Mechanisms, mechanics and function of epithelial–mesenchymal transitions in early development

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Abstract

Epithelial-mesenchymal transitions (EMTs) are an important mechanism for reorganizing germ layers and tissues during embryonic development. They have both a morphogenic function in shaping the embryo and a patterning function in bringing about new juxtapositions of tissues, which allow further inductive patterning events to occur [Genesis 28 (2000) 23]. Whereas the mechanics of EMT in cultured cells is relatively well understood [reviewed in Biochem. Pharmacol. 60 (2000) 1091; Cell 105 (2001) 425; Bioessays 23 (2001) 912], surprisingly little is known about EMTs during embryonic development [reviewed in Acta Anat. 154 (1995) 8], and nowhere is the entire process well characterized within a single species. Embryonic (developmental) EMTs have properties that are not seen or are not obvious in culture systems or cancer cells. Developmental EMTs are part of a specific differentiative path and occur at a particular time and place. In some types of embryos, a relatively intact epithelium must be maintained while some of its cells de-epithelialize during EMT. In most cases de-epithelialization (loss of apical junctions) must occur in an orderly, patterned fashion in order that the proper morphogenesis results. Interestingly, we find that de-epithelialization is not always necessarily tightly coupled to the expression of mesenchymal phenotypes.Developmental EMTs are multi-step processes, though the interdependence and obligate order of the steps is not clear. The particulars of the process vary between tissues, species, and specific embryonic context. We will focus on 'primary' developmental EMTs, which are those occurring in the initial epiblast or embryonic epithelium. 'Secondary' developmental EMT events are those occurring in epithelial tissues that have reassembled within the embryo from mesenchymal cells. We will review and compare a number of primary EMT events from across the metazoans, and point out some of the many open questions that remain in this field.

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How matrix metalloproteinases regulate cell behavior.

M Sternlicht, Z Werb (2001)

The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.

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N-Cadherin Promotes Motility in Human Breast Cancer Cells Regardless of Their E-Cadherin Expression

Marvin T. Nieman, Ryan S. Prudoff, Keith R. Johnson … (1999)

E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell–cell adhesion and plays a role in maintaining the normal phenotype of epithelial cells. Decreased expression of E-cadherin has been correlated with increased invasiveness of breast cancer. In other systems, inappropriate expression of a nonepithelial cadherin, such as N-cadherin, by an epithelial cell has been shown to downregulate E-cadherin expression and to contribute to a scattered phenotype. In this study, we explored the possibility that expression of nonepithelial cadherins may be correlated with increased motility and invasion in breast cancer cells. We show that N-cadherin promotes motility and invasion; that decreased expression of E-cadherin does not necessarily correlate with motility or invasion; that N-cadherin expression correlates both with invasion and motility, and likely plays a direct role in promoting motility; that forced expression of E-cadherin in invasive, N-cadherin–positive cells does not reduce their motility or invasive capacity; that forced expression of N-cadherin in noninvasive, E-cadherin–positive cells produces an invasive cell, even though these cells continue to express high levels of E-cadherin; that N-cadherin–dependent motility may be mediated by FGF receptor signaling; and that cadherin-11 promotes epithelial cell motility in a manner similar to N-cadherin.

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Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions.

Héctor Peinado, Miguel Quintanilla, Amparo Cano (2003)

The Snail transcription factor has been described recently as a strong repressor of E-cadherin in epithelial cell lines, where its stable expression leads to the loss of E-cadherin expression and induces epithelial-mesenchymal transitions and an invasive phenotype. The mechanisms regulating Snail expression in development and tumor progression are not yet known. We show here that transforming growth factor beta-1 (TGFbeta1) induces Snail expression in Madin-Darby canine kidney cells and triggers epithelial-mesenchymal transitions by a mechanism dependent on the MAPK signaling pathway. Furthermore, TGFbeta1 induces the activity of Snail promoter, whereas fibroblast growth factor-2 has a milder effect but cooperates with TGFbeta1 in the induction of Snail promoter. Interestingly, TGFbeta1-mediated induction of Snail promoter is blocked by a dominant negative form of H-Ras (N17Ras), whereas oncogenic H-Ras (V12Ras) induces Snail promoter activity and synergistically cooperates with TGFbeta1. The effects of TGFbeta1 on Snail promoter are dependent of MEK1/2 activity but are apparently independent of Smad4 activity. In addition, H-Ras-mediated induction of Snail promoter, alone or in the presence of TGFbeta1, depends on both MAPK and phosphatidylinositol 3-kinase activities. These data support that MAPK and phosphatidylinositol 3-kinase signaling pathways are implicated in TGFbeta1-mediated induction of Snail promoter, probably through Ras activation and its downstream effectors.