignancy and although some clinical features are associated with higher risk (e.g. non-homogenous, speckled or red lesions) there are still no reliable ways to predict which individuals or lesions will develop OSCC” (Speight & Warnakulasuriya 2010). The difficulty in interpreting some of the published work on malignant progression is that many studies do not actually investigate biopsy proven dysplasias but leucoplakias and therefore these may not actually be potentially malignant. One study showed that follow up of biopsy proven dysplasias showed a malignant transformation rate of 25% and an estimated 76% of patients will have one or other event in 5 years (Ho et al 2013). Another issue with reported studies is that they are carried out in parts of the world where oral cancer is far more prevalent and not comparable to the UK.

A systematic review of biomarkers in oral dysplasia found loss of heterozygosity (LOH) and elevated expression of survivin, matrix metalloproteinase (MMP 9), and DNA content are potential markers for increased risk of progression from oral dysplasia to cancer (Smith et al 2009). Another review suggested that epigenetic events, cell cycle molecules, angiogenic regulators, and S100 protein expression could predict malignant progression (Nikitakis et al 2018).

The PI3K-Akt signalling pathway is a well-established driver of cancer progression. Previous immunohistochemical analysis of VEGF positive human head and neck tumour tissues showed a significant increase in Akt phosphorylation at the T308 residue, suggesting that pAkt T308 may be associated with tumour progression in vivo. In addition a higher phosphorylation of Akt at S473 was shown to be a prognostic factor for HNSCC (Islam et al 2014). Another immunohistochemical study reported no pAkt staining in normal tissue compared to positive staining in the basal and parabasal cell layers, and partially in the spinous layer of epithelial dysplasia tissues, and in the spinous layer of early cancer tissues suggesting that activation of the PI3K-Akt signal pathway is associated with oral carcinogenesis.(Watanabe et al 2009) The PI3K/Akt pathway has also been implicated in perineural spread of oral cancer by stimulation by nerve growth factor which induced oral and salivary tumour cell scattering and migration (Alkhadar e al 2020).

The aim is to determine whether there is an association between the expression on PI3K-Akt in oral dysplastic lesions with recurrence, field cancerisation and malignant transformation. Also determine the efficacy of potential biomarkers such as cell cycle molecules, angiogenic markers and S100 protein expression.

Diversity statement

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.