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PubMed1999

Centrosomes, microtubules and cell migration.

Directed cell movement is an immensely complex process that depends on the co-operative interaction of numerous cellular components. Work over the past three decades has suggested that microtubules play an important role in the establishment and maintenance of the direction of cell migration. This chapter summarizes recent work from our laboratory designed to determine the roles of the microtubules and centrosome position relative to the direction of cell migration in a variety of cell types, and discusses these observations in the context of work from other laboratories. The results suggest that microtubules are required for stabilization of the direction of migration in many, but not all, cell types. For the centrosome to act as a stabilizer of cell migration requires that it is repositioned behind the leading edge. However, the process of repositioning does not precede the extension of a leading edge and the establishment of a new direction of cell migration. Rather, the centrosome follows the repositioning of the leading edge in response to other stimuli and, in doing so, stabilizes cell movement.

Animals↗
PubMed1980

Invited review: guidance cue patterns and cell migration in multicellular organisms.

In multicellular organisms, guidance cues are either diffusible molecules or cellular or extracellular surfaces that are found in reproducible locations and that orient migrating cells and cell processes. The pattern of the guidance cues usually determines the complex in vivo migration routes of motile cells and cell processes. Within organisms, guidance cues are found to be organized in two general patterns: a) broad gradients--such as diffuse chemotactic gradients; b) discrete routes (substrate pathways)--such as chemotactic gradients confined to long channels, and such as the axon surface which represents a long specific highway for migrating Schwann cells.

Amphibians↗
PubMed2005

Role of guanine nucleotide exchange factor P-Rex-2b in sphingosine 1-phosphate-induced Rac1 activation and cell migration in endothelial cells.

Endothelial cell (EC) migration has an important role in angiogenesis. Sphingosine-1 phosphate (S1P) stimulates EC migration via activation of Gi proteins. In this study, we characterized a mouse guanine nucleotide exchange factor (GEF) P-Rex2b for its regulation by Gbetagamma and PI3K and its role in S1P-induced Rac1 activation and cell migration in ECs. We found that co-expression of Gbetagamma or an active form of PI3K (PI3K(AC)) with P-Rex2b increased the SRE. Luciferase (SRE.L) reporter gene activity that can be stimulated by the Rho family of small GTPases including Rac1. Co-expression with P-Rex2b of Gbetagamma and PI3K(AC) or wild type PI3Kgamma that can be activated by Gbetagamma led to further increases in the reporter gene activity. Together with the finding that co-expression of Gbetagamma and/or PI3K(AC) increased the levels of active Rac1, we conclude that P-Rex2b is a Rac GEF that can be regulated by Gbetagamma and PI3K. Additionally, we demonstrated that Gbetagamma interacted with P-Rex2b, probably through P-Rex2b sequences at the PH domain and that the DEP and PDZ domains of P-Rex2b exerted an inhibitory effect on P-Rex2b's activity because their deletion increased the SER.L reporter gene activity. Furthermore, we found that P-Rex2b is involved in S1P-induced Rac1 activation and cell migration in ECs because siRNA-mediated suppression of P-Rex2b expression in ECs-diminished Rac1 activation and cell migration in response to S1P. Therefore, P-Rex2b is a physiologically significant Rac1 GEF that has an important role in the regulation of EC migration.

Animals↗
PubMed2004

Cell migration: mechanisms of rear detachment and the formation of migration tracks.

Cell migration is central to many biological and pathological processes, including embryogenesis, tissue repair and regeneration as well as cancer and the inflammatory response. In general, cell migration can be usefully conceptualized as a cyclic process. The initial response of a cell to a migration-promoting agent is to polarize and extend protrusions in the direction of migration. These protrusions can be large, broad lamellipodia or spike-like filopodia, are usually driven by actin polymerization, and are stabilized by adhering to the extracellular matrix (ECM) via transmembrane receptors of the integrin family linked to the actin cytoskeleton. These adhesions serve as traction sites for migration as the cell moves forward over them, and they must be disassembled at the cell rear, allowing it to detach. The mechanisms of rear detachment and the regulatory processes involved are not well understood. The disassembly of adhesions that is required for detachment depends on a coordinated interaction of actin and actin-binding proteins, signaling molecules and effector enzymes including proteases, kinases and phosphatases. Originally, the biochemically regulated processes leading to rear detachment of migrating cells were thought not to be necessarily accompanied by any loss of cell material. However, it has been shown that during rear detachment long tubular extensions, the retracting fibers, are formed and that "membrane ripping" occurs at the cell rear. By this process, a major fraction of integrin-containing cellular material is left behind forming characteristic migration tracks that exactly mark the way a cell has taken.

Animals↗
PubMed2006

A mathematical model of integrin-mediated haptotactic cell migration.

Haptotactic cell migration, a directed response to gradients of cell-extracellular matrix adhesion, is an important process in a number of biological phenomena such as wound healing and tumour cell invasion. Previously, mathematical models of haptotaxis have been developed on the premise that cells migrate in response to gradients in the density of the extracellular matrix. In this paper, we develop a novel mathematical model of haptotaxis which includes the adhesion receptors known as integrins and a description of their functional activation, local recruitment and protrusion as part of lamellipodia. Through the inclusion of integrins, the modelled cell matter is able to respond to a true gradient of cell-matrix adhesion, represented by functionally active integrins. We also show that previous matrix-mediated models are in fact a subset of the novel integrin-mediated models, characterised by specific choices of diffusion and haptotaxis coefficients in their model equations. Numerical solutions suggest the existence of travelling waves of cell migration that are confirmed via a phase plane analysis of a simplified model.

Algorithms↗
PubMed2000

Reciprocal functions of liver tumor cells and endothelial cells. Involvement of endothelial cell migration and tumor cell proliferation at a primary site in distant metastasis.

BACKGROUND: The mechanism by which tumor cells interact with endothelial cells at the primary site in metastasis remains obscure. MATERIALS AND METHODS: To disclose the precise mechanisms and processes of metastasis and angiogenesis, we investigated the interactions of endothelial cells (CPAE; calf pulmonary arterial endothelial cells) with two mouse liver tumor cell lines, G-5, a highly metastatic clone, and G-1, a poorly metastatic clone, based on the difference in their angiogenic activities in vivo at a primary site. RESULTS: G-5 cell cultured conditioned medium (CM) promoted migration of endothelial cells more than did G-1 cell CM, in migration assay using modified Boyden chambers. Anti-basic FGF antibody inhibited G-5-induced endothelial cell migration. Furthermore, endothelial cells stimulated proliferation of G-5 cells more than that of G-1 cells in coculture assay using Transwell chambers (pore size; 0.4 microm). Pretreated endothelial cells with bFGF enhanced tumor cell proliferation, suggesting the ability of activated endothelial cells to support tumor growth. In addition, incubation with endothelial cell CM also improved the proliferative activity of G-5 cells more than that of G-1 cells in a concentration-dependent fashion, indicating production and secretion of liver tumor cell growth substance by endothelial cells. CONCLUSION: These results provide evidence that liver tumor cells stimulate endothelial cell migration and migrated endothelial cells facilitate liver tumor cell proliferation. Tumor growth at a primary site may initially be dependent on migrated endothelial cells rather than vascularization or blood nutrient supply. This bi-directional paracrine relationship between liver tumor cells and endothelial cells may influence their metastatic ability.

Animals↗
PubMed2002

Perillyl Alcohol Inhibits Breast Cell Migration without Affecting Cell Adhesion.

The monoterpene d-limonene exhibits chemotherapeutic and chemopreventive potential in breast cancer patients. D-limonene and its related compounds, perillyl alcohol and perillyl aldehyde, were chosen as candidate drugs for application in a screen for nontoxic inhibitors of cell migration. Using the nontumorigenic human breast cell line MCF-10A, we delineated the toxicity as greatest for the perillyl aldehyde, intermediate for perillyl alcohol, and least for limonene. A noncytotoxic concentration of 0.5 mmol/L perillyl alcohol inhibited the migration, while the same concentration of limonene failed to do so. Adhesion of the MCF-10A cell line and the human breast cancer cell line MDA-MB 435 to fibronectin was unaffected by 1.5 mmol/L perillyl alcohol. 0.4 mmol/L perillyl alcohol inhibited the growth of MDA-MB 435 cells. All migration-inhibiting concentrations of perillyl alcohol for MDA-MB 435 cells proved to be toxic. These results suggest that subtoxic doses of perillyl alcohol may have prophylactic potential in the treatment of breast cancer.

Journal Article↗
PubMed2002

Upregulation of the cytoskeletal-associated protein Moesin in the neointima of coronary arteries after balloon angioplasty: a new marker of smooth muscle cell migration?

Migrating cells like coronary smooth muscle cells in restenosis change their cell shape and form cellular protrusions called filopodia. A prerequisite for filopodia formation is the rearrangement of the actin cytoskeleton. An essential role of the 78-kDa protein Moesin is described for Rho- and Rac-dependent assembly of actin filaments. In vivo Moesin is not observed in mature smooth muscle cells. The objective of this study was to demonstrate that Moesin is upregulated in migrating coronary smooth muscle cells during restenosis development. In vivo expression of Moesin was upregulated in neointimal coronary smooth muscle cells of dilated porcine coronary arteries compared to the undilated left circumflex coronary artery of the same swine. Concordant to these results Moesin expression was upregulated in migrating and invading human arterial smooth muscle cells in vitro analyzed by FACS, Western blotting and RT-PCR. In addition, the invasive potential of Moesin-positive Mel Im cells transfected with Moesin sense DNA increased by 28% as compared to mock-transfected control, whereas antisense transfected cells had a decreased invasive potential of 32%. Transfection of Moesin-negative HepG2 with Moesin sense cDNA increased the invasive potential by 43%. Finally, transfection of human arterial smooth muscle cells with Moesin sense cDNA caused an increased invasive potential of 30%. Transfection of haSMCs with antisense cDNA decreased the invasive potential by 37% in comparison to mock-transfected control. These results demonstrate for the first time an upregulation of Moesin expression in coronary smooth muscle cells of the neointima after arterial injury. The increased migrative and invasive potential of cells transfected with Moesin confirmed the functional role of Moesin in cell migration. This indicates an important role of Moesin during restenosis development.

Actins↗
PubMed1988

Production of a factor inhibiting tumor cell migration by spleen cells from tumor-bearing mice.

A factor inhibiting tumor cell migration was found in the culture supernatants of spleen cells of BALB/c mice transplanted with sarcoma cells 20 days before or injected with killed sarcoma cells 14 days before, when the spleen cells were stimulated in vitro for 2 or 24 hr with a 3 M KCl extract of the sarcoma. This factor did not inhibit the migration of guinea-pig macrophages or of theophylline-pretreated sarcoma cells. When the supernatants were fractioned on Sephadex G-100 columns, active fractions with molecular weights lower than 14,000 were distributed broadly.

Animals↗
PubMed1991

Effect of age on the proportion of mouse bone marrow cells migrating in response to newborn thymus supernatant. Cell migration and thymus evolution in mice.

The effect of mouse age on the in vitro migration of hemopoietic precursor cells from bone marrow of C57BL/6 to thymic supernatant from newborn mice was studied to determine whether a reduction in the migratory readiness or number of precursor cells might at lest partly explain thymic involution due to aging. The percentage of bone marrow cells migrating to the thymic supernatants increased to age of 7 weeks, and then decreased progressively. Thymus weight underwent almost exactly the same evolution. The decline of the population of migration-ready T-precursor in adult mice may this explain age-related thymic involution.

Aging↗
PubMed2000

Actin-dependent lamellipodia formation and microtubule-dependent tail retraction control-directed cell migration.

Migrating cells are polarized with a protrusive lamella at the cell front followed by the main cell body and a retractable tail at the rear of the cell. The lamella terminates in ruffling lamellipodia that face the direction of migration. Although the role of actin in the formation of lamellipodia is well established, it remains unclear to what degree microtubules contribute to this process. Herein, we have studied the contribution of microtubules to cell motility by time-lapse video microscopy on green flourescence protein-actin- and tubulin-green fluorescence protein-transfected melanoma cells. Treatment of cells with either the microtubule-disrupting agent nocodazole or with the stabilizing agent taxol showed decreased ruffling and lamellipodium formation. However, this was not due to an intrinsic inability to form ruffles and lamellipodia because both were restored by stimulation of cells with phorbol 12-myristate 13-acetate in a Rac-dependent manner, and by stem cell factor in melanoblasts expressing the receptor tyrosine kinase c-kit. Although ruffling and lamellipodia were formed without microtubules, the microtubular network was needed for advancement of the cell body and the subsequent retraction of the tail. In conclusion, we demonstrate that the formation of lamellipodia can occur via actin polymerization independently of microtubules, but that microtubules are required for cell migration, tail retraction, and modulation of cell adhesion.

Actins↗
PubMed2002

Attenuation of cell migration and induction of cell death by aged garlic extract in rat sarcoma cells.

Previous studies have shown that aged garlic extract suppresses cancer growth and enhances immune system against cancer, and yet little is known about inhibition of the cancer cell migration. In this study we investigated whether the aged garlic extract inhibits growth and migration of rat sarcoma tumor cells. The suppression of tumor cell growth was demonstrated by counting the cell number in three groups (control, cultured with 10 mg/ml, 20 mg/ml of aged garlic extracts) after culturing for 3 days and 5 days. The results showed that aged garlic extract inhibited the growth of rat sarcoma cancer cells in a dose-dependent manner, compared to the numbers of the cells grown in control group. The inhibition of tumor cell migration was examined by measuring the distance of trails left behind by the tumor cells when they passed through the polybeads overnight in four groups (control, 5 mg/ml, 10 mg/ml, 20 mg/ml aged garlic extracts). The average distance of trails in control group was 7.44 mm, whereas the average distance of cell movement is only 2.48 mm when treated with the highest concentration (20 mg/ml) of the aged garlic extract. The results also showed that the inhibitory effect of aged garlic extracts on tumor cell migration was dose-dependent. This is the first report to show that the aged garlic extract inhibits rat sarcoma cell migration, a critical feature of tumor cell metastasis. It can be thus envisioned that if tumor cell metastasis could be attenuated if not completely stopped, it would be possible to stabilize the tumor in the local area for surgical removal. The results suggest that garlic, as a natural plant, unlike other cancer treatment methods, may play a role in fighting cancer without significant side effects.

Animals↗
PubMed2001

Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration.

Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP-processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP-dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion.

Amino Acid Sequence↗
PubMed1997

p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells.

Vascular endothelial growth factor (VEGF) is a potent chemotactic agent for endothelial cells. Yet the signalling pathways that modulate the motogenic effects of VEGF in vascular endothelial cells are still ill defined. In the present study, we found in primary cultures of human umbilical vein endothelial cells (HUVEC) that VEGF increased cell migration and induced a marked reorganization of the microfilament network that was characterized by the formation of stress fibers and the recruitment of vinculin to focal adhesions. VEGF also stimulated the mitogen activated protein (MAP) kinases ERK (extracellular signal-regulated kinase) and p38 (stress activated protein kinase-2), but not SAPK1/JNK (stress activated protein kinase-1/c-Jun NH2-terminal kinase). Activation of p38 resulted in activation of MAP kinase activated protein kinase-2/3 and phosphorylation of the F-actin polymerization modulator, heat shock protein 27 (HSP27). Inhibiting the VEGF-induced activation of ERK with PD098059 did not influence actin organization or cell migration but totally inhibited the VEGF-induced incorporation of thymidine into DNA. Inhibition of p38 activity by the specific inhibitor SB203580 led to an inhibition of HSP27 phosphorylation, actin reorganization and cell migration. The results indicate that the p38 pathway conveys the VEGF signal to microfilaments inducing rearrangements of the actin cytoskeleton that regulate cell migration. By modulating cell migration, p38 may thus be an important regulator of angiogenesis.

Actins↗
PubMed2002

A continuum model to analyse spatial cell fluxes from positional labelling data applied to cell migration in oral mucosa.

A novel method is presented which allows the estimation of the velocity of migrating cells from positional 3HTdR labelling data in spatially organized epithelial tissues. In a continuum approach, wave-like profiles of labelling index (LI) data, which travel away from the basal layer, are followed and compared with experimental LI profiles. The method yields estimates of migration velocity, cell flow, and turnover time. Results for the ventral tongue mucosa in a group of 55 BDF1 mice that were labelled at the same time of the day and culled at different time points within a 24-h period have been analysed. The results show a strong circadian rhythm in the migration velocity and the related parameters.

Animals↗
PubMed2004

Investigating cell-material interactions by monitoring and analysing cell migration.

Cell-material interactions can on one hand be characterised by assessing the functional state and or shape of the cells at one or different discrete periods of time, on the other hand by observing cell migration and spreading behaviour. The object of this study was to investigate the migration behaviour of fluorescently labelled cells, and to evaluate the software analysing this migration. In the present study, the behaviour of fibroblasts cells on differently structured surfaces was taken as example. In the first step, the influence of seven different lipophilic dyes (Dil, DiO, DiA, DiD, DiR, PKH2 and PKH26) on cell performance was determined taking biochemical parameters as indices. In the second step, the fluorescence characteristics of these dyes were compared regarding their applicability. In the third step, migration behaviour of Dil-labelled fibroblastic cells on plane and grooved surfaces were monitored and analysed using specific software. Our data suggest that most of the dyes have optimal characteristics for studying cell-cell interactions. Cell migration behaviour regarding migration direction and cell spreading was different on plane and grooved surfaces. It could be shown that computer-based image analysis represents a practical, quick and objective tool to quantify exactly cell migration behaviour.

3T3 Cells↗
PubMed2000

Development of an ultralow-light-level luminescence image analysis system for dynamic measurements of transcriptional activity in living and migrating cells.

We have developed an approach to study in single living epithelial cells both cell migration and transcriptional activation, which was evidenced by the detection of luminescence emission from cells transfected with luciferase reporter vectors. The image acquisition chain consists of an epifluorescence inverted microscope, connected to an ultralow-light-level photon-counting camera and an image-acquisition card associated to specialized image analysis software running on a PC computer. Using a simple method based on a thin calibrated light source, the image acquisition chain has been optimized following comparisons of the performance of microscopy objectives and photon-counting cameras designed to observe luminescence. This setup allows us to measure by image analysis the luminescent light emitted by individual cells stably expressing a luciferase reporter vector. The sensitivity of the camera was adjusted to a high value, which required the use of a segmentation algorithm to eliminate the background noise. Following mathematical morphology treatments, kinetic changes of luminescent sources were analyzed and then correlated with the distance and speed of migration. Our results highlight the usefulness of our image acquisition chain and mathematical morphology software to quantify the kinetics of luminescence changes in migrating cells.

Animals↗
PubMed1992

Evidence for recent as well as long term activation of T cells migrating through endothelial cell monolayers in vitro.

As T cells actively extravasate from blood, they adhere to endothelium and then migrate out of the vessel with a locomotive activity. Although both adhesion and locomotion are properties associated with activated T cells, the two processes are not necessarily associated with identical activation states. Using human endothelial cells (EC) cultured to confluence on collagen gel, we examined the activation state of human peripheral blood T cells that adhere to and migrate through EC monolayers with three different methods: flow cytometric analysis of cell surface activation-related molecules, incorporation of tritiated nucleotide, and cell cycle analysis. The results were as follows. 1) Although expression of very late activation Ag integrins VLA-2 and VLA-3 by the initial blood T cell population (unseparated cells) and of adherent T cells was minimal, 40 to 45% of migrating cells were positive for VLA-2 and VLA-3. 2) The percentage of IL-2R+ cells in both unseparated and adherent cells was below 5% whereas the percentage of IL-2R+ cells among the migrating cells was 22 +/- 9% (range, 12 to 31%, n = 6). 3) Migrating cells expressed the highest CD26, whereas CD26 of adherent (nonmigrating) cells was divided into negative and high expression; in contrast, leukocyte adhesion molecule-1 (L-selectin) of both adherent and migrating cells was mostly low or negative. 4) [3H]Uridine incorporation of migrating and adherent cells was 2.1- to 2.5-fold and 1.4- to 1.7-fold higher, respectively, than that of unseparated cells, indicating that RNA synthesis of migrating cells as well as adherent cells was enhanced. 5) Cell cycle analysis showed that 23.5% of migrating cells appeared to enter the G1 phase but not S or G2 + M phases whereas 2.2% of unseparated cells and 8.0% of adherent cells that did not migrate had an RNA content consistent with entry into G1. These results suggest that cells migrating from normal human blood through unactivated EC have been activated recently as well as showing evidence of long term activation. The activation state of migrating cells is consistent with the hypothesis that previous in vivo activation is required for cells to migrate through EC in this system.

Animals↗