Most solid tumors are epithelial in origin, as shown in the EMT Figure Panel A. A loss of epithelial-cell markers and gain of mesenchymal-cell markers has been observed in patient tumor samples, particularly at the leading edge or invasive front of solid tumors such as non-small cell (NSCLC), pancreatic, colorectal, and hepatocellular cancers. Such changes in phenotypic epithelial-like and mesenchymal-like cellular markers have been associated with the degree of tumor progression. The loss of epithelial-cell markers (e.g. E-cadherin, gamma catenin, others) is associated with disease progression and metastatic potential of a tumor. It has become evident that cancer cells can dedifferentiate through activation of specific biological pathways associated with EMT, thereby gaining the ability to migrate and invade. Hence, what has been observed experimentally regarding EMT and normal organ development is also thought to apply in the progression of solid tumors: transcriptional reprogramming processes whereby epithelial tumor cells lose cell polarity and cell-junction proteins and at the same time acquire protein mesenchymal-cell markers (e.g. vimentin, fibronectin, others) and signal transduction activities associated with mesenchymal cells facilitating migration and survival in an anchorage-independent environment, and ultimately metastasis at distal sites as shown in the EMT Figure Panels B and C. Mesenchymal-like tumor cells gain migratory capacity at the expense of proliferative potential. As in normal EMT, pathological EMT in tumor cells results from a transcriptional reprogramming of the cell leading to its transition into mesenchymal-like cellular phenotype, promoted by EMT-related signaling pathways driven, in part, through abnormal survival signals via receptors such as platelet derived growth factor receptor (PDGFR); fibroblast growth factor receptor (FGFR); cMET; TGFbR; IGF-1R; and regulatory kinases such as PI3K, AKT and mTOR. Cellular changes resulting in a more mesenchymal-like state driven by pathological EMT in cancer are thought to play a major role in disease progression has been associated with poor prognosis.

The reverse, Mesenchymal Epithelial Transition (MET), whereby mesenchymal tumor cells change to become more epithelial-like in phenotype, is thought to be required to regenerate a proliferative state and form macrometastases resembling the primary tumor at distant sites, as shown in the EMT Figure Panel D. It has been hypothesized that MET facilitates proliferation and growth of epithelial tumor cells at the sites distal from the primary tumor. Changes in the expression levels of epithelial-cell and mesenchymal-cell markers has allowed OSI to begin to define the EMT-status of tumors and OSI has an active research program to characterize EMT biomarkers across a variety of patient samples.

References

1. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev/Mol Cell Biol 2006; 7:131-142
2. Christfori C. New signals from an invasive front. Nature 2006; 41:444-450
3. Brabletz T et al. Migrating cancer stem cells – an integrated concept of malignant tumor progression. Nature Rev 2005;5:744-749