Epithelial-mesenchymal transition

The meeting was designed to explore the intersections of signalling networks regulating and supporting epithelial-mesenchymal (EMT) and mesenchymal-epithelial transitions (MET) in development, fibrosis, and cancer. Particular emphasis was placed on correlations between tissue histology and molecular drivers and markers of EMT and on the therapeutic implications of EMT.

Growth factors in induction of epithelial-mesenchymal transition and metastasis

Epithelial to mesenchymal transition (EMT) has gained widespread acceptance over recent years as a mechanism by which normally sessile epithelial tumour cells can move away from the primary tumour and metastasize. This review article examines the role of a number of growth factors in inducing EMT, and the reverse process mesenchymal to epithelial transition. Unique and common intracellular signalling pathways are highlighted. A comprehensive understanding of the regulation of EMT will be critical in manipulating this process to develop novel anti-metastasis therapies.

The mesenchymal-to-epithelial reverting transition is enriched in metastatic castration resistant prostate cancer and correlates with poor survival

Despite recent recognition that the epithelial-mesenchymal transition (EMT) program acts in a dynamic manner (termed Epithelial to Mesenchymal Plasticity or EMP) during carcinoma metastasis, it has largely been ignored in the discovery and development of EMT-targeted therapies. In part, this has stemmed from a lack of preclinical models that can mimic the full dynamic nature of EMP and the perception that the EMT-reverting transition [or mesenchymal-epithelial reverting transition; (MErT)] is a mere antithesis of EMT. The objective of this study was to develop the first PCa model capable of recapitulating the dynamic nature of EMP.

Carcinoma invasion and metastasis : a role for epithelial-mesenchymal transition?

Carcinogenesis involves the accretion of unprogrammed genetic and epigenetic changes, which lead to dysregulation of the normal control of cell number. But a key clinical turning point in carcinoma progression is the establishment by emigrant cells of secondary growth sites (i.e., metastasis). The metastatic “cascade” comprises numerous steps, including escape from the primary tumor site, penetration of local stroma, entry of local vascular or lymphatic vessels (intravasation), aggregation with platelets, interaction with and adhesion to distant endothelia, extravasation, recolonization, and expansion ( 1), all the time avoiding effective immune clearance and being able to survive in these multiple contexts...

Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas : an exception to the norm

Cancer that arises from the ovarian surface epithelium (OSE) accounts for approximately 90% of human ovarian cancer, and is the fourth leading cause of cancer-related deaths among women in developed countries. The pathophysiology of epithelial ovarian cancer is still unclear because of the poor understanding of the complex nature of its development and the unusual mechanism(s) of disease progression. Recent studies have reported epithelial-mesenchymal transition (EMT) in cultured OSE and ovarian cancer cell lines in response to various stimuli, but our understanding of the importance of these observations for normal ovarian physiology and cancer progression is not well established. This review highlights the current literature on EMT-associated events in normal OSE and ovarian cancer cell lines, and discusses its implication for normal ovarian function as well as acquisition of neoplastic phenotypes. The pathological changes in OSE in response to EMT during neoplastic transformation and the contribution of hormones, growth factors, and cytokines that initiate and drive EMT to sustain normal ovarian function, as well as cancer development and progression are also discussed. Finally, emphasis is placed on the clinical implications of EMT and potential therapeutic opportunities that may arise from these observations have been proposed.

Epithelial-mesenchymal axis in head and neck cancer cell lines

Objectives: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumour type which necessitates multiple invitro models to attain an appreciation of its multiple subtypes. The phenomenon of epithelial-mesenchymal transition (EMT) isimportant to the development of a metastatic cancer cell phenotype being relevant to the ability of cancer cells to intravasate intovasculature and to invade tissues. The role of EMT in human papilloma virus (HPV) positive HNSCC is not well understood. Thispaper aims to characterize seven HNSCC cell lines (FaDu, SCC-25, SCC-15, CAL27, RPMI2650) including two new HPV-16positive HNSCC cell lines (UD-SCC2, 93-VU-147T) for their epithelial and mesenchymal properties. Materials and methods: A panel of HNSCC cell lines from multiple head and neck anatomical sites were profiled for basalexpression of epithelial and mesenchymal characteristics at mRNA, protein and functional levels (proliferative, migratory andinvasive properties). Furthermore, 3D spheroid forming capabilities were investigated. Results: We found that the HPV-16 positive cell line, in particular UD-SCC2 demonstrated a more invasive and mesenchymalphenotype at the molecular and functional levels suggesting HPV infection may mediate some of these cellular properties.Moreover, HPV-negative cell lines were not strictly epithelial presenting with a dynamic range of expression. Conclusions: This study presents the molecular and phenotypic diversity of HNSCC cell lines. It highlights the need formore studies in this field and a scoring system where HNSCC cell lines are ranked according to their respective epithelial andmesenchymal nature. This data will be useful to anyone modelling HNSCC behaviour, providing a molecular context which willenable them to decipher cell phenotypes and to develop therapies which block EMT progression.

Protein kinase B/Akt activity is involved in renal TGF-beta 1-driven epithelial-mesenchymal transition in vitro and in vivo

The molecular pathogenesis of diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, is complex and not fully understood. Transforming growth factor-beta (TGF-beta1) plays a critical role in many fibrotic disorders, including DN. In this study, we report protein kinase B (PKB/Akt) activation as a downstream event contributing to the pathophysiology of DN. We investigated the potential of PKB/Akt to mediate the profibrotic bioactions of TGF-beta1 in kidney. Treatment of normal rat kidney epithelial cells (NRK52E) with TGF-beta1 resulted in activation of phosphatidylinositol 3-kinase (PI3K) and PKB/Akt as evidenced by increased Ser473 phosphorylation and GSK-3beta phosphorylation. TGF-beta1 also stimulated increased Smad3 phosphorylation in these cells, a response that was insensitive to inhibition of PI3K or PKB/Akt. NRK52E cells displayed a loss of zona occludins 1 and E-cadherin and a gain in vimentin and alpha-smooth muscle actin expression, consistent with the fibrotic actions of TGF-beta1. These effects were blocked with inhibitors of PI3K and PKB/Akt. Furthermore, overexpression of PTEN, the lipid phosphatase regulator of PKB/Akt activation, inhibited TGF-beta1-induced PKB/Akt activation. Interestingly, in the Goto-Kakizaki rat model of type 2 diabetes, we also detected increased phosphorylation of PKB/Akt and its downstream target, GSK-3beta, in the tubules, relative to that in control Wistar rats. Elevated Smad3 phosphorylation was also detected in kidney extracts from Goto-Kakizaki rats with chronic diabetes. Together, these data suggest that TGF-beta1-mediated PKB/Akt activation may be important in renal fibrosis during diabetic nephropathy.