The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Erik Sahai - One of the best experts on this subject based on the ideXlab platform.
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localized and reversible tgfbeta signalling switches breast cancer Cells from cohesive to single Cell Motility
Nature Cell Biology, 2009Co-Authors: Silvia Giampieri, Cerys S Manning, Steven Hooper, L Jones, Caroline S Hill, Erik SahaiAbstract:Here we use intravital imaging to demonstrate a reversible transition to a motile state as breast cancer Cells spread. Imaging primary tumours revealed heterogeneity in Cell morphology and Motility. Two distinct modes of Motility were observed: collective and single-Celled. By monitoring the localization of Smad2 and the activity of a TGFbeta-dependent reporter gene during breast cancer Cell dissemination, we demonstrate that TGFbeta signalling is transiently and locally activated in motile single Cells. TGFbeta1 switches Cells from cohesive to single Cell Motility through a transcriptional program involving Smad4, EGFR, Nedd9, M-RIP, FARP and RhoC. Blockade of TGFbeta signalling prevented Cells moving singly in vivo but did not inhibit Cells moving collectively. Cells restricted to collective invasion were capable of lymphatic invasion but not blood-borne metastasis. Constitutive TGFbeta signalling promoted single Cell Motility and intravasation but reduced subsequent growth in the lungs. Thus, transient TGFbeta signalling is essential for blood-borne metastasis.
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The actin cytoskeleton in cancer Cell Motility
Clinical & Experimental Metastasis, 2008Co-Authors: Michael F. Olson, Erik SahaiAbstract:Cancer Cell metastasis is a multi-stage process involving invasion into surrounding tissue, intravasation, transit in the blood or lymph, extravasation, and growth at a new site. Many of these steps require Cell Motility, which is driven by cycles of actin polymerization, Cell adhesion and acto-myosin contraction. These processes have been studied in cancer Cells in vitro for many years, often with seemingly contradictory results. The challenge now is to understand how the multitude of in vitro observations relates to the movement of cancer Cells in living tumour tissue. In this review we will concentrate on actin protrusion and acto-myosin contraction. We will begin by presenting some general principles summarizing the widely-accepted mechanisms for the co-ordinated regulation of actin polymerization and contraction. We will then discuss more recent studies that investigate how experimental manipulation of actin dynamics affects cancer Cell invasion in complex environments and in vivo.
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PDK1 regulates cancer Cell Motility by antagonising inhibition of ROCK1 by RhoE
Nature cell biology, 2008Co-Authors: Sophie Pinner, Erik SahaiAbstract:In three-dimensional matrices cancer Cells move with a rounded, amoeboid morphology that is controlled by ROCK-dependent contraction of acto-myosin. In this study, we show that PDK1 is required for phosphorylation of myosin light chain and Cell Motility, both on deformable gels and in vivo. Depletion of PDK1 alters the localization of ROCK1 and reduces its ability to drive cortical acto-myosin contraction. This form of ROCK1 regulation does not require PDK1 kinase activity, but instead involves direct binding of PDK1 to ROCK1 at the plasma membrane; PDK1 competes directly with RhoE for binding to ROCK1. In the absence of PDK1, negative regulation by RhoE predominates, causing reduced acto-myosin contractility and Motility. This work uncovers a novel non-catalytic role for PDK1 in regulating cortical acto-myosin and Cell Motility.
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erk mapk signaling coordinately regulates activity of rac1 and rhoa for tumor Cell Motility
Cancer Cell, 2003Co-Authors: Emmanuel Vial, Erik Sahai, Christopher J MarshallAbstract:Abstract We describe two signaling events downstream of ERK-MAP kinase contributing to Cell Motility in colon carcinoma Cells. The Fos family member Fra-1 is expressed in an ERK-dependent manner. Silencing of Fra-1 expression with short interfering RNAs leads to losses of Cell polarization, Motility, and invasiveness in vitro. These effects of ablating Fra-1 are a consequence of activation of a RhoA-ROCK pathway by β1-integrin, leading to an increase in the amount of stress fibers and stabilization of focal adhesions. We propose that Fra-1 promotes Cell Motility by inactivating β1-integrin and keeping RhoA activity low. This depression of RhoA activity is necessary to permit a second ERK-dependent signaling event via uPAR, the receptor for urokinase-type plasminogen activator, to activate Rac and to drive Motility through polarized lamellipodia extension.
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erk mapk signaling coordinately regulates activity of rac1 and rhoa for tumor Cell Motility
Cancer Cell, 2003Co-Authors: Emmanuel Vial, Erik Sahai, Christopher J MarshallAbstract:We describe two signaling events downstream of ERK-MAP kinase contributing to Cell Motility in colon carcinoma Cells. The Fos family member Fra-1 is expressed in an ERK-dependent manner. Silencing of Fra-1 expression with short interfering RNAs leads to losses of Cell polarization, Motility, and invasiveness in vitro. These effects of ablating Fra-1 are a consequence of activation of a RhoA-ROCK pathway by beta1-integrin, leading to an increase in the amount of stress fibers and stabilization of focal adhesions. We propose that Fra-1 promotes Cell Motility by inactivating beta1-integrin and keeping RhoA activity low. This depression of RhoA activity is necessary to permit a second ERK-dependent signaling event via uPAR, the receptor for urokinase-type plasminogen activator, to activate Rac and to drive Motility through polarized lamellipodia extension.
James P Allison - One of the best experts on this subject based on the ideXlab platform.
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cytotoxic t lymphocyte antigen 4 blockade enhances antitumor immunity by stimulating melanoma specific t Cell Motility
Cancer immunology research, 2014Co-Authors: Tsvetelina Pentchevahoang, Tyler R Simpson, Welby Montalvoortiz, James P AllisonAbstract:It is now clear that anti-CTLA-4 (α-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-Cell function or by depletion of regulatory T Cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T Cells, thus interrupting T-Cell receptor signaling and subsequent T-Cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T Cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included α-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-Cell Motility. When α-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T Cells in tumor-draining lymph nodes also increased. Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-Cell Motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T Cells and tumor targets or antigen-presenting Cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-Cell Motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-Cell exhaustion in persistent viral infections.
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cytotoxic t lymphocyte antigen 4 blockade enhances antitumor immunity by stimulating melanoma specific t Cell Motility
Cancer immunology research, 2014Co-Authors: Tsvetelina Pentchevahoang, Tyler R Simpson, Welby Montalvoortiz, James P AllisonAbstract:It is now clear that anti–CTLA-4 (α-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-Cell function or by depletion of regulatory T Cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a “go” signal to effector T Cells, thus interrupting T-Cell receptor signaling and subsequent T-Cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T Cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included α-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-Cell Motility. When α-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T Cells in tumor-draining lymph nodes also increased. Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-Cell Motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T Cells and tumor targets or antigen-presenting Cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-Cell Motility paralysis by programmed death 1 (PD-1)–specific antibodies during T-Cell exhaustion in persistent viral infections. Cancer Immunol Res; 2(10); 970–80. ©2014 AACR .
Seok Hee Park - One of the best experts on this subject based on the ideXlab platform.
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galectin 3 increases gastric cancer Cell Motility by up regulating fascin 1 expression
Gastroenterology, 2010Co-Authors: Seok Jun Kim, Il Ju Choi, Teak Chin Cheong, Sangjin Lee, Reuben Lotan, Seok Hee Park, Kyunghee ChunAbstract:Background & Aims Galectin-3 is a β-galactoside–binding protein that increases gastric cancer Cell Motility in response to integrin signaling and is highly expressed in gastric tumor Cells. Galectin-3 induces cytoskeletal remodeling to increase Cell Motility, but the mechanisms of this process are not understood. We investigated the effects of galectin-3 on fascin-1, an actin-bundling protein. Methods We collected malignant and normal tissues from gastric cancer patients and examined the expression levels of galectin-3 and fascin-1. We silenced galectin-3 expression in human gastric cancer Cell lines using small interfering RNA and lenti-viral constructs and determined the effects on fascin-1 expression, Cell Motility, and invasion. Results Malignant gastric tissues expressed high levels of galectin-3 and fascin-1, compared with normal gastric tissues. Silencing of galectin-3 resulted in altered cancer Cell morphology, reduced fascin-1 expression, decreased Cell Motility, and reduced malignant Cell invasion. Galectin-3 overexpression reversed these effects. Silencing of fascin-1 also reduced Cell Motility and caused changes in Cell shape, as did silencing of galectin-3. Furthermore, galectin-3 silencing inhibited the interaction between glycogen synthase kinase (GSK)-3β, β-catenin, and T-Cell factor (TCF) 4, and the binding of β-catenin/TCF-4 to the fascin-1 promoter. Nuclear localization of GSK-3β and β-catenin were not detected when galectin-3 was silenced. Overexpression of mutated galectin-3 (with mutations in the GSK-3β binding and phosphorylation motifs) did not increase fascin-1 levels, in contrast to overexpression of wild-type galectin-3. Conclusions Galectin-3 increases Cell Motility by up-regulating fascin-1 expression. Galectin-3 might be a potential therapeutic target for the prevention and treatment of gastric cancer progression.
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ionising radiation induces changes associated with epithelial mesenchymal transdifferentiation and increased Cell Motility of a549 lung epithelial Cells
European Journal of Cancer, 2007Co-Authors: Jaewon Jung, Seok Hee Park, Soyoung Hwang, Jisun Hwang, Eoksoo OhAbstract:Radiotherapy remains a major therapeutic option for patients with advanced lung cancer. Nevertheless, the effects of irradiation on malignant biological behaviours (e.g. migration and transformation of cancer Cells) have yet to be clarified. We conducted an in vitro study to investigate the radiation-induced alterations including morphology, adhesion, and Cell Motility of A549 human lung cancer Cells. These changes, which are associated with epithelial-mesenchymal transdifferentiation (EMT), seem to be linked to radiation-induced fibrosis, which represents one of the most common long-term adverse effects of curative radiotherapy. In addition, loss of interCellular adhesion and increased Cell Motility may be involved in post-radiotherapy-associated metastasis. We showed that stress fibres and focal adhesions are increased and that Cell–Cell junctions are decreased in response to ionising radiation. Radiation also significantly increased Cell Motility. The p38-specific inhibitor, SB203580, reduced the radiation-promoted migration of A549 Cells, whereas SP600125, a JNK MAPK-specific inhibitor, inhibited both inherent and radiation-mediated Cell Motility. Consistent with this observation, radiation up-regulated the phosphorylation of p38 MAPK. Current approaches to cancer treatment involving more intensive radiotherapy regimens have been suggested to be associated with a higher incidence of local or distant metastasis. Therefore, a subset of patients may benefit from a combination of radiotherapy with inhibitors of EMT or Cell migration.
Yoshimi Takai - One of the best experts on this subject based on the ideXlab platform.
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involvement of rho p21 small gtp binding protein and its regulator in the hgf induced Cell Motility
Oncogene, 1994Co-Authors: Kenji Takaishi, Takuya Sasaki, Masaki Kato, Wataru Yamochi, Shinya Kuroda, T Nakamura, Masatoshi Takeichi, Yoshimi TakaiAbstract:Hepatocyte growth factor (HGF) induced Motility of cultured mouse keratinocytes (308R Cells). This HGF-induced Cell Motility was inhibited by microinjection of either rho GDI, an inhibitory GDP/GTP exchange protein for rho p21 small GTP-binding protein, or a botulinum exoenzyme C3 which is known to selectively impair the function of rho p21 by ADP-ribosylating its effector domain. The rho GDI action was prevented by comicroinjection with the guanosine 5'-(3-0-thio)triphosphate (GTP gamma S)-bound active form of rhoA p21, and the C3 action was prevented by comicroinjection with a rhoA p21 mutant (rhoAIle41 p21) which is resistant to the C3 action. The HGF-induced Cell Motility was not inhibited by microinjection of a dominant negative rac1 p21 mutant (rac1Asn17 p21) or a dominant negative Ki-ras p21 mutant (Ki-rasAsn17 p21). Microinjection of the GTP gamma S-bound form of rac1 p21 or a dominant active Ki-ras p21 mutant (Ki-rasVal12 p21) did not induce Cell Motility. These results indicate that both rho p21 and rho GDI, but neither rac p21 nor ras p21, are involved in the HGF-induced Cell Motility. However, microinjection of the GTP gamma S-bound form of rhoA p21 alone did not induce Cell Motility in the absence of HGF, suggesting that activation of rho p21 is necessary but not sufficient for the HGF-induced Cell Motility. The HGF-induced Cell Motility was mimicked by 12-0-tetradecanoyl-phorbol-13-acetate, a protein kinase C-activating phorbol ester, but not by Ca2+ ionophore. The phorbol ester-induced Cell Motility was also inhibited by microinjection of rho GDI or C3. These results indicate that both rho p21 and rho GDI are also involved in the phorbol ester-induced Cell Motility.
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involvement of rho p21 and its inhibitory gdp gtp exchange protein rho gdi in Cell Motility
Molecular and Cellular Biology, 1993Co-Authors: Kenji Takaishi, Akira Kikuchi, Takuya Sasaki, Shinya Kuroda, Ko Kotani, Yoshimi TakaiAbstract:Evidence is accumulating that rho p21, a ras p21-related small GTP-binding protein (G protein), regulates the actomyosin system. The actomyosin system is known to be essential for Cell Motility. In the present study, we examined the action of rho p21, its inhibitory GDP/GTP exchange protein (named rho GDI), its stimulatory GDP/GTP exchange protein (named smg GDS), and Clostridium botulinum ADP-ribosyltransferase C3, known to selectively ADP-ribosylate rho p21 and to impair its function, in Cell Motility (chemokinesis) of Swiss 3T3 Cells. We quantitated the capacity of Cell Motility by measuring Cell tracks by phagokinesis. Microinjection of the GTP gamma S-bound active form of rhoA p21 or smg GDS into Swiss 3T3 Cells did not affect Cell Motility, but microinjection of rho GDI into the Cells did inhibit Cell Motility. This rho GDI action was prevented by comicroinjection of rho GDI with the GTP gamma S-bound form of rhoA p21 but not with the same form of rhoA p21 lacking the C-terminal three amino acids which was not posttranslationally modified with lipids. The rho GDI action was not prevented by Ki-rasVal-12 p21 or any of the GTP gamma S-bound form of other small GTP-binding proteins including rac1 p21, G25K, and smg p21B. Among these small G proteins, rhoA p21, rac1 p21, and G25K are known to be substrates for rho GDI. The rho GDI action was not prevented by comicroinjection of rho GDI with smg GDS. Microinjection of C3 into Swiss 3T3 Cells also inhibited Cell Motility. These results indicate that the rho GDI-rho p21 system regulates Cell Motility, presumably through the actomyosin system.
Tsvetelina Pentchevahoang - One of the best experts on this subject based on the ideXlab platform.
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cytotoxic t lymphocyte antigen 4 blockade enhances antitumor immunity by stimulating melanoma specific t Cell Motility
Cancer immunology research, 2014Co-Authors: Tsvetelina Pentchevahoang, Tyler R Simpson, Welby Montalvoortiz, James P AllisonAbstract:It is now clear that anti-CTLA-4 (α-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-Cell function or by depletion of regulatory T Cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T Cells, thus interrupting T-Cell receptor signaling and subsequent T-Cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T Cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included α-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-Cell Motility. When α-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T Cells in tumor-draining lymph nodes also increased. Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-Cell Motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T Cells and tumor targets or antigen-presenting Cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-Cell Motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-Cell exhaustion in persistent viral infections.
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cytotoxic t lymphocyte antigen 4 blockade enhances antitumor immunity by stimulating melanoma specific t Cell Motility
Cancer immunology research, 2014Co-Authors: Tsvetelina Pentchevahoang, Tyler R Simpson, Welby Montalvoortiz, James P AllisonAbstract:It is now clear that anti–CTLA-4 (α-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-Cell function or by depletion of regulatory T Cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a “go” signal to effector T Cells, thus interrupting T-Cell receptor signaling and subsequent T-Cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T Cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included α-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-Cell Motility. When α-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T Cells in tumor-draining lymph nodes also increased. Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-Cell Motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T Cells and tumor targets or antigen-presenting Cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-Cell Motility paralysis by programmed death 1 (PD-1)–specific antibodies during T-Cell exhaustion in persistent viral infections. Cancer Immunol Res; 2(10); 970–80. ©2014 AACR .