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PubMed1998

Integrins, cell matrix interactions and cell migration strategies: fundamental differences in leukocytes and tumor cells.

The principles determining the migration of different cell types may results from their differences in origin, size and shape, function of adhesion receptors, and environmental factors, including the extracellular matrix. Polarized leukocytes (T lymphocytes and dendritic cells) migrating in three-dimensional collagen lattices are small developing a highly dynamic leading edge and a trailing uropod, whereas invasive melanoma cells are larger, highly polarized and less dynamic. In contrast to leukocyte, tumor cells may additionally develop migrating cell clusters maintaining intense cell-cell interaction and cluster polarity. Leukocytes show a speed-oriented, oscillating and directionally unpredictable path profile strongly guided by matrix fibers, while melanoma cells and migrating cell clusters exhibit slow yet highly directional migration. Whereas leukocytes form short-lived interactions with collagen fibers in complete absence of tissue remodeling, melanoma cells and neoplastic cell clusters reorganize the matrix via profound pulling at attachment sites, limited fiber disruption upon detachment, and the shedding of cell surface determinants. Using blocking anti-integrin antibodies, tumor cell migration and migration-associated matrix reorganization were shown to be dependent on beta 1 integrin-mediated adhesion, whereas migrating T cells cannot be inhibited by a panel of anti-beta 1-, beta 2-, beta 3-, and alpha-integrin antibodies, either alone or in combination. Consequently, migrating melanoma cells use focal adhesions of integrins coclustered with cytoskeletal components at contacts with collagen fibers. T cells, however, lack typical focal adhesions, redistribute beta 1 integrins to the uropod and the focal adhesion kinase to the leading edge. In conclusion, an adhesion-dependent and reorganizing migration type employed by melanoma cells may be distinct from largely integrin-independent and non-reorganizing migration strategies used by leukocytes.

Cell Movement↗

PubMed1998

Deconstructing (and reconstructing) cell migration.

An overriding objective in cell biology is to be able to relate properties of particular molecular components to cell behavioral functions and even physiology. In the "traditional" mode of molecular cell biology, this objective has been tackled on a molecule-by-molecule basis, and in the "future" mode sometimes termed "functional genomics," it might be attacked in a high-throughput, parallel manner. Regardless of the manner of approach, the relationship between molecular-level properties and cell-level function is exceedingly difficult to elucidate because of the large number of relevant components involved, their high degree of interconnectedness, and the inescapable fact that they operate as physico-chemical entities-according to the laws of kinetics and mechanics-in space and time within the cell. Cell migration is a prominent representative example of such a cell behavioral function that requires increased understanding for both scientific and technological advance. This article presents a framework, derived from an engineering perspective regarding complex systems, intended to aid in developing improved understanding of how properties of molecular components influence the function of cell migration. That is, cell population migration behavior can be deconstructed as follows: first in terms of a mathematical model comprising cell population parameters (random motility, chemotaxis/haptotaxis, and chemokinesis/haptokinesis coefficients), which in turn depend on characteristics of individual cell paths that can be analyzed in terms of a mathematical model comprising individual cell parameters (translocation speed, directional persistence time, chemotactic/haptotactic index), which in turn depend on cell-level physical processes underlying motility (membrane extension and retraction, cell/substratum adhesion, cell contractile force, front-vs.-rear asymmetry), which in turn depend on molecular-level properties of the plethora of components involved in governance and regulation of these processes. Hence, the influence of any molecular component on cell population migration can be understood by reconstructing these relationships from the molecular level to the physical process level to the individual cell path level to the cell population distribution level. This approach requires combining experimental, theoretical, and computational methodologies from molecular biology, biochemistry, biophysics, and bioengineering.

Cell Count↗

PubMed2005

Analysis of Cell Migration in Caenorhabditis elegans.

This chapter is concerned with a method of analysis and quantification of cell migration defects in mutants of the nematode worm Caenorhabditis elegans. The method takes advantage of transgenic expression of the green fluorescent protein to visualize migrating cells. By following these protocols, one will be able to analyze cell migration defects in new mutant strains for comparison to wild-type and to other mutants. Techniques described include obtaining wild-type and mutant worm strains as well as strains harboring green fluorescent protein transgenes; maintenance and manipulation of C. elegans in the laboratory; introducing transgenes into different genetic backgrounds; mounting worms for fluorescence microscopy; and scoring and analysis of cell migration defects.

Animals↗

PubMed1980

Cell migration through three-dimensional gels of native collagen fibres: collagenolytic activity is not required for the migration of two permanent cell lines.

Three dimensional gels of native type I collagen fibres have been used as a substratum for the growth and migration of Chinese hamster ovary cells (fibroblastoid cell line) and RPMI-3460 melanoma cells (tumorigenic cell line from Syrian hamster). Quantitative data concerning the migration of these cells from the gel surface into the 3-dimensional collagen gel matrix have been obtained. The migration of both cell types into the collagen gel matrix is not accompanied by the degradation of collagen fibres. The possible implications of these observations for tumour cell invasion in vivo are discussed.

Animals↗

PubMed2000

[The effect of nordihydroguaiaretic acid on endothelial cell migration induced by glioma cells].

OBJECTIVE: To investigate the effect of nordihydroguaiaretic acid (NDGA) on the migration of endothelial cells (ECs) induced by glioma cells (GCs) in vitro. METHODS: Cells of human umbilical vein endothelial cell line ECV-304 and human malignant glioma cell line SHG-44 were co-cultured in the Falcon Cell Culture Insert system, and the effect of NDGA on the migration of ECs induced by GCs was investigated. The expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was examined with immunohistochemistry. RESULTS: The expressions of VEGF and bFGF in SHG-44 cells were reduced after treatment with 100 micromol/L NDGA for 1 to 3 days. 100 micromol/L NDGA significantly inhibited not only the chemotactic migration of ECs induced by either glioma cells or glioma-conditioned media, but also the random motility of ECs (P < 0.01). NDGA at a concentration between 50 micromol/L and 200 micromol/L inhibited the chemotactic migration of ECs in a dose-dependent manner (the inhibition ratios were 12.0%, 37.4%, 86.7% and 82.2%). CONCLUSION: The results confirm the inhibitory effects of NDGA on the migration and angiogenic factor expression of ECs, which suggests that NDGA may suppress angiogenesis of glioma.

Brain Neoplasms↗

PubMed2003

Effect of platelet releasate on bone cell migration and recruitment in vitro.

The use of platelets and platelet products has become increasingly popular clinically as a means of accelerating endosseous wound healing. It is likely that growth factors released by activated platelets at the site of injury play a role in bone regeneration by stimulating the migration and proliferation of bone cells. In this study, a novel in vitro assay was developed to study the effects of platelet releasate (PR) collected from activated platelet concentrate on rat bone marrow-derived cells. Cultures of primary rat bone marrow cells were overlaid with a fibrin matrix, and the number of cells migrating within the three-dimensional matrix and the leading front of migration were quantified. The addition of PR to the top of the fibrin gels at different time points caused a 25% increase in the leading front of migration and a 3.5-fold increase in the number of migrating cells. Platelet releasate was also shown to have a mitogenic effect on bone cells in proliferation studies. Comparison between migration and proliferation data indicated that PR stimulates the initial recruitment of bone marrow cells to migration. This assay further allowed the determination that rat bone marrow cells are capable of exerting contractile forces on fibrin matrices and that matrix contraction is directly related to the migratory activity of cells. The results provide a potential mechanism to explain why biologically active platelet-derived factors enhance endosseous wound healing.

Animals↗

PubMed1990

Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity.

Previously we reported that activated T lymphocytes express a heparanase enzyme that degrades the heparan sulfate moiety of the proteoglycan of the extracellular matrix (ECM). Expression of the heparanase enzyme was found to be associated with the ability of activated T lymphocytes to penetrate blood vessel walls and accumulate in target organs. We recently found that relatively low doses of heparin administered to mice or rats inhibited T cell-mediated immune reactions. In the present study we investigated the effects in vitro and in vivo of the heparanase inhibitor, heparin, on the expression of T lymphocyte heparanase and on the ability of T lymphocytes to mediate a delayed-type hypersensitivity (DTH) reaction. We found that heparanase was induced by immunizing mice with antigen in vivo or by activating T lymphocytes with concanavalin A in vitro. Relatively low doses of heparin administered once daily in vivo (5 micrograms) or present in vitro (0.1 microgram/ml) inhibited the expression of heparanase induced by immunization or by concanavalin A incubation. Higher or lower doses of heparin did not have these effects. The same doses of heparin that inhibited expression of heparanase also inhibited the ability of the lymph node cells to migrate to a site of antigen and adoptively produce a DTH reaction. These findings suggest that modulation of cell-mediated immune reactions may be achieved by relatively low doses of heparin which inhibit expression of T lymphocyte heparanase.

Animals↗

PubMed2006

CD4 expression on activated NK cells: ligation of CD4 induces cytokine expression and cell migration.

NK cells play an important role in the innate immune response. We have isolated NK cells from human lymphoid tissues and found that these cells express the CD4 molecule on their surface at levels higher than those found on peripheral blood NK cells. To study the functional role of the CD4 molecule on NK cells, we developed an in vitro system by which we are able to obtain robust CD4 expression on NK cells derived from blood. CD4+ NK cells efficiently mediate NK cell cytotoxicity, and CD4 expression does not appear to alter lytic function. CD4+ NK cells are more likely to produce the cytokines gamma-IFN and TNF-alpha than are CD4- NK cells. Ligation of CD4 further increases the number of NK cells producing these cytokines. NK cells expressing CD4 are also capable of migrating toward the CD4-specific chemotactic factor IL-16, providing another function for the CD4 molecule on NK cells. Thus, the CD4 molecule is present and functional on NK cells and plays a role in innate immune responses as a chemotactic receptor and by increasing cytokine production, in addition to its well-described function on T cells as a coreceptor for Ag responsive cell activation.

Binding Sites, Antibody↗

PubMed2004

Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo.

Endostatin is a proteolytic fragment of collagen XVIII that inhibits endothelial cell migration in vitro and experimental tumor growth in vivo. To determine how endostatin affects the in vivo behavior of endothelial cells, we took advantage of a surrogate model of human angiogenesis, in which human endothelial cells are transferred to immunodeficient mice and develop into complex vessels in the course of 30 days. Systemic delivery of human yeast-derived endostatin (serum levels of 30-35 ng/mL) inhibited the number of human vessels dramatically (95% at day 20), as most endothelial cells remained suspended as single cells. The fraction of cells with a migratory phenotype (F-actin-positive, extending pseudopods) was strongly reduced (from 50% to 13% at day 10), while the number of apoptotic and mitotic cells remained unchanged. Endostatin also hampered the recruitment of alpha-smooth muscle actin-expressing perivascular cells and thus reduced the number of mature vessels (from 64.3% to 28.6% at day 30). Moreover, transcripts of pericyte-recruiting platelet-derived growth factor-B (PDGFB) were strongly reduced in endothelial cells of endostatin-treated mice. Our results are strong evidence that endostatin inhibits angiogenesis at several levels in vivo, including perivascular cell recruitment.

Angiogenesis Inhibitors↗

PubMed2004

TAT-mediated protein transduction into human corneal epithelial cells: p15(INK4b) inhibits cell proliferation and stimulates cell migration.

PURPOSE: The cell cycle inhibitor p15(INK4b) has been localized in migrating corneal epithelial cells. In this study, TAT-fusion protein technology was used to transduce p15(INK4b) into human corneal epithelial cells to examine the effect on cell proliferation and migration. METHODS: Human p15(INK4b), obtained by RT-PCR, was cloned into a TAT-HA vector, and the fusion protein was purified from bacteria transformed with the TAT-HA-p15 construct. Various dilutions of TAT-HA-p15 were applied to primary human corneal epithelial cells to test potency. In addition, the effect of exposure time was examined. Cells were labeled with bromodeoxyuridine to detect proliferation, and indirect immunofluorescence was performed. Ki67 expression was also examined. To assay cell migration, human corneal epithelial cells were plated inside a cylinder and exposed to TAT-HA-p15. The cylinder was removed, the cells were allowed to spread for 2 days, and the area of cell coverage was calculated. TAT-HA-beta-galactosidase served as the control in all experiments. Finally, the extent of retinoblastoma protein phosphorylation was assayed by Western blot in cells cultured with and without TAT-HA-p15. RESULTS: TAT-HA-p15 was successfully transduced into primary human corneal epithelial cells. TAT-HA-p15 decreased proliferation in a concentration- and time-dependent manner. The migration assay showed that TAT-HA-p15 stimulated cell migration 1.8-fold. TAT-HA-beta-galactosidase had no effect on proliferation or migration. Finally, TAT-HA-p15 decreased the level of phosphorylated retinoblastoma protein by 4.9-fold. CONCLUSIONS: Active p15(INK4b) can be efficiently transduced into primary human corneal epithelial cells using TAT-fusion protein technology. p15(INK4b) appears to be sufficient to inhibit corneal epithelial cell proliferation and to stimulate cell migration.

Base Sequence↗

PubMed2006

Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary.

Cell migration contributes to normal development and homeostasis as well as to pathological processes such as inflammation and tumor metastasis. Previous genetic screens have revealed signaling pathways that govern follicle cell migrations in the Drosophila ovary, but few downstream targets of the critical transcriptional regulators have been identified. To characterize the gene expression profile of two migratory cell populations and identify Slbo targets, we purified border cells and centripetal cells expressing the mouse CD8 antigen and carried out whole-genome microarray analysis. Genes predicted to control actin dynamics and the endocytic and secretory pathways were overrepresented in the migratory cell transcriptome. Mutations in five genes, including ttk, failed to complement previously isolated mutations that cause cell migration defects in mosaic clones. Functional analysis revealed a role for the Notch-activating protease Kuzbanian in border cell migration and identified Tie as a guidance receptor for the border cells.

Animals↗

PubMed2005

Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration.

Endogenous neurotrophins positively and negatively regulate migration of premyelinating Schwann cells before the initiation of myelination. Neurotrophin-3 (NT3) acting through the TrkC receptor tyrosine kinase stimulates Schwann cell migration via the Rho GTPases Rac1 and Cdc42. We previously demonstrated that TrkC directly phosphorylates and activates Dbs, the guanine-nucleotide exchange factor (GEF) for Cdc42, to partially mediate Schwann cell migration. Here, we identify T lymphoma invasion and metastasis (Tiam) 1 as the Rac1-specific guanine-nucleotide exchange factor involved in NT3-induced Schwann cell migration. Furthermore, the interaction between the small GTPase Ras and Tiam1 plays an essential role in the activation of Rac1. Taken together, these results suggest that NT3 activation of TrkC stimulates Schwann cell migration through two parallel signaling units, Ras/Tiam1/Rac1 and Dbs/Cdc42, and that Schwann cell migration is uniquely regulated in the case of Ras and Rac1, by two different types of small GTPases.

Analysis of Variance↗

PubMed1999

Cell migration as a five-step cycle.

The migration of cells over substrata is a fundamental and critical function that requires the co-ordination of several cellular processes which operate in a cycle. At the level of the light microscope, the cycle can be divided into five steps: (1) extension of the leading edge; (2) adhesion to matrix contacts; (3) contraction of the cytoplasm; (4) release from contact sites; and (5) recycling of membrane receptors from the rear to the front of the cell. Each step is dependent upon one or more cyclical biochemical processes. The development of many in vitro and subcellular assays for the fundamental biochemical processes involved has increased our understanding of each cycle dramatically in the last several years to include a definition of many of the protein and enzymic components, the role of the position of extracellular-matrix receptors on the cell, and the contribution of physical force. The next generation of questions are directed at resolving the roles of the many individual proteins in each step of the cell migration process. In this chapter we will examine each of the migration steps and discuss the biochemical mechanisms that may underlie them.

Cell Adhesion↗

PubMed1996

The role of plasminogen, plasminogen activators, and matrix metalloproteinases in primate arterial smooth muscle cell migration.

The migration of arterial smooth muscle cells (SMCs) plays an important role in normal vessel development as well as the pathobiology of blood vessels. Because it is difficult to study cell migration in primates, we used ex vivo explants. The response of baboon aortic medial explants incubated in vitro in a serum-free medium with insulin and transferrin was compared with the response of whole artery injured in vivo by a balloon catheter to establish the validity of the explant model. Both the time course of entry of SMCs into the S phase and the changes in matrix metalloproteinase 9 were similar in the artery and the explants. SMCs began migrating from explants after a lag of 3 days. By day 11, > 90% of the explants exhibited SMC migration from the tissue (percent of explants with > or = 1 migrating cell). Basal migration was inhibited by antibodies to urokinase and tissue-type plasminogen activator, whereas addition of plasminogen to the explants increased migration. An inhibitor of matrix metalloproteinases. BB-94 (Batimistat), decreased migration, as did alpha 2-macroglobulin. These data demonstrate that proteinases of the matrix metalloproteinase and plasminogen/plasminogen activator families play an important role in the migration of primate arterial SMCs through the extracellular matrix.

Animals↗

PubMed1996

Urokinase-type plasminogen activator regulates cranial neural crest cell migration in vitro.

Proper migration and differentiation of neural crest (NC) cells are required for normal development of craniofacial structures, heart and great vessels, sensory and autonomic nervous systems, and other organs with vertebrate embryos. Serine-protease inhibitors reduce NC cell migration in vitro, suggesting the extracellular proteases are important mediators of NC cell migration. While plasminogen activator activity levels are high in NC cells relative to other embryonic tissue, its ability to regulate NC cell migration has not been specifically tested in vivo or in vitro through its ability to convert plasminogen to plasmin. Using a transfilter migration assay, NC cell migration was measured in the presence or absence of plasminogen. Our results showed that plasminogen significantly enhanced NC cell migration. This increase could not be attributed to differences in initial NC cell attachment or cytotoxicity and did not require a chemotactic gradient. The plasminogen-enhanced NC cell migration was blocked by aprotinin (a plasmin inhibitor) and was mimicked by the direct addition of plasmin to the NC cells, indicating that the plasminogen effect was mediated through plasmin generation. Furthermore, anticatalytic-uPA antibody blocked the plasminogen-enhanced NC cell migration showing that NC cell-associated uPA activity was required for this effect. Finally, decreasing NC-uPA activity by treating cells with transforming growth factor-Beta, also blocked the plasminogen-dependent increase in cell migration. These data show that in vitro, NC cell migration is regulated by NC-associated uPA activity suggesting that growth factor-regulation of this activity may play a major role in regulating NC cell migratory capacity in vivo.

Animals↗

PubMed1999

The genetics of cell migration in Drosophila melanogaster and Caenorhabditis elegans development.

Cell migrations are found throughout the animal kingdom and are among the most dramatic and complex of cellular behaviors. Historically, the mechanics of cell migration have been studied primarily in vitro, where cells can be readily viewed and manipulated. However, genetic approaches in relatively simple model organisms are yielding additional insights into the molecular mechanisms underlying cell movements and their regulation during development. This review will focus on these simple model systems where we understand some of the signaling and receptor molecules that stimulate and guide cell movements. The chemotactic guidance factor encoded by the Caenorhabditis elegans unc-6 locus, whose mammalian homolog is Netrin, is perhaps the best known of the cell migration guidance factors. In addition, receptor tyrosine kinases (RTKs), and FGF receptors in particular, have emerged as key mediators of cell migration in vivo, confirming the importance of molecules that were initially identified and studied in cell culture. Somewhat surprisingly, screens for mutations that affect primordial germ cell migration in Drosophila have revealed that enzymes involved in lipid metabolism play a role in guiding cell migration in vivo, possibly by producing and/or degrading lipid chemoattractants or chemorepellents. Cell adhesion molecules, such as integrins, have been extensively characterized with respect to their contribution to cell migration in vitro and genetic evidence now supports a role for these receptors in certain instances in vivo as well. The role for non-muscle myosin in cell motility was controversial, but has now been demonstrated genetically, at least in some cell types. Currently the best characterized link between membrane receptor signaling and regulation of the actin cytoskeleton is that provided by the Rho family of small GTPases. Members of this family are clearly essential for the migrations of some cells; however, key questions remain concerning how chemoattractant and chemorepellent signals are integrated within the cell and transduced to the cytoskeleton to produce directed cell migration. New types of genetic screens promise to fill in some of these gaps in the near future.

Animals↗

PubMed1989

Cell migration into neural tube lumen provides evidence for the "fixed cortex" theory of cell motility.

We present a model of cell motility based on emigration of neural crest cells into the neural tube lumen under in vitro conditions (10% fetal calf serum or YIGSR) that inhibit their normal emigration from the base of the neuroepithelium into surrounding extracellular matrix (ECM). Ultrastructural observations reveal that cells lining the lumen are joined by zonulae adherentes (ZA), which are points of strong intercellular attachment, and thereby serve as markers for fixed regions of plasmalemma and cortical actin. Three major observations of the relationship of cells to the ZA support the "fixed cortex" model of mesenchymal cell migration. First, cells extend apical cell processes past the ZA into the lumen. To do this, they must make new apical plasmalemma and actin cortex that the endoplasm slides into. Second, elongated cells are observed in the lumen that are still attached via ZA to the neuroepithelium. This indicates that all of the endoplasm finally slides past the ZA. Third, numerous cytoplasmic pieces, often attached to each other and to the neuroepithelium via ZA, are found at the site where cells appear to have detached from the epithelium after entering the lumen. Since the ZA is fixed in location, the endoplasm must have slid past it into newly manufactured anterior cortex and plasmalemma, with the trailing end of the cell finally snapping off. The "fixed cortex" theory of cell migration agrees with existing data in that it predicts the polarized insertion of new plasmalemma and actin at the leading end of the cell, but it differs significantly from existing theories of mesenchymal cell migration in that it states that the cell surface remains firmly attached to the substratum while the myosin-rich endoplasm slides past it.

Animals↗

PubMed2004

Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration.

We have examined the role of endogenous 70-kDa S6 kinase (p70(S6K)) in actin cytoskeletal organization and cell migration in Swiss 3T3 fibroblasts. Association of p70(S6K) with the actin cytoskeleton was demonstrated by cosedimentation of p70(S6K) with F-actin and by subcellular fractionation in which p70(S6K) activity was measured in the F-actin cytoskeletal fraction. Immunocytochemical studies showed that p70(S6K), Akt1, PDK1, and p85 phosphoinositide 3-kinase (PI 3-kinase) were localized to the actin arc, a caveolin-enriched cytoskeletal structure located at the leading edge of migrating cells. Using a phospho-specific antibody to mammalian target of rapamycin (mTOR), we find that activated mTOR is enriched at the actin arc, suggesting that activation of the p70(S6K) signaling pathway is important to cell migration. Using the actin arc to assess migration, epidermal growth factor (EGF) stimulation was found to induce actin arc formation, an effect that was blocked by rapamycin treatment. We show further that actin stress fibers may function to down-regulate p70(S6K). Fibronectin stimulated stress fiber formation in the absence of growth factors and caused an inactivation of p70(S6K). Conversely, cytochalasin D and the Rho kinase inhibitor Y-27632, both of which cause stress fiber disruption, increased p70(S6K) activity. These studies provide evidence that the p70(S6K) pathway is important for signaling at two F-actin microdomains in cells and regulates cell migration.

Actins↗