Cancer Res Treat. 2012;44(3):151-156 frequent complication of lung cancer and is associated with significant morbidity and mortality [8]. Association of resistance to gefitinib and erlotinib in NSCLC cell lines with epithelial mesenchymal transition (EMT) has been reported [9]. Recently acquired evidence now indicates that EMT of tumor cells not only causes drug resistance, but also increases metastasis [10]. Therefore, in order to pursue possible EMT-inhibiting therapy, understanding of the biology of EMT in cancer is necessary. Findings from Pubmed analysis of EMT and cancer have demonstrated an exponential increase in the number of papers and reviews published under these terms in the last few years [11]. This review describes recent evidence of EMT involvement in drug resistance and metastasis of cancers, with an emphasis on lung cancer. E M T i n C a n c e r D e v e l o p m e n t a l S t a t e P r o g r e s s i o n a n d An epithelium is a collection of cells forming a relatively thin sheet or layer due to mutual and extensive lateral adherence of constituent cells by cell-to-cell junctions [12]. The layer is polarized, with the two sides showing non-identical properties, so that the sides can be defined as, say, inside or outside, or, more precisely, apical and basal [12]. Conversely, mesenchymal cells generally do not exhibit either regi- mented structure or tight intracellular adhesion [13]. Mesenchymal cells form structures that are irregular in shape, without uniformity in compo- sition or density. Adhesions between mesenchymal cells are not as strong as those of their epithelial counterparts, which allows for increased migratory capacity [13]. The term EMT refers to a complex molecular and cellular program by which epithelial cells shed their differentiated characteristics, including cell-cell adhesion, planar and apical-basal polarity, and lack of motility, and instead acquire mesenchymal features, including motility, invasiveness, and a heightened resistance to apoptosis [14]. The EMT program plays an important role during morphogenesis of multicellular organisms. For example, during gastrulation, epithelial cells located in the primitive streak undergo EMT followed by ingression and migration to a new location where they form endodermal and mesodermal embryonic tissues [15]. However, induction of EMT can compromise the mechanical and physiological integrity of the tissue, and the consequences of inappropriate induction of this process can be disastrous. This can occur in cases of chronic inflammation, which can stimulate fibrosis, a condition in which excess EMT compromises tissue integrity and organ function, or when EMT is acquired by tumor cells [16]. 152 CANCER RESEARCH AND TREATMENT C l a s s i f i c a t i o n o f E M T Classification of EMTs into three different biological subtypes based on the biological context in which they occur has been proposed. Kalluri and Weinberg [17] proposed the term ‘type 1’EMT. These EMTs, which are associated with implantation, embryo formation, and organ develop- ment, are organized for generation of diverse cell types that share common mesenchymal phenotypes. This class of EMTs does not cause fibrosis, nor does it induce an invasive phenotype resulting in systemic spread via the circulation. The type 2 EMT is associated with wound healing, tissue regeneration, and organ fibrosis [17]. In type 2 EMTs, the program begins as part of a repair-associated event that normally results in generation of fibroblasts and other related cells for reconstruction of tissues following trauma and inflammatory injury. However, in contrast to type 1 EMTs, type 2 EMTs are associated with inflammation, and cease once inflammation is attenuated, as observed during wound healing and tissue regeneration. Type 3 EMTs occur in neoplastic cells that have previously undergone genetic and epigenetic changes, specifically in genes that favor clonal outgrowth and development of localized tumors [17]. E-cadherin is a cell-cell adhesion molecule that participates in homotypic, calcium-dependent interactions for formation of epithelial adherent junctions and sequestration of -catenin [18]. Several transcription factors have been implicated in transcriptional repression of E-cadherin. EMT inducers can be classified according to: 1) their effects on the E-cadherin promoter, and 2) source of the stimuli. Based on their effects on the E-cadherin promoter, there are two types of EMT inducer. The first type, such as Snail, ZEB, E47, and KLF8 factors, represses the activity of the E-cadherin promoter [19], and the second type, such asTwist, Goosecoid, E2.2, and FoxC2, is involved in indirect repression of E-cadherin transcription [19]. Regardless of the mechanism, E-cadherin repressors function as full EMT inducers in many cellular contexts, regulating expression of a variety of genes involved in repression of the epithelial character and promotion of the mesenchymal state [19]. Meanwhile, based on the source of stimuli, EMT inducers can be classified into two groups: external stimuli (that is microenvironment) and internal stimuli. 1. External stimuli and transcriptional factors The tumor microenvironment, which is composed of extracellular matrix, cells, and soluble factors, plays an important role in EMT induction and further in metastasis [20]. Several stromal cell subtypes, including macrophages, contribute to tumor progression through induction of EMT at the invasive front, a mechanism also linked to metastasis [21]. Tissue-culture studies have been instrumental in defining molecular regulation of EMT. Findings from these studies have demonstrated that signalling pathways for induction of EMT have many common endpoints, including down-regulation of E-cadherin expression and expression of EMT-associated genes; in addition, triggering of EMT by several extra- cellular activators, and existence of extensive crosstalk between signalling