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IN THE NAME OF GODMaster: Dr.mashayekhi

Presented By: Mona Radmehr

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Epithelial Mesenchymal Transition (EMT)

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• The epithelial-mesenchymal transition (EMT) is an orchestrated series of events in which cell-cell and cell-extracellular matrix (ECM) interactions are altered to release epithelial cells from the surrounding tissue, the cytoskeleton is reorganized to confer the ability to move through a three-dimensional ECM, and a new transcriptional program is induced to maintain the mesenchymal phenotype.

Epithelial structure is maintained by cell-cell interactions.

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By contrast, many mesenchymal cells exist largely without direct cell-cell contacts and defined cell polarity

They have distinct cell-ECM interactions and cytoskeletal structures.

Mesenchymal cells can contribute to the ECM by synthesizing and organizing new components and by remodeling the ECM through the production of matrix- degrading metalloproteinases (MMPs).

Mesenchymal cells are also abundant sources of signaling proteins that act on epithelial cells, including EGF, HGF and FGF families, as well as TGF.

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• EMTs are encountered in three distinct biological settings that carry very different functional consequences.

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Type 1 EMT: EMT during implantation, embryogenesis, and organ development

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Type 2 EMT: EMT associated with tissue regeneration and organ fibrosis

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• The behavior of these cells provided one of the first indications that epithelial cells under inflammatory stresses can advance to various extents through an EMT, creating the notion of “partial EMTs”.

• More specifically, such EMTs are found to be associated with fibrosis occurring in kidney, liver, lung, and intestine.

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Type 3 EMT: EMT associated with cancer progression and metastasis

• Wnts also cooperate with FGF receptors to help regulate an EMT associated with gastrulation.

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Excessive epithelial cell proliferation and angiogenesis are hallmarks of the initiation and early growth of primary epithelial cancers.

The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane.

The EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological level, the primary tumor from which they arose; accordingly, they no longer exhibit the mesenchymal phenotypes.

• Reconciling this behavior with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during the course of secondary tumor formation.

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Conclusion

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References Epithelial-Mesenchymal Transition in Cancer: Parallels Between

Normal Development and Tumor Progression Douglas S. Micalizzi & Susan M. Farabaugh & Heide L. Ford. J Mammary Gland Biol Neoplasia(2010)15:117–134. DOI 10.1007/s10911-010-9178-9.

EMT: When epithelial cells decide to become mesenchymal-like cells Raghu Kalluri J. Clin. Invest. 119:1417–1419 (2009). doi:10.1172/JCI39675.

Buck E et al. Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther. 2007; 6:532-541.

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Thank You

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• The tendency of disseminated cancer cells to undergo MET likely reflects the local microenvironments that they encounter after extravasation into the parenchyma of a distant organ, quite possibly the absence of the heterotypic signals they experienced in the primary tumor.

• These considerations indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process.

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The full spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear.• In the case of many carcinomas,

EMT-inducing signals emanating from the tumor-associated stroma, notably HGF, EGF, PDGF, and TGF-β, appear to be responsible for the induction or functional activation in cancer cells of a series of EMT-inducing transcription factors, notably Snail, Slug...

• Thus, in vitro studies have demonstrated that TGF-β can induce an EMT in certain types of cancer cells.

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• The connection between loss of E-cadherin expression by cancer cells and passage through an EMT has been established by many studies. Epithelial cell adhesion complexes reorganize and cell proliferation is suppressed when the full-length or the cytoplasmic portion of E-cadherin (containing the β-catenin binding site) is ectopically expressed in cells that have passed through an EMT, causing such cells to lose their mesenchymal phenotype.

• Sequestration of β-catenin in the cytoplasm is important for the preservation of epithelial features of cancer cells.

• Cells that lose cell surface E-cadherin become more responsive to induction of an EMT by various growth factors.

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• E-cadherin expression levels vary dramatically in different human tumors, and an inverse relationship between levels of E-cadherin and patient survival has been documented.

• The central role played by E-cadherin loss in the EMT program is further illustrated by the actions of several EMT-inducing transcription factors that facilitate acquisition of a mesenchymal phenotype, such as Snail and Slug.

• These transcription factors are induced by TGF-β exposure. Loss of E-cadherin promotes Wnt signaling and is associated with high levels of Snail in the nucleus.

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Many studies have shown that there are relationships between FGFs and invasion acquision in breast cancer. Invasion and metastasis could occur during a phenomenon which call as Epithelial to Mesenchymal Transition (EMT).

Purpose of this study is to examine the effect of FGF10 on tumorgenesis and invasion of breast cancer cell lines during in vivo experiments.

In vivo study of FGF-10 tumorgenesis and invasion in Breast cancer cell

lines

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