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PubMed2006

Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive gene.

Knee osteoarthritis (OA) results, at least in part, from overloading and inflammation leading to cartilage degradation. Prostaglandin E2 (PGE2) is one of the main catabolic factors involved in OA. Its synthesis is the result of cyclooxygenase (COX) and prostaglandin E synthase (PGES) activities whereas NAD+-dependent 15 hydroxy prostaglandin dehydrogenase (15-PGDH) is the key enzyme implicated in the catabolism of PGE2. For both COX and PGES, three isoforms have been described: in cartilage, COX-1 and cytosolic PGES are constitutively expressed whereas COX-2 and microsomal PGES type 1 (mPGES-1) are inducible in an inflammatory context. COX-3 (a variant of COX-1) and mPGES-2 have been recently cloned but little is known about their expression and regulation in cartilage, as is also the case for 15-PGDH. We investigated the regulation of the genes encoding COX and PGES isoforms during mechanical stress applied to cartilage explants. Mouse cartilage explants were subjected to compression (0.5 Hz, 1 MPa) for 2 to 24 hours. After determination of the amount of PGE2 released in the media (enzyme immunoassay), mRNA and proteins were extracted directly from the cartilage explants and analyzed by real-time RT-PCR and western blotting respectively. Mechanical compression of cartilage explants significantly increased PGE2 production in a time-dependent manner. This was not due to the synthesis of IL-1, since pretreatment with interleukin 1 receptor antagonist (IL1-Ra) did not alter the PGE2 synthesis. Interestingly, COX-2 and mPGES-1 mRNA expression significantly increased after 2 hours, in parallel with protein expression, whereas COX-3 and mPGES-2 mRNA expression was not modified. Moreover, we observed a delayed overexpression of 15-PGDH just before the decline of PGE2 synthesis after 18 hours, suggesting that PGE2 synthesis could be altered by the induction of 15-PGDH expression. We conclude that, along with COX-2, dynamic compression induces mPGES-1 mRNA and protein expression in cartilage explants. Thus, the mechanosensitive mPGES-1 enzyme represents a potential therapeutic target in osteoarthritis.

Animals↗

PubMed2003

IRAS is an anti-apoptotic protein.

Active cell death, also known as apoptosis, has been implicated in the pathophysiology of diseases such as cancer, heart failure and neurodegenerative disorders. We report the anti-apoptotic function of IRAS, which was previously shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS) is unrelated to known proteins, except for rat IRAS and a mouse homologue named nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor. When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167 kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed normal serum growth responses. However, hIRAS expression led to prolonged cell survival against known apoptotic stimuli: serum starvation or thapsigargin or staurosporine treatments. The apoptotic population of hIRAS-expressing cells was significantly reduced, and this protection was achieved by a decrease in caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar protective effect was obtained in COS7 cells transiently transfected with hIRAS. A partial activation of the PI3 kinase pathway is possibly implicated in the anti-apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown anti-apoptotic protein involved in the regulation of cell survival.

Animals↗

PubMed2004

Effects of 3,5,3'-triiodothyronine on the invasive potential and the expression of integrins and matrix metalloproteinases in cultured early placental extravillous trophoblasts.

It is well known that T(3) plays a crucial role in the maintenance of early pregnancy through the induction of endocrine function in villous trophoblasts. The effects of T(3) on extravillous trophoblast (EVT) function, however, remain to be elucidated. To investigate the possible role of T(3) in the regulation of EVT invasion to the decidua, we have examined whether T(3) affects EVT invasive potential and the expression of matrix metalloproteinase-2 (MMP-2), MMP-3, tissue inhibitor metalloproteinase-1, fetal fibronectin (FN), and integrin alpha(5)beta(1) in cultured early placental EVTs. Isolation and purification of trophoblasts differentiating into EVTs were performed by the enzymatic digestion of the anchoring chorionic villi, with the use of human FN-precoated culture dishes and FN-precoated Matrigel Transwells. The cells attached to the dishes were subcultured in DMEM supplemented with 10% fetal bovine serum for 48 h and were characterized by RT-PCR analysis after 24-h subculture and immunocytochemical analysis after 48-h subculture for specific EVT markers. Thereafter, the cultured cells were stepped down to a 4% fetal bovine serum condition and cultured in the presence or absence of T(3) (10(-8) m) for the subsequent 72 h. Matrigel invasion assay demonstrated that the treatment with T(3) significantly increased the number of cell projections of subsequent 24-, 48-, and 72-h cultured EVTs. RT-PCR analysis revealed that the treatment with T(3) increased the expression of MMP-2, MMP-3, fetal FN, and integrin alpha(5)beta(1) mRNA in subsequent 24-h cultured EVTs compared with those in control cultures. Immunocytochemical and Western immunoblot analyses revealed that treatment with T(3) increased the expression of MMP-2 and MMP-3 in subsequent 48-h cultured EVTs compared with those in control cultures. The present results suggest that T(3) (10(-8) m) may play a vital role in up-regulating the invasive potential of EVTs into the decidua.

Blotting, Western↗

PubMed2003

Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin.

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for several growth factors of the VEGF family. Endothelial cells express a membrane-spanning form of VEGFR-1 and secrete a soluble variant of the receptor comprising only the extracellular region. The role of this variant has not yet been completely defined. In this study, we report that the secreted VEGFR-1 is present within the extracellular matrix deposited by endothelial cells in culture, suggesting a possible involvement in endothelial cell adhesion and migration. In adhesion assays, VEGFR-1 extracellular region specifically promoted endothelial cell attachment. VEGFR-1-mediated cell adhesion was divalent cation-dependent, and inhibited by antibodies directed against the alpha 5 beta 1 integrin. Moreover, VEGFR-1 promoted endothelial cell migration, and this effect was inhibited by anti-alpha 5 beta 1 antibodies. Direct binding of VEGFR-1 to the alpha 5 beta 1 integrin was also detected. Finally, binding to VEGFR-1 initiated endothelial cell spreading. Altogether these results indicate that the soluble VEGFR-1 secreted by endothelial cells becomes a matrix-associated protein that is able to interact with the alpha 5 beta 1 integrin, suggesting a new role of VEGFR-1 in angiogenesis, in addition to growth factor binding.

Amino Acid Sequence↗

PubMed2004

The surface of articular cartilage contains a progenitor cell population.

It is becoming increasingly apparent that articular cartilage growth is achieved by apposition from the articular surface. For such a mechanism to occur, a population of stem/progenitor cells must reside within the articular cartilage to provide transit amplifying progeny for growth. Here, we report on the isolation of an articular cartilage progenitor cell from the surface zone of articular cartilage using differential adhesion to fibronectin. This population of cells exhibits high affinity for fibronectin, possesses a high colony-forming efficiency and expresses the cell fate selector gene Notch 1. Inhibition of Notch signalling abolishes colony forming ability whilst activated Notch rescues this inhibition. The progenitor population also exhibits phenotypic plasticity in its differentiation pathway in an embryonic chick tracking system, such that chondroprogenitors can engraft into a variety of connective tissue types including bone, tendon and perimysium. The identification of a chondrocyte subpopulation with progenitor-like characteristics will allow for advances in our understanding of both cartilage growth and maintenance as well as provide novel solutions to articular cartilage repair.

Amyloid Precursor Protein Secretases↗

PubMed2005

New target genes for NOV/CCN3 in chondrocytes: TGF-beta2 and type X collagen.

UNLABELLED: We studied the involvement of NOV/CCN3, whose function is poorly understood, in chondrocyte differentiation. NOV was found to upregulate TGF-beta2 and type X collagen and to act as a downstream effector of TGF-beta1 in ATDC5 and primary chondrocytes. Thus, NOV is a positive modulator of chondrogenesis. INTRODUCTION: NOV/CCN3 is a matricellular protein that belongs to the CCN family. A growing body of evidence indicates that NOV could play a role in cell differentiation, particularly in chondrogenesis. During chick embryo development, NOV expression is tightly regulated in cartilage, and a high expression of NOV has been associated with cartilage differentiation in Wilms' tumors. However, a precise role for NOV and potential target genes of NOV in chondrogenesis are unknown. MATERIALS AND METHODS: ATDC5 cells and primary chondrocytes were either treated with NOV recombinant protein or transfected with a NOV-specific siRNA to determine, using quantitative RT-PCR, the effect of NOV on the expression of several molecules involved in chondrocyte differentiation. Stable ATDC5 clones expressing NOV were also established to show that NOV was a downstream effector of TGF-beta1. RESULTS: We established that NOV/CCN3 expression increases in ATDC5 cells at early stages of chondrogenic differentiation and precedes the appearance of TGF-beta2 and of several chondrocytic markers such as SOX9 or type X collagen. When exogenously administered, NOV recombinant protein up-regulates TGF-beta2 and type X collagen mRNA levels both in ATDC5 cells and in primary mouse chondrocytes but does not influence SOX9 expression. This regulation also occurs at the endogenous level because downregulation of NOV expression is correlated with an inhibition of TGF-beta2 and type X collagen in primary chondrocytes. Furthermore, we found that NOV expression is downregulated when chondrocytes are exposed to TGF-beta1-dedifferentiating treatment in chondrocytes, further providing evidence that NOV may counteract TGF-beta1 effects on chondrocytes. CONCLUSIONS: This study provides the first characterization of two new targets of NOV involved in chondrocyte differentiation, shows that NOV acts with TGF-beta1 in a cascade of gene regulation, and indicates that NOV is a positive modulator of chondrogenesis.

Animals↗

PubMed2003

Oral cancer test.

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Biomarkers, Tumor↗

PubMed2006

Mechanics of cellular adhesion to artificial artery templates.

We are using polymer templates to grow artificial artery grafts in vivo for the replacement of diseased blood vessels. We have previously shown that adhesion of macrophages to the template starts the graft formation. We present a study of the mechanics of macrophage adhesion to these templates on a single cell and single bond level with optical tweezers. For whole cells, in vitro cell adhesion densities decreased significantly from polymer templates polyethylene to silicone to Tygon (167, 135, and 65 cells/mm(2)). These cell densities were correlated with the graft formation success rate (50%, 25%, and 0%). Single-bond rupture forces at a loading rate of 450 pN/s were quantified by adhesion of trapped 2-microm spheres to macrophages. Rupture force distributions were dominated by nonspecific adhesion (forces <40 pN). On polystyrene, preadsorption of fibronectin or presence of serum proteins in the cell medium significantly enhanced adhesion strength from a mean rupture force of 20 pN to 28 pN or 33 pN, respectively. The enhancement of adhesion by fibronectin and serum is additive (mean rupture force of 43 pN). The fraction of specific binding forces in the presence of serum was similar for polystyrene and polymethyl-methacrylate, but specific binding forces were not observed for silica. Again, we found correlation to in vivo experiments, where the density of adherent cells is higher on polystyrene than on silica templates, and can be further enhanced by fibronectin adsorption. These findings show that in vitro adhesion testing can be used for template optimization and to substitute for in-vivo experiments.

Animals↗

PubMed2006

Despite inhibition of hematopoietic progenitor cell growth in vitro, the tyrosine kinase inhibitor imatinib does not impair engraftment of human CD133+ cells into NOD/SCIDbeta2mNull mice.

There is potential interest for combining allogeneic hematopoietic cell transplantation (HCT), and particularly allogeneic HCT with a nonmyeloablative regimen, to the tyrosine kinase inhibitor imatinib (Glivec; Novartis, Basel, Switzerland, http://www.novartis.com) in order to maximize anti-leukemic activity against Philadelphia chromosome-positive leukemias. However, because imatinib inhibits c-kit, the stem cell factor receptor, it could interfere with bone marrow engraftment. In this study, we examined the impact of imatinib on normal progenitor cell function. Imatinib decreased the colony-forming capacity of mobilized peripheral blood human CD133(+) cells but not that of long-term culture-initiating cells. Imatinib also decreased the proliferation of cytokine-stimulated CD133(+) cells but did not induce apoptosis of these cells. Expression of very late antigen (VLA)-4, VLA-5, and CXCR4 of CD133(+) cells was not modified by imatinib, but imatinib decreased the ability of CD133(+) cells to migrate. Finally, imatinib did not decrease engraftment of CD133(+) cells into irradiated nonobese diabetic/severe combined immunodeficient/beta2m(null) mice conditioned with 3 or 1 Gy total body irradiation. In summary, our results suggest that, despite inhibition of hematopoietic progenitor cell growth in vitro, imatinib does not interfere with hematopoietic stem cell engraftment.

AC133 Antigen↗

PubMed2004

Mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4.

Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key roles in homing and mobilization of hematopoietic stem cells (HSC). Active signaling through SDF-1/CXCR4 and upregulation of adhesion molecules are required for homing, whereas downregulation of adhesion molecules and disruption of SDF-1/CXCR4 signaling are required for mobilization of HSC. We studied the surface expression of CXCR4 very late activation antigen (VLA)-4 and VLA-5 on myeloma cells mobilized with cyclophosphamide and GM-CSF in 12 multiple myeloma patients undergoing HSC mobilization for autologous transplantation. We also studied the plasma levels of SDF-1 in apheresis collection of these patients. We observed a statistically significant decrease in the levels of SDF-1 and surface expression of CXCR4 on myeloma cells in four consecutive apheresis collections compared with premobilization bone marrow specimens. We also observed a statistically significant decrease in surface expression of VLA-4 in myeloma cells in the apheresis collections compared with premobilization bone marrow samples. Furthermore, myeloma cells derived from apheresis collections had decreased adhesion and trans-stromal migration in response to SDF-1, which could be reversed by short incubation with interleukin-6. Hence, mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4.

Cell Adhesion↗

PubMed2004

Biomimetic approach on human periodontal ligament cells using synthetic oligopeptides.

BACKGROUND: Periodontal ligament (PDL) cells, connecting root cementum with alveolar bone, are important for periodontal wound healing. In order to obtain a predictable periodontal regeneration, selective adhesion and proliferation of PDL cells are essential. The purpose of this study was to investigate the effects of synthetic peptides mimicking cell-binding domain of fibronectin (FN) on human PDL cells. METHODS: Two types of oligopeptides, Gly3-Pro-His-Ser-Arg-Asn-Gly6-Arg-Gly-Asp-Gly (G3PHSRNG6RGDG) and Gly3-His-Pro-Asn-Arg-Ser-Gly6-Arg-Gly-Asp-Gly (G3HPNRSG6RGDG), were constructed using a solid-phase peptide synthesizer. Fibronectin type III ninth to tenth domain (FN III 9-10) and Arg-Gly-Asp-Ser (RGDS) were prepared for comparison with the effects of synthetic peptides. These peptides were coated onto 96-well cell culture plates with 0.001 approximately 100 microM concentrations. Cultured human PDL cells were then applied to the peptide-coated wells at a density of 1 x 10(4)/well. After 1 hour incubation at 37 degrees C, adhered cells were fixed, stained, and examined by phase contrast microscopy for cell spreading assay. Attached PDL cells were solubilized with 2% sodium dodecyl sulfate (SDS) for the cell attachment assay by measuring absorbance at 595 nm in microplate reader. Western blot analysis was performed to determine extracellular signal-regulated kinase (ERK1/2) activity. RESULTS: Cell attachment and spreading assays revealed that G3PHSRNG6RGDG (> or = 10 microM) possesses similar adhesive behavior to FN III 9-10. G3PHSRNG6RGDG showed a comparable ERK1/2 activity when compared to FN III 9-10. CONCLUSIONS: G3PHSRNG6RGDG enhanced an attachment and spreading of human PDL cells thereby increasing ERK1/2 activity. Taken together, it is anticipated that this peptide might be a potential tool for arranging a biologically attractive environment for PDL cells, which would enhance periodontal regeneration efficacy.

Analysis of Variance↗

PubMed2006

Inhibitory effects of tumor necrosis factor-alpha on migration of human periodontal ligament cells.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is associated with chronic gingival inflammation and is suspected to influence periodontal destruction. However, the exact roles of TNF-alpha in wound healing and periodontal tissue regeneration are largely unknown. In the present study, we examined the effects of TNF-alpha on migration and proliferation of human periodontal ligament (PDL) cells. METHODS: PDL cells were cultured in the presence of TNF-alpha to determine its effects on cellular migration and proliferation. The protein expression profiles of alpha5 and beta1 integrin subunits and their related molecules, paxillin and focal adhesion kinases (FAK), were investigated. Gene expression of fibronectin also was assayed. Further, the activation of Rho-family small guanosine triphosphate (GTP)-binding protein (RhoA) was evaluated using a GTP-loading pull-down assay, and focal adhesion formation by PDL cells after transfection with the expression vector of paxillin-fused green fluorescent protein (GFP) also was observed with confocal microscopy. RESULTS: Cellular migration was impaired by TNF-alpha and recovered following the addition of anti-TNF-alpha antibodies. In contrast, PDL cell proliferation was not affected by TNF-alpha. TNF-alpha upregulated the expression of the alpha5 and beta1 integrin subunits, whereas fibronectin was not overexpressed. Phosphorylation of paxillin and FAK by PDL cells was induced, and RhoA activation also was induced. Confocal microscopic analysis revealed that TNF-alpha induced focal adhesion and stress fiber formation in all parts of the cells. CONCLUSION: Our results suggested that TNF-alpha impairs cellular migration by enhancing cellular adhesive ability following significant focal adhesion and stress fiber formation.

Adolescent↗

PubMed2005

Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model.

Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model. Here, we examine the effect of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in preventing progression in the type 1 diabetic nephropathy mouse model. Endostatin peptide did not affect hyperglycemia induced by streptozotocin (STZ). Glomerular hypertrophy, hyperfiltration, and albuminuria were significantly suppressed by endostatin peptide (5 mg/kg) in STZ-induced diabetic mice. Glomerular mesangial matrix expansion, the increase of glomerular type IV collagen, endothelial area (CD31(+)), and F4/80(+) monocyte/macrophage accumulation were significantly inhibited by endostatin peptide. Increase in the renal expression of VEGF-A, flk-1, Ang-2, an antagonist of angiopoietin-1, transforming growth factor-beta1, interleukin-6, and monocyte chemoattractant protein-1 was inhibited by endostatin peptide in diabetic mice. Decrease of nephrin mRNA and protein in diabetic mice was suppressed by treatment with endostatin peptide. The level of endostatin in the renal cortex and sera was increased in diabetic mice. Endogenous renal levels of endostatin were decreased in endostatin peptide-treated groups in parallel with VEGF-A. Although serum levels of endostatin were decreased in the low-dose endostatin-peptide group, high-dose administration resulted in elevated serum levels of endostatin. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in diabetic nephropathy.

Albuminuria↗

PubMed2004

Stem cells expressing homing receptors could be expanded from cryopreserved and unselected cord blood.

We assessed the cytokine combinations that are best for ex vivo expansion of cord blood (CB) and the increment for cell numbers of nucleated cells, as well as stem cells expressing homing receptors, by an ex vivo expansion of cryopreserved and unselected CB. Frozen leukocyte concentrates (LC) from CB were thawed and cultured at a concentration of 1 x 10(5)/mL in media supplemented with a combination of SCF (20 ng/mL)+TPO (50 ng/mL)+FL (50 ng/mL)+/-IL-6 (20 ng/mL)+/-G-CSF (20 ng/mL). After culturing for 14 days, the expansion folds of cell numbers were as follows: TNC 22.3+/-7.8 approximately 26.3+/-4.9, CFU-GM 4.7+/-5.1 approximately 11.7+/-2.6, CD34+CD38- cell 214.0+/-251.9 approximately 464.1+/-566.1, CD34+CXCR4+ cell 4384.5+/-1664.7 approximately 7087.2+/-4669.3, CD34+VLA4+ cell 1444.3+/-1264.0 approximately 2074.9+/-1537.0, CD34+VLA5+ cell 86.2+/-50.9 approximately 113.2+/-57.1. These results revealed that the number of stem cells expressing homing receptors could be increased by an ex vivo expansion of cryopreserved and unselected CB using 3 cytokines (SCF, TPO, FL) only. Further in vivo studies regarding the engraftment after expansion of the nucleated cells, as well as the stem cells expressing homing receptors will be required.

ADP-ribosyl Cyclase↗

PubMed2005

Cross talk between MyD88 and focal adhesion kinase pathways.

Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase involved in signaling downstream of integrins, linking bacterial detection, cell entry, and initiation of proinflammatory response through MAPKs and NF-kappaB activation. In this study, using protein I/II from Streptococcus mutans as a model activator of FAK, we investigated the potential link between FAK and TLR pathways. Using macrophages from TLR- or MyD88-deficient mice, we report that MyD88 plays a major role in FAK-dependent protein I/II-induced cytokine release. However, response to protein I/II stimulation was independent of TLR4, TLR2, and TLR6. The data suggest that there is a cross talk between FAK and MyD88 signaling pathways. Moreover, MyD88-dependent, LPS-induced IL-6 secretion by human and murine fibroblasts required the presence of FAK, confirming that MyD88 and FAK pathways are interlinked.

Adaptor Proteins, Signal Transducing↗

PubMed2005

NF-kappa B mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments.

Fibronectin fragments (FN-f) that bind to the alpha(5)beta(1) integrin stimulate chondrocyte-mediated cartilage destruction and could play an important role in the progression of arthritis. The objective of this study was to identify potential cytokine mediators of cartilage inflammation and destruction induced by FN-f and to investigate the mechanism of their stimulation. Human articular chondrocytes, isolated from normal ankle cartilage obtained from tissue donors, were treated with a 110-kDa FN-f in serum-free culture, and expression of various cytokine genes was analyzed by cDNA microarray and by a cytokine protein array. Compared with untreated control cultures, stimulation by FN-f resulted in a >2-fold increase in IL-6, IL-8, MCP-1, and growth-related oncogene beta (GRO-beta). Constitutive and FN-f-inducible expression of GRO-alpha and GRO-gamma were also noted by RT-PCR and confirmed by immunoblotting. Previous reports of IL-1beta expression induced by FN-f were also confirmed, while TNF expression was found to be very low. Inhibitor studies revealed that FN-f-induced stimulation of chondrocyte chemokine expression was dependent on NF-kappaB activity, but independent of IL-1 autocrine signaling. The ability of FN-f to stimulate chondrocyte expression of multiple proinflammatory cytokines and chemokines suggests that damage to the cartilage matrix is capable of inducing a proinflammatory state responsible for further progressive matrix destruction, which also includes the chemoattraction of inflammatory cells. Targeting the signaling pathways activated by FN-f may be an effective means of inhibiting production of multiple mediators of cartilage destruction.

Cartilage, Articular↗

PubMed2006

A critical role for prostaglandin E2 in podosome dissolution and induction of high-speed migration during dendritic cell maturation.

Dendritic cells (DCs) are professional APCs of the immune system that play a key role in regulating T cell-based immunity. The capacity of DCs to activate T cells depends on their maturation state as well as their ability to migrate to the T cell areas of draining lymph nodes. In this study, we investigated the effects of DC maturation stimuli on the actin cytoskeleton and beta(1) integrin-dependent adhesion and migration. Podosomes, specialized adhesion structures found in immature monocyte-derived DCs as well as myeloid DCs, rapidly dissolve in response to maturation stimuli such as TNF-alpha and PGE(2), whereas the TLR agonist LPS induces podosome dissolution only after a long lag time. We demonstrate that LPS-mediated podosome disassembly as well as the onset of high-speed DC migration are dependent on the production of PGs by the DCs. Moreover, both of these processes are inhibited by Ab-induced activation of beta(1) integrins. Together, these results show that maturation-induced podosome dissolution and loss of alpha(5)beta(1) integrin activity allow human DCs to undergo the transition from an adhesive to a highly migratory phenotype.

Cell Adhesion↗

PubMed2006

Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy.

Cancer dormancy is a poorly understood stage of cancer progression. However, the ability to control this step of the disease offers novel therapeutic opportunities. Here we summarize recent findings that implicate the extracellular matrix and adhesion receptor signaling in the escape or induction of tumor dormancy. We further review evidence suggesting that imbalances in the activity ratio of ERK to p38 signaling may determine the fate (i.e., tumorigenicity vs. dormancy) of different carcinoma cells. Special attention is placed on the mechanisms that p38 signaling regulates during the induction of dormancy and how modulation of these pathways may offer a therapeutic opportunity. We also review evidence for a novel drug-resistance mechanism in dormant tumor cells that when blocked may enable killing of dormant tumor cells. Finally, we explore the notion that dormancy of tumor cells may be the result of a selective adaptive response that allows disseminated tumor cells to pause their growth and cope with stress signaling imposed by dissemination and/or treatment until growth can be restored.

Animals↗