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1.
《Cell cycle (Georgetown, Tex.)》2013,12(14):2814-2820
Glioblastoma, the most common and aggressive primary brain tumor, is rapidly growing, and highly infiltrative. Incomplete knowledge of the molecular biology, genetics, causes and cellular origin of these tumors may limit the development of improved therapeutics. A major and fundamental advance in recent years has been the identification of microRNAs as highly conserved regulators of gene expression. Here we will discuss further our recently published data on the role of miR-451 in the biology of glioblastoma. We initially identified miR-451 due to its downregulation in a glioma cell migration assay. We then found that by targeting the LKB1 kinase complex miR-451 suppresses the activity of downstream protein kinases including the major energy biosensor AMPK. MiR-451 levels are regulated by glucose; under conditions of abundant energy miR-451 expression is high, and the suppression of AMPK signaling allows cells to maintain elevated proliferation rates via unrestrained mTOR activation. Under conditions of glucose withdrawal, miR-451 downregulation is necessary for AMPK pathway activation, leading to suppressed proliferation rates, increased cell survival, and migration. We also identified a potential feedback loop between LKB1 and miR-451, which allows a sustained and robust response to glucose deprivation. This data will be discussed in the context of potential biological significance and therapeutic implications. 相似文献
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Pankov R Endo Y Even-Ram S Araki M Clark K Cukierman E Matsumoto K Yamada KM 《The Journal of cell biology》2005,170(5):793-802
Directional migration moves cells rapidly between points, whereas random migration allows cells to explore their local environments. We describe a Rac1 mechanism for determining whether cell patterns of migration are intrinsically random or directionally persistent. Rac activity promoted the formation of peripheral lamellae that mediated random migration. Decreasing Rac activity suppressed peripheral lamellae and switched the cell migration patterns of fibroblasts and epithelial cells from random to directionally persistent. In three-dimensional rather than traditional two-dimensional cell culture, cells had a lower level of Rac activity that was associated with rapid, directional migration. In contrast to the directed migration of chemotaxis, this intrinsic directional persistence of migration was not mediated by phosphatidylinositol 3'-kinase lipid signaling. Total Rac1 activity can therefore provide a regulatory switch between patterns of cell migration by a mechanism distinct from chemotaxis. 相似文献
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Anne Blangy 《Biology of the cell / under the auspices of the European Cell Biology Organization》2017,109(3):115-126
Tensins are focal adhesion molecules that were identified and characterised in the late 1980s to early 1990s. They play an essential role in the control of cell adhesion. Tensins can bind the tail of ß integrin via their phospho tyrosine binding domain, they exhibit various protein interaction domains including a Src Homology 2 domain and they are serine‐, threonine‐ and tyrosine‐phosphorylated in response to various stimuli. Tensins serve as scaffolds to gather signalling molecules at the extracellular matrix adhesion complexes. Tensins have emerged as important regulators of cell adhesion and migration, in particular by participating in Rho GTPase signalling pathways. Tensins were shown to influence the activity of the GTPase RhoA, by regulating the Rho GTPase activating protein Deleted in Liver Cancer 1. More recently, Tensin 3 was also found to regulate Dock5, a guanine nucleotide exchange factor for the GTPase Rac, and to modulate podosome‐based adhesion structures in osteoclasts. This review focusses on the recent literature highlighting how Tensins can interplay with regulators of Rho GTPase signalling pathways and how this influences cell adhesion and migration. 相似文献
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A previously described model for cellular proliferation, based on the relationship of the cell cycle to redox parameters, is explored here to account for the origin of the cancerous cell and some of its key abnormal characteristics, such as the Warburg effect, apoptosis, aneuploidy, and uncontrolled proliferation. We describe how the redox switch that characterizes normal cells and its absence in cancer cells is responsible for the origin and characteristics of cancer cells. Metabolic and chromosomal changes resulting from the lack of such a redox switch in cancer cells are described. The effects of a well-known carcinogen, cigarette smoking, are also applied to the model. This report emphasizes the role of the threshold intracellular redox potential in regulating cells. 相似文献
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Calpain: a role in cell transformation and migration 总被引:7,自引:0,他引:7
Carragher NO Frame MC 《The international journal of biochemistry & cell biology》2002,34(12):1539-1543
Calpains represent a well conserved family of calcium-dependent proteolytic enzymes. Recent progress in determining the three-dimensional crystal structure of calpains and generation of calpain knock out animals have significantly advanced our understanding of both the activation mechanism and physiological role of this protease family. Studies applying molecular intervention strategies and genetic ablation of calpain now provide indisputable evidence that calpain activity contributes to remodelling of the actin cytoskeleton, cell migration and oncogenic transformation. Src and epidermal growth factor receptor (EGFR) stimulated cell motility is dependent upon calpain activation. In addition, calpain promotes accelerated cell-cycle progression and anchorage-independent growth of Src transformed cells. In vivo studies demonstrate a link between calpain expression levels and activity with tumour development and invasion. Thus, recent investigations suggest that the role of calpain in promoting cell transformation and cell migration may have important in vivo consequences in the context of cancer pathobiology. 相似文献
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In addition to mediating cell adhesion, many cell adhesion molecules act as tumor suppressors. These proteins are capable of restricting cell growth mainly through contact inhibition. Alterations of these cell adhesion molecules are a common event in cancer. The resulting loss of cell-cell and/or cell-extracellular matrix adhesion promotes cell growth as well as tumor dissemination. Therefore, it is conventionally accepted that cell adhesion molecules that function as tumor suppressors are also involved in limiting tumor cell migration. Paradoxically, in 2005, we identified an immunoglobulin superfamily cell adhesion molecule hepaCAM that is able to suppress cancer cell growth and yet induce migration. Almost concurrently, CEACAM1 was verified to co-function as a tumor suppressor and invasion promoter. To date, the reason and mechanism responsible for this exceptional phenomenon remain unclear. Nevertheless, the emergence of these intriguing cell adhesion molecules with conflicting roles may open a new chapter to the biological significance of cell adhesion molecules.Key words: hepaCAM, cell adhesion molecules, tumor suppressor, migration, E-cadherin, CADM1, integrin α7, CEACAM1It is well known that many cell adhesion molecules function as tumor suppressors (reviewed in ref. 1). These molecules exert their tumor suppressive effect mainly through cell-adhesion-mediated contact inhibition. Cell adhesion molecules allow cells to communicate with one another or to the extracellular environment by mediating cell-cell or cell-extracellular matrix (ECM) interactions (reviewed in refs. 2 and 3). Broadly, these proteins can be classified into five families including immunoglobulin superfamily, integrins, cadherins, selectins and CD44. Apart from participating in the development and maintenance of tissue architecture, cell adhesion molecules serve as cell surface receptors critical for capturing, integrating and transmitting signals from the extracellular milieu to the cell interior (reviewed in refs. 2 and 3). These signaling events are vital for the regulation of a wide variety of cellular functions including embryogenesis, immune and inflammatory responses, tissue repair, cell migration, differentiation, proliferation and apoptosis. Alterations of these cell adhesion molecules are a common event in cancer (reviewed in refs. 1, 2, 4 and 5). The disrupted cell-cell or cell-ECM adhesion significantly contributes to uncontrolled cell proliferation and progressive distortion of normal tissue architecture. More importantly, changes in cell adhesion molecules play a causal role in tumor dissemination. Loss of cell adhesion contacts allows malignant cells to detach and to escape from the primary mass. Gaining a more motile and invasive phenotype, these cells break down the ECM and eventually invade and metastasize to distal organs.Based on the above understanding, it is conventionally accepted that cell adhesion molecules with tumor suppressor activity, when expressed in cancer cells, are able to exert inhibitory effect on cell motility. The ability of cells in migration/motility is a prerequisite for cancer invasion and metastasis (reviewed in refs. 1 and 5). Indeed, a number of cell adhesion molecule-tumor suppressors have been reported to be capable of reducing cell migration. The most classical example is E-cadherin, a calcium-dependent cell adhesion molecule. E-cadherin is expressed exclusively in epithelial cells and its expression is commonly suppressed in tumors of epithelial origins. The cytoplasmic domain of E-cadherin interacts with catenins to establish an intracellular linkage with the actin cytoskeleton (reviewed in ref. 6). The assembly of E-cadherin with the cytoskeleton via catenins at the sites of adherens junctions is important for the stabilization of cell-cell adhesions. Disruption of E-cadherin-mediated cell-cell adhesion, due to loss of expression or function of E-cadherin and/or catenins, is assocated with tumor development and progression (reviewed in ref. 7). Forced expression of E-cadherin in several cancer cell lines not only slows down cell growth8,9 but also significantly reduces the invasiveness of the cells.10,11 On the other hand, inhibition of E-cadherin by function-blocking antibodies and antisense RNA restores the invasiveness in non-invasive transformed cells.11 Furthermore, using a transgenic mouse model of pancreatic beta-cell carcinogenesis, it has been demonstrated that E-cadherin-mediated cell adhesion is important in preventing the transition from well differentiated adenoma to invasive carcinoma.12Cell adhesion molecule 1 (CADM1), another example, has also been implicated in cancer progression. CADM1 is a member of the immunoglobulin superfamily and mediates cell-cell adhesion.13 The molecule associates with the actin cytoskeleton via the differentially expressed in adenocarcinoma of the lung (DAL1) protein; and the formation of CADM1-DAL1 complex is dependent on the integrity of actin cytoskeleton.14 Inactivation of the CADM1 and/or DAL1 gene usually through methylation has been reported in diverse human cancers.15,16 A paper by Ito et al. showed that restoration of CADM1 expression in esophageal squamous cell carcinoma cells not only suppresses cell growth, but also retards cell motility and invasion.16In contrast to E-cadherin and CADM1, integrin α7 is a cell-ECM adhesion molecule which also possesses tumor suppressor activity. Ren et al. showed that integrin α7 gene is mutated in several human malignances; and the mutations are associated with an increase in cancer recurrence.17 Forced expression of integrin α7 in integrin α7-deficient leiomyosarcoma cells results in decreased colony formation and slower cell motility. Conversely, knockdown of integrin α7 in lung cancer cells expressing wild-type integrin α7 increases the colony number and cell motility rate. In addition, the researchers revealed that mice bearing xenograft tumors overexpressing integrin α7 have reduced tumor size with no obvious metastasis.In 2005, we first reported the identification of a cell adhesion molecule belonging to the immunoglobulin superfamily, designated as hepaCAM.18 To date, we have shown that the gene is frequently downregulated in a variety of human cancers.18,19 Re-expression of hepaCAM in the hepatocellular carcinoma HepG2 cells18 and breast cancer MCF7 cells19 inhibits colony formation and retards cell proliferation. In addition, expression of hepaCAM in MCF7 cells results in cell cycle arrest at the G2/M phase and cellular senescence. Concurrently, the expression of several senescence-associated proteins including p53, p21 and p27 is enhanced. Moreover, downregulation of p53 by p53-specific small interfering RNA in cells expressing hepaCAM clearly reduces p21 without changing p27 and alleviates senescence, indicating that hepaCAM induces senescence through a p53/p21-dependent pathway.19 Together, the data suggest that hepaCAM is a tumor suppressor. Interestingly, the expression of hepaCAM in both HepG2 and MCF7 cells stimulates both cell-ECM adhesion and cell migration.18,20,21 The function of hepaCAM as a tumor suppressor in cell migration is contradictory to other cell adhesion molecule-tumor suppressors. Noteworthily, hepaCAM-mediated cell motility is evidenced by its direct interaction with the actin cytoskeleton.21Evidences are currently emerging to support the contradictory roles of cell adhesion molecules that both inhibit cell growth and promote cell motility when restored in cancer cells. In addition to hepaCAM, the immunoglobulin superfamily carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is implicated to function as a tumor suppressor and a metastasis promoter. The characteristics and functions of CEACAM1 have been demonstrated in individual reports. CEACAM1 is frequently downregulated or dysregulated in multiple human tumors,22–25 and is capable of suppressing cell growth and inducing apoptosis.26–28 Ebrahimnejad et al. demonstrated that exogenous expression of CEACAM1 enhances melanoma cell invasion and migration; and this enhanced motility can be reverted by anti-CEACAM antibodies.29 The ability of CEACAM to co-stimulate tumor suppression and invasion was finally established by Liu et al. in restricting thyroid cancer growth but promoting invasiveness.30 Introduction of CEACAM1 into CEACAM1-deficient thyroid cancer cells results in G1/S phase cell cycle arrest accompanied by elevated p21 expression and diminished Rb phosphorylation. Overexpression of CEACAM1 also increases cell-ECM adhesion and promotes cell migration and tumor invasiveness. In xenografted mice, CEACAM1 expression results in reduced tumor growth but increased tumor invasiveness. Conversely, silencing of endogenous CEACAM1 accelerates tumor growth and suppresses invasiveness.30It is an exciting issue to address why a cell adhesion molecule is able to suppress tumor growth yet promote tumor progression. Could there be a molecular switch that controls the functions of the gene between a tumor suppressor and a migration promoter in cancer or are the functions executed simultaneously? The expression level, the extracellular cues as well as the interacting partners of the cell adhesion molecules may likely play a critical role in regulating its functions. The question is under what circumstances these factors come into play. To answer all these questions, and maybe more, on the intriguing findings of these proteins, more extensive and intensive experimentation is required. Nevertheless, it is obvious that the emergence of these cell adhesion molecules that function in a contradictory manner opens a new chapter to the biological significance of cell adhesion molecules. 相似文献
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Cell polarity is fundamentally important to plant growth and development, yet the mechanism governing its development is understood poorly. Several studies have revealed a role for Rop GTPases in pollen polar tip growth. Rop is also localized to the future site of root hair development and the tip of root hairs, and expression of constitutively active Rop mutants impacts on the morphogenesis of tip-growing root hairs as well as on non-tip-growing cells. These findings highlight the importance of Rop as a common switch in cell polarity control in plants. 相似文献
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In our body cells move in three dimensions, embedded in an extracellular matrix that varies in composition, density and stiffness, and this movement is fundamental to life. Next to 3D cell migration assays, representing these physiological circumstances, still we need 2D migrations assays to perform detailed studies on the contribution of matrix‐components and (extra)cellular proteins to cell movements. Next to the debate on differences between 3D and 2D migration, there also are many new perspectives on the use and development of novel or modified 2D cell migration assays. Of special significance is the introduction of so‐called barrier migration assays, methods that avoid cell and matrix damage, as complementation or replacement of scratch/wound healing assays. Here, we discuss the possibilities and limitations of different 2D barrier migration assays. J. Cell. Physiol. 226: 288–290, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
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Cells are dependent on correct sorting of activated receptor tyrosine kinases (RTKs) for the outcome of growth factor signaling. Upon activation, RTKs are coupled through the endocytic machinery for degradation or recycled to the cell surface. However, the molecular mechanisms governing RTK recycling are poorly understood. Here, we show that Golgi-localized gamma ear-containing Arf-binding protein 3 (GGA3) interacts selectively with the Met/hepatocyte growth factor RTK when stimulated, to sort it for recycling in association with "gyrating" clathrin. GGA3 loss abrogates Met recycling from a Rab4 endosomal subdomain, resulting in pronounced trafficking of Met toward degradation. Decreased Met recycling attenuates ERK activation and cell migration. Met recycling, sustained ERK activation, and migration require interaction of GGA3 with Arf6 and an unexpected association with the Crk adaptor. The data show that GGA3 defines an active recycling pathway and support a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling. 相似文献
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An in vitro model of cell migration: evaluation of vascular endothelial cell migration 总被引:1,自引:0,他引:1
In vivo vascular endothelial cell (VEC) migration is thought to play a central role in the development of new capillaries as well as the resurfacing of large vessels. Recently, we have developed an in vitro VEC migration assay system based on the ability of VEC to migrate off of tissue culture microcarrier beads. For these studies, bovine pulmonary artery VEC were grown to confluence on Cytodex 3 microcarrier beads (MCB). Next, the confluent VEC covered microcarrier beads were pipetted into 4-cm2 wells of a tissue culture plate and incubated at 37 degrees C/5% CO2. At various time intervals, the movement of the VEC off of the MCB onto the tissue culture surface was evaluated microscopically. Using this assay, we have studied the effect of endothelial cell growth supplement and various matrices (i.e., fibronectin, gelatin, and Matrigel) on VEC migration. These studies demonstrated that: (i) gelatin had no effect on normal or mitomycin C-pretreated VEC migration; (ii) fibronectin had no effect on normal VEC migration, but stimulated the relative migration of mitomycin pretreated VEC; and (iii) Matrigel significantly suppressed both normal and mitomycin C-pretreated VEC migration. Endothelial cell growth supplement (ECGS) stimulated both normal and mitomycin C-pretreated VEC migration on fibronectin at concentrations of 10 micrograms/ml ECGS. Pretreatment with ECGS had no effect of normal or mitomycin C VEC migration on gelatin. Finally, ECGS stimulated a statistically significant increase in the migration of normal and mitomycin C-pretreated VEC migration on Matrigel.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Cell migration underlies tissue formation, maintenance, and regeneration as well as pathological conditions such as cancer invasion. Structural and molecular determinants of both tissue environment and cell behavior define whether cells migrate individually (through amoeboid or mesenchymal modes) or collectively. Using a multiparameter tuning model, we describe how dimension, density, stiffness, and orientation of the extracellular matrix together with cell determinants—including cell–cell and cell–matrix adhesion, cytoskeletal polarity and stiffness, and pericellular proteolysis—interdependently control migration mode and efficiency. Motile cells integrate variable inputs to adjust interactions among themselves and with the matrix to dictate the migration mode. The tuning model provides a matrix of parameters that control cell movement as an adaptive and interconvertible process with relevance to different physiological and pathological contexts.
Open in a separate windowAmoeboid migration commonly refers to the movement of rounded or ellipsoid cells that lack mature focal adhesions and stress fibers (Friedl et al., 2001; Lämmermann and Sixt, 2009). There are two subtypes of amoeboid movement. The first is the rounded, blebby migration of cells that do not adhere or pull on substrate but rather use a propulsive, pushing migration mode (Fackler and Grosse, 2008; Sanz-Moreno and Marshall, 2009). The second occurs in slightly more elongated amoeboid cells that generate actin-rich filopodia at the leading edge that engage in poorly defined, weak adhesive interaction with the substrate (Fig. 1; Yoshida and Soldati, 2006; Smith et al., 2007). In a special case of amoeboid movement, terminally matured nonadhesive dendritic cells produce dynamic actin-rich dendrites, instead of blebs, at their leading edge that cause these cell to become entangled with the ECM substrate during migration (Gunzer et al., 1997; Lämmermann et al., 2008). Individual cells with high levels of attachment and cytoskeletal contractility develop mesenchymal migration, which involves focalized cell–matrix interactions and movement in a fibroblast-like manner (Kaye et al., 1971; Maaser et al., 1999; Grinnell, 2008). The migration of individual cells that transiently form and resolve cell–cell contacts while moving along a common track is termed chain migration or cell streaming (Davis and Trinkaus, 1981; Teddy and Kulesa, 2004). Finally, the maintenance of stringent cell–cell adhesions can lead to partial or complete silencing of migration activity in cells inside a group yet supports cytoskeletal activity at outward edges or at basal cell–substrate contacts. The resulting collective migration occurs in the form of multicellular tubes, strands, irregularly shaped masses, or sheets (Vaughan and Trinkaus, 1966; Friedl et al., 1995; Farooqui and Fenteany, 2005).Most migration modes, although they can be observed in (mostly experimental) 2D environments, occur in vivo in the context of 3D tissue environments (Even-Ram and Yamada, 2005). Conversely, in vivo, some migration modes are dedicated exclusively to 2D environments. Epithelial keratocytes and keratinocytes migrate across flat 2D substrate using rapid spread-out cell gliding (Keren et al., 2008) that, if cell–cell junctions between the cells remain intact, form a collectively migrating 2D cell sheet (Vaughan and Trinkaus, 1966; Farooqui and Fenteany, 2005). In different cell types, these modes of migration are associated with different efficiencies yielding varying migration speeds, such as the fast migratory scanning of single leukocytes, the relatively slow invasive migration of fibroblasts into provisorial wound matrix, or, at the slowest end, the collective migration during organ formation (Friedl et al., 1998b).Single-cell and collective migration modes serve mutually exclusive purposes during morphogenesis, tissue regeneration, and in pathological conditions. Collective cell migration is essential in building, shaping, and remodeling complex tissues and tissue compartments, such as epithelia, ducts, glands, and vessels, but also contributes to cancer progression by local invasion (Alexander et al., 2008; Friedl and Gilmour, 2009). In contrast, single-cell migration allows cells either to cover local distances and integrate into tissues, such as neural crest cell migration, or to move from one location in the body to another and fulfill effector functions, such as immune cell trafficking (Friedl, 2004; Teddy and Kulesa, 2004; Lämmermann and Sixt, 2009). The latter process is recapitulated during cancer metastasis to distant sites (Thiery, 2002). Although not all molecular determinants of each migration mode are fully understood, some key parameters have been identified as “checkpoints” to either maintain a given migration type, or, by an increase or decrease of activity, initiate transitions.
Introduction
Cell migration is a complex and heterogeneous process executed by all nucleated cell types at a given time window of their development. For most cells, including epithelial, stromal, and neuronal cells, migration phases are confined to morphogenesis and cease with terminal differentiation toward intact tissue to become reactivated only for tissue regeneration or neoplastic processes. For other cell types, such as leukocytes, migration is integral to their function and maintained throughout their life span. Some cell types migrate only in the context of a defined substrate, such as epithelial cells moving along a basement membrane but not through interstitial tissues, whereas other cell types, including leukocytes, are versatile, as they interact with and migrate within virtually any substrate present in the body. Thus, although the same basic process is executed (i.e., cell translocation along or through tissue structures), each cell type exerts migration in different contexts using distinct molecular repertoires and extracellular guidance cues. We here summarize extra- and intracellular molecular parameters that regulate cell migration and integrate them into a parameter “matrix” to better classify how cell migration modes are being both achieved and modulated.The modes of cell migration
The mode of cell migration was originally classified based on the morphology of migration patterns. This terminology was then extended to include molecular parameters, such as cytoskeletal organization, the type of cell–matrix interaction and force generation, and the modification of the tissue structure imposed by migrating cells (Friedl et al., 1998b; Thiery, 2002; Friedl, 2004; Lämmermann and Sixt, 2009; Sanz-Moreno and Marshall, 2009). As main categories, cell move either individually (amoeboid or mesenchymal) or collectively (the migration of cohesive multicellular units; Fig. 1 and Friedl, 2004). Although these terms are arguably arbitrary and the molecular discrimination between the certain modes is incomplete, they help to simplify and categorize an otherwise diffuse literature and allow dissection of the molecular machineries underlying each mode.Open in a separate windowFigure 1.Cell morphologies, migration modes, and transitions. The nomenclature of interstitial migration modes is based on typical cell morphology (rounded or spindle-shaped) and pattern (individual, loosely connected, or collective). Each migration mode is governed by a set of molecular mechanisms (see details in Fig. 2), the regulation of which can change the style of migration. Most widely studied examples for alterations of migration mode are the mesenchymal-to-amoeboid transition or the collective-to-individual transition. The thick gray arrows indicate the direction of migration.Table I.
Different migration modes and selected determinantsMigration mode | Cell types | ECM determinants | Cell determinants | Related transitions | References |
Single | |||||
Amoeboid, blebby | Zebrafish macrophage, some stem cells | Poorly adhesive; soft embryonic connective tissue; obligate 3D | Asymmetric bleb-rich cortical actomyosin cytoskeleton, low polarity; low migration speed (below 1 µm/min) | Blebby-to-pseudopodal transitions | Blaser et al., 2006; Yoshida and Soldati, 2006 |
Amoeboid, pseudopodal | Leukocytes, including dendritic cells; Dictyostelium discoideum | Loose primordial or mature connective tissue; 2D or 3D | Poorly adhesive, no formation of focal adhesions; Rac-driven anterior protrusion with counterbalance by Rho/ROCK in other cell parts; relatively rapid migration (10 µm/min) | Amoeboid-to-mesenchymal transition | Yoshida and Soldati, 2006; Lämmermann et al., 2008 |
Mesenchymal | Fibroblasts, neural crest cells, sarcoma cells, dedifferentiated cancer cells of different origin | Loose or dense primordial or mature connective tissue; usually associated with fibrin or collagen remodeling | Moderately to highly adhesive; focal interactions with ECM; high contractility; high anterior Rac activity counterbalanced by Rho in other cell parts; slow migration (0.1–1 µm/min) | Mesenchymal-to-amoeboid transition; mesenchymal-to-epithelial/collective transition | Wolf et al., 2003a, 2007; Grinnell, 2008; Paňková et al., 2009; Thiery, 2002 |
Multicellular | |||||
Chain migration, cell streaming | Neural crest cells, fibroblasts | Joint ECM tracks? | Individual cells with temporary tiplike cell-cell contacts | Migration arrest and integration into terminal tissue | Davis and Trinkaus, 1981; Kulesa and Fraser, 2000 |
Collective | Dictyostelium at slug stage, lateral line (zebrafish), border cells (Drosophila egg chamber), sprouting vessels, many epithelial and other cancer types | Any 2D and 3D ECM environment, resulting in cohesive sheets or 3D strands, tubes, clusters or amorphous masses | Intact and stable cell–cell adhesions; coordination of multicellular leading edge protrusion and rear retraction; cell–cell communication during migration | Collective-to-single cell transitions (epithelial/collective-to-mesenchymal; collective-to-amoeboid) | Hegerfeldt et al., 2002; Thiery, 2002; Alexander et al., 2008; Friedl and Gilmour, 2009 |
Keratocyte-like | Keratinocytes | Obligate 2D surface or tissue | Persistent gliding-type migration of spread-out cells with broad continuous leading lamella cadherin-based cell–cell junctions | Not known | Keren et al., 2008 |
Determinants of cell migration
The common process underlying all migration modes of nucleated mammalian cells is polarized actomyosin-driven shape change of the cell body (Lauffenburger and Horwitz, 1996; Ridley et al., 2003; Keren et al., 2008). This basic program is regulated and “shaped” by several distinct yet interdependent physical and molecular parameters of the tissue and the cell itself that together determine how a cell migrates (Fig. 2). The extracellular environment strongly impacts migration type and efficiency by providing ECM ligands of different macromolecular and structural organization, which includes dimension, density, stiffness, and orientation. In response to environmental determinants, the actomyosin cytoskeleton adapts in a dynamic manner and generates different geometries in space and time, ranging from flat and spread out to roundish, elongated, or multipolar shapes (Grinnell, 2008; Keren et al., 2008). To transmit actomyosin-driven forces to surrounding tissue structures, the cell either develops actin-polymerization–driven protrusions that bind to adhesion sites of the tissue through adhesion receptors (Yamada et al., 2003), or it utilizes poorly adhesive intercalation and propulsion (Paluch et al., 2006a). In both cases, subsequent to leading edge protrusion, actomyosin contraction leads to retraction of the cell rear and translocation of the cell body (Paluch et al., 2006a; Lämmermann and Sixt, 2009). The cyclic repetition of protrusion, interaction with the extracellular environment, and retraction of the cell rear result in cell movement that, depending on the molecular repertoire of the cell, yields distinct migratory modes (Lauffenburger and Horwitz, 1996; Friedl and Wolf, 2009). Additional parameters impacting the type and efficiency of cell migration are the availability of surface proteases that remodel the surrounding tissue (Wolf and Friedl, 2009), and whether the cells retain stringent, loose, or no cell–cell junctions (Friedl and Gilmour, 2009).Open in a separate windowFigure 2.The tuning model of cell migration. An integrated multiscale model to combine multiple interdependent parameters that impact migration mode. Each parameter is experimentally testable individually; however, in most cases they are interconnected with others (see text for details). Approximated parameter profiles of selected migration modes are indicated (colored lines). Modulation by increasing or decreasing the magnitude of any parameter may impact the resulting migration mode as well as the input strength of coregulated parameters. The format of the tuning model mimics the popular display of a graphic equalizer, which is integral to modern media display programs (e.g., Windows Media Player or QuickTime); the graphic interface serves to adjust the intensity of different wavelengths of the phono output independently to modify the sound profile.ECM determinants
The ECM provides a structural and molecular frame for the moving cell body and thereby impacts the mode and efficiency of cell migration.ECM dimension.
Extracellular tissue structures encountered by migrating cells are either flat 2D sheets or 3D tissue networks. Cell migration across 2D surfaces occurs during reepithelialization of wounds or the scanning of leukocytes along the inner blood vessel wall or inner epithelial surfaces (Farooqui and Fenteany, 2005). Hallmarks of 2D migration are the requirement of unilateral adhesion to the substrate, which provides stable-enough but transient attachment; a flattened, spread-out cell morphology guided by a leading lamellipod; and, due to the flat geometry of the substrate, a largely barrier-free migration (Ridley et al., 2003; Farooqui and Fenteany, 2005; Keren et al., 2008; Vitorino and Meyer, 2008). In contrast, when cells move through 3D interstitial tissue consisting of a network of interwoven collagen fibers, which impose space limitations against the moving cell body, their morphology undergoes characteristic changes. First, spread-out morphology is abandoned in favor of a spindle-like shape; second, instead of lamellipodia formation, with its unilateral polarization to the underlying substrate, leading edge protrusion occurs by formation of thin tiplike cylindrical pseudopodia that orient in three dimensions; and third, the cell either deforms its shape to accommodate small tissue gaps or executes remodeling of the ECM structure by pericellular proteolysis (Maaser et al., 1999; Wolf et al., 2003a; Jiang and Grinnell, 2005).ECM density and gap size.
In vivo, interstitial tissues greatly vary in structural organization, such as collagen content, fibrillar texture, fiber bundle thickness, and interfiber porosity. In vivo, migration efficiency is optimal at pore diameters that match or range slightly below the diameter of polarized cells. If the tissue gaps exceed the cell size, migration rates decrease (Haston et al., 1982; Harley et al., 2008) because of a loss of most cell–fiber interactions until only very few or even a single fiber remain engaged with the cell body; the latter is termed “1D” migration (Doyle et al., 2009). Conversely, if pores range below the cell diameter, cells slow down and eventually may become trapped due to the physical hindrance (unpublished data; Haston et al., 1982; Harley et al., 2008). In response to extracellular confinement, migrating cells elongate to a spindle-like shape and thereby stretch and reduce their cell diameter, whereas large pore sizes favor cell rounding, a hallmark of amoeboid migration (unpublished data; Fig. 2).The deformability of the cell and its most rigid compartment, the nucleus, is controlled by nuclear lamins A/C, which mechanically stabilize the nuclear membrane and potentially impact the minimum tissue gaps that can be transmigrated (Lammerding et al., 2006; Dahl et al., 2008). Besides shape adaptation, cells that can proteolytically cleave ECM structures counteract physical hindrance by enlarging pores and forming trails of variable caliber so they match their own diameters (Wolf et al., 2007). Thus, the ability of the cell to deform relative to the available space and to remodel tissues through proteolysis determines both the mode and efficiency of migration in 3D ECM.Stiffness.
ECM stiffness (synonymous with rigidity) or elasticity (synonymous with pliability), which can be measured as elastic modulus, depends on molecular properties of the tissue, including collagen content, fiber thickness, and the extent of intrafibrillar cross-links, which define the stability and deformability of the tissue scaffold (Shoulders and Raines, 2009). Cells detect matrix rigidity via integrin-mediated adhesions and downstream mechanosensor protein signaling (i.e., via talin and p130CAS; Giannone and Sheetz, 2006). Increased substrate stiffness reinforces cell protrusions at outward edges so that focal adhesions form and become reinforced by RhoA-mediated actomyosin contraction, ultimately leading to cell spreading, the generation of high-traction force, and elongated cell movement (Peyton et al., 2008; Ulrich et al., 2009). Conversely, soft matrix does not reinforce focal adhesion formation and cytoskeletal contractility; rather, it supports cell rounding (Ulrich et al., 2009). Consequently, matrix rigidity stimulates directed cell migration, similar to chemotaxis, so that cells tend to migrate toward substrate of greater stiffness, a process termed durotaxis (Lo et al., 2000; Li et al., 2005; Isenberg et al., 2009).Orientation.
Connective tissue comprises a range of physical textures, ranging from loose and random to highly aligned structures (Petrie et al., 2009; Wolf et al., 2009). All mobile cells show a tendency to align in parallel along oriented structural discontinuities, such as at interfaces of muscle fibers, blood vessels, or ECM fiber strands and patterns created by the cells themselves (Provenzano et al., 2008; Petrie et al., 2009). Contact guidance along such structures is mediated by mechanosensory integrins that, together with Rho/ROCK-mediated cytoskeletal stiffening, provide directional persistence (Dickinson et al., 1994; Provenzano et al., 2008; Petrie et al., 2009). Although aligned fiber orientation in collagen-rich ECM does not seemingly impact cell shape (Provenzano et al., 2008), it favors multicellular streaming in chainlike patterns in 3D tissue (Friedl and Wolf, 2009) and migration of 2D cell sheets along tissue clefts (unpublished data).In summary, different ECM environments provide an array of interconnected input parameters that modulate cell adhesion and cytoskeletal organization, and directly impact cell shape, guidance, and mode of migration.Cell determinants
Cell–cell adhesion.
A key determinant of how cells move is whether cell–cell junctions are retained or not, resulting in either collective or single-cell migration, respectively (Vitorino and Meyer, 2008; Friedl and Gilmour, 2009). Cell–cell adhesion is mainly mediated by cadherins, including E-cadherin in epithelial cells, VE-cadherin in endothelial cells, and N-cadherin in stromal cells (Ewald et al., 2008; Vitorino and Meyer, 2008; Friedl and Gilmour, 2009). As opposed to individually migrating cells, during collective migration, the rear of the front cell retains intact cell–cell junctions to the successor cell, thereby mechanically holding the cells together and augmenting the efficiency of paracrine cell–cell signaling and multicellular coordination (Fig. 1). Coordinated cycles of protrusion and rear retraction of the front cells as well as of cells inside the group that engage with underlying substrate lead to movement as a multicellular unit (Farooqui and Fenteany, 2005; Blanchard et al., 2009). If cell–cell junctions are intermittent or less stable, multicellular streaming in a loose tail-to-head fashion results in the coordinated but individual migration of many cells through the tissue, with repetitive short-lived contacts between cells that are resolved and reestablished upon further migration (Fig. 1; Teddy and Kulesa, 2004). Lastly, if cell–cell contacts are absent, cells move independently in both speed and direction (Hegerfeldt et al., 2002). Thus, the presence of stable or transient cell–cell junctions, or their absence, determines whether collective translocation, cell streaming, or single-cell migration, respectively, is being generated.Cell–matrix adhesion.
Cell adhesions to ECM ligands are predominantly generated by integrins via coupling to cytoskeletal and signaling proteins. The strength and turnover rates of cell attachments to the extracellular environment determine which cell shapes and forces are being generated during migration (Ridley et al., 2003). Distinct cell types use adhesive strength over different magnitudes, ranging from strong adhesion by stromal fibroblasts or myoblasts (Huttenlocher et al., 1996), to moderate adhesion of epithelial and endothelial cells (Zhang et al., 2006; Schober et al., 2007), to weak adhesion forces of rapidly gliding fish keratocytes and crawling leukocytes (Friedl et al., 1998b; Keren et al., 2008; Lämmermann et al., 2008). High integrin expression levels are mandatory for high-attachment forces, but are also associated with relatively slow turnover of adhesion sites (Friedl et al., 1998b; Mc Henry et al., 2008) and, consequently, associated with slow migration (Palecek et al., 1997). As an underlying mechanism, integrins and downstream mechanotransducing adaptors, such as p130CAS, become activated with increased mechanical tension and, in turn, further strengthen focal adhesions and actin stress fiber formation (Tamada et al., 2004; Sawada et al., 2006). Strong cell–substrate adhesions thus promote cell contractility and the formation of elongated spread-out (2D) or spindle-shaped (3D) morphologies in many cell types, including fibroblasts, smooth muscle cells, and neoplastic cells (Lauffenburger and Horwitz, 1996; Friedl et al., 1998b; Maaser et al., 1999; Jiang and Grinnell, 2005).If cell adhesion is reduced to a moderate or low level, such as by interfering with the integrin-talin axis, focal adhesions and stress fibers do not form or do not reach full maturation (Zhang et al., 2008). As a consequence, the cells convert to a less elongated or spread-out morphology, generate smaller lamellipodia and pseudopodia, and transmit limited adhesion strength toward the substrate (Zhang et al., 2008). Rapidly moving lymphocytes and neutrophils that still adhere to ECM and other ligands but do not form focal adhesions or stress fibers constitutively use the pseudopodal amoeboid type of movement (Friedl et al., 1998a; Smith et al., 2007).At the very low end of cell adhesion strength, cells are unable to form unilateral attachments to 2D ECM substrate and thus fail to spread out, form lamellipodia, and move, whereas in a 3D environment, they move by amoeboid blebbing or dendritic intercalation (Haston et al., 1982; Fackler and Grosse, 2008; Lämmermann and Sixt, 2009). Given such low adhesion capability, the mechanisms that generate force in this blebby (or dendritic) amoeboid translocation remain to be shown. Likely, the irregular cell shape maintained by cortical actin provides high cytoskeletal rigidity locally, which allows mechanical intercalation between anterior parts of the cell with the surrounding tissue while the rear part of the cell retracts (Blaser et al., 2006; Paluch et al., 2006a; Lämmermann and Sixt, 2009).Cell protrusion and rounding.
Cell protrusions control leading edge dynamics and the migration mode in at least two distinct ways. First, the protrusion of pseudopodia, filopodia, and lamellipodia that adhere to cell and ECM substrates is directed by the small GTPases Rac and Cdc42 (Nobes and Hall, 1999; Sanz-Moreno and Marshall, 2009). Consequently, high Rac activity conveys leading edge extension, elongated morphology, focal integrin engagement, and mesenchymal migration (Nobes and Hall, 1999; Sahai and Marshall, 2003; Sanz-Moreno et al., 2008). Second, bleb-like protrusions that contain cortical actin filaments are nonadhesive or poorly adhesive but contribute to lateral anchoring (“elbowing”) of the cell to tissue structures during actomyosin-mediated rear retraction (Paluch et al., 2006a,b; Fackler and Grosse, 2008). In most cells, Rac-mediated protrusion of the leading edge is counterbalanced by Rho/ROCK signaling, which controls actomyosin-mediated retraction of the trailing edge. Together, they form a cyclic balance in distinct regions of the cell and contribute, concurrently, to the migration cycle (Ridley et al., 2003; Sanz-Moreno and Marshall, 2009). High Rac activity generates cell elongation and mesenchymal migration, whereas active Rho in the presence of little or no Rac activity supports rounded cell shapes associated with amoeboid pseudopodal or blebbing migration, respectively (Sahai and Marshall, 2003; Sanz-Moreno et al., 2008). Besides inducing cell protrusions, active Rac negatively regulates Rho/ROCK signaling and inhibits cell rounding, whereas active Rho/ROCK limits Rac, which inhibits cell extension and elongation (Sanz-Moreno et al., 2008).The formation and elongation of cell protrusions during migration are further controlled by tubulins. Posttranslational tubulin acetylation supports high microtubule stability and is associated with mesenchymal movement, whereas microtubules composed of deacetylated tubulin are subject to enhanced depolymerization by the microtubule-destabilizing factor stathmin and therefore support a rounded, amoeboid migration mode (Piperno et al., 1987; Belletti et al., 2008; Berton et al., 2009). Whether tubulin stability dictates cell shape by modulating to the balance between Rac and Rho activity or by other mechanisms, such as delivery of cargo or a direct mechanical function, is unknown.Mode of force generation.
The force required to move a cell body forward is generated by two principal and often interdependent physical mechanisms: cell propulsion, which leads to forward pushing of the cell body; or traction force generated by pulling of an ECM substrate. A phase of actin polymerization–driven forward pushing of the plasma membrane is indispensible for leading edge protrusion, so it is included in most migration types (Lauffenburger and Horwitz, 1996). In adhesive cells, pushing then leads to local adhesion, cytoskeletal anchorage, and, in a second phase, focal adhesion maturation and pulling on ECM substrate by actomyosin contraction (Ridley et al., 2003; Zhang et al., 2008). Pulling is proportional to adhesion strength and cytoskeletal contractility, such as in fibroblasts and myoblasts, to generate forces sufficient for substrate contraction (Beningo et al., 2001; Miron-Mendoza et al., 2008). In contrast, if leading edge protrusion is coupled to low adhesion force, amoeboid pseudopodal migration occurs at very low traction force, as in moving neutrophils (Smith et al., 2007; Wang, Y.-L., personal communication). On the very low end of adhesion and force generation, amoeboid blebbing cells tend to lack any attachment to 2D surfaces but rather float and oscillate on the spot (unpublished data; Paluch et al., 2006a). However, if included in a loose 3D ECM, such as a collagen matrix or matrigel, blebby cells that are deficient in pseudopodia or filopodia are still able to connect to the 3D substrate and generate movement, despite negligible attachment forces (Blaser et al., 2006; Sanz-Moreno et al., 2008). Thus, whereas mesenchymal migration depends on alternating pushing/pulling cycles, amoeboid migration is mechanically equally complex and comprises stronger pushing combined with a small or completely absent phase of adhesive pulling of the substrate.Protease functions.
Depending on the deformability of the migrating cell and the size of gaps and trails available in the 3D tissue, cells proteolytically remodel surrounding ECM and generate gaps, a hallmark of mesenchymal migration; otherwise, they move without engaging proteases by filling available spaces with their cell body (Friedl and Wolf, 2003a, 2009). In interstitial tissues, MT1-MMP is rate-limiting for collagen degradation, as it executes pericellular proteolysis of collagen fibers that physically impede the moving cell (Wolf et al., 2007; Sabeh et al., 2009). After cleavage, collagen fibers become displaced and realigned, which generates tubelike matrix gaps and trails of least resistance (Friedl and Wolf, 2008). In collagen-rich interstitial tissue, MT1-MMP is further involved in the remodeling of already existing trails to even larger macrotracks, which then accommodate the collective invasion of multicellular strands (Wolf et al., 2007).In contrast to mesenchymal cells that are usually large, smaller amoeboid leukocytes employ much faster movement that lacks signs of pericellular proteolysis of the 3D interstitial substrate (Friedl and Wolf, 2003a). A mechanism of coping with narrow trails is cell deformation and squeezing through the pores so that extracellular structures imprint into the cell body and form local zones of cell compression (Wolf et al., 2003b). If tissue densities are high, such as in basement membranes or dense connective tissue, inhibition of pericellular proteolysis cannot be compensated by shape change; instead, cell bodies get stuck in narrow pores (Sabeh et al., 2004, 2009). Likewise, if proteolytic macropatterning is prevented by protease inhibition, collective cell invasion is ablated and only individual amoeboid dissemination persists (Wolf et al., 2007). Thus, proteolytic ECM remodeling is obligatory in tissues in which cell caliber and deformability fail to match available gaps and trails.The tuning model
Because of its physical and molecular modularity, cell migration must be viewed as a consequence of a continuum of states that are determined by cell mechanics and signaling events. These cellular properties are integrated by the cell or cell groups in a given tissue environment. The tuning model predicts that several parameters simultaneously control how a cell migrates and that their combined magnitudes impact which migration type a cell adopts (Fig. 2). With the exception of ECM dimension, which is either 2D or 3D, all other parameters are scalar; i.e., they can be absent or at low, intermediate, or high levels. Therefore, these parameters are assumed to be tunable and thereby control the migration mode and efficiency in a continuous rather than a discrete “on” or “off” manner. By increasing or decreasing their input, they “tune” how moving cells polarize and engage with encountered tissue substrate. Because all parameters act concurrently but at a different strength, each parameter profile (Fig. 2, colored lines) then generates a different type of migration. Whereas most molecular studies tend to address isolated parameters, the tuning model integrates several denominators in context and may help to understand cell migration as a multimodal cell function.Each component, although experimentally amenable as an individual parameter, is interdependent and positively or negatively coregulated with other determinants. The density of fibrillar ECM is positively interconnected with stiffness and inversely proportional to pore size, so alterations of either parameter impacts the overall tissue geometry (unpublished data). Accordingly, integrin-mediated cell attachment to a deformable yet rigid substrate, but not to a soft substrate, enhances substrate tension and stiffness, which reinforces Rho-mediated traction force generation (Paszek et al., 2005; Peyton et al., 2008; Ulrich et al., 2009). Likewise, traction force generation requires sufficient adhesion mediated by integrins, some Rac-mediated protrusion, and Rho-mediated cytoskeletal contraction (Rhee and Grinnell, 2006). The physical tissue geometry is interdependent with protease acitivity of the cells; consequently, collective migration in 3D tissue depends on sufficiently high a priori porosity or the cell-mediated proteolytic generation of macrotracks (Wolf et al., 2007). Therefore, alteration of a given parameter has likely consequences for other interconnected determinants.Plasticity: tuning the mode of migration
At a given differentiation state, each cell type preferentially employs a particular “default” migration type, such as leukocytes using amoeboid migration, stromal cells moving by a mesenchymal mode, or epithelial cell sheets moving collectively (Friedl, 2004). However, in recent years, it has become clear that naturally occurring or experimentally induced modifications of either the environment or cell properties may result in striking adaptation reactions that alter the migration mode rather than abrogating migration per se. Because any parameter may become altered in the course of migration—such as the transition from dense to loose connective tissue, modulation of adhesion receptor expression, or the availability of cytoskeletal adaptor proteins due to altered gene expression—each alteration of parameter may prompt such secondary alteration of migration mode.Because cell–cell junctions can form de novo and resolve again, individual and collective migration modes are interconvertible (Friedl and Gilmour, 2009). If multicellular cohesion is weakened by the down-modulation of cell–cell junctions, individual cells detach from the multicellular unit which, dependent on the molecular repertoire and environment encountered, disseminate individually. Epithelial-to-mesenchymal transition is involved in many developmental processes and in invasive cancers, and leads to the delamination of spindle-shaped cells that use integrin-mediated force generation for tissue invasion either as single cells or by multicellular streaming (Thiery, 2002; Carmona-Fontaine et al., 2008). Collective-to-amoeboid transition occurs when the detached individual cells disseminate using amoeboid migration (Hegerfeldt et al., 2002; Wolf et al., 2007). Conversely, if individually moving cells up-regulate cell–cell adhesion molecules, then cell aggregation leads to individual-to-collective transition (Thiery, 2002).A central pathway controlling the interconversion between mesenchymal and rounded, amoeboid migration is the balance between Rac and Rho signaling (Sahai and Marshall, 2003). In many experimental examples, mesenchymal-to-amoeboid transitions depend, directly or indirectly, on pathways that weaken Rac and/or strengthen Rho/ROCK signaling (Sanz-Moreno et al., 2008; Paňková et al., 2009; Sanz-Moreno and Marshall, 2009). Thus, upstream pathways that suppress Rac activity induce this conversion, including the activation of the GTPase-activating protein (GAP) ARHGAP22, which directly inhibits Rac (Sanz-Moreno et al., 2008); inhibition of the Rac-activating guanine nucleotide exchange factor DOCK3/NEDD9 or of the down-stream Rac effector and Rho inhibitor WAVE-II (Sanz-Moreno et al., 2008); interference with Rab5-mediated endocytosis and recycling of Rac to cell protrusions (Palamidessi et al., 2008); and the inhibition of E3 ubiquitin ligase Smurf1, which enzymatically degrades Rho near the leading edge and thereby secures the dominance of Rac in cell protrusions (Sahai et al., 2007). Likewise, inhibition of chemokine-meditated Rac activation favors amoeboid movement in otherwise mesenchymal cells (Gérard et al., 2007). Pathways that activate Rho lead to mesenchymal-to-amoeboid transition, including inhibition of negative Rho regulators (e.g., p90RhoGAP) through an indirect, reactive oxygen species-dependent mechanism (Nimnual et al., 2003) or the activation of Ephrin2A receptor tyrosine kinase signaling, which indirectly activates Rho (Parri et al., 2009).Alteration of adhesion force by modulating integrin function leads to similar plasticity. The transition from amoeboid myeloid precursor cells to adhesive elongated and contractile macrophages is initiated by the up-regulation and activation of β1, β2, and β3 integrins (McNally and Anderson, 2002). Conversely, mesenchymal cells convert to amoeboid movement in experimental 3D matrices after limiting pathways that control focal adhesion formation, including inhibition of β1 integrin–mediated adhesion or of the tyrosine kinase cSrc (Carragher et al., 2006; Zaman et al., 2006). Plasticity imposed by altered tissue architecture occurs when cells transit from a 2D interface into 3D tissue. The initial spread-out or cuboidal 2D phenotype then converts toward a spindle-shaped mesenchymal phenotype with vertical penetration and migration into the 3D matrix (Alt-Holland et al., 2008). Lastly, in loose interstitial tissues with gaps that accommodate the cell body, the inhibition of surface protease activity causes a transition from protease-dependent mesenchymal migration to amoeboid migration involving shape change and squeezing without tissue remodeling (Wolf et al., 2003a, 2007).Thus, alterations of cell–cell and cell–matrix adhesion, cytoskeletal signaling and mechanics, and protease function determine whether and how cells switch between distinct migration modes. These transitions of migration mode are best studied for cancer cells and likely contribute to the metastatic cascade (Friedl and Wolf, 2003b; Sanz-Moreno and Marshall, 2009), yet they are also relevant to cell migration and function in physiological contexts, such as the delamination of cells during morphogenesis and the distribution of stem cells or leukocytes in tissues and organs (Blaser et al., 2006; Lämmermann and Sixt, 2009).Outlook
The multiparameter tuning model integrates observations from many different cell types and experimental models. The model thus may be helpful to understand and experimentally test the adaptability of cell movement and its consequence for tissue formation and remodeling, particularly in morphogenesis and cancer metastasis. The model may further be a useful starting point for computational modeling of cell migration in different contexts. Although the parameters and migration modes discussed here are best established for interstitial migration of cells in fibrillar collagen-rich tissues, they likely fail to sufficiently represent the movement of other cell types and tissue contexts. This may be the case particularly for cells of neural origin that predominantly move along scaffold tracks formed by other cells, rather than ECM, or cell trafficking across basement membrane during transendothelial migration or the early invasion of epithelial cancer. Likewise, complex movements in ductal gland or vessel formation represent special cases with complex topography, such as lumen formation and deposition of a basement membrane, which may require the inclusion of additional modules. Besides integrin-mediated adhesion structures, special cases of cell–substrate interaction include cadherin- or ephrin-based cell–cell junctions that guide cell migration along cell scaffolds, and podosomes and invadopodia that degrade ECM underneath the cell body but not at leading edges. The contribution of these structures to force generation and the mode of migration remain to be established and, potentially, included in the model. Ultimately, although each parameter has its own contribution to how efficiently cells migrate, the model still lacks prioritization; that is, the importance of each input parameter relative to others still remains undefined. Therefore, future wet-laboratory and computational studies will not only have to integrate additional or exclude existing determinants for special migration modes and contexts, but they also should take coregulated synergistic or antagonistic multiparameter modules into account. 相似文献17.
Proteolysis and cell migration: creating a path? 总被引:32,自引:0,他引:32
Both serine and metalloproteinases have been implicated in the complex integrated events underlying cell migration but no definitive single mechanism has emerged. Work over the past two years linking both membrane and soluble proteinases with integrins and other adhesion proteins and with intracellular signalling systems could herald the beginnings of a potential expansion of our understanding of the role and regulation of proteolysis in cell migration. 相似文献
18.
Martinov MV Vitvitsky VM Mosharov EV Banerjee R Ataullakhanov FI 《Journal of theoretical biology》2000,204(4):521-532
We propose a simple mathematical model of liver S -adenosylmethionine (AdoMet) metabolism. Analysis of the model has shown that AdoMet metabolism can operate under two different modes. The first, with low metabolic rate and low AdoMet concentration, serves predominantly to supply the cell with AdoMet, the substrate for various cellular methylation reactions. The second, with high metabolic rate and high AdoMet concentration, provides an avenue for cleavage of excess methionine and can serve as a source of cysteine when its increased synthesis is necessary. The switch that triggers interconversion between the "low" and "high" modes is methionine concentration. Under a certain set of parameters both modes may coexist. This behavior results from the kinetic properties of (i) the two isoenzymes of AdoMet synthetase, MATI and MATIII, that catalyse AdoMet production; one is inhibited by AdoMet, whereas the other is activated by it, and (ii) glycine- N -methyltransferase that displays highly cooperative kinetics that is different from that of other AdoMet-dependent methyltransferases. Thus, the model provides an explanation for how different cellular needs are met by regulation of this pathway. The model also correctly identifies a critical role for glycine N -methyltransferase in depleting excess methionine in the high mode, thus avoiding the toxicity associated with elevated levels of this essential amino acid. 相似文献
19.
NELIN, a new F-actin associated protein, stimulates HeLa cell migration and adhesion 总被引:1,自引:0,他引:1
Wang W Zhang W Han Y Chen J Wang Y Zhang Z Hui R 《Biochemical and biophysical research communications》2005,330(4):1127-1131
A new gene (GenBank Accession No. AF114264) was cloned from umbilical vein wall tissue by using RT-PCR. The gene shares high similarity to the gene encoding F-actin binding protein nexilin, so named as NELIN. A clone of 2737bp contains open reading frame of 1344bp extending from 412 to 1755. NELIN was expressed primarily in the heart and skeletal muscle among eight tested normal tissues. Immunofluorescence and immunoprecipitation demonstrated that NELIN product was associated with F-actin. Stable transfection of NELIN into HeLa cells increased the cell migration by 2.17-fold and the adhesion by 1.67-fold, respectively, compared to cells with the empty vector (P<0.05). The results support that NELIN product is an F-actin associated protein and mediates cell motility. 相似文献
20.