TGFβ and matrix-regulated epithelial to mesenchymal transition

Background

The progression of cancer through stages that guide a benign hyperplastic epithelial tissue towards a fully malignant and metastatic carcinoma, is driven by genetic and microenvironmental factors that remodel the tissue architecture. The concept of epithelial–mesenchymal transition (EMT) has evolved to emphasize the importance of plastic changes in tissue architecture, and the cross-communication of tumor cells with various cells in the stroma and with specific molecules in the extracellular matrix (ECM).

Scope of the review

Among the multitude of ECM-embedded cytokines and the regulatory potential of ECM molecules, this article focuses on the cytokine transforming growth factor β (TGFβ) and the glycosaminoglycan hyaluronan, and their roles in cancer biology and EMT. For brevity, we concentrate our effort on breast cancer.

Major conclusions

Both normal and abnormal TGFβ signaling can be detected in carcinoma and stromal cells, and TGFβ-induced EMT requires the expression of hyaluronan synthase 2 (HAS2). Correspondingly, hyaluronan is a major constituent of tumor ECM and aberrant levels of both hyaluronan and TGFβ are thought to promote a wounding reaction to the local tissue homeostasis. The link between EMT and metastasis also involves the mesenchymal–epithelial transition (MET). ECM components, signaling networks, regulatory non-coding RNAs and epigenetic mechanisms form the network of regulation during EMT-MET.

General significance

Understanding the mechanism that controls epithelial plasticity in the mammary gland promises the development of valuable biomarkers for the prognosis of breast cancer progression and even provides new ideas for a more integrative therapeutic approach against disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.     

Mitochondria and aging: a role for the permeability transition?

When mitochondria are subjected to oxidative stress and relatively high [Ca2+], they undergo a "permeability transition" in which the inner membrane becomes freely permeable to low-molecular-weight solutes. This phenomenon reflects reversible deformation of the adenine nucleotide translocase, the loss of its native gating properties and the stabilization of the deformed state by cyclophilin-D. The permeability transition may be a factor in cell dysfunction associated with aging. This can manifest in a number of ways ranging, in the most severe, from impaired energy transduction and compromised viability to more subtle influences on the propagation of Ca2+ signals. This article critically examines data relevant to this issue.     

Feeding biomechanics in Acanthostega and across the fish–tetrapod transition

Acanthostega is one of the earliest and most primitive limbed vertebrates. Its numerous fish-like features indicate a primarily aquatic lifestyle, yet cranial suture morphology suggests that its skull is more similar to those of terrestrial taxa. Here, we apply geometric morphometrics and two-dimensional finite-element analysis to the lower jaws of Acanthostega and 22 other tetrapodomorph taxa in order to quantify morphological and functional changes across the fish–tetrapod transition. The jaw of Acanthostega is similar to that of certain tetrapodomorph fish and transitional Devonian taxa both morphologically (as indicated by its proximity to those taxa in morphospace) and functionally (as indicated by the distribution of stress values and relative magnitude of bite force). Our results suggest a slow tempo of morphological and biomechanical changes in the transition from Devonian tetrapod jaws to aquatic/semi-aquatic Carboniferous tetrapod jaws. We conclude that Acanthostega retained a primitively aquatic lifestyle and did not possess cranial adaptations for terrestrial feeding.     

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signalling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signalling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.     

Temperament and character in cross-cultural comparisons between Swedish and Iranian people and Iranian refugees in Sweden--personality in transition?

The aim of the study was a cross-cultural comparison of personality traits between individuals from two very different cultures and refugees who resettled several years before from one to the other. Four hundred forty four Swedish individuals of the normal population; and 100 Iranian refugees in Sweden, and a group of 335 individuals from Tehran, capital of Iran, were investigated by means of the Temperament and Character Inventory, a questionnaire to assess temperament and character Iranians are those that are most frequently correctly classified followed by the Swedish based on temperament scores by means of a Discriminance analyses. Iranian refugees in Sweden were classified to about 50 per cent as Swedish and to slightly more then one-third as Iranians. Especially concerning character, 4 per cent only could be correctly classified as refugees. The results give some perspective on the adaptation process and personality changes in refugees several years after resettlement in another country with a complete different culture.     

Mitochondria and aging: A role for the mitochondrial transition pore?

The cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.     

Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer

Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell proliferation,cell-matrix interactions,migration and differentiation,and has been shown to be involved in cancer and other diseases.The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream.This cellular transformation process,which is associated by morphological change,loss of epithelial traits and gain of mesenchymal markers,is triggered by the secreted cytokine transforming growth factor-β(TGF-β).TGF-βbioactivity is carefully regulated,and its effects on cells are mediated by its receptors on the cell surface.In this review,we first provide a brief overview of major types of glycans,namely,N-glycans,O-glycans,glycosphingolipids and glycosaminoglycans that are involved in cancer progression.Thereafter,we summarize studies on how the glycosylation of TGF-βsignaling components regulates TGF-βsecretion,bioavailability and TGF-βreceptor function.Then,we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer.Identifying and understanding the mechanisms by which glycosylation affects TGF-βsignaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.     

Epithelial–mesenchymal transition in the formation of hypertrophic scars and keloids

Abnormal wound healing is likely to induce the formation of hypertrophic scars and keloids, which leads to dysfunction, deformity, and mental problem in the patients. Despite the advances in prevention and management of hypertrophic scar and keloids, the mechanism underlying scar and keloid formation has not been fully elucidated. Recent insights into the role of the epithelial–mesenchymal transition (EMT) in development, wound healing, stem cell regulation, fibrosis, and tumorigenesis have increased our understanding of the pathophysiology of hypertrophic scarring and keloids and suggested new therapeutic targets. This review summarizes recent progress in the elucidation of the role of EMT in physiologic wound healing and pathologic scar formation. This knowledge will facilitate an understanding of EMT roles in scar formation and shed new light on the modulation and potential treatment of hypertrophic scars and keloids.     

Is protein folding hierarchic? II. Folding intermediates and transition states

The folding reactions of some small proteins show clear evidence of a hierarchic process, whereas others, lacking detectable intermediates, do not. Evidence from folding intermediates and transition states suggests that folding begins locally, and that the formation of native secondary structure precedes the formation of tertiary interactions, not the reverse. Some notable examples in the literature have been interpreted to the contrary. For these examples, we have simulated the local structures that form when folding begins by using the LINUS program with nonlocal interactions turned off. Our results support a hierarchic model of protein folding.     

Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion

Epithelial-to-mesenchymal transition (EMT), an important cellular process, occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Dioscin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as anti-tumor, anti-inflammatory, anti-obesity, anti-fungal, and anti-viral activities. However, the possible role of dioscin in the EMT is unclear. We investigated the suppressive effect of dioscin on the EMT. Transforming growth factor-beta 1 (TGF-β1) is known to induce EMT in a number of cancer cell types and promote lung adenocarcinoma migration and invasion. To verify the inhibitory role of dioscin in lung cancer migration and invasion, we investigated the use of dioscin as inhibitors of TGF-β1-induced EMT in A549 lung cancer cells in vitro. Here, we found that dioscin prominently increased expression of the epithelial marker E-cadherin and expression of the mesenchymal marker N-cadherin and Snail during the TGF-β1-induced EMT. In addition, dioscin inhibited the TGF-β1-induced increase in cell migration and invasion of A549 lung cancer cells. Also, dioscin remarkably inhibited TGF-β1-regulated activation of MMP-2/9, Smad2, and p38. Taken together, our findings provide new evidence that dioscin suppresses lung cancer migration, and invasion in vitro by inhibiting the TGF-β1-induced EMT.     

Microtubule organization in cultured soybean and black spruce cells: Interphase —mitosis transition and spindle morphology

Summary Microtubule (MT) distribution during the cell cycle, especially spindle organization, has been investigated using immunofluorescence light microscopy in cultured cells of two higher plant species, soybean (angiosperm) and black spruce (gymnosperm). In soybean, the prophase and metaphase spindles were different in morphology and structure. The prophase spindle covering the nucleus was barrel-shaped and MTs extended between poles. The metaphase spindle consisted mainly of short MT bundles on either side of the chromosome mass. During prometaphase, the polarity and shape of the prophase spindle disappeared, suggesting that the metaphase spindle is newly formed in prometaphase and not derived from the prophase spindle. A striking feature of MT organization in black spruce was sharply defined poles during prometaphase and anaphase. They were located close to the cell edge, suggesting that a structure in the cytoplasm or associated with the plasma membrane is responsible for their formation. In black spruce the metaphase spindle was long with pointed poles and MT fir tree structures. In contrast, the metaphase spindle of soybean was short with very broad poles and lacked MT fir trees. These results suggest that MT fir tree structure may not be necessary for a functional spindle.     

LIM-domain proteins in transforming growth factor β-induced epithelial-to-mesenchymal transition and myofibroblast differentiation

Epithelial to mesenchymal transition (EMT) is a process during which junctions of the cell-cell contacts are dissolved, actin cytoskeleton is deformed, apical-basolateral cell polarity is lost and cell motility is increased. EMT is needed during normal embryonal development and wound healing, but may also lead to pathogenic transformation and formation of myofibroblasts. Transforming growth factor β (TGFβ) is a multifunctional cytokine promoting EMT and myofibroblast differentiation, and its dysregulation is involved in pathological disorders like cancer and fibrosis. Lin11, Isl-1 and Mec-3 (LIM) domain proteins are associated with actin cytoskeleton and linked to regulation of cell growth, damage signaling, cell fate determination and signal transduction. LIM-domain proteins generally do not bind DNA, but are more likely to function via protein-protein interactions. Despite being a disparate group of proteins, similarities in their functions are observed. In this review we will discuss the role of LIM-domain proteins in TGFβ-signaling pathway and in EMT-driven processes. LIM-domain proteins regulate TGFβ-induced actin cytoskeleton reorganization, motility and adhesion, but also dissolution of cell-cell junctions during EMT. Finally, the role of LIM-domain proteins in myofibroblasts found in fibrotic foci and tumor stroma will be discussed.     

Exosome and epithelial–mesenchymal transition: A complex secret of cancer progression

This short communication will enlighten the readers about the exosome and the epithelial-mesenchymal transition (EMT) related to several complicated events. It also highlighted the therapeutic potential of exosomes against EMT. Exosome toxicology, exosome heterogeneity, and a single exosome profiling approach are also covered in this article. In the future, exosomes could help us get closer to cancer vaccine and precision oncology.     

The transition state of coupled folding and binding for a flexible β-finger

Flexible and fully disordered protein regions that fold upon binding mediate numerous protein-protein interactions. However, little is known about their mechanism of interaction. One such coupled folding and binding occurs when a flexible region of neuronal nitric oxide synthase adopts a β-finger structure upon binding to its protein ligand, a PDZ [PSD-95 (postsynaptic density protein-95)/Discs large/ZO-1] domain from PSD-95. We have analyzed this binding reaction by protein engineering combined with kinetic experiments. Mutational destabilization of the β-finger changed mainly the dissociation rate constant of the proteins and, to a lesser extent, the association rate constant. Thus, mutation affected late events in the coupled folding and binding reaction. Our results therefore suggest that the native binding interactions of the β-finger are not present in the rate-limiting transition state for binding but form on the downhill side in a cooperative manner. However, by mutation, we could destabilize the β-finger further and change the rate-limiting step such that an initial conformational change becomes rate limiting. This switch in rate-limiting step shows that multistep binding mechanisms are likely to be found among flexible and intrinsically disordered regions of proteins.