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At least 217 records · Page 12Linked to original sources
PubMed2006

Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites.

Our previous study demonstrated successful treatment of an established rat brain tumor through the bystander effect by intra-tumoral injection of neural stem cells transduced with herpes simplex virus-thymidine kinase gene (NSCtk) followed by systemic ganciclovir (GCV) administration (NSCtk therapy). Since glioma has a strong tendency to infiltrate into surrounding brain tissue and that is one of the main causes of local treatment failure, we, in the present study, injected NSCtk cells at distant sites of rat brain tumors and evaluated migratory potential of NSCtk toward the tumor and anti-tumor effects of the NSCtk therapy of this experimental setting. NSCtk cells were intracranially implanted either at 2mm medial in the ipsilateral hemisphere or at the mirror point in the contralateral hemisphere to the C6 rat glioma cell implantation. Active migration of NSCtk cells toward C6 cells was observed even when NSCtk cells were implanted in the contralateral hemisphere. When GCV was systemically administered, growth of intracranial tumor was markedly inhibited and the survival was significantly prolonged through the bystander effect by NSCtk cells migrated from distant injection sites of the tumor. The results of the present study suggest that NSCtk therapy is still effective in the area far from the NSCtk injection site and, therefore, suitable for treatment of malignant gliomas that deeply infiltrate and widely disseminate in the brain.

Animals↗
PubMed1994

Nerve growth factor and its low-affinity receptor promote Schwann cell migration.

Migrating Schwann cells in developing or regenerating peripheral nerves are known to express dramatically increased levels of nerve growth factor (NGF) and the low-affinity NGF receptor (LNGFR). Schwann cells do not express detectable pp140trk, the NGF-activated receptor tyrosine kinase which is essential for neuronal responses to NGF. The temporal correlation observed in Schwann cells between migration and the enhanced expression of NGF and LNGFR suggests that NGF and LNGFR may promote Schwann cell migration. To test this possibility, we examined the effects of NGF on Schwann cell migration on cryostat sections of biologically relevant NGF-poor and NGF-rich substrates--normal or denervated peripheral (sciatic) nerve, untreated or pretreated with NGF. Results show that Schwann cells migrate more rapidly on denervated than on normal sciatic nerve. Antibodies to NGF or to LNGFR strongly, but incompletely, inhibit enhanced migration on denervated nerves. Pretreatment of denervated nerve sections with NGF increases further the rate of Schwann cell migration. The same antibodies to NGF or to LNGFR abolish this response. These results suggest that one function of the elevated levels of NGF known to be present in embryonic and regenerating peripheral nerves is to promote the migration of Schwann cells. In contrast to neurons, where pp140trk appears to be the functionally critical NGF receptor, NGF responses in Schwann cells depend on LNGFR.

Animals↗
PubMed1990

Quasi-dynamic test of in vitro cell migration developed to characterize dividing cells of spontaneously metastasizing rat sarcomas.

A "Quasi-dynamic Test of in vitro Cell Migration" (QTCM) was developed in which the quantitative estimation of migration of dividing cells is based on a comparative evaluation of their dispersion in single-cell-derived colonies after 72 h of clonal growth under standard and test conditions. Expert visual evaluation of microscopic images of cell colonies including estimation of dispersion of cells in the colonies is checked and made more precise by computerized evaluation of digitized outlines of cells in the colonies. Using QTCM, distinctions in the pattern of migration between three neoplastic cell populations differing by their origin and degree of malignancy were found. Although transfer of cells into slightly acid conditions did not always increase the mean value of cell dispersion in the colonies, each cell population was found to include a cell fraction that did manifest considerably greater migration and this fraction was markedly larger in the more malignant cell populations. The results of both types of evaluation, visual and computerized, were in mutual accord, with accuracy being greater on the computer side. Thus, the QTCM proved useful for qualified estimation and/or computer measurement of in vitro migration of dividing cells on a population level.

Analog-Digital Conversion↗
PubMed2003

Signaling systems, guided cell migration, and organogenesis: insights from genetic studies in Drosophila.

During development, cells change their position extensively. Although the basic cellular mechanisms involved in cell locomotion have been studied mostly in cultured cells, genetic and molecular approaches using model organisms are starting to shed light on the complex events influencing cell migration during development. Recent technical advances in following and analyzing migrating cells inside the living embryo offer the possibility of understanding how different signaling systems regulate the fundamental cellular processes underlying guided cell migration in vivo. In Drosophila melanogaster, studies of migrating cells have concentrated mainly on hemocytes, germ cells, border cells, and tracheal cells. Interestingly, most of these cells were recently shown to make different cellular extensions and to use receptor tyrosine kinases to sense the chemoattractive signal. This review describes our current understanding of how different signaling networks control guided migration in these four systems and discusses the impact of novel imaging techniques on the study of guided cell migration during development.

Animals↗
PubMed2002

Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc genotype.

Colonic epithelial cell migration is required for normal differentiated cell function. This migratory phenotype is dependent upon wild-type adenomatous polyposis coli (Apc) expression. Non-tumorigenic murine colon epithelial cell lines with distinct Apc genotypes, i.e. young adult mouse colon (YAMC; Apc(+/+)) and immortomouse/Min colon epithelial (IMCE; Apc(Min/+) cells) were used to assess the association between the Apc genotype, cell motility and matrix metalloproteinase (MMP) activity. Cells were treated with epidermal growth factor (EGF; 1, 10 and 25 ng/ml), hepatocyte growth factor (HGF; 1, 10 and 25 ng/ml) and/or curcumin (0.1-100 microM). EGF (25 ng/ml) and HGF (25 ng/ml) induced a greater migratory response in YAMC compared with IMCE cells after 24 h (P < 0.05). Treatment with curcumin induced a greater or equivalent migratory response in IMCE than YAMC cells. When migrating cells were treated with Ilomastat (MMP inhibitor), migration was inhibited in both cell types. High concentrations of Ilomastat (25 and 50 microM) inhibited migration in both cell types, while low concentrations (10 microM) inhibited HGF-induced IMCE migration. Curcumin-induced migration was inhibited in both cell types at the highest concentration of Ilomastat (50 microM). Immuno-localization analysis of membrane type-1 (MT1)-MMP indicated that migration is associated with the redistribution of this protein from the endoplasmic reticulum to the plasma membrane. Addition of neutralizing polyclonal antibodies against MT1-MMP or a mixture of MT1, 2- and 3-MMPs demonstrated partial or complete inhibition of cell migration in both cell types, respectively. The data provide the first evidence that migration in non-tumorigenic murine colon epithelial cells is: (i) inducible by EGF and HGF in an Apc genotype-dependent manner, (ii) dependent on MT-MMP activity and (iii) inducible by curcumin in an Apc genotype-independent manner. The data suggest a potential mechanism by which curcumin may induce cells heterozygous for Apc to overcome defective cell migration, a phenotype associated with cell differentiation and apoptosis.

Adenomatous Polyposis Coli↗
PubMed1989

Laminin induces the stable expression of surface galactosyltransferase on lamellipodia of migrating cells.

We have previously shown that cell surface galactosyltransferase (GalTase) mediates cell spreading and migration on basal lamina matrices by binding N-linked oligosaccharide substrates within laminin. In this study we have examined the distribution and expression of cell surface GalTase during mesenchymal cell migration on various extracellular matrices. Antisera raised against affinity-purified beta 1,4 GalTase, as well as anti-GalTase Fab fragments, inhibited cell migration on laminin-containing matrices, whereas under identical conditions, anti-GalTase IgG had no effect on the rate of cell migration on fibronectin substrates. Cells migrating on laminin had three times the level of surface GalTase, assayed by 125I-antibody binding and by direct enzyme assay, than similar cells migrating on fibronectin. On the other hand, total cellular GalTase, assayed either enzymatically or by Northern blot analysis, was similar when cells were grown on laminin or fibronectin. The laminin-dependent increase in surface GalTase was due to its expression onto the leading and trailing edges of migrating cells in association with actin-containing microfilaments assayed by double-label indirect immunofluorescence. On stationary cells, surface GalTase levels were low, but as cells began to migrate on laminin GalTase became polarized to the growing lamellipodia. GalTase was not detectable on lamellipodia or filopodia when cells migrated on fibronectin substrates. These results show that laminin-containing matrices induce the stable expression of GalTase onto cell lamellipodia and filopodia where it mediates subsequent cell spreading and migration. Since fibronectin was unable to induce GalTase expression onto lamellipodia, these studies also suggest that the extracellular matrix can selectively influence which intracellular components are maintained on the cell surface.

Actins↗
PubMed1998

Overexpression of EGFR and c-erbB2 causes enhanced cell migration in human breast cancer cells and NIH3T3 fibroblasts.

Overexpression of EGFR and c-erbB2 frequently occurs in human breast cancers, correlating with poor prognosis. Here we show that overexpression of EGFR and c-erbB2 in cell lines increases cell migration, an important step in metastasis formation. The effect of EGFR on migration is dependent on the addition of EGF to the cells. In contrast, c-erbB2 seems to act independently of its ligand in these assays. Overexpression of this receptor is sufficient to induce cell migration. In addition, we investigated the involvement of a number of signal transduction pathways known to be activated by the EGFR. We found that inactivation of MAPKK results in a decreased migration, while inactivation of PI3K increases migration.

3T3 Cells↗
PubMed2006

Rho-dependent, Rho kinase-independent inhibitory regulation of Rac and cell migration by LPA1 receptor in Gi-inactivated CHO cells.

Lysophosphatidic acid (LPA) is a major serum lysophospholipid that stimulates cell migration in diverse cell types including ovarian cancer cells. We report here that in the absence of Gi function, LPA induces inhibition, rather than stimulation, of cellular Rac activity, lamellipodium formation, and cell migration in response to insulin like growth factor I (IGF-I) in Chinese hamster ovary (CHO) cells, which solely express LPA1 as a LPA receptor. The inhibitory effects of LPA are abrogated by the expression of either Galpha13 C-terminal peptide or C3 toxin pretreatment, but not a Rho kinase inhibitor. Without PTX pretreatment, LPA stimulates Rac and cell migration yet similarly activates Rho, indicating that Rho activation by itself is not sufficient for inhibition of cell migration. Conversely, the expression of a dominant negative Rac mutant sufficiently mimics the LPA inhibition of cell migration. LPA inhibits IGF I-induced Akt activation by only 40% in a manner dependent on Rho kinase. These results demonstrate that inhibition of Gi function converts LPA regulation on Rac and cell migration to an inhibitory mode, which is mediated by G13 and Rho but not Rho kinase, and raise a possibility of Gi as a new therapeutic target for LPA-dependent tumor progression.

Actins↗
PubMed1999

Trio amino-terminal guanine nucleotide exchange factor domain expression promotes actin cytoskeleton reorganization, cell migration and anchorage-independent cell growth.

Rho family GTPases regulate diverse cellular processes, including extracellular signal-mediated actin cytoskeleton reorganization and cell growth. The functions of GTPases are positively regulated by guanine nucleotide exchange factors, which promote the exchange of GDP for GTP. Trio is a complex protein possessing two guanine nucleotide exchange factor domains, each with adjacent pleckstrin homology and SH3 domains, a protein serine/threonine kinase domain with an adjacent immunoglobulin-like domain and multiple spectrin-like domains. To assess the functional role of the two Trio guanine nucleotide exchange factor domains, NIH 3T3 cell lines stably expressing the individual guanine nucleotide exchange factor domains were established and characterized. Expression of the amino-terminal guanine nucleotide exchange factor domain results in prominent membrane ruffling, whereas cells expressing the carboxy-terminal guanine nucleotide exchange factor domain have lamellae that terminate in miniruffles. Moreover, cells expressing the amino-terminal guanine nucleotide exchange factor domain display more rapid cell spreading, haptotactic cell migration and anchorage-independent growth, suggesting that Trio regulates both cell motility and cell growth. Expression of full-length Trio in COS cells also alters actin cytoskeleton organization, as well as the distribution of focal contact sites. These findings support a role for Trio as a multifunctional protein that integrates and amplifies signals involved in coordinating actin remodeling, which is necessary for cell migration and growth.

3T3 Cells↗
PubMed2004

RACK1-mediated integration of adhesion and insulin-like growth factor I (IGF-I) signaling and cell migration are defective in cells expressing an IGF-I receptor mutated at tyrosines 1250 and 1251.

The scaffolding protein receptor for activated C kinase (RACK1) has been proposed to mediate the integration of insulin-like growth factor I receptor (IGF-IR) and adhesion signaling. Here we investigated the mechanism of this integration of signaling, by using an IGF-IR mutant (Y1250F/Y1251F) that is deficient in anti-apoptotic and transforming function. RACK1 was found to associate with the IGF-IR only in adherent cells and did not associate with the IGF-IR in nonadherent cells, lymphocytic cells, or cells expressing the Y1250F/Y1251F mutant. In R- cells transiently expressing the Y1250F/Y1251F mutant RACK1 became constitutively associated with beta1 integrin and did not associate with Shc, Src, or Shp2. This was accompanied by the loss of formation of a complex containing the IGF-IR, RACK1, and beta1 integrin; loss of migratory capacity; enhanced Src and FAK activity; enhanced Akt phosphorylation; and decreased p38 mitogen-activated protein kinase activity. Shc was not phosphorylated in response to IGF-I in cells expressing the Y1250F/Y1251F mutant and remained associated with protein phosphatase 2A. Similar alterations in signaling were observed in cells that were stimulated with IGF-I in nonadherent cultures. Our data suggest that disruption of RACK1 scaffolding function in cells expressing the Y1250F/Y1251F mutant results in the loss of adhesion signals that are necessary to regulate Akt activity and to promote turnover of focal adhesions and cell migration.

Animals↗
PubMed1985

Retinal development in humans: the roles of differential growth rates, cell migration and naturally occurring cell death.

The distribution of ganglion cells throughout the retinal ganglion cell layer is non-uniform in adult mammals. This paper reviews some of our data describing the development of retinal ganglion cell topography in the human fetus. Results indicated that early in the fetal period the distribution of cells in the ganglion cell layer is almost uniform, but by the end of gestation there is a gradient in cell density of about 10:1 (central:peripheral). Peripheral retina grows more rapidly than the central retina prior to about 23 weeks gestation, but this differential growth rate apparently has little effect on the development of a centro-peripheral density gradient. The gradient appears between about 18 and 30 weeks gestation, and during this period there appears to be a greater rate of cell death in the ganglion cell layer of the peripheral retina. Cell density at the developing fovea is less than the perifoveal cell density at all ages, suggesting that ganglion cells migrate from foveal into perifoveal regions throughout the fetal period.

Cell Count↗
PubMed2005

Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharmacological approach to inhibit invasion and metastasis development.

The migration of tumor cells is a prerequisite for tumor cell invasion and metastasis development, which accounts for over 90% of cancer mortality. Therefore a major focus of current tumor biological research is the study of those factors that regulate tumor cell migration. Those chemokines and neurotransmitters that bind to G-protein coupled receptors (also known as serpentine receptors) are the most prominent of these factors. Neurotransmitters have been identified that have not only a stimulatory (e.g. norepinephrine) effect, but an inhibitory effect (e.g. GABA) as well. This is an especially fortuitous development, because many known agonists and antagonists of neurotransmitter receptors are currently being successfully used in the treatment of other pathological conditions (e.g. beta-blockers in the treatment of cardiovascular diseases). Likewise, chemokine receptor antagonists, which are under development for the treatment of HIV or rheumatoid arthritis, may be effective tools for the inhibition of chemokine-driven tumor cell migration as well. A further approach to inhibit tumor cell migration arises from the investigation of the relevant signal transduction pathways. The PKC alpha, for example, is a key enzyme in the regulation of tumor cell migration, but not of leukocyte migration. It thus offers a selective target opportunity for specific pharmacological agents to interfere with tumor cell migration. In this review we therefore summarize the current findings on those serpentine receptors involved in the neurotransmitter- and chemokine-regulated tumor cell migration, on the underlying signal transduction pathways, and on the opportunities to inhibit tumor cell migration and ultimately metastasis development with pharmaceutical agents.

Cell Movement↗
PubMed2006

Dominant-negative Rac increases both inherent and ionizing radiation-induced cell migration in C6 rat glioma cells.

Rho-like GTPases, including Cdc42, Rac1 and RhoA, regulate distinct actin cytoskeleton changes required for cell adhesion, migration and invasion. In the present study, we examined the role of Rac signaling in inherent migration, as well as radiation-induced migration, of rat glioma cells. Stable overexpression of dominant-negative Rac1N17 in a C6 rat glioma cell line (C6-RacN17) promoted cell migration, and ionizing radiation further increased this migration. Migration was accompanied by decreased expression of the focal adhesion molecules FAK and paxillin. Focal contacts and actin stress fibers were also reduced in C6-RacN17 cells. Downstream effectors of Rac include JNK and p38 MAP kinases. Irradiation transiently activated p38, JNK and ERK1/2 MAP kinases in C6-RacN17 cells, while p38 and JNK were constitutively activated in C6 control cells. Blocking JNK activity with JNK inhibitor SP600125 inhibited migration, suggesting that the JNK pathway may regulate radiation-induced, as well as inherent, migration of C6-RacN17 cells. Additionally, the radiation-induced migration increase was also inhibited by SB203580, a specific inhibitor of p38 MAP kinase. However, PD98059, a MEK kinase 1 inhibitor, failed to influence migration. This is the first evidence that suppression of Rac signaling may be involved in invasion or metastasis of glioma cells before and/or after radiotherapy. These data further suggest that radiotherapy for malignant glioma needs to be used with caution because of the potential for therapy-induced cell migration or invasion and that pharmacological inhibition of cell migration and invasion through targeting the Rac signaling pathway may represent a new approach for improving the therapeutic efficacy of radiotherapy for malignant glioma.

Animals↗
PubMed2002

Activation of protein kinase A accelerates bovine bronchial epithelial cell migration.

Bronchial epithelial cell migration is required for the repair of damaged airway epithelium. We hypothesized that bronchial epithelial cell migration during wound repair is influenced by cAMP and the activity of its cyclic nucleotide-dependent protein kinase, protein kinase A (PKA). We found that, when confluent monolayers of bronchial epithelial cells are wounded, an increase in PKA activity occurs. Augmentation of PKA activity with a cell-permeable analog of cAMP, dibutyryl adenosine 3',5'-cyclic monophosphate, isoproterenol, or a phosphodiesterase inhibitor accelerated migration of normal bronchial epithelial cells in in vitro wound closure assays and Boyden chamber migration assays. A role for PKA activity was also confirmed with a PKA inhibitor, KT-5720, which reduced stimulated migration. Augmentation of PKA activity reduced the levels of active Rho and the formation of focal adhesions. These studies suggest that PKA activation modulates Rho activity, migration mechanisms, and thus bronchial epithelial repair mechanisms.

Animals↗
PubMed1993

Environmental influences on neural crest cell migration.

Neural crest cells migrate extensively and interact with numerous tissues and extracellular matrix components during their movement. Cell marking techniques have shown that neural crest cells in the trunk of the avian embryo migrate through the anterior, but not posterior, half of each sclerotome and avoid the region around the notochord. A possible mechanism to account for this migratory pattern is that neural crest cells may be inhibited from entering the posterior sclerotome and the perinotochordal space. Thus, interactions with other tissue may prescribe the pattern of neural crest cell migration in the trunk. In contrast, interactions between neural crest cells and the extracellular matrix may mediate the primary interactions controlling neural crest cells migration in the head region.

Animals↗
PubMed2004

Anti-Gal IgG potentiates natural killer cell migration across porcine endothelium via endothelial cell activation and increased natural killer cell motility triggered by CD16 cross-linking.

Xenoreactive antibodies (Ab) are important for the development of acute vascular rejection (AVR) of xenografts characterized by monocytes, natural killer (NK) cells and neutrophils infiltrating the graft. The mechanisms by which anti-galactose alpha 1,3galactose (alpha-Gal) IgG influence NK cell migration across porcine aortic endothelium (PAEC) were investigated. NK cell migration across PAEC increased in the presence of anti-alpha-Gal IgG. Anti-alpha-Gal IgG exposure activated PAEC as shown by an increased expression of CD62E and CD106. NK cells adhered, spread and showed motile forms on plastic surfaces coated with human IgG, IgG Fc and on mAb against CD16, but not on mouse IgG or BSA, suggesting that CD16 cross-linking can mediate increased adhesiveness. Increased NK cell motility was observed on Boyden filters coated with human IgG, IgG Fc, and mAb against CD16 and the alpha 4, alpha 5, alpha L, beta 1 and beta 2 integrin chains. No motile response was seen on mouse IgGor CD7, CD56 and alpha 6 integrin mAb. NK cell migration on human IgG and anti-CD16 Ab was blocked by anti-CD16 or anti-beta 2, but not anti-beta 1 Ab, implying that the motile response triggered by CD16 cross-linking is mediated via beta 2 integrins. Preformed or induced anti-alpha-Gal IgG may therefore contribute to AVR by stimulating innate immune cell infiltration of the graft.

Animals↗
PubMed1999

Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells.

Metastatic breast tumor Met-1 cells express CD44v(3,8-10), a major adhesion receptor that binds extracellular matrix components at its extracellular domain and interacts with the cytoskeletal protein, ankyrin, at its cytoplasmic domain. In this study, we have determined that CD44v(3,8-10) and RhoA GTPases are physically associated in vivo, and that CD44v(3,8-10)-bound RhoA displays GTPase activity, which can be inhibited by botulinum toxin C3-mediated ADP-ribosylation. In addition, we have identified a 160 kDa Rho-Kinase (ROK) as one of the downstream targets for CD44v(3,8-10)-bound RhoA GTPase. Specifically, RhoA (complexed with CD44v(3, 8-10)) stimulates ROK-mediated phosphorylation of certain cellular proteins including the cytoplasmic domain of CD44v(3,8-10). Most importantly, phosphorylation of CD44v(3,8-10) by ROK enhances its interaction with the cytoskeletal protein, ankyrin. We have also constructed two ROK cDNA constructs that encode for proteins consisting of 537 amino acids [designated as the constitutively active form of ROK containing the catalytic domain (CAT, also the kinase domain)], and 173 amino acids [designated as the dominant-negative form of ROK containing the Rho-binding domain (RB)]. Microinjection of the ROK's CAT domain into Met-1 cells promotes CD44-ankyrin associated membrane ruffling and projections. This membrane motility can be blocked by CD44 antibodies and cytochalasin D (a microfilament inhibitor). Furthermore, overexpression of a dominant-negative form of ROK by transfection of Met-1 cells with ROK's Rho-binding (RB) domain cDNA effectively inhibits CD44-ankyrin-mediated metastatic behavior (e.g., membrane motility and tumor cell migration). These findings support the hypothesis that ROK plays a pivotal role in CD44v(3,8-10)-ankyrin interaction and RhoA-mediated oncogenic signaling required for membrane-cytoskeleton function and metastatic tumor cell migration.

Amino Acid Sequence↗
PubMed2002

Lack of ERK activation and cell migration in FGF-2-deficient endothelial cells.

The formation of blood capillaries from preexisting vessels (angiogenesis) and vascular remodeling secondary to atherosclerosis or vessel injury are characterized by endothelial cell migration and proliferation. Numerous growth factors control these cell functions. Basic fibroblast growth factor (FGF-2), a potent angiogenesis inducer, stimulates endothelial cell proliferation, migration, and proteinase production in vitro and in vivo. However, mice genetically deficient in FGF-2 have no apparent vascular defects. We have observed that endothelial cell migration in response to mechanical damage in vitro is accompanied by activation of the extracellular signal-regulated kinase (ERK) pathway, which can be blocked by neutralizing anti-FGF-2 antibodies. Endothelial cells from mice that are genetically deficient in FGF-2 neither migrate nor activate ERK in response to mechanical wounding. Addition of exogenous FGF-2 restores a normal cell response, which shows that impaired migration results from the genetic deficiency of this growth factor. Injury-induced ERK activation in endothelial cells occurs only at the edge of the wound. In addition, FGF-2-induced ERK activation mediates endothelial cell migration in response to wounding without a significant effect on proliferation. These data show that FGF-2 is a key regulator of endothelial cell migration during wound repair.

Animals↗