Epithelial to Mesenchymal Transition in Lung Cancer: When It Starts?

Epithelial to mesenchymal transition (EMT) represents a phenotypic change that occurs in epithelial tumors that is required for cancer cells to acquire metastatic potential. This phenotypic transition occurs by downregulating the epithelial-specific markers such as E-cadherin and activation of the mesenchymal markers represented by fibronectin, vimentin, and N-cadherin. This process is associated with morphologic alterations of the tumor cells, as they are losing the intercellular junctions, lose cellular polarity, and undergo a cytoskeletal architectural reorganization which results in changes of the cell shape. EMT is a dynamic process that occurs in both directions; therefore cells that underwent a mesenchymal transition have the ability to change their phenotype in an epithelial one by reactivating cellular pathways during the mesenchymal to epithelial transition (MET). This two-way process is essential in the process of metastasis, surviving in the blood or lymphatic circulation and once seeded in the secondary site to be able to adapt and proliferate in the new environmental conditions. EMT is generally regarded as a cellular process that occurs in the late phases of tumorigenesis once the primary tumor is well established. New studies that investigated the process of EMT in lung cancer revealed that EMT actually occurs in the initial stages of tumor development. Several studies indicate the identification of circulating tumor cells, a hallmark of the EMT process, as early as in situ stage of lung adenocarcinoma. Therefore, understanding the mechanisms that trigger the EMT process by decoding the complex network of noncoding RNAs that initiate and regulate this phenotype transition can uncover new biomarkers, cellular vulnerabilities, and therapeutic pathways.