PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of canmicrospringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
Cancer Microenviron. Apr 2012; 5(1): 29–38.
Published online Jul 12, 2011. doi:  10.1007/s12307-011-0076-5
PMCID: PMC3343202
Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues
Nikolce Gjorevski, Eline Boghaert, and Celeste M. Nelsoncorresponding author
Department of Chemical & Biological Engineering, Princeton University, A321 Engineering Quadrangle, Princeton, NJ 08544 USA
Celeste M. Nelson, Phone: +1-609-2588851, Fax: +1-609-2580211, celesten/at/princeton.edu.
corresponding authorCorresponding author.
Received December 20, 2010; Accepted June 30, 2011.
Epithelial-mesenchymal transition (EMT) is a phenotypic shift wherein epithelial cells lose or loosen attachments to their neighbors and assume a mesenchymal-like morphology. EMT drives a variety of developmental processes, but may also be adopted by tumor cells during neoplastic progression. EMT is regulated by both biochemical and physical signals from the microenvironment, including mechanical stress, which is increasingly recognized to play a major role in development and disease progression. Biological systems generate, transmit and concentrate mechanical stress into spatial patterns; these gradients in mechanical stress may serve to spatially pattern developmental and pathologic EMTs. Here we review how epithelial tissues generate and respond to mechanical stress gradients, and highlight the mechanisms by which mechanical stress regulates and patterns EMT.
Keywords: Force, Contractility, MRTF, Morphogenesis
Epithelial-mesenchymal transition (EMT) is critical for embryonic development [1]. During gastrulation, the embryonic epithelium undergoes EMT to give rise to the mesoderm. During delamination of the neural crest, EMT is used to form a population of highly motile cells that ultimately incorporate into many different tissues [2, 3]. Induction of EMT alters cytoskeletal structure and leads to the breakdown of interactions between cells, their neighbors, and the underlying substratum. These phenotypic changes are driven by alterations in the expression of many genes including cytoskeletal components, transcription factors, and enzymes. Although the role of EMT in tumorigenesis and metastasis is currently a topic of active debate [4, 5], processes related to developmental EMTs are involved in key steps of tumor development [6, 7]. The biochemical and mechanical signals that regulate EMT are thus of critical interest.
The role of the mechanical microenvironment in the regulation of morphogenesis and pathogenesis is becoming ever more recognized. Mechanical cues from the environment direct basic cellular processes such as cell survival [8], proliferation [9], stem cell lineage commitment [10, 11] and EMT [12, 13]. At the tissue-level, mechanical signals have emerged as indispensable regulators of embryogenesis. Development of Xenopus laevis embryos requires that mesoderm and notochord be sufficiently mechanically stiff so as to resist buckling [14, 15]. Actomyosin contractility is necessary for dorsal closure of the Drosophila embryo [16, 17], and forces due to apoptosis significantly contribute to the process [18]. External forces applied to the Drosophila embryo enhance expression of Twist, a key morphogenetic protein and promoter of EMT [19, 20]. Mechanical influences have also been implicated in the branching development of the mammalian lung [21], kidney [22] and mammary gland [23], and in breast involution following engorgement [24]. Importantly, dysregulation of mechanical signals has been shown to contribute to malignant transformation and progression. Increased activity of the small GTPase Rho—responsible for regulating cellular contractility—has been observed in human breast tumors [25] and increase in Rho-generated contractility promotes malignant progression by inducing tumor dissemination and angiogenesis [26]. Enzymatic crosslinking of the extracellular matrix (ECM) and its subsequent stiffening induce invasive behavior by otherwise non-metastatic breast cancer cells and drive tumor progression and malignancy [2729]. Here we discuss the origins of mechanical stress within epithelial tissues, and describe how endogenous stresses may cooperate with biochemical signals in the microenvironment to regulate and spatially pattern EMT.
Epithelial cells form functional polarized tissues by maintaining close contacts with their neighbors. These interactions are disrupted during EMT, which is characterized by the loss of cell-cell adhesion, loss of apical-basal polarity and the acquisition of migratory properties resulting in loosely organized mesenchymal cells [30]. Changes in gene expression associated with EMT include down-regulation of epithelial markers including E-cadherin and up-regulation of mesenchymal markers including vimentin, α-smooth muscle actin, N-cadherin, and fibronectin [31]. The reverse of this process, mesenchymal-epithelial transition (MET), occurs during the formation of epithelial organs and secondary tumors [32].
EMT plays an important role in normal developmental processes including embryogenesis, organogenesis, wound healing, and tissue regeneration as well as in diseases such as fibrosis and cancer [30]. During gastrulation, EMT governs the cell migration and rearrangement required for the formation of the three distinct germ layers [3, 30, 33]. EMT is also responsible for development of the neural crest and heart valves [30]. In cancer, EMT has been noted at the invasive front of the tumor mass, and may be instrumental in the acquisition of motility required for invasion and metastasis. Once tumor cells have circulated, MET may allow migratory cancer cells to establish a secondary tumor [30, 32].
It has been proposed that EMT occurs in three distinct biological settings (type 1, type 2, and type 3), each of which result in fundamentally different functional consequences. Type 1 EMT is associated with the developmental processes of implantation, embryogenesis and organ development. Diverse cell types are generated, including the primary mesenchyme which can later undergo MET to generate secondary epithelia. Importantly, type 1 EMT does not cause fibrosis and cannot induce an invasive phenotype. Inflammation induces type 2 EMT, which is involved in wound healing and tissue regeneration. Chronic inflammation results in persistent type 2 EMT which leads to fibrosis. Genetic and epigenetic abnormalities of neoplastic cells conspire with the EMT regulatory circuitry to generate type 3 EMT, a program by which epithelial carcinoma cells acquire the ability to invade and metastasize. Remarkably, a common set of genetic and biochemical elements is thought to underlie and enable these three types of EMT with fundamentally different functional consequences and outwardly diverse phenotypic programs [33, 34].
Just as there are several different EMT programs with different functional consequences, there are also several different biochemical signals that can induce EMT, including cytokines, growth factors, and matrix metalloproteinases (MMPs) [30]. Perhaps the most well-studied EMT stimulus is transforming growth factor (TGF)-β, which initiates and maintains EMT in a variety of biological systems [35]. In response to activation by binding to TGFβ, type I and type II TGFβ receptors dimerize and induce signaling that results in phosphorylation of receptor-activated Smad2 and Smad3. These phosphorylated Smads partner with cytoplasmic Smad4 and translocate to the nucleus where Smad complexes control the transcription of target genes that regulate EMT [3538]. The expression of the Snail family of transcription factors is induced directly in response to TGFβ [38, 39]. Snail transcription factors are structurally similar, containing a characteristic zinc finger-rich C-terminal domain that mediates sequence-specific binding to E-box elements within the regulatory regions of different genes [39, 40]. The activation of Snail transcription factors represses the expression of epithelial markers (claudins, occludin, E-cadherin, cytokeratins, etc.) and upregulates that of mesenchymal markers (fibronectin, N-cadherin, Twist, etc.) [38]. For example, both Snail1 and Snail2 repress the expression of CDH1 (the gene that encodes E-cadherin) by binding to E-box elements in the promoter and recruiting a combination of co-repressors [4145].
TGFβ also activates Rho-family GTPases by targeting guanine nucleotide exchange factors, thereby affecting actin cytoskeletal dynamics, stress fiber formation, and the acquisition of mesenchymal characteristics [46]. Activation of the Rho pathway is fundamental to the formation of stress fibers and cytoskeletal contractility. Furthermore E-cadherin clustering, adherens junction maturation, and linkage to the actin cytoskeleton are controlled by RhoA, Rac1 and Cdc42 [42], respectively [47]. TGFβ-induced EMT can also be modulated by signaling through phosphatidylinositol 3-kinase, mitogen-activated protein kinase, Jagged/Notch (reviewed in [35]), and myocardin-related transcription factor (MRTF)-A (discussed below).
Similarly, MMP3-induced EMT is modulated by members of the Rho GTPase family. In the presence of MMP3 in culture or in vivo, mammary epithelial cells scatter, downregulate epithelial markers, upregulate mesenchymal markers [48], form large lamellipodia, and spread out substantially [13]. Radisky and colleagues have shown that MMP3-induced EMT is not dependent on RhoA and Cdc42; however, the expression of Rac1b, an alternatively spliced variant of Rac1, causes an increase in cellular reactive oxygen species (ROS), which ultimately stimulates the expression of Snail and EMT [48]. MMP3-induced spreading is a consequence of Rac1b expression and is required for downstream EMT. Blocking cell spreading by plating cells at high density effectively inhibits induction of Rac1b and EMT-related gene expression. Therefore, cell shape regulates MMP3-induced EMT [13], suggesting that cytoskeletal contraction and mechanical stress play an indirect role in this process.
Generation of Mechanical Stress
Before we discuss the role of mechanical stress in EMT, we begin with a review of how cells create stresses. In physics, force is defined as an influence that accelerates a given mass. In simple terms, force is a mechanical quantity associated with a “push” or a “pull”. A closely related (but not universally interchangeable) quantity is mechanical stress, defined as force per unit area. Mechanical stress arises within deformable bodies from the application of internal or external forces. Stresses acting perpendicular to a surface are called normal stresses, whereas those acting parallel to a surface are called shear stresses. For example, blood pressure is a normal stress that prevents veins from collapsing, whereas blood flow induces a shear stress across the surface of endothelial cells lining the vessels.
The ability of biological systems—cells and tissues—to generate and transmit mechanical forces over a distance has long been recognized. Harris and co-workers visualized cell-generated forces nearly three decades ago by demonstrating that fibroblasts plated on silicone membranes pull on their substratum, creating wrinkles [49]. Such forces have since been extensively analyzed and measured [5052]. Endogenous forces arise from the tendency of cells to contract. In response to various stimuli, non-muscle myosin II motors undergo ATP-dependent activation and “walk” along actin filaments, thus creating contractile, force-generating actomyosin bundles [53, 54]. The best-described regulators of myosin II and the overall contractile machinery of the cell include myosin light chain kinase (MLCK) and the Rho effector Rho-associated kinase (ROCK) [5557]. MLCK directly phosphorylates the regulatory myosin light chain (MLC), whereas ROCK has a dual role: it promotes myosin activation both by phosphorylating MLC and by inactivating MLC phosphatase. These regulatory proteins thus form the machinery that enables cells to contract and pull.
Cellular contraction alone is not sufficient for the generation of stress. Mechanical stress necessitates cellular attachment and contraction against a substratum capable of resisting deformation [58, 59]. The ability of a substratum to resist deformation, thus balancing cytoskeletal forces and giving rise to stress, is quantified by its elastic modulus (stiffness), a physical parameter implicated in the regulation of normal and pathologic processes [29, 60]. How matrix stiffness affects the generation of mechanical stress has been tested by plating cells on a substratum comprised of ECM-coated beads of submicrometer (i.e. subcellular) size. The beads were not physically linked, allowing the cells to displace them without encountering resistance. These experiments demonstrated that cells plated on such substrata fail to produce stress, which suggests that substratum stiffness is necessary for generation of stress [59] (Fig. 1a). In fact, matrix stiffness not only maintains cell-generated mechanical stress, but also modulates it: stiffer two-dimensional (2D) substrata and three-dimensional (3D) matrices lead to activation of the Rho pathway, stronger cell-matrix adhesion and ultimately enhanced generation of force [29, 60] (Fig. 1b). Cell-generated stresses thus require both cytoskeletal contraction and attachment to ECM or neighboring cells.
Fig. 1
Fig. 1
Intercellular transmission of endogenous contraction. a Cells in suspension or attached to soft matrices incapable of resisting deformation fail to generate mechanical stress. b Cells attached to a stiff substratum contract isometrically, giving rise (more ...)
Transmission and Concentration of Mechanical Stress
Epithelial cells rarely function individually in vivo. Instead, they are connected to their neighbors via cell-cell junctions and to the ECM via cell-matrix adhesions, thus forming functional epithelial tissues. Importantly, the junctional proteins are directly or indirectly linked to the force-generating cytoskeletal machinery, thus creating a supra-structure capable of long-range transmission of mechanical stresses produced at the cellular level.
It is by now widely accepted that the actin cytoskeleton is physically linked to the ECM at focal adhesions, comprised of transmembrane integrin receptors and numerous scaffolding proteins [61, 62]. This link not only tethers the cell to the ECM, which resists deformation leading to mechanical stress, but also serves as a conduit for inside-out channeling of mechanical force. Techniques used to quantify cell-generated forces, such as 2D or 3D traction force microscopy, rely upon the transmission of force from cells to 2D substratum or 3D matrix [23, 50]. Here, matrix deformations induced by cells are visualized, measured and, when possible, converted to mechanical stresses. Cells may transmit stress over long distances through compliant matrices in order to communicate mechanically with adjacent cells or tissues. Hammer and co-workers have demonstrated that endothelial cells in culture can detect and respond to substratum deformation due to stresses originating from neighboring cells [63]. The extent of matrix deformation depends upon its stiffness, suggesting that ECM stiffness determines the maximum distance over which cells can communicate mechanical signals.
Cells can also transmit stresses directly to coherent neighbors. Adherens junctions are a type of intercellular junction maintained by calcium-dependent homophilic interactions between cadherins. The engagement between the extracellular cadherin domains of adjacent cells triggers the recruitment of structural and signaling proteins on the cytoplasmic face, which anchor the junction to actin creating physical continuity between the cytoskeletons of adjacent cells [64]. Actin cables which circumscribe wounds in epithelial sheets appear to be continuous from cell to cell and connected by clusters of E-cadherin at cell-cell contacts [65, 66]. The collective contraction of the interlinked actin cables generates force which is transmitted at ranges that are considerably longer than the length of a single cell and span the entire perimeter of the wound, driving wound closure [65, 66].
Collective cellular contraction and transmission of the resulting stress within tissues of anisotropic (i.e. non-spherical) geometries leads to concentration of stress and formation of spatial stress gradients. The existence of mechanical gradients in cellular monolayers and engineered 3D epithelial tissues has been predicted computationally and confirmed experimentally [9, 12, 23]. Here, lithography-based microfabrication methods were used to control the 2D or 3D geometry of the tissues, and maximum stress was observed at sharp corners and regions of high convex curvature (Fig. 1c). As expected, preventing transmission of stress by disrupting the physical link between the cadherins and the actin cytoskeleton abrogated the gradients, rendering the mechanical stress spatially uniform [23]. Tissue-level heterogeneities in the distribution of mechanical stress have also been demonstrated in amphibian embryos and correlated with morphological patterns and mechanochemical processes in vivo [67]. Cellular contraction may thus be used as a microenvironmental cue to signal over large distances during development.
Mechanosensing and Mechanotransduction
Endogenous and exogenous mechanical forces influence a variety of biological behaviors. High local mechanical stress has been correlated and causatively linked with basic cellular processes such as proliferation [9], stem cell differentiation [68], EMT [12], and morphogenetic processes such as branch formation [23]. However, we still have a poor grasp of cellular mechanosensing and mechanotransduction, the mechanisms whereby cells and tissues sense and interpret physical signals and convert them into a functional response.
A number of cellular structures are emerging as mechanosensors, including the focal adhesion machinery. Numerous proteins are recruited at focal adhesions and phosphorylated in a stress-dependent manner [58]. Focal adhesion kinase (FAK) and Src, in particular, have been implicated as mechanosensors. FAK undergoes enhanced phosphorylation in response to mechanical stress [23, 69, 70] and is required for sensing of substratum stiffness during fibroblast migration [71]. Similarly, fluorescence-resonance energy transfer analysis has shown that Src is activated at adhesion sites in response to mechanical stress [72]. Active FAK and Src direct a plethora of cellular processes including proliferation, differentiation, adhesion, motility and invasion [71, 73, 74]. It must be emphasized, however, that mechanosensitive pathways often feed back to regulate the generation of force, thus serving as more than passive sensors. This feedback complicates studies aimed at defining specific roles within the mechanobiological machinery of the cell [75, 76].
We discussed the cellular structures likely responsible for sensing mechanical stress, but the question remains: how does mechanotransduction occur? That is, what are the molecular-level effects of force responsible for causing biochemical and functional response? One relatively well-documented mechanism is force-induced changes in protein conformation. Studies in molecular mechanics report stress-triggered alteration in a number of protein structural motifs (reviewed in [77, 78]). For instance, cellular contractile activity is sufficient to partially unfold fibronectin, exposing otherwise hidden (cryptic) regions [79]. Physical forces also open ion channels tethered to the ECM or cytoskeletal filaments, and thus influence the flux of ions into or out of the cells [77, 78]. The nucleus itself has been implicated as another potential site for mechanotransduction. Accumulating evidence suggests the existence of physical continuity between the ECM, the cytoskeleton, the nuclear lamina, and chromatin [8082]. One could speculate that force transmitted to the nucleus may directly unravel chromatin, allowing access to transcription factors and thereby regulating gene expression. Identification of mechanosensing and mechanotransduction machinery is an active area of investigation.
Mechanosensing and mechanotransduction have recently been implicated as playing crucial roles in the regulation of EMT events. Biochemical cues such as TGFβ induce EMT, but these signals cooperate with mechanical stress to yield spatial patterns within tissues [12]. Indeed, spatial variations and patterns in EMT are widely observed and may be necessary for development [3] and disease progression [30, 32]. The relationship between mechanical stress and EMT is demonstrated by signaling through MRTF-A, a cofactor of serum response factor (SRF) [83, 84]. Rho activation triggers the nuclear translocation of MRTF-A, which can thereby activate two parallel pathways during EMT in cooperation with SRF. First, the expression of EMT-regulating genes is enhanced, leading to the dissolution of cell-cell contacts. Second, the expression of cytoskeletal genes is up-regulated, thereby affecting remodeling of the cytoskeleton [84].
The activation of MRTF-A thus connects mechanical stress and actin dynamics to the regulation of transcription [85, 86]. Under conditions of low mechanical stress, the actin cytoskeleton is in a relaxed state, with a relatively high pool of actin monomers. Monomeric actin associates with the three Arg-Pro-X-X-X-Glu-Leu (RPEL) motifs (RPEL1, RPEL2, and RPEL3) located in the amino-terminus of myocardin-family proteins [8588]. Point mutations to RPEL2 and RPEL3 abolish the association between actin and MRTF-A; therefore, these regions of the amino-terminal sequence are essential for MRTF-A to bind to monomeric actin and be sequestered in the cytoplasm [87, 89]. Activation of the Rho-actin signaling pathway due to increased mechanical stress is necessary and sufficient to promote the nuclear accumulation of MRTF-A [87]. Under conditions of high mechanical stress, the activation of Rho small GTPases and subsequent cytoskeletal polymerization reduces the cytoplasmic pool of G-actin, thereby favoring the dissociation of MRTF-A from G-actin and ultimately resulting in nuclear translocation (Fig. 2) [84, 87, 9092].
Fig. 2
Fig. 2
Regulation of MRTF-A by mechanical stress. a Increased mechanical stress causes increased actin polymerization, thereby decreasing the cytoplasmic pool of G-actin and increasing the nuclear localization of MRTF-A by triggering its dissociation from G-actin. (more ...)
Cell deformation or perceived tension thus regulates the nuclear accumulation of MRTF-A [90], which can thereby determine which cells within a tissue will undergo EMT. As described above, the endogenous contractility and cohesion of epithelial sheets causes mechanical stresses to be transmitted between cells. If the epithelium has any degree of geometric asymmetry—that is, if the epithelium is not spherical—then mechanical stresses will concentrate within subpopulations of cells. This spatial patterning of endogenous mechanical stress would be expected to template patterns of Rho activation and cytoskeletal assembly within the epithelium, which could result in patterning of the activation of MRTF-A and initiation of transcription. We recently found that this is indeed the case, at least for mammary epithelial sheets in culture. When treated with TGFβ, microfabricated monolayers of mammary epithelial cells undergo EMT at regions of high mechanical stress; cells located within these regions show increased nuclear localization of MRTF-A [12] (Fig. 3). Disrupting the connections between cells removes the patterning of mechanical stress and leads to uniform activation of EMT across the entire epithelium. Conversely, forcing MRTF-A to translocate to the nucleus of cells located within low stress regions of the monolayer induces aberrant EMT. Intercellular transmission of mechanical stress between cells within epithelial tissues may thus serve to pattern the response of constituent cells to biochemical inducers of EMT, even those as potent as TGFβ. The relationships between these signals is complex, and complicated by recent findings that Smad3 may also act to inhibit transcription downstream of TGFβ [93, 94].
Fig. 3
Fig. 3
Endogenous mechanical stress patterns EMT. a In monolayers of epithelial cells, stress is concentrated at the free edges and corners of the tissues. b Under these conditions, MRTF-A accumulates in the nuclei of cells located at the free edges and corners (more ...)
Tissue morphogenesis is by nature a highly patterned, intensely physical process. Tissues are sculpted and pulled into the final architectures that comprise mature organs; these mechanical stresses are likely involved in the realization of developmental EMTs. Gene expression changes consistent with EMT have been proposed to play a role in the branching morphogenesis process that builds the arborous structures of the epithelial ducts in the kidney, lung, and mammary gland [9597]. We recently found that branching regions of mammary epithelial tissues are templated by patterns of endogenous mechanical stress such that regions of high stress induced the local emergence of nascent multicellular branches [23]. The branch sites also express genes within the EMT proteome [98, 99], consistent with the possibility that patterns of endogenous mechanical stress play a role in EMT gene expression during branching morphogenesis. This possibility awaits further exploration.
In pathological conditions, EMT has been observed to be spatially segregated to specific subpopulations of cells as well. During re-epithelialization of the skin, EMT events were found to be localized to the edges of the healing wounds [100]. As discussed above, the free edges of epithelial tissues would be expected to experience the highest amounts of mechanical stress simply from endogenous cellular contraction. Indeed, strain-gauge devices have shown significant forces generated by skin wounds as they heal [101]. It remains unclear whether mechanical stress plays a role in the EMT events occurring at the free edges of healing wounds, but mechanical stress, MRTF-A, and CArG boxes are all involved in the generation and maintenance of myofibroblasts present within granulation tissue [102, 103]. Mechanical signaling may augment the EMT pathway in the epithelial regions of skin wounds.
Patterns of mechanical stress may also play a role in the induction of EMT during tumor progression. Tumors are invariably stiffer than the surrounding normal tissue [28], and this increase in stiffness plays a fundamental role in the generation of the tumorigenic phenotype [28, 29]. As discussed above, the stiffness of the surrounding substratum affects cellular contractility. Increased stiffness enhances cellular contractility, which would be expected to increase the magnitude of endogenous mechanical stresses within the tumor tissue. Mechanical stress helps to induce EMT downstream of at least two different stimuli common to the tumor microenvironment (TGFβ and MMPs), so it is plausible that the physical properties of the tumor enhance EMT pathways thought to be necessary for tumor invasion and metastasis. During tumor invasion itself, EMT has been localized to the leading edges of metastatic cohorts of colorectal carcinomas [104, 105]. This patterned localization of EMT may be due to transmission and concentration of intercellular tension.
Mechanical stress arises from the contractile nature of the actin cytoskeleton and is transmitted through and concentrated within epithelial tissues by virtue of the cohesion between neighboring cells. Mechanical stress acts as an independent signal that can integrate with other (soluble) signals within the microenvironment to direct the phenotypes of constituent cells. By altering cytoskeletal dynamics, mechanical stress directly impacts the regulation of transcription through modulation of the subcellular localization of proteins including the transcription factor MRTF-A. High mechanical stress—from exogenous application, from increased ECM stiffness, or from endogenous contractility—can thus influence the subpopulations of cells within a tissue (normal, healing, or tumorigenic) that will undergo EMT. Because the EMT process generates cells of mesenchymal, migratory, contractile phenotype, these signals may cause both feed-back and feed-forward loops that dynamically impact the patterning of the tissues. Future studies investigating the signaling and mechanical regulatory networks within tissues undergoing EMT may reveal points and targets to augment the process (in the case of wound healing) or cut it short (in the case of metastasis).
Acknowledgements
Work from the authors’ laboratory was supported in part by the National Institutes of Health (GM083997 and CA128660), the David & Lucile Packard Foundation, the Alfred P. Sloan Foundation, and Susan G. Komen for the Cure. C.M.N. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. E.B. was supported by a Predoctoral Fellowship from the New Jersey Commission on Cancer Research.
Conflict of interest
The authors declare they have no conflict of interest.
Glossary
ECMExtracellular matrix
EMTEpithelial-mesenchymal transition
FAKFocal adhesion kinase
METMesenchymal-epithelial transition
MLCMyosin light chain
MLCKMyosin light chain kinase
MMPMatrix metalloproteinase
MRTFMyocardin-related transcription factor
SRFSerum response factor
ROCKRho-associated kinase
ROSReactive oxygen species
TGFβTransforming growth factor-beta
2DTwo-dimensional
3DThree-dimensional


1. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 1995;154:8–20. doi: 10.1159/000147748. [PubMed] [Cross Ref]
2. Nieto MA. The early steps of neural crest development. Mech Dev. 2001;105:27–35. doi: 10.1016/S0925-4773(01)00394-X. [PubMed] [Cross Ref]
3. Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120:1351–1383. doi: 10.1016/j.mod.2003.06.005. [PubMed] [Cross Ref]
4. Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 2005;65:5996–6000. doi: 10.1158/0008-5472.CAN-05-0699. [PubMed] [Cross Ref]
5. Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res. 2005;65:5991–5995. doi: 10.1158/0008-5472.CAN-05-0616. [PubMed] [Cross Ref]
6. Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277–279. doi: 10.1016/j.cell.2004.07.011. [PubMed] [Cross Ref]
7. Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004;18:1131–1143. doi: 10.1101/gad.294104. [PubMed] [Cross Ref]
8. Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE. Geometric control of cell life and death. Science. 1997;276:1425–1428. doi: 10.1126/science.276.5317.1425. [PubMed] [Cross Ref]
9. 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 USA. 2005;102:11594–11599. doi: 10.1073/pnas.0502575102. [PubMed] [Cross Ref]
10. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–689. doi: 10.1016/j.cell.2006.06.044. [PubMed] [Cross Ref]
11. 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. doi: 10.1016/S1534-5807(04)00075-9. [PubMed] [Cross Ref]
12. Gomez EW, Chen QK, Gjorevski N, Nelson CM. Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction. J Cell Biochem. 2010;110:44–51. [PMC free article] [PubMed]
13. 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. doi: 10.1002/jcb.21821. [PMC free article] [PubMed] [Cross Ref]
14. Adams DS, Keller R, Koehl MAR. The mechanics of notochord elongation, straightening and stiffening in the embryo of xenopus-laevis. Development. 1990;110:115–130. [PubMed]
15. Keller R, Jansa S. Xenopus gastrulation without a blastocoele roof. Dev Dyn. 1992;195:162–176. doi: 10.1002/aja.1001950303. [PubMed] [Cross Ref]
16. Kiehart DP, Galbraith CG, Edwards KA, Rickoll WL, Montague RA. Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. J Cell Biol. 2000;149:471–490. doi: 10.1083/jcb.149.2.471. [PMC free article] [PubMed] [Cross Ref]
17. Hutson MS, Tokutake Y, Chang MS, Bloor JW, Venakides S, Kiehart DP, Edwards GS. Forces for morphogenesis investigated with laser microsurgery and quantitative modeling. Science. 2003;300:145–149. doi: 10.1126/science.1079552. [PubMed] [Cross Ref]
18. Toyama Y, Peralta XG, Wells AR, Kiehart DP, Edwards GS. Apoptotic force and tissue dynamics during Drosophila embryogenesis. Science. 2008;321:1683–1686. doi: 10.1126/science.1157052. [PMC free article] [PubMed] [Cross Ref]
19. Desprat N, Supatto W, Pouille PA, Beaurepaire E, Farge E. Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos. Dev Cell. 2008;15:470–477. doi: 10.1016/j.devcel.2008.07.009. [PubMed] [Cross Ref]
20. Farge E. Mechanical induction of twist in the Drosophila foregut/stomodeal primordium. Curr Biol. 2003;13:1365–1377. doi: 10.1016/S0960-9822(03)00576-1. [PubMed] [Cross Ref]
21. Moore KA, Polte T, Huang S, Shi B, Alsberg E, Sunday ME, Ingber DE. Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by Rho and cytoskeletal tension. Dev Dyn. 2005;232:268–281. doi: 10.1002/dvdy.20237. [PubMed] [Cross Ref]
22. Michael L, Sweeney DE, Davies JA. A role for microfilament-based contraction in branching morphogenesis of the ureteric bud. Kidney Int. 2005;68:2010–2018. doi: 10.1111/j.1523-1755.2005.00655.x. [PubMed] [Cross Ref]
23. Gjorevski N, Nelson CM. Endogenous patterns of mechanical stress are required for branching morphogenesis. Integr Biol. 2010;2:424–434. doi: 10.1039/c0ib00040j. [PMC free article] [PubMed] [Cross Ref]
24. Stull MA, Pai V, Vomachka AJ, Marshall AM, Jacob GA, Horseman ND. Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. Proc Natl Acad Sci USA. 2007;104:16708–16713. doi: 10.1073/pnas.0708136104. [PubMed] [Cross Ref]
25. Fritz G, Just I, Kaina B. Rho GTPases are over-expressed in human tumors. Int J Cancer. 1999;81:682–687. doi: 10.1002/(SICI)1097-0215(19990531)81:5<682::AID-IJC2>3.0.CO;2-B. [PubMed] [Cross Ref]
26. Croft DR, Sahai E, Mavria G, Li SX, Tsai J, Lee WMF, Marshall CJ, Olson MF. Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis. Cancer Res. 2004;64:8994–9001. doi: 10.1158/0008-5472.CAN-04-2052. [PubMed] [Cross Ref]
27. Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N, Kessler O, Cohen T, Resnick M, Neeman M, Neufeld G. Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res. 2003;63:1657–1666. [PubMed]
28. 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. doi: 10.1016/j.cell.2009.10.027. [PMC free article] [PubMed] [Cross Ref]
29. 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. doi: 10.1016/j.ccr.2005.08.010. [PubMed] [Cross Ref]
30. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–890. doi: 10.1016/j.cell.2009.11.007. [PubMed] [Cross Ref]
31. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–1437. doi: 10.1172/JCI36183. [PMC free article] [PubMed] [Cross Ref]
32. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454. doi: 10.1038/nrc822. [PubMed] [Cross Ref]
33. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–1428. doi: 10.1172/JCI39104. [PMC free article] [PubMed] [Cross Ref]
34. Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest. 2009;119:1417–1419. doi: 10.1172/JCI39675. [PMC free article] [PubMed] [Cross Ref]
35. Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005;24:5764–5774. doi: 10.1038/sj.onc.1208927. [PubMed] [Cross Ref]
36. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005;16:1987–2002. doi: 10.1091/mbc.E04-08-0658. [PMC free article] [PubMed] [Cross Ref]
37. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 2004;23:1155–1165. doi: 10.1038/sj.emboj.7600069. [PubMed] [Cross Ref]
38. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156–172. doi: 10.1038/cr.2009.5. [PubMed] [Cross Ref]
39. Yang YC, Piek E, Zavadil J, Liang D, Xie D, Heyer J, Pavlidis P, Kucherlapati R, Roberts AB, Bottinger EP. Hierarchical model of gene regulation by transforming growth factor beta. Proc Natl Acad Sci USA. 2003;100:10269–10274. doi: 10.1073/pnas.1834070100. [PubMed] [Cross Ref]
40. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3:155–166. doi: 10.1038/nrm757. [PubMed] [Cross Ref]
41. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–89. doi: 10.1038/35000034. [PubMed] [Cross Ref]
42. Hemavathy K, Guru SC, Harris J, Chen JD, Ip YT. Human Slug is a repressor that localizes to sites of active transcription. Mol Cell Biol. 2000;20:5087–5095. doi: 10.1128/MCB.20.14.5087-5095.2000. [PMC free article] [PubMed] [Cross Ref]
43. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499–511. doi: 10.1242/jcs.00224. [PubMed] [Cross Ref]
44. Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62:1613–1618. [PubMed]
45. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, Barrio MG, Portillo F, Nieto MA. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83. doi: 10.1038/35000025. [PubMed] [Cross Ref]
46. 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. [PMC free article] [PubMed]
47. Fukata M, Kaibuchi K. Rho-family GTPases in cadherin-mediated cell-cell adhesion. Nat Rev Mol Cell Biol. 2001;2:887–897. doi: 10.1038/35103068. [PubMed] [Cross Ref]
48. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436:123–127. doi: 10.1038/nature03688. [PMC free article] [PubMed] [Cross Ref]
49. Harris AK, Wild P, Stopak D. Silicone-rubber substrata—new wrinkle in the study of cell locomotion. Science. 1980;208:177–179. doi: 10.1126/science.6987736. [PubMed] [Cross Ref]
50. Dembo M, Wang YL. Stresses at the cell-to-substrate interface during locomotion of fibroblasts. Biophys J. 1999;76:2307–2316. doi: 10.1016/S0006-3495(99)77386-8. [PubMed] [Cross Ref]
51. Pelham RJ, Wang YL. High resolution detection of mechanical forces exerted by locomoting fibroblasts on the substrate. Mol Biol Cell. 1999;10:935–945. [PMC free article] [PubMed]
52. 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 USA. 2003;100:1484–1489. doi: 10.1073/pnas.0235407100. [PubMed] [Cross Ref]
53. ChrzanowskaWodnicka M, Burridge K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol. 1996;133:1403–1415. doi: 10.1083/jcb.133.6.1403. [PMC free article] [PubMed] [Cross Ref]
54. Landsverk ML, Epstein HF. Genetic analysis of myosin II assembly and organization in model organisms. Cell Mol Life Sci. 2005;62:2270–2282. doi: 10.1007/s00018-005-5176-2. [PubMed] [Cross Ref]
55. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase) J Biol Chem. 1996;271:20246–20249. doi: 10.1074/jbc.271.34.20246. [PubMed] [Cross Ref]
56. Ishizaki T, Naito M, Fujisawa K, Maekawa M, Watanabe N, Saito Y, Narumiya S. p160(ROCK), a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions. FEBS Lett. 1997;404:118–124. doi: 10.1016/S0014-5793(97)00107-5. [PubMed] [Cross Ref]
57. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase) Science. 1996;273:245–248. doi: 10.1126/science.273.5272.245. [PubMed] [Cross Ref]
58. Chen CS. Mechanotransduction—a field pulling together? J Cell Sci. 2008;121:3285–3292. doi: 10.1242/jcs.023507. [PubMed] [Cross Ref]
59. Galbraith CG, Yamada KM, Sheetz MP. The relationship between force and focal complex development. J Cell Biol. 2002;159:695–705. doi: 10.1083/jcb.200204153. [PMC free article] [PubMed] [Cross Ref]
60. Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ. ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J Cell Biol. 2003;163:583–595. doi: 10.1083/jcb.200305010. [PMC free article] [PubMed] [Cross Ref]
61. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions—transmembrane junctions between the extracellular-matrix and the cytoskeleton. Annu Rev Cell Biol. 1988;4:487–525. doi: 10.1146/annurev.cb.04.110188.002415. [PubMed] [Cross Ref]
62. Miyamoto S, Akiyama SK, Yamada KM. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science. 1995;267:883–885. doi: 10.1126/science.7846531. [PubMed] [Cross Ref]
63. Reinhart-King CA, Dembo M, Hammer DA. Cell-cell mechanical communication through compliant substrates. Biophys J. 2008;95:6044–6051. doi: 10.1529/biophysj.107.127662. [PubMed] [Cross Ref]
64. McNeill H, Ryan TA, Smith SJ, Nelson WJ. Spatial and temporal dissection of immediate and early events following cadherin-mediated epithelial cell adhesion. J Cell Biol. 1993;120:1217–1226. doi: 10.1083/jcb.120.5.1217. [PMC free article] [PubMed] [Cross Ref]
65. Adams CL, Nelson WJ. Cytomechanics of cadherin-mediated cell-cell adhesion. Curr Opin Cell Biol. 1998;10:572–577. doi: 10.1016/S0955-0674(98)80031-8. [PubMed] [Cross Ref]
66. Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol. 2001;91:1487–1500. [PubMed]
67. Beloussov LV, Dorfman JG, Cherdantzev VG. Mechanical stresses and morphological patterns in amphibian embryos. J Embryol Exp Morphol. 1975;34:559–574. [PubMed]
68. Ruiz SA, Chen CS. Emergence of patterned stem cell differentiation within multicellular structures. Stem Cells. 2008;26:2921–2927. doi: 10.1634/stemcells.2008-0432. [PMC free article] [PubMed] [Cross Ref]
69. Tang D, Mehta D, Gunst SJ. Mechanosensitive tyrosine phosphorylation of paxillin and focal adhesion kinase in tracheal smooth muscle. Am J Physiol. 1999;276:C250–C258. [PubMed]
70. Yano Y, Geibel J, Sumpio BE. Tyrosine phosphorylation of pp 125FAK and paxillin in aortic endothelial cells induced by mechanical strain. Am J Physiol. 1996;271:C635–C649. [PubMed]
71. Wang HB, Dembo M, Hanks SK, Wang YL. Focal adhesion kinase is involved in mechanosensing during fibroblast migration. Proc Natl Acad Sci USA. 2001;98:11295–11300. doi: 10.1073/pnas.201201198. [PubMed] [Cross Ref]
72. Wang Y, Botvinick EL, Zhao Y, Berns MW, Usami S, Tsien RY, Chien S. Visualizing the mechanical activation of Src. Nature. 2005;434:1040–1045. doi: 10.1038/nature03469. [PubMed] [Cross Ref]
73. Schlaepfer DD, Mitra SK. Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev. 2004;14:92–101. doi: 10.1016/j.gde.2003.12.002. [PubMed] [Cross Ref]
74. Wichert G, Krndija D, Schmid H, Haerter G, Adler G, Seufferlein T, Sheetz MP. Focal adhesion kinase mediates defects in the force-dependent reinforcement of initial integrin-cytoskeleton linkages in metastatic colon cancer cell lines. Eur J Cell Biol. 2008;87:1–16. doi: 10.1016/j.ejcb.2007.07.008. [PubMed] [Cross Ref]
75. Lim Y, Lim ST, Tomar A, Gardel M, Bernard-Trifilo JA, Chen XL, Uryu SA, Canete-Soler R, Zhai J, Lin H, Schlaepfer WW, Nalbant P, Bokoch G, Ilic D, Waterman-Storer C, Schlaepfer DD. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J Cell Biol. 2008;180:187–203. doi: 10.1083/jcb.200708194. [PMC free article] [PubMed] [Cross Ref]
76. Pirone DM, Liu WF, Ruiz SA, Gao L, Raghavan S, Lemmon CA, Romer LH, Chen CS. An inhibitory role for FAK in regulating proliferation: a link between limited adhesion and RhoA-ROCK signaling. J Cell Biol. 2006;174:277–288. doi: 10.1083/jcb.200510062. [PMC free article] [PubMed] [Cross Ref]
77. Bao L, Locovei S, Dahl G. Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett. 2004;572:65–68. doi: 10.1016/j.febslet.2004.07.009. [PubMed] [Cross Ref]
78. Sukharev S, Corey DP (2004) Mechanosensitive channels: multiplicity of families and gating paradigms. Sci STKE 2004:re4. [PubMed]
79. Baneyx G, Baugh L, Vogel V. Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension. Proc Natl Acad Sci USA. 2002;99:5139–5143. doi: 10.1073/pnas.072650799. [PubMed] [Cross Ref]
80. Starr DA, Han M. ANChors away: an actin based mechanism of nuclear positioning. J Cell Sci. 2003;116:211–216. doi: 10.1242/jcs.00248. [PubMed] [Cross Ref]
81. Zastrow MS, Vlcek S, Wilson KL. Proteins that bind A-type lamins: integrating isolated clues. J Cell Sci. 2004;117:979–987. doi: 10.1242/jcs.01102. [PubMed] [Cross Ref]
82. Zhang Q, Skepper JN, Yang F, Davies JD, Hegyi L, Roberts RG, Weissberg PL, Ellis JA, Shanahan CM. Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. J Cell Sci. 2001;114:4485–4498. [PubMed]
83. 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. doi: 10.1152/ajprenal.00142.2007. [PubMed] [Cross Ref]
84. 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. doi: 10.1083/jcb.200708174. [PMC free article] [PubMed] [Cross Ref]
85. Posern G, Treisman R. Actin’ together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol. 2006;16:588–596. doi: 10.1016/j.tcb.2006.09.008. [PubMed] [Cross Ref]
86. Olson EN, Nordheim A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol. 2010;11:353–365. doi: 10.1038/nrm2890. [PMC free article] [PubMed] [Cross Ref]
87. Miralles F, Posern G, Zaromytidou AI, Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell. 2003;113:329–342. doi: 10.1016/S0092-8674(03)00278-2. [PubMed] [Cross Ref]
88. Vartiainen MK, Guettler S, Larijani B, Treisman R. Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science. 2007;316:1749–1752. doi: 10.1126/science.1141084. [PubMed] [Cross Ref]
89. Rosenblatt J, Raff MC, Cramer LP. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol. 2001;11:1847–1857. doi: 10.1016/S0960-9822(01)00587-5. [PubMed] [Cross Ref]
90. Somogyi K, Rorth P. Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration. Dev Cell. 2004;7:85–93. doi: 10.1016/j.devcel.2004.05.020. [PubMed] [Cross Ref]
91. 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. doi: 10.1038/ncb2074. [PubMed] [Cross Ref]
92. Mouilleron S, Langer CA, Guettler S, McDonald NQ, Treisman R (2011) Structure of a pentavalent G-Actin*MRTF-A complex reveals how G-Actin controls nucleocytoplasmic shuttling of a transcriptional coactivator. Sci Signal 4:ra40. [PubMed]
93. 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. doi: 10.1083/jcb.200906155. [PMC free article] [PubMed] [Cross Ref]
94. Masszi A, Kapus A. Smaddening complexity: the role of smad3 in epithelial-myofibroblast transition. Cells Tissues Organs. 2011;193:41–52. doi: 10.1159/000320180. [PubMed] [Cross Ref]
95. Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol. 2005;6:622–634. doi: 10.1038/nrm1699. [PubMed] [Cross Ref]
96. Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15:117–134. doi: 10.1007/s10911-010-9178-9. [PMC free article] [PubMed] [Cross Ref]
97. O’Brien LE, Zegers MM, Mostov KE. Opinion: building epithelial architecture: insights from three-dimensional culture models. Nat Rev Mol Cell Biol. 2002;3:531–537. doi: 10.1038/nrm859. [PubMed] [Cross Ref]
98. Nelson CM, Vanduijn MM, Inman JL, Fletcher DA, Bissell MJ. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science. 2006;314:298–300. doi: 10.1126/science.1131000. [PMC free article] [PubMed] [Cross Ref]
99. Lee K, Gjorevski N, Boghaert E, Radisky DC, Nelson CM (2011) Snail1, Snail2, and E47 promote mammary epithelial branching morphogenesis. EMBO J. [PubMed]
100. Arnoux V, Come C, Kusewitt D, Hudson L, Savagner P. Cutaneous wound reepithelialization: a partial and reversible EMT. In: Savagner P, editor. Rise and fall of epithelial phenotype: concepts of epithelial-mesenchymal transition. Berlin: Springer; 2005. pp. 111–134.
101. Higton DI, James DW. The force of contraction of full-thickness wounds of rabbit skin. Br J Surg. 1964;51:462–466. doi: 10.1002/bjs.1800510616. [PubMed] [Cross Ref]
102. 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. doi: 10.1038/nrm809. [PubMed] [Cross Ref]
103. Tomasek JJ, McRae J, Owens GK, Haaksma CJ. Regulation of alpha-smooth muscle actin expression in granulation tissue myofibroblasts is dependent on the intronic CArG element and the transforming growth factor-beta1 control element. Am J Pathol. 2005;166:1343–1351. doi: 10.1016/S0002-9440(10)62353-X. [PubMed] [Cross Ref]
104. Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 1998;8:1243–1252. doi: 10.1016/S0960-9822(07)00533-7. [PubMed] [Cross Ref]
105. 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 USA. 2001;98:10356–10361. doi: 10.1073/pnas.171610498. [PubMed] [Cross Ref]
Articles from Cancer Microenvironment are provided here courtesy of
Springer Science+Business Media B.V.