Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis.

The epithelial-to-mesenchymal transition (EMT) is a developmental programme that regulates embryonic morphogenesis and involves significant morphological and molecular changes in cells. Experimental models have revealed that EMT also contributes to various malignant features of cancer cells, including motile, invasive, anti-apoptotic and stem-like phenotypes. Clinically, correlative studies have indicated that mesenchymal-like features of tumour cells are associated with poor tumour differentiation as well as worse patient prognosis. Nevertheless, due to its transitory nature, demonstration of an actual occurrence of EMT during human carcinogenesis is challenging, and most of the evidence to date has been limited to breast and colorectal cancers. However, recent studies suggest that EMT may occur during lung cancer development, although such evidence is still limited. We propose three approaches for obtaining direct evidence of EMT in human cancers and use these criteria to review the available data. We suggest that multiple intrinsic and extrinsic factors cooperatively induce EMT in lung cancer. Intrinsic factors include oncogenic genetic changes such as mutant K-RAS. Extrinsic factors are associated with a tumour microenvironment that is inflammatory and hypoxic. The induction of EMT is primarily mediated by various EMT-inducing transcription factors that suppress E-cadherin expression, including SLUG and ZEB1. miR-200 family expression can reverse EMT by suppressing EMT- inducing transcription factors. Obviously, more data demonstrating the clinical relevance of EMT in lung cancer are required, and further elucidation of how EMT is regulated in lung cancer will enable us to develop novel therapeutics that specifically target molecules with critical roles in EMT.