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Biomechanics of TGFβ‐induced epithelial‐mesenchymal transition: implications for fibrosis and cancer

Joseph W O’Connor, Esther W Gomez

Clinical and Translational Medicine · 2014 · Review · CC BY

doi:10.1186/2001-1326-3-23

Abstract

Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial‐mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)‐β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ‐induced intracellular signaling cascades that are affected by cell‐ and tissue‐level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Fibrotic diseases promote loss of function in a variety of organs including the heart, liver, lung, and kidney resulting in a significant number of deaths worldwide. Fibrosis arises from deregulation of wound healing processes and is characterized by a stiff and collagen-rich extracellular matrix (ECM) that is resistant to degradation. Inappropriate activation and activity of myofibroblasts drives the development of fibrosis. An increased risk of developing cancer in a variety of tissues has been linked to high stromal collagen content and to the presence of fibrotic lesions. Indeed, fibrosis has been found in close proximity of tumors within the pancreas, liver, and kidney and myofibroblasts have been identified as residents of the tumor microenvironment. The purpose of this article is to review the role of myofibroblasts in fibrosis and cancer and to discuss how physical cues contribute to epithelial-mesenchymal transition and to the development of myofibroblasts.

Myofibroblasts in health and disease

2Myofibroblasts are specialized cells within the body that aid in wound healing. Upon activation by biochemical and mechanical signals, myofibroblasts secrete and organize ECM, develop specialized matrix adhesions, and exhibit cytoskeletal organization characterized by contractile actin filaments. Together, these features allow for re-establishment of mechanical integrity and stability to the damaged tissue and enable the myofibroblasts to exert large contractile forces on their microenvironment thus assisting in both the closure of the wound and remodeling of the tissue. When wound healing is complete, myofibroblasts undergo apoptosis which decreases the cellularity of the granulation tissue and promotes the formation of scar tissue. Due to their important role in wound healing, these cells have attracted much interest for regenerative medicine applications.

3Upon aberrant and chronic activation, myofibroblasts can mediate the development of fibrosis. The sustained activation of myofibroblasts results in the enhanced production of ECM components, including collagen types I, III, IV, V, and VI and fibronectin. Through integrin engagement with ECM components and cytoskeletal contractility, myofibroblasts exert large forces on the ECM thus enabling matrix assembly and alignment. Together, these factors can lead to stiffening of the tissue and disruption of tissue architecture and function.

4Studies suggest that myofibroblasts are key players in the progression of a variety of cancer types including lung, liver, breast, and gastric cancer. Myofibroblasts have been found at the invasive fronts of tumors where they secrete pro-invasive cytokines, proteases, and inflammatory mediators. Fibrotic lesions and myofibroblasts have also been found in the tumor microenvironment prior to cancer cell invasion into the stroma suggesting that myofibroblasts may mediate an invasive phenotype. Indeed, myofibroblasts are found in higher proportions in the stroma of invasive breast cancers than in in situ carcinoma and their presence has been correlated with lymph node metastasis and increased histological grade in invasive ductal carcinoma. Contrary to these reports, a recent study found that myofibroblasts may serve a protective role in the context of pancreatic cancer as depletion of myofibroblasts and fibrosis in a mouse model of pancreatic ductal adenocarcinoma leads to a more invasive cancer cell phenotype and reduced survival. Depletion of myofibroblasts promoted remodeling of the pancreatic tumor stroma as well as changes in immune cell infiltration to the tumor. Thus, the effect of myofibroblasts on cancer progression appears to be complex and multifaceted and may vary depending upon organ or stage of cancer. Future investigation of the effect of in vivo myofibroblast depletion in other cancer types will be informative and will shed further light on the role of myofibroblasts in tumor progression.

Differentiation of myofibroblasts from fibroblasts

5Following the identification of myofibroblasts, studies focused primarily on factors that regulate the differentiation of myofibroblasts from stromal fibroblasts. Transforming growth factor (TGF)-β is a potent inducer of the myofibroblast phenotype and TGFβ-induced differentiation of fibroblasts to myofibroblasts was found to depend on the ED-A domain of fibronectin. Hallmarks of differentiated myofibroblasts include de novo expression of alpha smooth muscle actin (αSMA) and the incorporation of αSMA into stress fibers which confers high contractile activity to myofibroblasts. In this process, mechanical tension is crucial for the development of contractile features and for the acquisition of a myofibroblast phenotype. Culture of fibroblasts on two-dimensional compliant substrata or within three-dimensional collagen gels has revealed that increased microenvironmental stiffness and tension results in increased differentiation of fibroblasts to myofibroblasts. In vitro and in vivo experiments have also shown that changes in tensional loads to either collagen gels with embedded fibroblasts or granulation tissue at wound sites results in altered contractility of myofibroblasts. Likewise, myofibroblasts can actively remodel both the chemical and physical properties of their microenvironment through the secretion of ECM and exertion of contractile forces. Thus, mechanical signals are essential for the development of myofibroblasts from fibroblasts and for proper physiological function.

Epithelial cells mediate fibrogenesis

6Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity that is important in normal embryonic development and is co-opted in the progression of pathological conditions including fibrosis and cancer. In EMT, epithelial cells, which form monolayers that line many body structures and compartments, loosen attachments to neighboring cells, acquire an elongated morphology, and display increased motility (Figure 1). In addition to these phenotypic shifts, cells exhibit alterations in gene expression including upregulation of a variety of transcription factors including Snail, Slug, and Twist, decreased expression of epithelial markers such as E-cadherin and cytokeratins, and de novo expression of mesenchymal markers such as N-cadherin and vimentin. Following early EMT marker changes, further progression through EMT can stimulate a myogenic program characterized by the expression of αSMA and a myofibroblast phenotype. EMT is believed to contribute to fibrogenesis by serving as a source of myofibroblasts and by promoting paracrine signaling between epithelial cells and stromal cells. Several recent reviews highlight the role of EMT in epithelial-mesenchymal interactions in the context of fibrotic diseases.

7Many studies have identified cells demonstrating features of EMT in fibrotic disease models and in human biopsy samples. In a model of liver fibrosis, hepatocytes upregulate the expression of the EMT-associated transcription factor Snail and hepatocyte-specific ablation of Snail protects mice from fibrotic progression. In this study, it was found that hepatocyte expression of Snail has a multifaceted effect on the progression of liver fibrosis through regulation of growth factor expression and ECM synthesis, which impacts hepatocytes themselves and other cell types. Furthermore, hyperplastic type II alveolar epithelial cells from patients suffering from idiopathic pulmonary fibrosis co-express epithelial and mesenchymal markers including αSMA. In addition, human renal biopsy samples from patients with a variety of fibrotic kidney diseases display cells within the tubular structures that exhibit both epithelial and mesenchymal features. Together, these findings lend strong support for an important role for the epithelium in fibrogenesis either as a precursor of myofibroblasts or as a mediator influencing the development of myofibroblasts from other cell types.

8Given the importance of myofibroblasts in health and disease, much effort has been directed toward identification of myofibroblast progenitor cell types through lineage tracing studies in in vivo disease models. Studies have revealed a variety of candidates including resident fibroblasts, mesenchymal stem cells, and endothelial cells, with a number of reports finding that a portion of myofibroblasts within fibrotic lesions arise from epithelium through EMT. Fate tracking of alveolar epithelial cells in genetically modified mice has demonstrated that mesenchymal cells arising during the progression of pulmonary fibrosis can originate from epithelial cells. Moreover, lineage tracing in animal models has also identified epithelial cells as one of the cell types from which myofibroblasts can originate in kidney, liver, and intestinal fibrosis with the proportion of myofibroblasts arising from epithelial cells being tissue specific. However, a series of recent fate mapping studies using different epithelial and mesenchymal tags showed no evidence of epithelial precursors to myofibroblasts in the kidney and liver suggesting an alternate precursor cell type or that the role of the epithelium in fibrogenesis may be organ or disease specific. Thus, whether epithelial cells are indeed a source of myofibroblasts in vivo is currently debated and yet to be resolved definitively. Several recent reviews provide a summary of the different viewpoints with regard to this debate.

Biochemical induction of EMT by TGFβ

9EMT is triggered by a variety of soluble factors including epidermal growth factor (EGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and TGFβ. Other stimuli, such as hypoxia and adhesion to ECM components can also induce EMT. TGFβ, a ubiquitously expressed cytokine, is a potent inducer of EMT and is regarded as a key mediator of wound healing, fibrosis, and cancer. Epithelial cells derived from a variety of tissues including lung, kidney, and breast display myofibroblast features following exposure to TGFβ. TGFβ is perhaps the best characterized promoter of EMT and therefore we will focus this review specifically on TGFβ-mediated EMT.

10In the canonical TGFβ signaling pathway, active TGFβ ligands initiate signaling by binding to type I and type II receptor serine/threonine kinases. Following receptor activation, Smad2 and Smad3 associate with the TGFβ receptor complex and are phosphorylated by the type I TGFβ receptor. Phosphorylated Smad2 and Smad3 then form a complex with Smad4 and translocate to the nucleus. Once in the nucleus, the Smads can regulate the transcription of target genes in conjunction with other nuclear co-factors. Activation of several Smad-independent pathways including phosphoinositide 3-kinase (PI3K)-Akt, focal adhesion kinase (FAK), p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase (Erk) have been identified as crucial for EMT induction by TGFβ and recent studies implicate hyaluronan synthase 2 (HAS2), Krüppel-like factor (KLF)-8, and microRNA miR-203 as critical regulators of EMT. During the progression of TGFβ-induced EMT, cells exhibit dramatic cytoskeletal reorganization that is mediated by signaling through the Rho GTPase pathway which stimulates stress fiber formation, the acquisition of a mesenchymal morphology, and increased cytoskeletal contractility. Evidence implicates the RhoA pathway as a necessity for induction of EMT by TGFβ. These changes in cell morphology and cytoskeletal architecture suggest an important role for physical cues in regulating EMT.

Mechanical activation of TGFβ

11TGFβ is synthesized by cells and stored in a latent form crosslinked to the ECM in the cellular microenvironment. TGFβ can be activated via a number of mechanisms, one of which is through integrin binding. Integrin αvβ6, which is expressed at high levels predominantly on injured epithelial cells or cancer cells, binds to and locally activates TGFβ in vivo and in vitro. Treatment of lung epithelial cells with cytochalasin D, an inhibitor of actin polymerization, blocks activation of TGFβ by αvβ6 demonstrating an important role for the actin cytoskeleton in inducing TGFβ bioactivity. A recent study suggests that cellular contractility is required for TGFβ activation by αvβ6 as treatment of lung epithelial cells with Y27632 or blebbistatin, which inhibit Rho associated kinase (ROCK) and non-muscle myosin II respectively, abrogates TGFβ activation. Myofibroblasts can also activate TGFβ through a combination of αvβ5 and αvβ3 integrin engagement and contractile forces in vitro. Thus, cytoskeletal tension and cellular force generation are key mediators of the activation of TGFβ signaling.

EMT alters the mechanical properties of cells

12Cellular mechanics are influenced in part by the combination of cell morphology and cytoskeletal organization with the formation of stress fibers enabling increased cellular contractility. Atomic force microscopy (AFM) is a useful tool to determine mechanical properties through gently applying a force to induce cell deformation from which the modulus of the cell can be determined. By employing AFM on kidney, alveolar, and mammary epithelial cells, researchers have identified a significant increase in the stiffness of cells following TGFβ treatment. Tension within the membrane, as determined by tether pulling experiments, was also found to increase after EMT induction. In addition, the topography of cells changes following treatment with TGFβ with a rougher surface profile and nodular protrusions at intercellular junctions accompanying the transition to a mesenchymal phenotype. These mechanical changes, in addition to cytoskeletal rearrangements, demonstrate a correlation between cytoskeletal architecture and increased cell stiffness as epithelial cells progress through EMT. Furthermore, EMT has been observed at the edges of epithelial wounds and AFM studies have found that cell stiffness peaks approximately 10-20 μm from the wound edge with lower localized mechanical stiffness at the wound edge and far from the wound edge within the intact epithelial monolayer. This peak in mechanical stiffness was nullified with the expression of a dominant negative form of RhoA. These data suggest that wound sites may serve as focal points for mechanical signaling events and that changes in cellular stiffness may provide signals for cellular processes including cell spreading and migration which are required for the early stages of epithelial wound healing.

Increased cell spreading and elongation promote EMT

13The shape of a cell is regulated by microenvironmental cues and has been shown to play a pivotal role in tissue morphogenesis, proliferation, apoptosis, and differentiation. Cell shape is a consequence of intrinsic cellular mechanical properties and of forces exerted on the cell due to its adhesion to environmental components including ECM proteins and neighboring cells. During EMT, cells experience drastic shape changes as they transition from a cuboidal, cobblestone morphology characteristic of epithelial cells to an elongated, spindle-like shape typical of mesenchymal cells.

14Through the use of micropatterned cell culture substrata, which enable precise control over cell spreading, studies have shown that cell shape regulates the expression levels of the epithelial marker cytokeratin and the mesenchymal marker vimentin in matrix metalloproteinase (MMP)-3-induced EMT but not in TGFβ-induced EMT. More recently, we have demonstrated that cell spreading and elongation are critical factors that regulate TGFβ-induced expression of the myofibroblast marker αSMA during EMT. Culturing epithelial cells on microcontact printed islands of fibronectin of varying sizes and shapes enabled control of cell morphology. Adhesion to large square islands (2500 μm2) which permitted cells to spread promoted an increase in the percentage of cells expressing αSMA after 48 hours of TGFβ treatment in comparison to cells blocked from spreading (400 μm2) and to control cells not treated with TGFβ (Figure 2A). We found that cell shape regulates αSMA expression in part by controlling the subcellular localization of myocardin related transcription factor (MRTF)-A (Figure 2B). MRTFA is a co-factor of serum response factor (SRF) and together these proteins regulate the transcription of a variety of genes associated with actin dynamics and cell contractile function including αSMA. Indeed, MRTFA plays a key role in TGFβ-induced EMT and contributes to experimental fibrosis and metastasis. The activity of MRTFA is regulated in part by its association with monomeric (G)-actin and polymerization of actin monomers into filamentous (F)-actin disrupts the association between MRTFA and G-actin thus enabling nuclear accumulation of MRTFA. Increased cell spreading promotes an increase in F-actin levels which then leads to MRTFA nuclear localization and transcriptional activity (Figure 2C). These data suggest that cell shape changes that accompany EMT are critical for induction of the myofibroblast phenotype.

Matrix rigidity controls EMT

15Microenvironmental physical properties, such as stiffness and tension, are becoming increasingly acknowledged as contributing to normal cellular processes and to the development of diseases. In wound healing, fibrosis, and cancer, epithelial cells exist in a heterogeneous microenvironment in which the chemical and mechanical properties are dynamic. For example, during wound healing the mechanical properties at the wound site evolve with time, from compliant (with a Young's modulus of approximately 1 kPa) after initial wounding to a stiffness of 25 kPa or greater for contracting wound granulation tissue. In fibrotic tissues, the elastic modulus can reach values as high as 15-100 kPa. Interestingly, a recent study found that increased microenvironmental rigidity may precede liver fibrosis suggesting that the mechanical properties of the matrix may promote activation of pro-fibrotic pathways. In vivo and in vitro studies have also linked increased tissue stiffness and collagen content to the tumor phenotype and metastasis. For example, during the progression of breast cancer, the stiffness of the mammary gland can range from approximately 200 Pa for normal tissue to 5000 Pa or greater for the average breast tumor. High mammographic density, a strong risk factor for breast cancer, is associated with a significantly greater collagen content within the mammary gland in comparison to breast tissue with less mammographic density.

16Recent studies have identified matrix rigidity as a crucial regulator of TGFβ-induced EMT through several pathways. Mammary and kidney epithelial cells exhibit a switch between TGFβ-induced apoptosis and EMT when cultured on compliant or rigid substrata, respectively. In these studies, soft substrata blocked and rigid substrata promoted EMT regardless of whether the cells were cultured on fibronectin, collagen I, or recombinant basement membrane. The switch between apoptosis and EMT is controlled by activation of the PI3K/Akt signaling pathway, with increasing matrix rigidity promoting increased phosphorylation of Akt. Furthermore, cells cultured on rigid matrices are able to generate contractile forces which promote TGFβ activation from its latent complex by αv integrins while compliant matrices block this process. Activation of TGFβ on rigid substrata is promoted by Rho/ROCK signaling in lung epithelial cells and this induces EMT (Figure 3). On fibronectin-coated substrata, this response can be abrogated by culturing cells on rigid substrata coated with a fibronectin mutant which contains a stabilized RGD and PHSRN synergy site that supports α3 and α5 integrin engagement. These results highlight the complex interplay between epithelial cells and both the chemical and physical properties of their microenvironment during induction of EMT. Moreover, these studies suggest that activation of EMT may create a positive feedback loop that enhances myofibroblast activation and ECM synthesis thereby further increasing the rigidity of the matrix and disease progression.

Tissue geometry patterns EMT

17During tissue development and wound healing, cellular behaviors are spatially patterned thus conferring cells at specific locations unique attributes and functions. Indeed, patterning within developing embryos is ensured in part by the temporal and spatial regulation of EMT. Moreover, myofibroblasts have been observed at the edges of epithelial wounds and pathological EMT and myofibroblasts are found along the invasion front of metastatic tumors.

18Spatial variations in the mechanical properties of tissues are controlled by tissue composition and architecture as well as by the interaction of individual cells with the surrounding matrix and neighboring cells. Within epithelial tissues, neighboring cells exhibit cell-cell adhesions that are mediated by tight junctions and adherens junctions. These cell-cell junctions are functionally and dynamically connected to the actin cytoskeleton thus enabling transmission of forces between neighboring cells. In culture, intercellular transmission of mechanical stress through cell-cell adhesions can establish mechanical gradients with regions of maximal stress defined by the geometry of the tissue. Spatial patterns in EMT can arise in two-dimensional epithelial sheets with downregulation of cytokeratins and upregulation of mesenchymal markers vimentin and αSMA occurring in regions of the tissue that experience the highest mechanical stresses. The observed spatial patterning of TGFβ-induced EMT correlates with the subcellular localization of MRTFA, with EMT occurring in regions of the tissues with the highest frequencies of MRTFA nuclear localization.

Cyclic stretch promotes EMT

19Some cells within the body experience cyclic stretch during normal function, such as alveolar epithelia during respiration. Under conditions associated with fibrosis, epithelial cells may experience pathologically high levels of stretch arising from tissue distortion associated with injury or scar tissue formation. The effects of pathological levels of stretch on the induction of EMT have recently been highlighted in several studies. In a model system examining the pathological effects of renal tubular distension, kidney epithelial cells exposed to cyclic mechanical stretch exhibited increased EMT. This effect was mediated by upregulation of TGFβ by more than two-fold in stretched cells in comparison to non-stretched cells. Cyclic mechanical stretch also promotes EMT in type II alveolar epithelial cells, not through upregulation of TGFβ, but rather by inducing actin polymerization and upregulation of low molecular weight hyaluronan which facilitates signaling through Wnt/β-catenin and MyD88 pathways. Together, these studies demonstrate yet another important way in which mechanical cues can promote EMT and the fibrotic response of tissues to injury.

Myocardin related transcription factors

20Acquisition of mesenchymal features during TGFβ-induced EMT is regulated in part by the SRF/MRTFA signaling pathway and we have highlighted several studies demonstrating the interplay between this pathway and mechanics in EMT. Thus far, a majority of studies examining this pathway in the context of EMT have focused on how MRTFA regulates the expression of cytoskeletal-associated genes such as αSMA. MRTFA also regulates the expression of EMT-associated transcription factors including Snail, Slug, and Twist and therefore may have an impact on the expression of the epithelial gene E-cadherin. Further studies are necessary to define the role of MRTFA in the regulation of epithelial markers during EMT and to determine the impact of mechanical cues on the loss of epithelial features during EMT.

Hippo pathway

21The Hippo pathway is critical for cell growth and cell fate decisions and dysregulation of signaling through this pathway or of its downstream effectors is implicated in fibrosis and cancer. Downstream effectors in this pathway, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), interact with the canonical TGFβ signaling cascade by regulating the subcellular localization of phosphorylated Smads. Activation of these factors is controlled in part by cell-cell contact and recent studies have demonstrated that YAP and TAZ mediate how cells respond to cell geometry and ECM elasticity to control cell growth and stem cell differentiation. Indeed, cell shape and matrix rigidity modulate the subcellular localization of YAP and TAZ and cytoskeletal destabilization and inhibition of cell contractility inactivate YAP and TAZ. TAZ is a critical regulator of local EMT at wound sites and overexpression of TAZ can induce EMT. Downregulation of TAZ blocks αSMA expression along wound edges and it has been suggested that TAZ may control αSMA expression either through association with MRTFA or through interaction with the αSMA promoter as a co-activator to the TEA domain (TEAD) transcription factors. Given that YAP and TAZ are mechanosensitive and cytoskeletal architecture is linked to Hippo pathway signaling, it is plausible that mechanical signals control YAP and TAZ activity to regulate aspects of EMT. Future studies addressing the interplay of mechanical cues and YAP and TAZ signal transduction during TGFβ-induced EMT will be informative and may shed light on mechanisms mediating fibrosis and cancer.

Targeting TGFβ-induced EMT

22The multipotent nature of TGFβ signaling in normal and diseased tissues presents challenges for the development of therapeutics targeting this pathway. Nevertheless, much effort has been directed toward the development of antagonists of TGFβ. Small molecule inhibitors are in various stages of development and clinical trials are testing the efficacy of TGFβ monoclonal antibodies for treatment of diabetic nephropathy and idiopathic pulmonary fibrosis. Furthermore, neutralizing antibodies against TGFβ have been found to reduce metastatic cancer progression in mice. In addition, a promising approach which has demonstrated efficacy as an anti-fibrotic in lung, kidney, and liver disease models is targeting the integrin- and contractility-induced activation of TGFβ from it latent complex through the use of a monoclonal antibody to αvβ6 integrin. This method may also be an effective therapeutic approach for blocking tumor progression, as anti-αvβ6 integrin monoclonal antibody prevents xenograft tumor growth in vivo. Inhibiting TGFβ activation may present lower risk to the disruption of beneficial effects of TGFβ than targeting TGFβ itself since αvβ6 is expressed primarily within epithelial cells and is highly upregulated in diseased tissues.

23Targeting intracellular signaling cascades downstream of TGFβ rather than TGFβ itself may also be a viable approach for blocking fibrogenesis and cancer progression. Indeed, a recent study demonstrated that troglitazone, a peroxisome proliferator activated receptor (PPAR)-γ agonist that suppresses TGFβ-mediated fibrogenesis, attenuates TGFβ-induced phosphorylation of Akt and upregulation of Snail. This is one of the major pathways activated within epithelial cells by the combination of TGFβ and matrix rigidity. In addition, small molecule inhibitors including CCG-1423 and its analogs block SRF/MRTFA signaling. Namely, CCG-1423 blocks the interaction of MRTFA with importin alpha/beta 1 thus preventing the nuclear import of MRTFA. Furthermore, CCG-1423 has been shown to successfully inhibit TGFβ-induced expression of αSMA. Interestingly, a recent study reported that the small molecule isoxazole can induce a myofibroblast phenotype by regulating the stability and activity of MRTFA. Isoxazole enhanced cutaneous wound closure in mice suggesting that therapeutics aimed at promoting MRTFA signaling and the myofibroblast phenotype may also be promising methods for improving wound healing.

24Given the link between TGFβ-induced EMT, fibrosis, and cancer, therapeutics directly targeting EMT may prove to be fruitful approaches for treating these diseases. Bone morphogenetic protein (BMP)-7 exhibits anti-fibrotic effects in animal models of renal fibrosis and reverses EMT in renal tubular cells in vitro. Furthermore, a recent study found that a variety of anti-proliferative agents also inhibit EMT suggesting that the most effective compounds for cancer treatment may be those that target multiple aspects of cancer progression.

Conclusions

25The ability of epithelial cells to transition to a mesenchymal phenotype is regulated by cytokines, ECM components, cell-cell contacts, and mechanical cues and a combination of these factors is likely required for EMT induction. The studies highlighted within this review have identified an important role for mechanics in TGFβ-induced EMT and suggest that mechanical signaling pathways, including those involved in mechanotransduction, cell contractility, and regulation of matrix rigidity, could serve as potential targets for new therapies directed toward fibrosis and cancer. To achieve this though, a better understanding of the mechanistic underpinnings of how cell and tissue level physical properties contribute to EMT in pathological settings is needed.

Abbreviations

26AFM: Atomic force microscopy; BMP: Bone morphogenetic protein; ECM: Extracellular matrix; EGF: Epidermal growth factor; EMT: Epithelial-mesenchymal transition; FAK: Focal adhesion kinase; FGF: Fibroblast growth factor; Fn: Fibronectin; FSP-1: Fibroblast-specific protein-1; HAS2: Hyaluronan synthase 2; HGF: Hepatocyte growth factor; KLF8: Krüppel-like factor 8; Ln: Laminin; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; MRTF: Myocardin related transcription factor; NMuMG: Normal murine mammary gland; PI3K: Phosphoinositide-3-kinase; PPAR: Peroxisome proliferator activated receptor; ROCK: Rho associated kinase; SRF: Serum response factor; TAZ: Transcriptional co-activator with PDZ-binding motif; TEAD: TEA domain; TGF: Transforming growth factor; YAP: Yes-associated protein; αSMA: Alpha smooth muscle actin.

Competing interests

27The authors declare that they have no competing interests.

Authors’ contributions

28JWO and EWG reviewed the literature, wrote, and revised the manuscript. Both authors read and approved the final manuscript.

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Sivridis E Giatromanolaki A Koukourakis MI Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stressJ Clin Pathol2005 310331038
Not in our library10.1136/jcp.2005.026260
34.
Ohtani H Motohashi H Sato H Seiki M Nagura H Dual over-expression pattern of membrane-type metalloproteinase-1 in cancer and stromal cells in human gastrointestinal carcinoma revealed by in situ hybridization and immunoelectron microscopyInt J Cancer1996 3565570
Not in our library10.1002/(sici)1097-0215(19961127)68:5<565::aid-ijc2>3.0.co;2-x
35.
Gress TM Muller-Pillasch F Lerch MM Friess H Buchler M Adler G Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancerInt J Cancer1995 3407413
Not in our library10.1002/ijc.2910620409
36.
Vermeulen L De Sousa EMF van der Heijden M Cameron K de Jong JH Borovski T Tuynman JB Todaro M Merz C Rodermond H Sprick MR Kemper K Richel DJ Stassi G Medema JP Wnt activity defines colon cancer stem cells and is regulated by the microenvironmentNat Cell Biol2010 3468476
Not in our library10.1038/ncb2048
37.
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Not in our library10.1002/path.1398
38.
Yazhou C Wenlv S Weidong Z Licun W Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breastTumour Biol2004 3290295
Not in our library10.1159/000081394
39.
De Wever O Mareel M Role of myofibroblasts at the invasion frontBiol Chem2002 35567
Not in our library10.1515/bc.2002.006
40.
Ozdemir BC Pentcheva-Hoang T Carstens JL Zheng X Wu CC Simpson TR Laklai H Sugimoto H Kahlert C Novitskiy SV De Jesus-Acosta A Sharma P Heidari P Mahmood U Chin L Moses HL Weaver VM Maitra A Allison JP LeBleu VS Kalluri R Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survivalCancer Cell2014 3719734
Not in our library10.1016/j.ccr.2014.04.005
41.
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Not in our library10.1083/jcb.142.3.873
42.
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Not in our library10.1016/s0002-9440(10)65334-5
43.
Grinnell F Ho CH Lin YC Skuta G Differences in the regulation of fibroblast contraction of floating versus stressed collagen matricesJ Biol Chem1999 3918923
Not in our library10.1074/jbc.274.2.918
44.
Grinnell F Zhu M Carlson MA Abrams JM Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissueExp Cell Res1999 3608619
Not in our library10.1006/excr.1999.4440
45.
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Not in our library10.1007/bf00210512
46.
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Not in our library10.1002/ar.1092320305
47.
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Not in our library10.1002/hep.21792
48.
Brown RA Prajapati R McGrouther DA Yannas IV Eastwood M Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substratesJ Cell Physiol1998 3323332
Not in our library10.1002/(sici)1097-4652(199806)175:3<323::aid-jcp10>3.0.co;2-6
49.
Hinz B Mastrangelo D Iselin CE Chaponnier C Gabbiani G Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiationAm J Pathol2001 310091020
Not in our library10.1016/s0002-9440(10)61776-2
50.
Leung LY Tian D Brangwynne CP Weitz DA Tschumperlin DJ A new microrheometric approach reveals individual and cooperative roles for TGF-beta1 and IL-1beta in fibroblast-mediated stiffening of collagen gelsFASEB J2007 320642073
Not in our library10.1096/fj.06-7510com
51.
Kalluri R Weinberg RA The basics of epithelial-mesenchymal transitionJ Clin Invest2009 314201428
Not in our library10.1172/jci39104
52.
Shook D Keller R Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early developmentMech Dev2003 313511383
Not in our library10.1016/j.mod.2003.06.005
53.
Thiery JP Acloque H Huang RY Nieto MA Epithelial-mesenchymal transitions in development and diseaseCell2009 3871890
Not in our library10.1016/j.cell.2009.11.007
54.
Xu J Lamouille S Derynck R TGF-beta-induced epithelial to mesenchymal transitionCell Res2009 3156172
Not in our library10.1038/cr.2009.5
55.
Lamouille S Xu J Derynck R Molecular mechanisms of epithelial-mesenchymal transitionNat Rev Mol Cell Biol2014 3178196
Not in our library10.1038/nrm3758
56.
Masszi A Speight P Charbonney E Lodyga M Nakano H Szaszi K Kapus A Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3J Cell Biol2010 3383399
Not in our library10.1083/jcb.200906155
57.
Chapman HA Epithelial-mesenchymal interactions in pulmonary fibrosisAnnu Rev Physiol2011 3413435
Not in our library10.1146/annurev-physiol-012110-142225
58.
Duffield JS Lupher M Thannickal VJ Wynn TA Host responses in tissue repair and fibrosisAnnu Rev Pathol2013 3241276
Not in our library10.1146/annurev-pathol-020712-163930
59.
Friedman SL Sheppard D Duffield JS Violette S Therapy for fibrotic diseases: nearing the starting lineSci Transl Med2013 3167sr161
Not in our library10.1126/scitranslmed.3004700
60.
Rowe RG Lin Y Shimizu-Hirota R Hanada S Neilson EG Greenson JK Weiss SJ Hepatocyte-derived Snail1 propagates liver fibrosis progressionMol Cell Biol2011 323922403
Not in our library10.1128/mcb.01218-10
61.
Kim KK Kugler MC Wolters PJ Robillard L Galvez MG Brumwell AN Sheppard D Chapman HA Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrixProc Natl Acad Sci U S A2006 31318013185
Not in our library10.1073/pnas.0605669103
62.
Willis BC Borok Z TGF-beta-induced EMT: mechanisms and implications for fibrotic lung diseaseAm J Physiol Lung Cell Mol Physiol2007 3L525L534
Not in our library10.1152/ajplung.00163.2007
63.
Marmai C Sutherland RE Kim KK Dolganov GM Fang X Kim SS Jiang S Golden JA Hoopes CW Matthay MA Chapman HA Wolters PJ Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosisAm J Physiol Lung Cell Mol Physiol2011 3L71L78
Not in our library10.1152/ajplung.00212.2010
64.
Quaggin SE Kapus A Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transitionKidney Int2011 34150
Not in our library10.1038/ki.2011.77
65.
Rastaldi MP Ferrario F Giardino L Dell'Antonio G Grillo C Grillo P Strutz F Muller GA Colasanti G D'Amico G Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsiesKidney Int2002 3137146
Not in our library10.1046/j.1523-1755.2002.00430.x
66.
Flier SN Tanjore H Kokkotou EG Sugimoto H Zeisberg M Kalluri R Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosisJ Biol Chem2010 32020220212
Not in our library10.1074/jbc.m110.102012
67.
Hinz B Phan SH Thannickal VJ Galli A Bochaton-Piallat ML Gabbiani G The myofibroblast: one function, multiple originsAm J Pathol2007 318071816
Not in our library10.2353/ajpath.2007.070112
68.
Iwano M Plieth D Danoff TM Xue C Okada H Neilson EG Evidence that fibroblasts derive from epithelium during tissue fibrosisJ Clin Invest2002 3341350
Not in our library10.1172/jci15518
69.
Kim KK Wei Y Szekeres C Kugler MC Wolters PJ Hill ML Frank JA Brumwell AN Wheeler SE Kreidberg JA Chapman HA Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosisJ Clin Invest2009 3213224
Not in our library10.1172/jci36940
70.
Tanjore H Xu XC Polosukhin VV Degryse AL Li B Han W Sherrill TP Plieth D Neilson EG Blackwell TS Lawson WE Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosisAm J Respir Crit Care Med2009 3657665
Not in our library10.1164/rccm.200903-0322oc
71.
Zeisberg M Yang C Martino M Duncan MB Rieder F Tanjore H Kalluri R Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transitionJ Biol Chem2007 32333723347
Not in our library10.1074/jbc.m700194200
72.
LeBleu VS Taduri G O'Connell J Teng Y Cooke VG Woda C Sugimoto H Kalluri R Origin and function of myofibroblasts in kidney fibrosisNat Med2013 310471053
Not in our library10.1038/nm.3218
73.
Zeisberg M Duffield JS Resolved: EMT produces fibroblasts in the kidneyJ Am Soc Nephrol2010 312471253
Not in our library10.1681/asn.2010060616
74.
Humphreys BD Lin SL Kobayashi A Hudson TE Nowlin BT Bonventre JV Valerius MT McMahon AP Duffield JS Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosisAm J Path2010 38597
Not in our library10.2353/ajpath.2010.090517
75.
Koesters R Kaissling B Lehir M Picard N Theilig F Gebhardt R Glick AB Hahnel B Hosser H Grone HJ Kriz W Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cellsAm J Path2010 3632643
Not in our library10.2353/ajpath.2010.091012
76.
Taura K Miura K Iwaisako K Osterreicher CH Kodama Y Penz-Osterreicher M Brenner DA Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in miceHepatology2010 310271036
Not in our library10.1002/hep.23368
77.
Scholten D Osterreicher CH Scholten A Iwaisako K Gu G Brenner DA Kisseleva T Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in miceGastroenterology2010 3987998
Not in our library10.1053/j.gastro.2010.05.005
78.
Lo H-W Hsu S-C Xia W Cao X Shih J-Y Wei Y Abbruzzese JL Hortobagyi GN Hung M-C Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expressionCancer Res2007 390669076
Not in our library10.1158/0008-5472.can-07-0575
79.
Lu ZM Ghosh S Wang ZY Hunter T Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasionCancer Cell2003 3499515
Not in our library10.1016/s1535-6108(03)00304-0
80.
Elliott BE Hung WL Boag AH Tuck AB The role of hepatocyte growth factor (scatter factor) in epithelial-mesenchymal transition and breast cancerCan J Physiol Pharm2002 391102
Not in our library10.1139/y02-010
81.
Grotegut S von Schweinitz D Christofori G Lehembre F Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of SnailEMBO J2006 335343545
Not in our library10.1038/sj.emboj.7601213
82.
Valles AM Boyer B Badet J Tucker GC Barritault D Thiery JP Acidic Fibroblast growth-factor is a modulator of epithelial plasticity in a rat bladder-carcinoma cell-lineProc Natl Acad Sci U S A1990 311241128
Not in our library10.1073/pnas.87.3.1124
83.
Ciruna B Rossant J FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streakDev Cell2001 33749
Not in our library10.1016/s1534-5807(01)00017-x
84.
Miettinen PJ Ebner R Lopez AR Derynck R TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells - involvement of type-I receptorsJ Cell Biol1994 320212036
Not in our library10.1083/jcb.127.6.2021
85.
Xie L Law BK Aakre ME Edgerton M Shyr Y Bhowmick NA Moses HL Transforming growth factor beta-regulated gene expression in a mouse mammary gland epithelial cell lineBreast Cancer Res2003 3R187R198
Not in our library10.1186/bcr640
86.
Sahlgren C Gustafsson MV Jin S Poellinger L Lendahl U Notch signaling mediates hypoxia-induced tumor cell migration and invasionProc Natl Acad Sci U S A2008 363926397
Not in our library10.1073/pnas.0802047105
87.
Higgins DF Kimura K Bernhardt WM Shrimanker N Akai Y Hohenstein B Saito Y Johnson RS Kretzler M Cohen CD Eckardt K-U Iwano M Haase VH Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transitionJ Clin Invest2007 338103820
Not in our library10.1172/jci30487
88.
Espinosa Neira R Perez Salazar E Native type IV collagen induces an epithelial to mesenchymal transition-like process in mammary epithelial cells MCF10AInt J Biochem Cell B2012 321942203
Not in our library10.1016/j.biocel.2012.08.018
89.
Zeisberg M Bonner G Maeshima Y Colorado P Muller GA Strutz F Kalluri R Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiationAm J Path2001 313131321
Not in our library10.1016/s0002-9440(10)62518-7
90.
Klass BR Grobbelaar AO Rolfe KJ Transforming growth factor beta 1 signalling, wound healing and repair: a multifunctional cytokine with clinical implications for wound repair, a delicate balancePostgrad Med J2009 3914
Not in our library10.1136/pgmj.2008.069831
91.
Levine JH Moses HL Gold LI Nanney LB Spatial and temporal patterns of immunoreactive transforming growth factor-beta-1, beta-2, beta-3 during excisional wound repairAm J Path1993 3368380
Not in our library
92.
Ask K Bonniaud P Maass K Eickelberg O Margetts PJ Warburton D Groffen J Gauldie J Kolb M Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta 3Int J Biochem Cell B2008 3484495
Not in our library10.1016/j.biocel.2007.08.016
93.
Bottinger EP TGF-beta in renal injury and diseaseSemin Nephrol2007 3309320
Not in our library10.1016/j.semnephrol.2007.02.009
94.
Gorsch SM Memoli VA Stukel TA Gold LI Arrick BA Immunohistochemical staining for transforming growth factor-beta-1 associates with disease progression in human breast cancerCancer Res1992 369496952
Not in our library
95.
Oft M Heider KH Beug H TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasisCurr Biol1998 312431252
Not in our library10.1016/s0960-9822(07)00533-7
96.
Willis BC Liebler JM Luby-Phelps K Nicholson AG Crandall ED du Bois RM Borok Z Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosisAm J Pathol2005 313211332
Not in our library10.1016/s0002-9440(10)62351-6
97.
Zhou B Buckley ST Patel V Liu Y Luo J Krishnaveni MS Ivan M DeMaio L Kim KJ Ehrhardt C Crandall ED Borok Z Troglitazone attenuates TGF-beta1-induced EMT in alveolar epithelial cells via a PPARgamma-independent mechanismPLoS One2012 3e38827
Not in our library10.1371/journal.pone.0038827
98.
Elberg G Chen L Elberg D Chan MD Logan CJ Turman MA MKL1 mediates TGF-beta1-induced alpha-smooth muscle actin expression in human renal epithelial cellsAm J Physiol Renal Physiol2008 3F1116F1128
Not in our library10.1152/ajprenal.00142.2007
99.
Leight JL Wozniak MA Chen S Lynch ML Chen CS Matrix rigidity regulates a switch between TGF-beta 1-induced apoptosis and epithelial-mesenchymal transitionMol Biol Cell2012 3781791
Not in our library10.1091/mbc.e11-06-0537
100.
Zeisberg M Hanai J Sugimoto H Mammoto T Charytan D Strutz F Kalluri R BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injuryNat Med2003 3964968
Not in our library10.1038/nm888
101.
Masszi A Fan L Rosivall L McCulloch CA Rotstein OD Mucsi I Kapus A Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-cateninAm J Path2004 319551967
Not in our library10.1016/s0002-9440(10)63247-6
102.
Gomez EW Chen QK Gjorevski N Nelson CM Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransductionJ Cell Biochem2010 34451
Not in our library10.1002/jcb.22545
103.
Nelson CM Khauv D Bissell MJ Radisky DC Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cellsJ Cell Biochem2008 32533
Not in our library10.1002/jcb.21821
104.
O'Connor JW Gomez EW Cell adhesion and shape regulate TGF-beta1-induced epithelial-myofibroblast transition via MRTF-A signallingPLoS One2013 3e83188
Not in our library10.1371/journal.pone.0083188
105.
Morita T Mayanagi T Sobue K Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodelingJ Cell Biol2007 310271042
Not in our library10.1083/jcb.200708174
106.
Shi YG Massague J Mechanisms of TGF-beta signaling from cell membrane to the nucleusCell2003 3685700
Not in our library10.1016/s0092-8674(03)00432-x
107.
Zavadil J Bitzer M Liang D Yang YC Massimi A Kneitz S Piek E Bottinger EP Genetic programs of epithelial cell plasticity directed by transforming growth factor-betaProc Natl Acad Sci U S A2001 366866691
Not in our library10.1073/pnas.111614398
108.
Bakin AV Tomlinson AK Bhowmick NA Moses HL Arteaga CL Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migrationJ Biol Chem2000 33680336810
Not in our library10.1074/jbc.m005912200
109.
Cicchini C Laudadio I Citarella F Corazzari M Steindler C Conigliaro A Fantoni A Amicone L Tripodi M TGFbeta-induced EMT requires focal adhesion kinase (FAK) signalingExp Cell Res2008 3143152
Not in our library10.1016/j.yexcr.2007.09.005
110.
Bhowmick NA Zent R Ghiassi M McDonnell M Moses HL Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticityJ Biol Chem2001 34670746713
Not in our library10.1074/jbc.m106176200
111.
Activation of the Erk Pathway Is Required for TGF-β1-Induced EMT In Vitro · 2004
Not checked
112.
Porsch H Bernert B Mehic M Theocharis AD Heldin CH Heldin P Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2Oncogene2013 343554365
Not in our library10.1038/onc.2012.475
113.
Zhang H Liu L Wang Y Zhao G Xie R Liu C Xiao X Wu K Nie Y Fan D KLF8 involves in TGF-beta-induced EMT and promotes invasion and migration in gastric cancer cellsJ Cancer Res Clin Oncol2013 310331042
Not in our library10.1007/s00432-012-1363-3
114.
Ding X Park SI McCauley LK Wang CY Signaling between transforming growth factor beta (TGF-beta) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasisJ Biol Chem2013 31024110253
Not in our library10.1074/jbc.m112.443655
115.
Bhowmick NA Ghiassi M Bakin A Aakre M Lundquist CA Engel ME Arteaga CL Moses HL Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanismMol Biol Cell2001 32736
Not in our library10.1091/mbc.12.1.27
116.
Bandyopadhyay A Raghavan S Defining the role of integrin alphavbeta6 in cancerCurr Drug Targets2009 3645652
Not in our library10.2174/138945009788680374
117.
Munger JS Huang X Kawakatsu H Griffiths MJ Dalton SL Wu J Pittet JF Kaminski N Garat C Matthay MA Rifkin DB Sheppard D The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosisCell1999 3319328
Not in our library10.1016/s0092-8674(00)80545-0
118.
Giacomini MM Travis MA Kudo M Sheppard D Epithelial cells utilize cortical actin/myosin to activate latent TGF-beta through integrin alpha(v)beta(6)-dependent physical forceExp Cell Res2012 3716722
Not in our library10.1016/j.yexcr.2012.01.020
119.
Wipff PJ Rifkin DB Meister JJ Hinz B Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrixJ Cell Biol2007 313111323
Not in our library10.1083/jcb.200704042
120.
Tan JL Tien J Pirone DM Gray DS Bhadriraju K Chen CS Cells lying on a bed of microneedles: an approach to isolate mechanical forceProc Natl Acad Sci U S A2003 314841489
Not in our library10.1073/pnas.0235407100
121.
Thoelking G Reiss B Wegener J Oberleithner H Pavenstaedt H Riethmuller C Nanotopography follows force in TGF-beta1 stimulated epitheliumNanotechnology2010 3265102
Not in our library10.1088/0957-4484/21/26/265102
122.
Buckley ST Medina C Davies AM Ehrhardt C Cytoskeletal re-arrangement in TGF-beta1-induced alveolar epithelial-mesenchymal transition studied by atomic force microscopy and high-content analysisNanomedicine2012 3355364
Not in our library10.1016/j.nano.2011.06.021
123.
Schneider D Baronsky T Pietuch A Rother J Oelkers M Fichtner D Wedlich D Janshoff A Tension monitoring during epithelial-to-mesenchymal transition links the switch of phenotype to expression of moesin and cadherins in NMuMG cellsPLoS One2013 3e80068
Not in our library10.1371/journal.pone.0080068
124.
Arnoux V Come C Kusewitt D Hudson L Savagner P Savagner PCutaneous wound reepithelialization: A partial and reversible EMTRise and fall of epithelial phenotype: Concepts of epithelial-mesenchymal transition2005 Berlin: Springer111134
Not in our library
125.
Wagh AA Roan E Chapman KE Desai LP Rendon DA Eckstein EC Waters CM Localized elasticity measured in epithelial cells migrating at a wound edge using atomic force microscopyAm J Physiol Lung Cell Mol Physiol2008 3L54L60
Not in our library10.1152/ajplung.00475.2007
126.
Watanabe T Takahashi Y Tissue morphogenesis coupled with cell shape changesCurr Opin Genet Devel2010 3443447
Not in our library10.1016/j.gde.2010.05.004
127.
Locascio A Nieto MA Cell movements during vertebrate development: integrated tissue behaviour versus individual cell migrationCurr Opin Genet Devel2001 3464469
Not in our library10.1016/s0959-437x(00)00218-5
128.
Chen CS Mrksich M Huang S Whitesides GM Ingber DE Geometric control of cell life and deathScience1997 314251428
Not in our library10.1126/science.276.5317.1425
129.
Folkman J Moscona A Role of cell shape in growth controlNature1978 3345349
Not in our library10.1038/273345a0
130.
Watt FM Jordan PW Oneill CH Cell-shape controls terminal differentiation of human epidermal-keratinocytesProc Natl Acad Sci U S A1988 355765580
Not in our library10.1073/pnas.85.15.5576
131.
Roskelley CD Desprez PY Bissell MJ Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transductionProc Natl Acad Sci U S A1994 31237812382
Not in our library10.1073/pnas.91.26.12378
132.
McBeath R Pirone DM Nelson CM Bhadriraju K Chen CS Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitmentDev Cell2004 3483495
Not in our library10.1016/s1534-5807(04)00075-9
133.
Connelly JT Gautrot JE Trappmann B Tan DW Donati G Huck WT Watt FM Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisionsNat Cell Biol2010 3711718
Not in our library10.1038/ncb2074
134.
Paluch E Heisenberg C-P Biology and physics of cell shape changes in developmentCurr Biol2009 3R790R799
Not in our library10.1016/j.cub.2009.07.029
135.
Lecuit T Lenne PF Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesisNat Rev Mol Cell Biol2007 3633644
Not in our library10.1038/nrm2222
136.
Hautmann MB Adam PJ Owens GK Similarities and differences in smooth muscle alpha-actin induction by TGF-beta in smooth muscle versus non-smooth muscle cellsArterioscler Thromb Vasc Biol1999 320492058
Not in our library10.1161/01.atv.19.9.2049
137.
Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent · 2004
No notice
138.
Fan L Sebe A Peterfi Z Masszi A Thirone AC Rotstein OD Nakano H McCulloch CA Szaszi K Mucsi I Kapus A Cell contact-dependent regulation of epithelial-myofibroblast transition via the rho-rho kinase-phospho-myosin pathwayMol Biol Cell2007 310831097
Not in our library10.1091/mbc.e06-07-0602
139.
Small EM Thatcher JE Sutherland LB Kinoshita H Gerard RD Richardson JA Dimaio JM Sadek H Kuwahara K Olson EN Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarctionCirc Res2010 3294304
Not in our library10.1161/circresaha.110.223172
140.
Medjkane S Perez-Sanchez C Gaggioli C Sahai E Treisman R Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasisNat Cell Biol2009 3257268
Not in our library10.1038/ncb1833
141.
Miralles F Posern G Zaromytidou AI Treisman R Actin dynamics control SRF activity by regulation of its coactivator MALCell2003 3329342
Not in our library10.1016/s0092-8674(03)00278-2
142.
Engler AJ Sen S Sweeney HL Discher DE Matrix elasticity directs stem cell lineage specificationCell2006 3677689
Not in our library10.1016/j.cell.2006.06.044
143.
Georges PC Hui JJ Gombos Z McCormick ME Wang AY Uemura M Mick R Janmey PA Furth EE Wells RG Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosisAm J Physiol Gastrointest Liver Physiol2007 3G1147G1154
Not in our library10.1152/ajpgi.00032.2007
144.
Levental KR Yu H Kass L Lakins JN Egeblad M Erler JT Fong SF Csiszar K Giaccia A Weninger W Yamauchi M Gasser DL Weaver VM Matrix crosslinking forces tumor progression by enhancing integrin signalingCell2009 3891906
Not in our library10.1016/j.cell.2009.10.027
145.
Paszek MJ Zahir N Johnson KR Lakins JN Rozenberg GI Gefen A Reinhart-King CA Margulies SS Dembo M Boettiger D Hammer DA Weaver VM Tensional homeostasis and the malignant phenotypeCancer Cell2005 3241254
Not in our library10.1016/j.ccr.2005.08.010
146.
Hinz B The myofibroblast: paradigm for a mechanically active cellJ Biomech2010 3146155
Not in our library10.1016/j.jbiomech.2009.09.020
147.
Brown AC Fiore VF Sulchek TA Barker TH Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitionsJ Pathol2013 32535
Not in our library10.1002/path.4114
148.
Hinz B Tissue stiffness, latent TGF-β1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosisCurr Rheumatol Rep2009 3120126
Not in our library10.1007/s11926-009-0017-1
149.
Levental I Levental KR Klein EA Assoian R Miller RT Wells RG Janmey PA A simple indentation device for measuring micrometer-scale tissue stiffnessJ Phys Condens Matter2010 3194120
Not in our library10.1088/0953-8984/22/19/194120
150.
Liu F Mih JD Shea BS Kho AT Sharif AS Tager AM Tschumperlin DJ Feedback amplification of fibrosis through matrix stiffening and COX-2 suppressionJ Cell Biol2010 3693706
Not in our library10.1083/jcb.201004082
151.
Wells RG Tissue mechanics and fibrosisBiochimica et Biophysica Acta2013 3884890
Not in our library10.1016/j.bbadis.2013.02.007
152.
Collagen density promotes mammary tumor initiation and progression · 2008
No notice
153.
Lopez JI Kang I You WK McDonald DM Weaver VM In situ force mapping of mammary gland transformationIntegr Biol (Camb)2011 3910921
Not in our library10.1039/c1ib00043h
154.
Boyd NF Lockwood GA Byng JW Tritchler DL Yaffe MJ Mammographic densities and breast cancer riskCancer Epidemiol Biomarkers Prev1998 311331144
Not in our library
155.
Yaffe MJ Boyd NF Byng JW Jong RA Fishell E Lockwood GA Little LE Tritchler DL Breast cancer risk and measured mammographic densityEur J Cancer Prev1998 3Suppl 1S47S55
Not in our library10.1097/00008469-199802001-00010
156.
Markowski MC Brown AC Barker TH Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cuesJ Biomed Mater Res A2012 321192127
Not in our library10.1002/jbm.a.34068
157.
Brabletz T Jung A Reu S Porzner M Hlubek F Kunz-Schughart LA Knuechel R Kirchner T Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environmentProc Natl Acad Sci U S A2001 31035610361
Not in our library10.1073/pnas.171610498
158.
Jung A Schrauder M Oswald U Knoll C Sellberg P Palmqvist R Niedobitek G Brabletz T Kirchner T The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferationAm J Path2001 316131617
Not in our library10.1016/s0002-9440(10)63007-6
159.
Nelson CM Jean RP Tan JL Liu WF Sniadecki NJ Spector AA Chen CS Emergent patterns of growth controlled by multicellular form and mechanicsProc Natl Acad Sci U S A2005 31159411599
Not in our library10.1073/pnas.0502575102
160.
Sato M Muragaki Y Saika S Roberts AB Ooshima A Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstructionJ Clin Invest2003 314861494
Not in our library10.1172/jci19270
161.
Heise RL Stober V Cheluvaraju C Hollingsworth JW Garantziotis S Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunityJ Biol Chem2011 31743517444
Not in our library10.1074/jbc.m110.137273
162.
Chan SW Lim CJ Guo K Ng CP Lee I Hunziker W Zeng Q Hong W A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cellsCancer Res2008 325922598
Not in our library10.1158/0008-5472.can-07-2696
163.
Mitani A Nagase T Fukuchi K Aburatani H Makita R Kurihara H Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in miceAm J Respir Crit Care Med2009 3326338
Not in our library10.1164/rccm.200812-1827oc
164.
Harvey KF Zhang X Thomas DM The Hippo pathway and human cancerNat Rev Cancer2013 3246257
Not in our library10.1038/nrc3458
165.
Johnson R Halder G The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatmentNat Rev Drug Discov2014 36379
Not in our library10.1038/nrd4161
166.
Varelas X Sakuma R Samavarchi-Tehrani P Peerani R Rao BM Dembowy J Yaffe MB Zandstra PW Wrana JL TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewalNat Cell Biol2008 3837848
Not in our library10.1038/ncb1748
167.
Varelas X Samavarchi-Tehrani P Narimatsu M Weiss A Cockburn K Larsen BG Rossant J Wrana JL The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathwayDev Cell2010 3831844
Not in our library10.1016/j.devcel.2010.11.012
168.
Dupont S Morsut L Aragona M Enzo E Giulitti S Cordenonsi M Zanconato F Le Digabel J Forcato M Bicciato S Elvassore N Piccolo S Role of YAP/TAZ in mechanotransductionNature2011 3179183
Not in our library10.1038/nature10137
169.
Halder G Dupont S Piccolo S Transduction of mechanical and cytoskeletal cues by YAP and TAZNat Rev Mol Cell Biol2012 3591600
Not in our library10.1038/nrm3416
170.
Sun Y Yong KM Villa-Diaz LG Zhang X Chen W Philson R Weng S Xu H Krebsbach PH Fu J Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cellsNat Mater2014 3599604
Not in our library10.1038/nmat3945
171.
Aragona M Panciera T Manfrin A Giulitti S Michielin F Elvassore N Dupont S Piccolo S A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factorsCell2013 310471059
Not in our library10.1016/j.cell.2013.07.042
172.
Speight P Nakano H Kelley TJ Hinz B Kapus A Differential topical susceptibility to TGFbeta in intact and injured regions of the epithelium: key role in myofibroblast transitionMol Biol Cell2013 333263336
Not in our library10.1091/mbc.e13-04-0220
173.
Lei QY Zhang H Zhao B Zha ZY Bai F Pei XH Zhao S Xiong Y Guan KL TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathwayMol Cell Biol2008 324262436
Not in our library10.1128/mcb.01874-07
174.
Mana-Capelli S Paramasivam M Dutta S McCollum D Angiomotins link F-actin architecture to Hippo pathway signalingMol Biol Cell2014 316761685
Not in our library10.1091/mbc.e13-11-0701
175.
Chua KN Ma J Thiery JP Targeted therapies in control of EMT in carcinoma and fibrosisDrug Discov Today2008 3261267
Not in our library
176.
Connolly EC Freimuth J Akhurst RJ Complexities of TGF-beta targeted cancer therapyInt J Biol Sci2012 3964978
Not in our library10.7150/ijbs.4564
177.
Akhurst RJ Hata A Targeting the TGFbeta signalling pathway in diseaseNat Rev Drug Discov2012 3790811
Not in our library10.1038/nrd3810
178.
Biswas S Guix M Rinehart C Dugger TC Chytil A Moses HL Freeman ML Arteaga CL Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progressionJ Clin Invest2007 313051313
Not in our library10.1172/jci30740
179.
Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. · 2011
Not checked
180.
Nam JS Terabe M Mamura M Kang MJ Chae H Stuelten C Kohn E Tang B Sabzevari H Anver MR Lawrence S Danielpour D Lonning S Berzofsky JA Wakefield LM An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartmentsCancer Res2008 338353843
Not in our library10.1158/0008-5472.can-08-0215
181.
Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis · 2010
No notice
182.
Bouquet F Pal A Pilones KA Demaria S Hann B Akhurst RJ Babb JS Lonning SM DeWyngaert JK Formenti SC Barcellos-Hoff MH TGFbeta1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivoClin Cancer Res2011 367546765
Not in our library10.1158/1078-0432.ccr-11-0544
183.
Crunkhorn S Deal watch: Biogen acquires Stromedix to pursue novel fibrosis therapyNat Rev Drug Discov2012 3260
Not in our library10.1038/nrd3708
184.
Katsumoto TR Violette SM Sheppard D Blocking TGFbeta via inhibition of the alphavbeta6 integrin: a possible therapy for systemic sclerosis interstitial lung diseaseInt J Rheumatol2011 3208219
Not in our library10.1155/2011/208219
185.
Horan GS Wood S Ona V Li DJ Lukashev ME Weinreb PH Simon KJ Hahm K Allaire NE Rinaldi NJ Goyal J Feghali-Bostwick CA Matteson EL O'Hara C Lafyatis R Davis GS Huang X Sheppard D Violette SM Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammationAm J Respir Crit Care Med2008 35665
Not in our library10.1164/rccm.200706-805oc
186.
Puthawala K Hadjiangelis N Jacoby SC Bayongan E Zhao Z Yang Z Devitt ML Horan GS Weinreb PH Lukashev ME Violette SM Grant KS Colarossi C Formenti SC Munger JS Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosisAm J Respir Crit Care Med2008 38290
Not in our library10.1164/rccm.200706-806oc
187.
Van Aarsen LA Leone DR Ho S Dolinski BM McCoon PE LePage DJ Kelly R Heaney G Rayhorn P Reid C Simon KJ Horan GS Tao N Gardner HA Skelly MM Gown AM Thomas GJ Weinreb PH Fawell SE Violette SM Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanismCancer Res2008 3561570
Not in our library10.1158/0008-5472.can-07-2307
188.
Cheng HC Ho TC Chen SL Lai HY Hong KF Tsao YP Troglitazone suppresses transforming growth factor beta-mediated fibrogenesis in retinal pigment epithelial cellsMol Vis2008 395104
Not in our library
189.
Kawai T Masaki T Doi S Arakawa T Yokoyama Y Doi T Kohno N Yorioka N PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-betaLab Invest2009 34758
Not in our library10.1038/labinvest.2008.104
190.
Jeon KI Kulkarni A Woeller CF Phipps RP Sime PJ Hindman HB Huxlin KR Inhibitory effects of PPARgamma ligands on TGF-beta1-induced corneal myofibroblast transformationAm J Path2014 314291445
Not in our library10.1016/j.ajpath.2014.01.026
191.
Evelyn CR Wade SM Wang Q Wu M Iniguez-Lluhi JA Merajver SD Neubig RR CCG-1423: a small-molecule inhibitor of RhoA transcriptional signalingMol Cancer Ther2007 322492260
Not in our library10.1158/1535-7163.mct-06-0782
192.
Evelyn CR Bell JL Ryu JG Wade SM Kocab A Harzdorf NL Showalter HD Neubig RR Larsen SD Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423Bioorg Med Chem Lett2010 3665672
Not in our library10.1016/j.bmcl.2009.11.056
193.
Hayashi K Watanabe B Nakagawa Y Minami S Morita T RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signalingPLoS One2014 3e89016
Not in our library10.1371/journal.pone.0089016
194.
Johnson LA Rodansky ES Haak AJ Larsen SD Neubig RR Higgins PDR Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-beta-induced fibrogenesis in human colonic myofibroblastsInflamm Bowel Dis2014 3154165
Not in our library10.1097/01.mib.0000437615.98881.31
195.
Velasquez LS Sutherland LB Liu Z Grinnell F Kamm KE Schneider JW Olson EN Small EM Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healingProc Natl Acad Sci U S A2013 31685016855
Not in our library10.1073/pnas.1316764110
196.
Zeisberg M Bottiglio C Kumar N Maeshima Y Strutz F Muller GA Kalluri R Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse modelsAm J Physiol Renal Physiol2003 3F1060F1067
Not in our library10.1152/ajprenal.00191.2002
197.
Chua KN Sim WJ Racine V Lee SY Goh BC Thiery JP A cell-based small molecule screening method for identifying inhibitors of epithelial-mesenchymal transition in carcinomaPLoS One2012 3e33183
Not in our library10.1371/journal.pone.0033183

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