Introduction Squamous cell carcinoma is believed to develop in a step-wise fashion from squamous metaplasia (SqMet), through low- and high-grade dysplasia (LGDys; HGDys) and carcinoma-in-situ (CIS) to invasive disease (InvSCC). Epithelial mesenchymal transition (EMT) is an important process by which epithelial cells shed their differentiated characteristics and acquire mesenchymal, fibroblast-like properties including increased motility and invasiveness. There is now convincing phenotypic, genetic and functional evidence that EMT plays a central role in carcinogenesis. To date, EMT is believed to occur during transition from pre-invasive disease to invasive disease. A hallmark of EMT is the down-regulation of E-cadherin, a cell adhesion molecule present in the plasma membrane of epithelial cells. We have examined the role of EMT during the progression of bronchial dysplasia.
Methods Using immunohistochemistry, 170 formalin-fixed paraffin-embedded blocks from lung cancer biopsies and resection specimens were stained for epithelial markers E-cadherin and MNF116 and the mesenchymal marker S100A4. In each sample, areas of SqMet, LGDys, HGDys (incorporating CIS) and InvSCC were identified. Up to three representative areas were assessed for each lesion type present and an aggregate score assigned which took into account strength and extent of staining. Specimens were also stained for β-catenin which translocates from the membrane to the nucleus during EMT. One hundred cells per high power field were counted and the proportion of membranous, cytoplasmic and nuclear staining calculated.
Results There was a progressive loss of epithelial markers and a concurrent gain in S100A4 with increasing dysplasia. The switch from expression of epithelial to mesenchymal markers began as early as SqMet and reached significance for all three markers between LGDys and HGDys. Likewise, β-catenin showed translocation from membranous to cytoplasmic expression; this also reached significance between LGDys and HGDys. The difference in nuclear expression between groups did not reach significance.
Conclusions In order to improve lung cancer survival there is increasing interest in identifying early stage disease. The mechanisms underlying progression of bronchial dysplasia are poorly understood. Our results suggest that EMT is occurring much earlier in bronchial dysplasia than previously appreciated and this may have implications for the surveillance and treatment of pre-invasive disease.
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