Epithelial-mesenchymal transition (EMT) is an evolutionary conserved developmental process, which is evoked during tumour invasion and metastasis. In the tumour microenvironment, a variety of ...resident and recruited cells participate in tumour progression. Kawata et al. demonstrated an experimental model where proinflammatory cytokines derived from macrophages could enhance EMT of cancer cells. Endothelial-mesenchymal transition (EndMT) is originally observed during heart development, and recent studies suggest its role in pathological settings such as cancer and fibrosis. Mihira et al. demonstrated a line of evidence showing endothelial cell plasticity to undergo EndMT in vitro. Both in EMT and EndMT, transforming growth factor-β played pivotal roles, and multiple downstream mechanisms were used, depending on cell context. These recent works unraveled discrete regulatory networks in mesenchymal transition of epithelial and endothelial cells.
Generation of structural color is one of the essential functions realized by living organisms, and its industrial reproduction can result in numerous applications. From this viewpoint, the ...mechanisms, materials, analytical methods and fabrication technologies of the structural color are reviewed in this paper. In particular, the basic principles of natural photonic materials, the ideas developed from these principles, the directions of applications and practical industrial realizations are presented by summarizing the recent research results.
TGF-β Signaling in Lung Health and Disease Saito, Akira; Horie, Masafumi; Nagase, Takahide
International journal of molecular sciences,
08/2018, Letnik:
19, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Transforming growth factor (TGF)-β is an evolutionarily conserved pleiotropic factor that regulates a myriad of biological processes including development, tissue regeneration, immune responses, and ...tumorigenesis. TGF-β is necessary for lung organogenesis and homeostasis as evidenced by genetically engineered mouse models. TGF-β is crucial for epithelial-mesenchymal interactions during lung branching morphogenesis and alveolarization. Expression and activation of the three TGF-β ligand isoforms in the lungs are temporally and spatially regulated by multiple mechanisms. The lungs are structurally exposed to extrinsic stimuli and pathogens, and are susceptible to inflammation, allergic reactions, and carcinogenesis. Upregulation of TGF-β ligands is observed in major pulmonary diseases, including pulmonary fibrosis, emphysema, bronchial asthma, and lung cancer. TGF-β regulates multiple cellular processes such as growth suppression of epithelial cells, alveolar epithelial cell differentiation, fibroblast activation, and extracellular matrix organization. These effects are closely associated with tissue remodeling in pulmonary fibrosis and emphysema. TGF-β is also central to T cell homeostasis and is deeply involved in asthmatic airway inflammation. TGF-β is the most potent inducer of epithelial-mesenchymal transition in non-small cell lung cancer cells and is pivotal to the development of tumor-promoting microenvironment in the lung cancer tissue. This review summarizes and integrates the current knowledge of TGF-β signaling relevant to lung health and disease.
Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in ...various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are core components of the Hippo pathway, which have multiple biological functions in the development, homeostasis, and regeneration of tissues and organs. YAP/TAZ act as sensors of the structural and mechanical features of the cell microenvironment. Recent studies have shown aberrant YAP/TAZ activation in both fibrosis and cancer in animal models and human tissues. In fibroblasts, ECM stiffness mechanoactivates YAP/TAZ, which promote the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, thus establishing a feed-forward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ are activated by the disruption of cell polarity and increased ECM stiffness in fibrotic tissues, which promotes the proliferation and survival of epithelial cells. YAP/TAZ are also involved in the epithelial⁻mesenchymal transition (EMT), which contributes to tumor progression and cancer stemness. Importantly, the crosstalk with transforming growth factor (TGF)-β signaling and Wnt signaling is essential for the profibrotic and tumorigenic roles of YAP/TAZ. In this article, we review the latest advances in the pathobiological roles of YAP/TAZ signaling and their function as a molecular link between fibrosis and cancer.
Fibroblasts constitute a ubiquitous mesenchymal cell type and produce the extracellular matrix (ECM) of connective tissue, thereby providing the structural basis of various organs. Fibroblasts ...display differential transcriptional patterns unique to the organ of their origin and they can be activated by common stimuli such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) signaling. Cancer-associated fibroblasts (CAFs) reside in the cancer tissue and contribute to cancer progression by influencing cancer cell growth, invasion, angiogenesis and tumor immunity. CAFs impact on the tumor microenvironment by remodeling the ECM and secreting soluble factors such as chemokines and growth factors. Differential expression patterns of molecular markers suggest heterogeneous features of CAFs in terms of their function, pathogenic role and cellular origin. Recent studies elucidated the bimodal action of CAFs on cancer progression and suggest a subgroup of CAFs with tumor-suppressive effects. This review attempts to describe cellular features of colorectal CAFs with an emphasis on their heterogeneity and functional diversity.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful ...decision-making is required for the treatment of lung cancer associated with IPF. Transforming growth factor (TGF)-β signaling plays a central role in tissue fibrosis and tumorigenesis. TGF-β-mediated pathological changes that occur in IPF lung tissue may promote the process of field cancerization and provide the microenvironment favorable to cancer initiation and progression. This review summarizes the current knowledge related to IPF pathogenesis and explores the molecular mechanisms that underlie the occurrence of lung cancer in the background of IPF, with an emphasis on the multifaceted effects of TGF-β signaling.
Tight junctions (TJs) are composed of a claudin-based anastomosing network of TJ strands at which plasma membranes of adjacent epithelial cells are closely attached to regulate the paracellular ...permeability. Although the TJ proteins occludin and tricellulin have been known to be incorporated in the TJ strand network, their molecular functions remain unknown. Here, we established tricellulin/occludin-double knockout (dKO) MDCK II cells using a genome editing technique and evaluated the structure and barrier function of these cells. In freeze-fracture replica electron microscopy, the TJ strands of tricellulin/occludin-dKO cells had fewer branches and were less anastomosed compared with the controls. The paracellular permeability of ions and small tracers was increased in the dKO cells. A single KO of tricellulin or occludin had limited effects on the morphology and permeability of TJs. Mathematical simulation using a simplified TJ strand network model predicted that reduced cross-links in TJ strands lead to increased permeability of ions and small macromolecules. Furthermore, overexpression of occludin increased the complexity of TJ strand network and strengthened barrier function. Taken together, our data suggest that tricellulin and occludin mediate the formation and/or stabilization of TJ-strand branching points and contribute to the maintenance of epithelial barrier integrity.
Epithelial tissues cover the surfaces and lumens of the internal organs of multicellular animals and crucially contribute to internal environment homeostasis by delineating distinct compartments ...within the body. This vital role is known as epithelial barrier function. Epithelial cells are arranged like cobblestones and intricately bind together to form an epithelial sheet that upholds this barrier function. Central to the restriction of solute and fluid diffusion through intercellular spaces are occluding junctions, tight junctions in vertebrates and septate junctions in invertebrates. As part of epithelial tissues, cells undergo constant renewal, with older cells being replaced by new ones. Simultaneously, the epithelial tissue undergoes relative rearrangement, elongating, and shifting directionally as a whole. The movement or shape changes within the epithelial sheet necessitate significant deformation and reconnection of occluding junctions. Recent advancements have shed light on the intricate mechanisms through which epithelial cells sustain their barrier function in dynamic environments. This review aims to introduce these noteworthy findings and discuss some of the questions that remain unanswered.
•Epithelial barrier function is maintained even in highly dynamic environments.•Barrier maintenance is achieved through the rearrangement of occluding junctions.•The rearrangement process and its associated molecular mechanisms are discussed.
TJs maintain the epithelial barrier by regulating paracellular permeability. Since TJs are under dynamically fluctuating intercellular tension, cells must continuously survey and repair any damage. ...However, the underlying mechanisms allowing cells to sense TJ damage and repair the barrier are not yet fully understood. Here, we showed that proteinases play an important role in the maintenance of the epithelial barrier. At TJ break sites, EpCAM-claudin-7 complexes on the basolateral membrane become accessible to apical membrane-anchored serine proteinases (MASPs) and the MASPs cleave EpCAM. Biochemical data and imaging analysis suggest that claudin-7 released from EpCAM contributes to the rapid repair of damaged TJs. Knockout (KO) of MASPs drastically reduced barrier function and live-imaging of TJ permeability showed that MASPs-KO cells exhibited increased size, duration, and frequency of leaks. Together, our results reveal a novel mechanism of TJ maintenance through the localized proteolysis of EpCAM at TJ leaks, and provide a better understanding of the dynamic regulation of epithelial permeability.
Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies ...have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter‐individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we undertook transcriptional network‐defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ) (YAP/TAZ subgroup). The YAP/TAZ subgroup displayed adherent cell morphology, lower expression of achaete‐scute complex homolog 1 (ASCL1) and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of the YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC.
Subtypes of SCLC cell lines defined by expression patterns of transcription factors. Two‐dimensional hierarchical clustering of expression levels of 1520 transcription factors in SCLC cell lines.
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