Abstract
Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer that is associated with poor 5-year patient survival. Disease treatment is further compounded by the difficulty in predicting pre-cancerous tissues that will progress to OSCC and the high recurrence rates following surgical resection. Here we have assessed expression of the oral epithelial markers E-cadherin, EMP1 and 5T4 and the pro-invasive N-cadherin proteins using fully characterised antibodies and quantitative immunofluorescence microscopy in normal tissue (NT), fibroepithelial polyp (FEP), low-grade dysplasia (LGD), high-grade dysplasia (HGD), T1 OSCC and T4 OSCC biopsies. Decreased E-cadherin expression was associated with FEP, LGD and HGD biopsies, demonstrating that loss of E-cadherin is an early event within abnormal epithelium and occurs in the absence of an E- to N-cadherin switch, the latter of which was only observed in T4 OSCC. Furthermore, loss of E-cadherin and EMP1 is an indicator of LGD (p = 0.0006) and loss of E-cadherin, EMP1 and 5T4 an indicator of HGD (p = 0.0006). Expression patterns of E-cadherin, EMP1 and N-cadherin could predict abnormal epithelium in LGD, HGD, T1 and T4 OSCC biopsies (z-value = 0 for all disease grades) and allowed classification of LGD (z = 1.47), HGD (z = 2.138), T1 (z = 1.05) and T4 OSCC (z = 1.49) biopsies. Therefore, these markers provide a useful means to predict abnormal epithelium in patient biopsies. Linear regression and coefficient of determination analysis revealed positive correlation with a NT>LGD>HGD disease transition but low correlation with a putative HGD>T1 OSCC>T4 OSCC disease transition. Furthermore, expression of E-cadherin, EMP1, 5T4 and N-cadherin in pathologically normal surgical safety margins of LGD, HGD and T1 OSCC patient biopsies revealed significant differences to NT and the use of safety margins or FEP as ‘normal tissue’ controls introduced Type II errors in all patient cohorts. This work forms the basis for further investigation of the role of E-cadherin loss in abnormal epithelium and in the development of automated analyses for use in cancer diagnostics.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity, representing at least 90% of such malignancies, and is associated with poor 10-year survival rate compared to other cancers
The disease is further compounded by the difficulty in predicting pre-cancerous abnormal tissues that will progress to OSCC and the high recurrence rates following surgical resection of the latter
Our study shows that a panel of markers can be utilised to assess the epithelial state of oral tissues, comprising of E-cadherin, Epithelial Membrane Protein1 (EMP1), 5T4 and N-cadherin
Summary
Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity, representing at least 90% of such malignancies, and is associated with poor 10-year survival rate compared to other cancers. Oral epithelial dysplasia is believed to be one of the progenitor populations from which OSCC arises, with transformation rates reported between 0.3 and 17.5% [1], depending on the population studied [2,3,4,5]. The mechanism by which normal oral epithelium becomes dysplastic and transforms into OSCC is not well understood and the current treatment strategy is resection of the diseased tissue to leave a disease-free margin of at least 5mm [6]. OSCC and dysplasia are associated with high recurrence rates at or near the original site, even in histologically and clinically normal tissue, leading to proposal of the field cancerization theory [7] and the multi-foci growth potential of cancer cells [8,9]. Shaw et al (2013) [13] have recently reported that a significant proportion of OSCC surgical margins exhibited abnormal CpG island methylation [13], the results were not prognostic, showing a clear need for the investigation of the epithelial phenotype within tissue associated with OSCC genesis
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