- Open Access
Biomechanics of TGFβ-induced epithelial-mesenchymal transition: implications for fibrosis and cancer
Clinical and Translational Medicine volume 3, Article number: 23 (2014)
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.
Fibrotic 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 [1, 2]. 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 [3–5]. 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 [9, 10]. 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
Myofibroblasts 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 [13, 14]. 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.
Upon aberrant and chronic activation, myofibroblasts can mediate the development of fibrosis [16–20]. The sustained activation of myofibroblasts results in the enhanced production of ECM components, including collagen types I, III, IV, V, and VI and fibronectin [21–23]. 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.
Studies suggest that myofibroblasts are key players in the progression of a variety of cancer types including lung , liver [3, 25], breast , and gastric  cancer. Myofibroblasts have been found at the invasive fronts of tumors where they secrete pro-invasive cytokines, proteases, and inflammatory mediators [28–36]. 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 [38, 39]. 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
Following 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 [42–46]. 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 [43, 47]. 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 [48, 49]. 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
Epithelial-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 [51–54]. 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 [51, 55]. 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 [57–59].
Many 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 [61–63]. 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 [64, 65]. 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.
Given 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 [27, 61, 66–71]. 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 [61, 69, 70]. 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 [66, 71, 72]. 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 [64, 73–77]. 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 [58, 64, 73].
Biochemical induction of EMT by TGFβ
EMT is triggered by a variety of soluble factors including epidermal growth factor (EGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and TGFβ [55, 78–85]. Other stimuli, such as hypoxia [86, 87] and adhesion to ECM components can also induce EMT [69, 88, 89]. TGFβ, a ubiquitously expressed cytokine, is a potent inducer of EMT and is regarded as a key mediator of wound healing [90, 91], fibrosis [92, 93], and cancer [94, 95]. Epithelial cells derived from a variety of tissues including lung [69, 96, 97], kidney [98–101], and breast [85, 102–104] 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.
In 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 [105–107]. 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 [108, 115]. These changes in cell morphology and cytoskeletal architecture suggest an important role for physical cues in regulating EMT.
Mechanical activation of TGFβ
TGFβ 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
Cellular 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 [101, 124] 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
The shape of a cell is regulated by microenvironmental cues and has been shown to play a pivotal role in tissue morphogenesis [126, 127], proliferation [128, 129], apoptosis , and differentiation [130–133]. 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 [134, 135]. 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.
Through 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 [136, 137]. 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
Microenvironmental physical properties, such as stiffness and tension, are becoming increasingly acknowledged as contributing to normal cellular processes and to the development of diseases [142–145]. 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 [147–150]. 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 [143, 151]. In vivo and in vitro studies have also linked increased tissue stiffness and collagen content to the tumor phenotype and metastasis [144, 145, 152]. 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 [145, 149, 153]. High mammographic density, a strong risk factor for breast cancer [154, 155], is associated with a significantly greater collagen content within the mammary gland in comparison to breast tissue with less mammographic density .
Recent studies have identified matrix rigidity as a crucial regulator of TGFβ-induced EMT through several pathways [99, 118, 147, 156]. 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 [118, 119]. Activation of TGFβ on rigid substrata is promoted by Rho/ROCK signaling in lung epithelial cells and this induces EMT (Figure 3) [118, 147, 156]. 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
During 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 [101, 124] and pathological EMT and myofibroblasts are found along the invasion front of metastatic tumors [95, 157, 158].
Spatial 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 [102, 159]. 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
Some 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.
Mechanosensitive signaling cascades in EMT
Myocardin related transcription factors
Acquisition 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.
The 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 [162–165]. 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 [166, 167]. 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 [168–171]. 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
The 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 [175–177]. 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 [178–182]. 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 [183–186]. 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 .
Targeting 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 [188–190], 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 [191, 192]. 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 [102, 104, 194]. 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.
Given 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[100, 196]. 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 .
The 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.
Atomic force microscopy
Bone morphogenetic protein
Epidermal growth factor
Focal adhesion kinase
Fibroblast growth factor
Hyaluronan synthase 2
Hepatocyte growth factor
Krüppel-like factor 8
Mitogen-activated protein kinase
Myocardin related transcription factor
Normal murine mammary gland
Peroxisome proliferator activated receptor
Rho associated kinase
Serum response factor
Transcriptional co-activator with PDZ-binding motif
Transforming growth factor
Alpha smooth muscle actin.
Zeisberg M, Kalluri R: Cellular mechanisms of tissue fibrosis. 1: common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol 2013, 304: C216-C225.
Wynn TA: Cellular and molecular mechanisms of fibrosis. J Pathol 2008, 214: 199–210.
Bissell DM: Chronic liver injury, TGF-beta, and cancer. Exp Mol Med 2001, 33: 179–190.
Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, Paterson AD: Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005, 6: 798–808.
Daniels CE, Jett JR: Does interstitial lung disease predispose to lung cancer? Curr Opin Pulm Med 2005, 11: 431–437.
Shields MA, Dangi-Garimella S, Redig AJ, Munshi HG: Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J 2012, 441: 541–552.
Zhang DY, Friedman SL: Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 2012, 56: 769–775.
Lopez-Novoa JM, Nieto MA: Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 2009, 1: 303–314.
Bhowmick NA, Neilson EG, Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature 2004, 432: 332–337.
Elenbaas B, Weinberg RA: Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 2001, 264: 169–184.
Hinz B, Dugina V, Ballestrem C, Wehrle-Haller B, Chaponnier C: Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts. Mol Biol Cell 2003, 14: 2508–2519.
Gabbiani G, Ryan GB, Majne G: Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971, 27: 549–550.
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002, 3: 349–363.
Hinz B: Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007, 127: 526–537.
Desmouliere A, Redard M, Darby I, Gabbiani G: Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Path 1995, 146: 56–66.
Brown RD, Ambler SK, Mitchell MD, Long CS: The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. Annu Rev Pharmacol Toxicol 2005, 45: 657–687.
Gressner AM, Weiskirchen R: Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006, 10: 76–99.
Liu Y: Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006, 69: 213–217.
Phan SH: The myofibroblast in pulmonary fibrosis. Chest 2002, 122: 286S-289S.
Thannickal VJ, Toews GB, White ES, Lynch JP III, Martinez FJ: Mechanisms of pulmonary fibrosis. Annu Rev Med 2004, 55: 395–417.
Klingberg F, Hinz B, White ES: The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol 2013, 229: 298–309.
Zhang K, Rekhter MD, Gordon D, Phan SH: Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis: a combined immunohistochemical and in situ hybridization study. Am J Path 1994, 145: 114–125.
Balza E, Borsi L, Allemanni G, Zardi L: Transforming growth factor beta regulates the levels of different fibronectin isoforms in normal human cultured fibroblasts. FEBS Lett 1988, 228: 42–44.
Zhong C, Chrzanowska-Wodnicka M, Brown J, Shaub A, Belkin AM, Burridge K: Rho-mediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly. J Cell Biol 1998, 141: 539–551.
Neaud V, Faouzi S, Guirouilh J, Le Bail B, Balabaud C, Bioulac-Sage P, Rosenbaum J: Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor. Hepatology 1997, 26: 1458–1466.
Radisky DC, Kenny PA, Bissell MJ: Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 2007, 101: 830–839.
Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, Friedman R, Varro A, Tycko B, Wang TC: Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011, 19: 257–272.
Nielsen BS, Sehested M, Timshel S, Pyke C, Dano K: Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer. Lab Invest 1996, 74: 168–177.
Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ: The origin of the myofibroblasts in breast cancer: recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 1995, 95: 859–873.
Bisson C, Blacher S, Polette M, Blanc JF, Kebers F, Desreux J, Tetu B, Rosenbaum J, Foidart JM, Birembaut P, Noel A: Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells. Int J Cancer 2003, 105: 7–13.
Offersen BV, Nielsen BS, Hoyer-Hansen G, Rank F, Hamilton-Dutoit S, Overgaard J, Andreasen PA: The myofibroblast is the predominant plasminogen activator inhibitor-1-expressing cell type in human breast carcinomas. Am J Path 2003, 163: 1887–1899.
Nielsen BS, Rank F, Lopez JM, Balbin M, Vizoso F, Lund LR, Dano K, Lopez-Otin C: Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res 2001, 61: 7091–7100.
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 stress. J Clin Pathol 2005, 58: 1033–1038.
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 microscopy. Int J Cancer 1996, 68: 565–570.
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 cancer. Int J Cancer 1995, 62: 407–413.
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 microenvironment. Nat Cell Biol 2010, 12: 468–476.
De Wever O, Mareel M: Role of tissue stroma in cancer cell invasion. J Pathol 2003, 200: 429–447.
Yazhou C, Wenlv S, Weidong Z, Licun W: Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast. Tumour Biol 2004, 25: 290–295.
De Wever O, Mareel M: Role of myofibroblasts at the invasion front. Biol Chem 2002, 383: 55–67.
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 survival. Cancer Cell 2014, 25: 719–734.
Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G: The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol 1998, 142: 873–881.
Arora PD, Narani N, McCulloch CA: The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am J Pathol 1999, 154: 871–882.
Grinnell F, Ho CH, Lin YC, Skuta G: Differences in the regulation of fibroblast contraction of floating versus stressed collagen matrices. J Biol Chem 1999, 274: 918–923.
Grinnell F, Zhu M, Carlson MA, Abrams JM: Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp Cell Res 1999, 248: 608–619.
Squier CA: The effect of stretching on formation of myofibroblasts in mouse skin. Cell Tissue Res 1981, 220: 325–335.
Tomasek JJ, Haaksma CJ, Eddy RJ, Vaughan MB: Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum. Anat Rec 1992, 232: 359–368.
Li Z, Dranoff JA, Chan EP, Uemura M, Sevigny J, Wells RG: Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007, 46: 1246–1256.
Brown RA, Prajapati R, McGrouther DA, Yannas IV, Eastwood M: Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substrates. J Cell Physiol 1998, 175: 323–332.
Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G: Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol 2001, 159: 1009–1020.
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 gels. FASEB J 2007, 21: 2064–2073.
Kalluri R, Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest 2009, 119: 1420–1428.
Shook D, Keller R: Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev 2003, 120: 1351–1383.
Thiery JP, Acloque H, Huang RY, Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139: 871–890.
Xu J, Lamouille S, Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009, 19: 156–172.
Lamouille S, Xu J, Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014, 15: 178–196.
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 Smad3. J Cell Biol 2010, 188: 383–399.
Chapman HA: Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 2011, 73: 413–435.
Duffield JS, Lupher M, Thannickal VJ, Wynn TA: Host responses in tissue repair and fibrosis. Annu Rev Pathol 2013, 8: 241–276.
Friedman SL, Sheppard D, Duffield JS, Violette S: Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013, 5: 167sr161.
Rowe RG, Lin Y, Shimizu-Hirota R, Hanada S, Neilson EG, Greenson JK, Weiss SJ: Hepatocyte-derived Snail1 propagates liver fibrosis progression. Mol Cell Biol 2011, 31: 2392–2403.
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 matrix. Proc Natl Acad Sci U S A 2006, 103: 13180–13185.
Willis BC, Borok Z: TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007, 293: L525-L534.
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 fibrosis. Am J Physiol Lung Cell Mol Physiol 2011, 301: L71-L78.
Quaggin SE, Kapus A: Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int 2011, 80: 41–50.
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 biopsies. Kidney Int 2002, 62: 137–146.
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 fibrosis. J Biol Chem 2010, 285: 20202–20212.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G: The myofibroblast: one function, multiple origins. Am J Pathol 2007, 170: 1807–1816.
Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG: Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002, 110: 341–350.
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 fibrosis. J Clin Invest 2009, 119: 213–224.
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 fibrosis. Am J Respir Crit Care Med 2009, 180: 657–665.
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 transition. J Biol Chem 2007, 282: 23337–23347.
LeBleu VS, Taduri G, O'Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R: Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013, 19: 1047–1053.
Zeisberg M, Duffield JS: Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 2010, 21: 1247–1253.
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 fibrosis. Am J Path 2010, 176: 85–97.
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 cells. Am J Path 2010, 177: 632–643.
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 mice. Hepatology 2010, 51: 1027–1036.
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 mice. Gastroenterology 2010, 139: 987–998.
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 expression. Cancer Res 2007, 67: 9066–9076.
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 invasion. Cancer Cell 2003, 4: 499–515.
Elliott BE, Hung WL, Boag AH, Tuck AB: The role of hepatocyte growth factor (scatter factor) in epithelial-mesenchymal transition and breast cancer. Can J Physiol Pharm 2002, 80: 91–102.
Grotegut S, von Schweinitz D, Christofori G, Lehembre F: Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 2006, 25: 3534–3545.
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-line. Proc Natl Acad Sci U S A 1990, 87: 1124–1128.
Ciruna B, Rossant J: FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell 2001, 1: 37–49.
Miettinen PJ, Ebner R, Lopez AR, Derynck R: TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells - involvement of type-I receptors. J Cell Biol 1994, 127: 2021–2036.
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 line. Breast Cancer Res 2003, 5: R187-R198.
Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U: Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A 2008, 105: 6392–6397.
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 transition. J Clin Invest 2007, 117: 3810–3820.
Espinosa Neira R, Perez Salazar E: Native type IV collagen induces an epithelial to mesenchymal transition-like process in mammary epithelial cells MCF10A. Int J Biochem Cell B 2012, 44: 2194–2203.
Zeisberg M, Bonner G, Maeshima Y, Colorado P, Muller GA, Strutz F, Kalluri R: Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am J Path 2001, 159: 1313–1321.
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 balance. Postgrad Med J 2009, 85: 9–14.
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 repair. Am J Path 1993, 143: 368–380.
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 3. Int J Biochem Cell B 2008, 40: 484–495.
Bottinger EP: TGF-beta in renal injury and disease. Semin Nephrol 2007, 27: 309–320.
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 cancer. Cancer Res 1992, 52: 6949–6952.
Oft M, Heider KH, Beug H: TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998, 8: 1243–1252.
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 fibrosis. Am J Pathol 2005, 166: 1321–1332.
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 mechanism. PLoS One 2012, 7: e38827.
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 cells. Am J Physiol Renal Physiol 2008, 294: F1116-F1128.
Leight JL, Wozniak MA, Chen S, Lynch ML, Chen CS: Matrix rigidity regulates a switch between TGF-beta 1-induced apoptosis and epithelial-mesenchymal transition. Mol Biol Cell 2012, 23: 781–791.
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 injury. Nat Med 2003, 9: 964–968.
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-catenin. Am J Path 2004, 165: 1955–1967.
Gomez EW, Chen QK, Gjorevski N, Nelson CM: Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction. J Cell Biochem 2010, 110: 44–51.
Nelson CM, Khauv D, Bissell MJ, Radisky DC: Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells. J Cell Biochem 2008, 105: 25–33.
O'Connor JW, Gomez EW: Cell adhesion and shape regulate TGF-beta1-induced epithelial-myofibroblast transition via MRTF-A signalling. PLoS One 2013, 8: e83188.
Morita T, Mayanagi T, Sobue K: Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodeling. J Cell Biol 2007, 179: 1027–1042.
Shi YG, Massague J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003, 113: 685–700.
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-beta. Proc Natl Acad Sci U S A 2001, 98: 6686–6691.
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 migration. J Biol Chem 2000, 275: 36803–36810.
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) signaling. Exp Cell Res 2008, 314: 143–152.
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 plasticity. J Biol Chem 2001, 276: 46707–46713.
Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL: Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia 2004, 6: 603–610.
Porsch H, Bernert B, Mehic M, Theocharis AD, Heldin CH, Heldin P: Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene 2013, 32: 4355–4365.
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 cells. J Cancer Res Clin Oncol 2013, 139: 1033–1042.
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 metastasis. J Biol Chem 2013, 288: 10241–10253.
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 mechanism. Mol Biol Cell 2001, 12: 27–36.
Bandyopadhyay A, Raghavan S: Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets 2009, 10: 645–652.
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 fibrosis. Cell 1999, 96: 319–328.
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 force. Exp Cell Res 2012, 318: 716–722.
Wipff PJ, Rifkin DB, Meister JJ, Hinz B: Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 2007, 179: 1311–1323.
Tan JL, Tien J, Pirone DM, Gray DS, Bhadriraju K, Chen CS: Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc Natl Acad Sci U S A 2003, 100: 1484–1489.
Thoelking G, Reiss B, Wegener J, Oberleithner H, Pavenstaedt H, Riethmuller C: Nanotopography follows force in TGF-beta1 stimulated epithelium. Nanotechnology 2010, 21: 265102.
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 analysis. Nanomedicine 2012, 8: 355–364.
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 cells. PLoS One 2013, 8: e80068.
Arnoux V, Come C, Kusewitt D, Hudson L, Savagner P: Cutaneous wound reepithelialization: A partial and reversible EMT. In Rise and fall of epithelial phenotype: Concepts of epithelial-mesenchymal transition. Edited by: Savagner P. Berlin: Springer; 2005:111–134.
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 microscopy. Am J Physiol Lung Cell Mol Physiol 2008, 295: L54-L60.
Watanabe T, Takahashi Y: Tissue morphogenesis coupled with cell shape changes. Curr Opin Genet Devel 2010, 20: 443–447.
Locascio A, Nieto MA: Cell movements during vertebrate development: integrated tissue behaviour versus individual cell migration. Curr Opin Genet Devel 2001, 11: 464–469.
Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE: Geometric control of cell life and death. Science 1997, 276: 1425–1428.
Folkman J, Moscona A: Role of cell shape in growth control. Nature 1978, 273: 345–349.
Watt FM, Jordan PW, Oneill CH: Cell-shape controls terminal differentiation of human epidermal-keratinocytes. Proc Natl Acad Sci U S A 1988, 85: 5576–5580.
Roskelley CD, Desprez PY, Bissell MJ: Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc Natl Acad Sci U S A 1994, 91: 12378–12382.
McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS: Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 2004, 6: 483–495.
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 decisions. Nat Cell Biol 2010, 12: 711–718.
Paluch E, Heisenberg C-P: Biology and physics of cell shape changes in development. Curr Biol 2009, 19: R790-R799.
Lecuit T, Lenne PF: Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesis. Nat Rev Mol Cell Biol 2007, 8: 633–644.
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 cells. Arterioscler Thromb Vasc Biol 1999, 19: 2049–2058.
Selvaraj A, Prywes R: Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent. BMC Mol Biol 2004, 5: 13.
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 pathway. Mol Biol Cell 2007, 18: 1083–1097.
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 infarction. Circ Res 2010, 107: 294–304.
Medjkane S, Perez-Sanchez C, Gaggioli C, Sahai E, Treisman R: Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis. Nat Cell Biol 2009, 11: 257–268.
Miralles F, Posern G, Zaromytidou AI, Treisman R: Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 2003, 113: 329–342.
Engler AJ, Sen S, Sweeney HL, Discher DE: Matrix elasticity directs stem cell lineage specification. Cell 2006, 126: 677–689.
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 fibrosis. Am J Physiol Gastrointest Liver Physiol 2007, 293: G1147-G1154.
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 signaling. Cell 2009, 139: 891–906.
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 phenotype. Cancer Cell 2005, 8: 241–254.
Hinz B: The myofibroblast: paradigm for a mechanically active cell. J Biomech 2010, 43: 146–155.
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 transitions. J Pathol 2013, 229: 25–35.
Hinz B: Tissue stiffness, latent TGF-β1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 2009, 11: 120–126.
Levental I, Levental KR, Klein EA, Assoian R, Miller RT, Wells RG, Janmey PA: A simple indentation device for measuring micrometer-scale tissue stiffness. J Phys Condens Matter 2010, 22: 194120.
Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, Tschumperlin DJ: Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol 2010, 190: 693–706.
Wells RG: Tissue mechanics and fibrosis. Biochimica et Biophysica Acta 2013, 1832: 884–890.
Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ: Collagen density promotes mammary tumor initiation and progression. BMC Med 2008, 6: 11.
Lopez JI, Kang I, You WK, McDonald DM, Weaver VM: In situ force mapping of mammary gland transformation. Integr Biol (Camb) 2011, 3: 910–921.
Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ: Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev 1998, 7: 1133–1144.
Yaffe MJ, Boyd NF, Byng JW, Jong RA, Fishell E, Lockwood GA, Little LE, Tritchler DL: Breast cancer risk and measured mammographic density. Eur J Cancer Prev 1998, 7(Suppl 1):S47-S55.
Markowski MC, Brown AC, Barker TH: Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cues. J Biomed Mater Res A 2012, 100: 2119–2127.
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 environment. Proc Natl Acad Sci U S A 2001, 98: 10356–10361.
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 proliferation. Am J Path 2001, 159: 1613–1617.
Nelson CM, Jean RP, Tan JL, Liu WF, Sniadecki NJ, Spector AA, Chen CS: Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci U S A 2005, 102: 11594–11599.
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 obstruction. J Clin Invest 2003, 112: 1486–1494.
Heise RL, Stober V, Cheluvaraju C, Hollingsworth JW, Garantziotis S: Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J Biol Chem 2011, 286: 17435–17444.
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 cells. Cancer Res 2008, 68: 2592–2598.
Mitani A, Nagase T, Fukuchi K, Aburatani H, Makita R, Kurihara H: Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. Am J Respir Crit Care Med 2009, 180: 326–338.
Harvey KF, Zhang X, Thomas DM: The Hippo pathway and human cancer. Nat Rev Cancer 2013, 13: 246–257.
Johnson R, Halder G: The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov 2014, 13: 63–79.
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-renewal. Nat Cell Biol 2008, 10: 837–848.
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 pathway. Dev Cell 2010, 19: 831–844.
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 mechanotransduction. Nature 2011, 474: 179–183.
Halder G, Dupont S, Piccolo S: Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat Rev Mol Cell Biol 2012, 13: 591–600.
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 cells. Nat Mater 2014, 13: 599–604.
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 factors. Cell 2013, 154: 1047–1059.
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 transition. Mol Biol Cell 2013, 24: 3326–3336.
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 pathway. Mol Cell Biol 2008, 28: 2426–2436.
Mana-Capelli S, Paramasivam M, Dutta S, McCollum D: Angiomotins link F-actin architecture to Hippo pathway signaling. Mol Biol Cell 2014, 25: 1676–1685.
Chua KN, Ma J, Thiery JP: Targeted therapies in control of EMT in carcinoma and fibrosis. Drug Discov Today 2008, 4: 261–267.
Connolly EC, Freimuth J, Akhurst RJ: Complexities of TGF-beta targeted cancer therapy. Int J Biol Sci 2012, 8: 964–978.
Akhurst RJ, Hata A: Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov 2012, 11: 790–811.
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 progression. J Clin Invest 2007, 117: 1305–1313.
Biswas S, Nyman JS, Alvarez J, Chakrabarti A, Ayres A, Sterling J, Edwards J, Rana T, Johnson R, Perrien DS, Lonning S, Shyr Y, Matrisian LM, Mundy GR: Anti-transforming growth factor β antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. PLoS One 2011, 6: e27090.
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 compartments. Cancer Res 2008, 68: 3835–3843.
Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, Reiss M: Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer 2010, 9: 122.
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 vivo. Clin Cancer Res 2011, 17: 6754–6765.
Crunkhorn S: Deal watch: Biogen acquires Stromedix to pursue novel fibrosis therapy. Nat Rev Drug Discov 2012, 11: 260.
Katsumoto TR, Violette SM, Sheppard D: Blocking TGFbeta via inhibition of the alphavbeta6 integrin: a possible therapy for systemic sclerosis interstitial lung disease. Int J Rheumatol 2011, 2011: 208219.
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 inflammation. Am J Respir Crit Care Med 2008, 177: 56–65.
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 fibrosis. Am J Respir Crit Care Med 2008, 177: 82–90.
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 mechanism. Cancer Res 2008, 68: 561–570.
Cheng HC, Ho TC, Chen SL, Lai HY, Hong KF, Tsao YP: Troglitazone suppresses transforming growth factor beta-mediated fibrogenesis in retinal pigment epithelial cells. Mol Vis 2008, 14: 95–104.
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-beta. Lab Invest 2009, 89: 47–58.
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 transformation. Am J Path 2014, 184: 1429–1445.
Evelyn CR, Wade SM, Wang Q, Wu M, Iniguez-Lluhi JA, Merajver SD, Neubig RR: CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. Mol Cancer Ther 2007, 6: 2249–2260.
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-1423. Bioorg Med Chem Lett 2010, 20: 665–672.
Hayashi K, Watanabe B, Nakagawa Y, Minami S, Morita T: RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signaling. PLoS One 2014, 9: e89016.
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 myofibroblasts. Inflamm Bowel Dis 2014, 20: 154–165.
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 healing. Proc Natl Acad Sci U S A 2013, 110: 16850–16855.
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 models. Am J Physiol Renal Physiol 2003, 285: F1060-F1067.
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 carcinoma. PLoS One 2012, 7: e33183.
This work was supported by start-up funds from the Pennsylvania State University.
The authors declare that they have no competing interests.
JWO and EWG reviewed the literature, wrote, and revised the manuscript. Both authors read and approved the final manuscript.
About this article
Cite this article
O’Connor, J.W., Gomez, E.W. Biomechanics of TGFβ-induced epithelial-mesenchymal transition: implications for fibrosis and cancer. Clin Trans Med 3, 23 (2014). https://doi.org/10.1186/2001-1326-3-23
- Epithelial-mesenchymal transition
- Transforming growth factor
- Cell shape
- Matrix rigidity