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Metastasis:

Metastasis:. The Role of the Epithelial to Mesenchyme Transition ( EMT ) in Cancer Progression and Invasion. Richard T. Arkwright Wayne State University Cancer Biology Program. Overview:. What is EMT? Developmental Perspectives Pathological Perspectives What is Metastasis?

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Metastasis:

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  1. Metastasis: The Role of the Epithelial to Mesenchyme Transition (EMT) in Cancer Progression and Invasion. Richard T. Arkwright Wayne State University Cancer Biology Program

  2. Overview: • What is EMT? • Developmental Perspectives • Pathological Perspectives • What is Metastasis? • Models of Tumor Progression • Roles of EMT in Progression: • Invasion • Seeding • What is the significance of this knowledge? • Clinical Applications

  3. Epithelial-to-Mesenchymal Transition (EMT) • A necessary process for embryonic development, tumor progression and organ fibrosis. • During EMT epithelial characteristics are lost and the mesenchymal phenotype is acquired.

  4. EMT and MET in health and disease. • The evidence for EMT is compelling in embryonic development, organ formation, wound healing, tissue regeneration, organ fibrosis, cancer progression, and metastasis. • The role for MET in wound healing, tissue regeneration, organ fibrosis, cancer progression, and metastasis is only speculated and rigorous evidence is still lacking.

  5. EMT and MET in health and disease.

  6. Embryogenesis & Development

  7. Development of Human Embryonic Tissues

  8. Video: • http://www.youtube.com/watch?v=UgT5rUQ9EmQ&feature=related

  9. Introduction to Germ Layers

  10. Germ Layers: • Ectoderm- The outermost of the three primary germ layers of an embryo, from which the epidermis, nervous tissue, and, in vertebrates, sense organs develop. • Mesoderm- The middle embryonic germ layer, lying between the ectoderm and the endoderm, from which the connective tissues, including muscle and bone, and the urogenital and circulatory systems develop. • Endoderm- The innermost of the three primary germ layers of an animal embryo, developing into the epithelial linings of the gastrointestinal tract, the lungs, and associated structures.

  11. Migrating Cells:

  12. So How do They Migrate?

  13. Types of EMT • Type 1 EMT: Associated with implantation and embryonic gastrulation and gives rise to the mesoderm and endoderm and to mobile neural crest cells. • The primitive epithelium, specifically the epiblast, gives rise to primary mesenchyme via an EMT. • This primary mesenchyme can be re-induced to form secondary epithelia by a MET. • Type 2 EMT: Re-engaged in the context of inflammation and fibrosis • Expressed over extended periods of time and can eventually destroy an affected organ if the primary inflammatory insult is not removed or attenuated. • Type 3 EMT: Enable invasion and metastasis. • Secondary epithelia can transform into cancer cells that later undergo the EMTs

  14. EMT Phenotypes

  15. The epithelial and mesenchymal cell markers commonly used by EMT researchers are listed. Colocalizationof these two sets of distinct markers defines an intermediate phenotype of EMT, indicating cells that have passed only partly through an EMT. Detection of cells expressing both sets of markers makes it impossible to identify all mesenchymal cells that originate from the epithelia via EMT, as many mesenchymal cells “likely” shed all epithelial markers once a transition is completed EMT

  16. How does this Relate to Cancer Progression?

  17. Tumor Progression:

  18. Metastasis Facts • Up to 70% of patients with invasive cancer have overt or occult metastases at diagnosis. • Millions of tumor cells are shed daily into the circulation. Less than 0.01% of circulating tumor cells successfully initiate a metastatic focus. • Circulating tumor cells can be detected in patients who do not develop overt metastatic disease. • Angiogenesis is a ubiquitous and early event that is necessary for and promotes metastatic dissemination. • Cancer Medicine 6th edition 3

  19. Routes of Metastatic Spread

  20. Preferential metastatic sites

  21. Theories of metastasis • Seed and Soil • Anatomical and Mechanical • Homing and Chemoattraction

  22. Evidence for EMT in Cancer

  23. EMTs Role in Progression:

  24. Adhesion Receptor Interactions

  25. Adhesion Molecules • Integrins • Cadherins • Selectins • Catenins

  26. Mechanism of Induction

  27. Molecular Mechanisms of EMT

  28. TGF-B in Emergence and Progression of Carcinomas

  29. Significance of this Knowledge • By understanding the processes that trigger EMT, we might also be able to prevent it. • Potential to block metastasis • Perhaps even prevents cancer recurrence?

  30. Unanswered Questions • How can EMTs be targeted with specificity in the treatment of Cancer? • Are there distinct markers? • Prognostic Value? • Detection? • What is the role of the Micro Environment in EMT Induction?

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