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Burthem, John. "Hairy cell adhesion and migration." Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240394.
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Sundar, Rajan Vinoth Edal Joseph. "Adhesion and transendothelial migration of cancer cells." Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV065/document.
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Les métastases sont responsables de 90 % des décès causés par le cancer. Les métastases sont des foyers cancéreux secondaires qui se forment à distance de la tumeur d’origine. Des cellules cancéreuses quittent la tumeur primaire, rejoignent la circulation sanguine puis colonisent des organes voisins par migration à travers l’endothélium vasculaire. Ce phénomène d’adhésion à l’endothélium et de migration à travers l’endothélium appelé l’extravasation est une étape clé du processus métastatique. L’identification des molécules impliquées constitue une priorité dans le but d’élaborer de nouvelles drogues anticancéreuses. Nous avons précédemment montré que la molécule d’adhésion cellulaire InterCellular Adhesion Molecule-1 (ICAM-1) exprimée par les cellules endothéliales, est impliquée dans l’interaction des cellules de cancer de la vessie (BCs) avec l’endothélium. Cependant les ligands d’ICAM-1 n’ont pas été étudiés. Dans cette étude, nous utilisons des tests d'adhésion cellulaire et la microscopie à force atomique (AFM) afin d’identifier les ligands d’ICAM-1 et de mesurer les forces impliquées dans l’interaction ligand-ICAM-1. Nous avons identifié que les protéines MUC1 et CD43 exprimées par les BCs les plus invasives se lient à ICAM-1 en développant des forces d’intensité différente selon le couple considéré. Une analyse détaillée des événements de rupture suggère que CD43 est fortement lié au cytosquelette et que son interaction avec ICAM-1 correspond principalement à des sauts brusques. Au contraire, MUC1 semble être lié faiblement au cytosquelette et ses interactions avec ICAM-1 sont principalement associées à la formation de filaments membranaires ou « tethers ». Les forces mises en jeu lors de la migration des cellules cancéreuses à travers l'endothélium ont été étudiées par microscopie de forces de traction (TFM). Les résultats préliminaires montrent que les tractions exercées par les cellules cancéreuses lors de l’extravasation sont mesurables par TFMCancer metastasis is associated with 90% cancer-associated deaths, when cancer cells escape from the primary tumor and form metastatic colonies in secondary sites. Extravasation is an important step in cancer metastasis, where cancer cells carried in blood, adhere and transmigrate through the endothelium. Therefore identifying the key molecules involved during the adhesion process could enable to develop new anticancer cancer drugs able to inhibit the adhesion of cancer cells to the endothelium. We have previously shown that InterCellular Adhesion Molecule-1 (ICAM-1) expressed by endothelial cells is involved in the interactions of bladder cancer cells (BCs) with the endothelium. However the ICAM-1 ligands have never been investigated. In this study, we combined adhesion assays and Atomic Force Microscopy (AFM) to identify the ligands involved and to quantify the forces relevant in such interactions. We report the expression of MUC1 and CD43 on BCs and demonstrate that these ligands interact with ICAM-1 to mediate cancer cell-endothelial cell adhesion in the case of the more invasive BCs. AFM experiments were performed to quantify the force ranges involved by MUC1 and CD43 during their interaction with ICAM-1. AFM measurements combined with a Gaussian Mixture Model showed distinct force ranges for the interaction of ICAM-1 with MUC1 and ICAM-1 with CD43. Furthermore, a detailed analysis of the rupture events suggests that CD43 is strongly connected to the cytoskeleton and that its interaction with ICAM-1 mainly corresponds to force ramps followed by sudden jumps. On the contrary, MUC1 seems to be weakly connected to the cytoskeleton as its interactions with ICAM-1 are mainly associated with the formation of tethers. The forces involved during the transmigration of cancer cells through the endothelium was investigated using Traction Force Microscopy (TFM). Preliminary results showed that tractions exerted by cancer cells during transmigration can be studied and quantified using TFM
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Baghdadchi, Negin. "CYTOKINE CONTROL OF GLIOMA ADHESION AND MIGRATION." CSUSB ScholarWorks, 2014. https://scholarworks.lib.csusb.edu/etd/93.
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Glioblastoma multiforme (GBM) is the most lethal primary central nervous system tumor, with median survival after diagnosis of less than 12 months because dissemination into the brain parenchyma limits the long-term effectiveness of surgical resection, and because GBM cells are resistant to radiation and chemotherapy. This sad dismal prognosis for patients with GBM emphasizes the need for greater understand of the fundamental biology of the disease.
Invasion is one of the major causes of treatment failure and death from glioma, because disseminated tumor cells provide the seeds for tumor recurrence. Inflammation is increasingly recognized as an important component of invasion. In the brain, inflammation can occur by activation of microglia, the resident macrophages of the brain, or by tumor-associated blood macrophages. Therefore, we hypothesize that activity of the innate immune system in the brain can influence tumor progression by secreting cytokines such as Tumor Necrosis Factor alpha (TNF-α). In this study, we show that patient-derived glioma spheres undergo morphological changes in response to TNF‑α that are associated with changes in migration behavior in vitro. These morphological changes include appearance of tumor islands in site different from where the primary tumor cells were seeded. We further showed that TNF‑α treated cells significantly increased expression of cell adhesion molecules such as CD44 and VCAM-1. Furthermore, we demonstrate increased cell density also caused increased in expression of cell adhesion molecules. The extent to which these are recapitulated in vivo will be investigated.
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Chen, Ning. "Role of cell adhesion molecules in melanoma transendothelial migration." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58734.pdf.
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Golé, Laurent. "Migration of Dictyostelium Amoeba : role of Adhesion and Quorum sensing." Phd thesis, Université Claude Bernard - Lyon I, 2011. http://tel.archives-ouvertes.fr/tel-00846586.
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This thesis focuses on the analysis of the role of adhesion between substrate and cell and factors of Quorum sensing on the migration of Dictyostelium amoeba. Tools to automate the recordings of videomicroscopy and image analysis have been developed to work with very large samples of cells and toquantify cell migration. A microfluidic device for cell detachment in hydrodynamic flow combined witha motorized stage has allowed a statistical study of adhesion but also the dynamics of detachment. The analysis of the migration of Dictyostelium in non nutritive medium highlights the role of density on celldifferentiation and migration capacity. We observe the presence of a maximum speed of migration after6 hours of starvation. We show that the adhesion to glass is twice as low in deprivation buffer as inthe nutrient medium. The experiences of migration in growth medium revealed the presence of a factorof detection of density secreted by the cells and regulating their random migration. The diffusion coefficient, the persistence of the movement and morphology of cells vary depending on the concentrationof this factor. This factor does not affect cell adhesion but only the dynamics of detachment. Finally, the testing protocol developed allowed us to make a comparative study of migration by varying otherparameters such as surface or the chemical composition of experimental medium. This work concludesby outlining the possible role of adhesion to the migration of Dictyostelium in nutrient medium.
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Boespflug, Nicholas. "ATF3 regulates neutrophil migration in mice." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382372804.
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Li, Yi-Yang Cheung H. Tak. "Basement membrane and its components on lymphocyte adhesion, migration, and proliferation." Normal, Ill. Illinois State University, 1992. http://wwwlib.umi.com/cr/ilstu/fullcit?p9234466.
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Thesis (Ph. D.)--Illinois State University, 1992.Title from title page screen, viewed January 27, 2006. Dissertation Committee: H. Tak Cheung (chair), Anthony Otsuka, Alan Katz, Brian Wilkinson, David Weber. Includes bibliographical references (leaves 108-120) and abstract. Also available in print.
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Li, ShuShun. "Thrombospondin 1, an autocrine regulator in T cell adhesion and migration." Doctoral thesis, Umeå : Klinisk mikrobiologi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-599.
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Cichon, Monika Agnieszka. "Axl regulates adhesion, migration and stem-like properties of cancer cells." Thesis, Queen Mary, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610930.
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Vielkind, Susina. "Role of the GTPase Rho in T cell adhesion and migration." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406052.
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Rabut, Anne. "Regulation of Drosophila E-cadherin mediated adhesion during border cell migration." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. https://publication-theses.unistra.fr/public/theses_doctorat/2004/RABUT_Anne_2004.pdf.
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Au cours du développement, les cadhérines sont des médiateurs importants de l'adhérence entre cellules. Dans de nombreux processus développementaux, ces interactions intercellulaires sont très probablement régulées. De multiples mécanismes régulateurs de l'adhérence intercellulaire ont été étudiés dans des cellules en culture ; leur signification physiologique n'est cependant pas connue. Nous avons utilisé la Drosophile comme modèle d'étude de ces mécanismes in vivo. Nous avons généré plusieurs formes mutantes de la DE-cadhérine (Drosophila Epithelial Cadherin) et testé leur capacité à remplacer la DE-cadhérine endogène au cours du développement et de l'ovogenèse, en particulier au cours de la migration des cellules de bordure. Différents mutants DE-cadhérine nous ont permis de montrer que ni l'interaction entre la DE-cadhérine et p120ctn, ni le domaine juxtamembranaire de la DE-cadhérine, ni les tyrosines conservées présentes dans le domaine cytoplasmique ne sont essentielles pour la fonction de la DE-cadhérine. DE-cadhérine-Db/a-caténine (a-caténine fusionnée après le domaine juxtamembranaire de la DE-cadhérine) se substitue partiellement à la DE-cadhérine endogène dans les cellules de bordure, montrant que la régulation du lien entre la DE-cadhérine et a-caténine n'est pas strictement nécessaire à la migration. DE-cadhérine-DCyt/a-caténine (a-caténine fusionnée après le domaine transmembranaire de la DE-cadhérine) se substitue à la DE-cadhérine endogène dans l'épithélium folliculaire mais pas dans les cellules de bordure, suggérant que des signaux régulateurs importants pour la migration pourraient être présents dans le domaine cytoplasmique. Des expériences supplémentaires seront nécessaires pour confirmer que les défauts de migration observés avec DE-cadhérine-DCyt/a-caténine sont bien dus à une absence de régulation. Si cela s'avère être le cas, il restera à identifier plus précisement le(s) mécanisme(s) régulant DE-cadhérine dans les cellules de bordureClassic cadherins are major mediators of homophilic cell-cell adhesion during animal development. In many developmental processes cadherin-dependent adhesive interactions between cells are likely to be regulated. A lot has been done to understand how adhesion is regulated in tissue culture experiments, but so far little is known about the relevance of the studied regulatory mechanisms in vivo. We used Drosophila as a model to study these putative regulatory mechanisms during development. Several mutant variants of Drosophila Epithelial cadherin (DE-cadherin) were generated. Their ability to substitute for endogenous DE-cadherin activity was analyzed in multiple cadherin-dependent processes during Drosophila development and oogenesis, in particular during border cell migration, a process that probably requires dynamic adhesion. Using different DE-cadherin variants, I showed that DE-cadherin/p120ctn interaction, DE-cadherin juxtamembrane domain as well as the conserved tyrosines in DE-cadherin cytoplasmic domain are surprisingly all dispensable for DE-cadherin function. DE-cadherin-Db/a-catenin (a-catenin fused after DE-cadherin juxtamembrane domain) partially substitutes for endogenous DE-cadherin in border cells, showing that regulation of the link between DE-cadherin and a-catenin is not strictly required for the migration. DE-cadherin-DCyt/a-catenin (a-catenin fused after DE-cadherin transmembrane domain) is able to mediate adhesion in the follicular epithelium but does not substitute for endogenous DE-cadherin in border cells, suggesting that some regulatory signals important for the migration may be located in DE-cadherin cytoplasmic domain. However, DE-cadherin-DCyt/a-catenin also have some clear subcellular localization defects and it is so far not completely clear if the observed migration defects are really due to lack of adhesion regulation. If this is the case, the precise regulatory mechanisms will still need to be identified
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Lamberti, Giuseppina. "A BIOMIMETIC MICROFLUIDIC DEVICE FOR MODELING THE LEUKOCYTE ADHESION/MIGRATION CASCADE." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/265841.
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Mechanical EngineeringPh.D.
There is a clear need for testing targeted drug carrier systems in a more realistic microenvironment where both biochemical interactions and shear forces are present. This is critical both for understanding of the molecular mechanisms involved in this process and during the drug discovery process. Current in vitro models of the leukocyte adhesion cascade cannot be used for real-time studies of the entire leukocyte adhesion cascade including rolling, adhesion and migration in a single assay. In this study, we have developed and validated a novel bioinspired microfluidic device (bMFD) and used it to test the hypothesis that blocking of specific steps in the adhesion/migration cascade significantly affects other steps of the cascade. The bMFD consists of an endothelialized microvascular network in communication with a tissue compartment via a 3 µm porous barrier. Human neutrophils in bMFD preferentially adhered to activated human endothelial cells near bifurcations with rolling and adhesion patterns in close agreement with in vivo observations. Treating endothelial cells with monoclonal antibodies to E-selectin or ICAM-1 or treating neutrophils with wortmannin reduced rolling, adhesion, and migration of neutrophils to 60%, 20% and 18% of their respective control values. Antibody blocking of specific steps in the adhesion/migration cascade (e.g. mAb to E-selectin) significantly downregulated other steps of the cascade (e.g. migration). This novel in vitro assay provides a realistic human cell based model for basic science studies, identification of new treatment targets, selection of pathways to target validation, and rapid screening of candidate agents.
Temple University--Theses
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Lee, Eun-ju Yousaf Muhammad. "Development of dynamic substrates for studies of cell adhesion and migration." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2284.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Jun. 26, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.
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Bliss, Katherine Theresa. "Elucidating the Role of Lasp-2 in Cell Adhesion and Migration." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/255198.
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In order for cells to migrate, communicate, and facilitate attachment to the surrounding extraceullar matrix, they must form intricate protein complexes called focal adhesions. The number of identified focal adhesion components continues to grow and the field is an area of active study.Lasp-2 is a member of the nebulin family of actin-binding proteins that has been identified as a member of focal adhesion complexes. To gain further insights into the functional role of lasp-2, we identified two additional binding partners of lasp-2, the integral focal adhesion proteins, vinculin and paxillin. Interestingly, the interaction of lasp-2 with its binding partners vinculin and paxillin was significantly reduced in presence of lasp-1, another nebulin family member. The presence of lasp-2 appears to enhance the interaction of vinculin and paxillin with each other, however, as with the interaction of lasp-2 with vinculin or paxillin, this effect is greatly diminished in the presence of excess lasp-1 suggesting the interplay between lasp-2 and lasp-2 could be an adhesion regulatory mechanism. Lasp-2's potential role in metastasis was revealed as overexpression of lasp-2 in SW620 cells, a highly metastatic cancer cell line, increased cell migration, but impeded cell invasion.Lasp-2 transcript and protein is readily detected in neural tissues. Preliminary experiments involving the knockdown of lasp-2- in frog embryos revealed gross morphological abnormalities in the head region as well as the inability to move normally. Neural crest derived melanocytes also failed to migrate normally.Taken together, these data suggest that lasp-2 has an important role in coordinating and regulating the composition and dynamics of focal adhesions.
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Newe, Abigail Lucy. "Unearthing the molecular mechanisms that govern L-selectin-dependent adhesion and migration." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/unearthing-the-molecular-mechanisms-that-govern-lselectindependent-adhesion-and-migration(8f22370e-34b7-447f-98c2-dd1713036a84).html.
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L-selectin has been well characterised as a cell adhesion molecule, which plays a role in the recruitment of leukocytes to sites of inflammation and is responsible for the recirculation of lymphocytes to secondary lymphoid organs. Recent evidence has shown that L-selectin also acts as a signalling molecule to activate pathways and regulate the inflammatory response. The cytosolic tail of L-selectin plays a crucial role in regulating its activity through its interaction with binding partners, such as calmodulin (CaM) and the ERM protein family. However, little is known about how the interaction between L-selectin and its binding partners is regulated. The aim of this multidisciplinary PhD project is to use biophysical and cell biological methods to address the role of the interaction between L-selectin and its binding partners during leukocyte recruitment. To this end, the interaction between CaM and the L-selectin cytosolic tail was assessed using isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. Analysis revealed that phosphorylation of serine residues within the cytosolic tail of L-selectin did not affect CaM binding. To enable the observation of the interaction between L-selectin and CaM whilst leukocytes are undergoing transendothelial migration (TEM), the THP-1 monocytic cell line was engineered to stably express L-selectin-GFP and CaM-RFP so their interaction could be monitored at different stages of TEM. The data showed that phosphorylation of serine 364 in the L-selectin tail is important for regulating CaM interaction. Discrepancies were identified between the biophysical and cell biological results, implying the leukocyte plasma membrane may play a vital role in regulating the interaction between L-selectin and CaM. This highlights the importance of studying transmembrane proteins in the correct context.
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Mangiante, Lee Elena Taylor Joan M. "The role of focal adhesion kinase in vascular smooth muscle cell migration." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2137.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Pathology and Laboratory Medicine." Discipline: Pathology and Laboratory Medicine; Department/School: Medicine.
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Deem, Tracy L. "VCAM-1 Signaling in Endothelial Cells for Lymphocyte Migration." University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1096565014.
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Tse, Kathy Wan-Kei. "The role of Pyk2 and FAK in B cell migration, adhesion, and spreading." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/25041.
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The ability of the B cell receptor (BCR) to stimulate integrin-mediated adhesion, and induce cytoskeletal reorganization and cell spreading enhances the ability of B cells to bind and respond to antigens (Ag). The proper localization and trafficking of B cells in the secondary lymphoid organs are also critical for B cells to encounter Ags and to be activated. Proline-rich tyrosine kinase (Pyk2) and focal adhesion kinase (FAK) are related cytoplasmic tyrosine kinases that have been shown to regulate cell adhesion, morphology, and migration. However, their functions in B cells are not clear. The overall hypothesis of this thesis was that Pyk2 and FAK are downstream targets of BCR, integrin, and chemokine receptor signaling, and that they are involved in B cell morphological regulation, migration, and adhesion. I showed that the BCR and integrins collaborate to induce the phosphorylation of Pyk2 and FAK on key tyrosine residues, modifications that increase the kinase activity of Pyk2 and FAK. Activation of the Rap1 GTPase is critical for BCR-induced integrin activation and for BCR-induced reorganization of the actin cytoskeleton and I showed that inhibition of Pyk2 and FAK function by either gene knockdown or the use of chemical inhibitors impaired B cell spreading.
Marginal zone (MZ) B cells are innate-like B cells that are responsible for T cell-independent responses to microbial pathogens. The proper localization of MZ B cells is dependent on integrated migration and retention signals provided by the stromal cells in the spleen. Because MZ B cells are not found in Pyk2-/- mice, I hypothesized that Pyk2 and FAK are involved in MZ B cell retention in the spleen. I showed that Pyk2 and FAK are required for MZ B cell migration and that Pyk2 is required for integrin-dependent adhesion in response to chemoattractant stimulation. Moreover, I found that FAK is involved in chemokine-induced Akt phosphorylation in MZ B cells.
In summary, Pyk2 and FAK are downstream targets of the Rap GTPases and play a key role in regulating B cell morphology, migration, and adhesion.
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Kang, Inkyung. "CHANGES IN THE BIOMECHANICAL PROPERTIES OF ENDOTHELIAL CELLS DURING NEUTROPHIL ADHESION AND MIGRATION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1149881623.
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FERRARIS, G. M. SARRA. "NON-INTEGRIN CELL ADHESION TRIGGERS LIGAND-INDEPENDENT INTEGRIN SIGNALING." Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/157459.
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Integrins are the major family of cell surface adhesion receptors responsible for the regulation of the physical contact and biochemical communication between the cell and the surrounding extracellular matrix (ECM). Binding of the extracellular domains of integrins to components in the ECM triggers a series of molecular events commonly referred to as “outside-in” signaling, leading to context-dependent changes in cell morphology, migration and proliferation. In this prevailing paradigm of cell adhesion induced signaling the primary functions of the integrin is to provide the physical transmembrane bridge connecting the intracellular signaling machinery and cytoskeleton to the extracellular environment.
We now present evidence that most, if not all, cell adhesion receptors trigger integrin-dependent outside-in signaling independently of direct contacts between the integrins and their ligands in the ECM. The urokinase-type plasminogen activator receptor (uPAR/CD87) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the outer membrane leaflet by a GPI-anchor. Through an extensive structure-function analysis of uPAR, VN, β1 and β3 we document that cell adhesion induced by the uPAR/VN-interaction triggers integrin-mediated, but ligand independent, cell spreading and signaling. This signaling is fully active on VN lacking functional integrin binding sites and by integrin mutants deficient in ligand binding, but is crucially dependent on an “active” conformation of the integrin as well as its binding to intracellular adaptor proteins including talin and kindlin. This novel paradigm of ligand-independent integrin signaling is not restricted to uPAR as it poses no identifiable constraints to the adhesion receptor with respect to ternary-structure, ligand type or means of membrane anchorage. In full accordance with a general validity of this paradigm, we show that cell adhesion physically mediated by a signaling-incompetent β3 integrin is effectively translated into cell spreading and signaling by the β1 integrin.
Our results show that integrins are active in transducing adhesion-induced signaling in the absence of their cognate ligands, suggesting that the bi-directional signaling capability of these receptors may have evolved primarily to allow for tightly regulated inside-out signaling.
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Chon, John H. "Mediation of vascular smooth muscle cell adhesion and migration by cell surface heparan sulfate glycosaminoglycans." Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/11315.
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Imtiaz, Sarah [Verfasser], Philippe [Akademischer Betreuer] Philippe, and Leif [Gutachter] Dehmelt. "Distinct focal adhesion protein modules control the adhesion site segregation and cell migration behavior / Sarah Imtiaz ; Gutachter: Leif Dehmelt ; Betreuer: Philippe Philippe." Dortmund : Universitätsbibliothek Dortmund, 2017. http://d-nb.info/1175625469/34.
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Hu, Shiqiong. "Mechanics and Dynamics of Cell Adhesion : Experimental Study of the Osteoclasts." Lyon, Ecole normale supérieure, 2010. http://www.theses.fr/2010ENSL0594.
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Osteoclasts are large, multinucleated cells, which resorb mineralized bone. When an osteoclast encounters a substrate, dot-like actin-rich structures, the podosomes, appear and assemble into clusters, rings or a belt. We experimentally investigate, from a cell population to a single podosome, their function and dynamics. Over a cell population, kinetic measurements show that the cell surface area A scales as A ~ K2, where K is the number of nuclei, indicating a flat morphology. By defining quantities that account for the spatial distribution of the actin within the cell, we demonstrate that the podosomes organization only depends on the time after differentiation, and not on K. In a single osteoclast, the observation of a strong coupling between cell spreading and podosomes formation lead us to propose that podosomes play an important role in osteoclast motility. Analysis of osteoclast migration, and the forces it applies on the substrate, demonstrates that the internal dynamics of the actin within the cell does not only correlate with cell migration, but drives it. Finally, in order to understand the internal dynamics of a single podosome, we improved the model of Biben et al. (2005) by considering on the one hand, actin polymerization, and on the other hand, diffusion and attachment kinetics of the gelsolin, an actin severing protein. We find that podosomes are mainly governed by the actin dynamics, regardless of gelsolin concentrationLes ostéoclastes sont des cellules multinucléées, responsables de la résorption osseuse. Quand ils sont déposés sur un substrat, des structures ponctuelles riches en actine, les podosomes, apparaissent et s'assemblent en clusters, anneaux ou ceinture. Nous avons étudié expérimentalement leur fonction et leur dynamique, depuis une population entière jusqu'à l'échelle d'un unique podosome. Sur une population de cellules, des mesures cinétiques montrent que la surface de la cellule A varie comme A ~ K2, où K est le nombre de noyaux ; ce résultat indique une forme aplatie. Par ailleurs, la mesure de quantités qui prennent en compte l'organisation spatiale de l'actine dans la cellule montre que l'organisation des podosomes ne dépend que du temps écoulé après différentiation, et non de K. Dans un seul ostéoclaste, l'observation d'un fort couplage entre l'étalement d'une cellule et la formation des podosomes nous a conduit a suggérer que les podosomes jouent un rôle important dans la mobilité des ostéoclastes. L'analyse de la migration d'ostéoclastes, ainsi que des forces appliquées sur le substrat, montre que la dynamique interne de l'actine dans la cellule est non seulement corrélée avec la migration cellulaire, mais la gouverne. Enfin, afin de comprendre la dynamique interne d'un podosome, nous avons amélioré le modèle de Biben et al. (2005), en prenant en compte d'une part, la polymérisation de l'actine, et d'autre part, la diffusion et la cinétique d'attachement de la gelsoline, une protéine responsable de la coupe des filaments d'actine. Nous montrons que les podosomes sont principalement gouvernés par la dynamique de l'actine, indépendamment de la concentration en gelsoline
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Jennifer, Leigh Quizi. "SLK-mediated Phosphorylation of Paxillin Is Required for Focal Adhesion Turnover and Cell Migration." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20483.
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The precise mechanism regulating focal adhesion disassembly has yet to be elucidated. Recently, we have implicated the Ste20-like kinase SLK in mediating efficient focal adhesion turnover and cell migration in a Rac-1 and FAK-dependent manner. Although an indirect association of this kinase with the microtubule network has been determined, the exact involvement of SLK in the disassembly of the adhesion complex remains unclear. With the identification of the focal adhesion protein paxillin as a substrate of SLK, we show that SLK regulates adhesion turnover through its phosphorylation at S250. Mutation of S250 to a threonine residue ablates SLK phosphorylation of paxillin in vitro and results in reduced adhesion turnover and migration in vivo. Additionally, our studies demonstrate that overexpression of the paxillin S250T mutation prevents the redistribution of paxillin to the membrane ruffle in migrating cells. The complete loss of polyubiquitylation in the S250T mutant, combined with no observed reduction in S250T protein expression, suggests that S250 phosphorylation is required for a ubiquitin-mediated modification that regulates paxillin redistribution within the cell. Moreover, we show that phosphorylation of S250 is required for paxillin to interact with FAK. An observed accumulation of phospho-FAKY397 in cells overexpressing the paxillin S250T mutant suggests that phosphorylation of S250 is involved in regulating FAK-dependent focal adhesion dynamics. Consequently, our data suggests that SLK regulates adhesion turnover through the phosphorylation of paxillin at S250.
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Lemma, S. (Siria). "Migration and adhesion associated molecules in lymphoma biology and their potential roles as biomarkers." Doctoral thesis, Oulun yliopisto, 2017. http://urn.fi/urn:isbn:9789526216041.
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Abstract Lymphomas are a heterogeneous group of malignancies that arise from lymphatic tissues. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma sub-type. It is an aggressive malignancy with an increasing incidence. The prognosis of DLBCL has improved significantly, but problems also remain. The clinical significance of central nervous system (CNS) relapses has become increasingly important. As secondary CNSL (sCNSL) and primary CNS lymphoma (PCNSL) are known to have poor prognoses; the prevention of sCNSL is of crucial importance. Peripheral T-cell lymphomas (PTCL) are rare neoplasms and include several lymphoma subtypes that possess complex and also overlapping morphological and immunophenotypic characteristics. The identification of different entities has improved, but the biological knowledge remains scarce when compared to DLBCL. The optimal treatment schemas for PTCLs are still lacking and they have long been treated with the same therapies as B-cell lymphomas, mainly with suboptimal treatment results. The aim of this study was to identify poor prognostic markers in DLBCL and PTCLs and potential biological markers for the prediction of DLBCL CNS relapse. The study material included patients with systemic DLBCL without CNS affision (sDLBCL), sCNSL, PCNSL and PTCLs. The expression of epithelial-mesenchymal transition (EMT) transcription factors (TFs), chemokines and their receptors and adhesion-, migration- and inflammatory responses-associated molecules were studied by means of immunohistochemistry. IEM was used to verify the specific subcellular location of the studied molecules. GEP was performed on 12 PTCL samples in order to compare the poor prognosis group with the good prognosis group and on one sDLBCL and one sCNSL sample from the time of primary diagnosis. The EMT TFs were found to be expressed in both DLBCL and PTCLs, where they ultimately proved to have prognostic relevance as well. In PTCLs, these TFs were able to delineate a disease group with a specific gene-expression profile. CXCR4, CXCR5, ITGA10, PTEN and CD44 were found to be differently expressed between DLBCL cases with CNS affision when compared to those without CNS disease. These molecules seem to play a role in the development of CNS relapse and hopefully, if further verified, will lead towards the identification of biological markers for CNS relapse predictionTiivistelmä Lymfoomat ovat heterogeeninen ryhmä imukudossyöpiä, joista diffuusi suurisoluinen B-solulymfooma (DLBCL) on yleisin alatyyppi. Se on aggressiivinen maligniteetti, jonka insidenssi on noussut viime vuosina. DLBCL potilaiden ennuste on parantunut merkittävästi, mutta yhä osa potilaista menehtyy tautiinsa. DLBCL:n keskushermostorelapsin kliininen merkitys on tänä päivänä aiempaa suurempi. Sekundaarisen keskushermostolymfooman (sCNSL) ja primaarin aivolymfooman (PCNSL) ennusteet ovat nykyhoidoilla huonoja, joten keskushermostorelapsin ennaltaehkäiseminen on tärkeää. Perifeeriset T-solulymfoomat (PTCLs) ovat ryhmä harvinaisia neoplasioita, joka sisältää useita eri alatyyppejä, joiden morfologiset ja immunofenotyyppiset ominaisuudet ovat monimuotoisia ja osin päällekkäisiä. Eri entiteettien indentifiointi on parantunut, mutta PTCL:ien biologinen tietämys on yhä DLBCL:aa heikompaa. PTCL:ien optimaalinen hoito ei ole selvillä ja tätä tautiryhmää on pitkään hoidettu samoilla hoidoilla kuin DLBCL:aa, mutta huonommilla hoitotuloksilla. Tutkimuksen tavoitteena oli löytää huonon ennusteen markkereita, joilla myös pystyttäisiin ennustamaan DLBCL:n keskushermostorelapsia. Aineisto koostui DLBCL, sCNSL, PCNSL ja PTCL näytteistä. Immunohistokemiallisilla värjäyksillä tutkittiin epiteliaalis-mesenkymaalisen transition (EMT) transkriptiotekijöitä (TF), kemokiinireseptoreita sekä adheesioon-, migraatioon ja inflammaatioon assosioituja molekyylejä. Immunoelektronimikroskopialla varmennettiin molekyylien lokalisaatio soluissa. Geeniekspressioprofiloinnilla (GEP) verrattiin kahdentoista hyvän ja huonon ennusteen ryhmään kuuluvan PTCL näytteen välisiä geeniekspressioeroja sekä kahden DLBCL potilaan näytteitä, joista toiselle kehittyi keskushermostorelapsi. EMT TF:ien ekspressiota nähtiin DLBCL ja PTCL näytteissä, joissa niillä myös todettiin olevan ennusteellista merkitystä. PTCL:ssa TF:t pystyivät erottelemaan tautiryhmän, jolla oli oma spesifinen geeniekspressioprofiilinsa. CXCR4, CXCR5, ITGA10, PTEN ja CD44 ekspressio oli erilaista systeemisissä DLBCL tapauksissa verrattuna sCNSL tapauksiin. Edellä mainituilla molekyyleillä näyttää olevan oma roolinsa keskushermostotaudin kehittymisessä ja jos nämä tulokset pystytään vahvistamaan tulevissa tutkimuksissa, johtavat ne toivottavasti kohti keskushermostorelapsiriskin tarkempaa tunnistamista
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Ferro, Valerie Anne. "The role of endothelial cells in promoting adhesion, spreading and migration of B16F10 cells." Thesis, University of St Andrews, 1989. http://hdl.handle.net/10023/14067.
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For the successful establishment of secondary tumours, blood-borne metastatic tumour cells must adhere and spread on the vascular endothelium before they can migrate through it to form secondary growths in the tissue beneath. In this study an in vitro assay was developed to study the behavourial interactions between B16F10 cells and Bovine aortic endothelial cells. It was hypothesized that molecules synthesized by the endothelial cells may be involved in the mediation of the adhesion, spreading and migration events and hence that such molecules may possibly be involved in the process of haematogenic metastasis. Endothelial derived extracts were obtained from the cell surface and from conditioned medium. The extracts were tested for their adhesion promoting abilities in a quick dot blot adhesion assay. To verify that these molecules promoted adhesion, antibodies were raised against the extracts. Partial characterisation of the molecules was achieved using SDS-PAGE and immunoprobing. The extracts were also tested for their spreading and migration promoting properties. An attempt was made to block the adhesion, spreading and migration events using antibodies directed against components of the extracts. Clearly, if endothelial-derived molecules are involved in metastasis, then preventing the mediation of adhesion, spreading and migration may ultimately have relevance in the clinical situation.
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Timpson, Paul. "A study examining the role of Rho family GTPases in the intracellular targeting of Src kinase during cell polarisation and migration." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248188.
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El-Hariry, Iman Ahmed. "The relationship between FGF/FGFR and E-cadherin/catenin systems in pancreatic adenocarcinoma." Thesis, Imperial College London, 1999. http://hdl.handle.net/10044/1/7552.
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Ports, Michael O. "LATERALLY ASSOCIATED PROTEINS MODULATE A6 INTEGRIN CLEAVAGE, A PERMISSIVE PROCESS UTILIZED DURING CANCER METASTASIS." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/194361.
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Expression of A6 integrin, a laminin receptor, on tumor cell surfaces is associated with reduced patient survival and increased metastasis in a variety of tumors. In prostate cancer, tumor extra capsular escape occurs in part via laminin coated nerves and vascular dissemination, resulting in clinically significant bone metastases. Our group previously identified a novel form of A6 integrin, called A6p, generated by urokinase (uPA) dependent cleavage of the laminin binding domain from the tumor cell surface. Although functional consequences of cleavage have been characterized, little is known about how this process is regulated.Regulation of uPA mediated cleavage was identified by a laterally interacting protein expressed on the cellular surface. A direct interaction between the urokinase receptor (uPAR) and A6 integrin was characterized. This direct interaction was responsible for the extracellular cleavage of A6. Transient knockout of A3 integrin, a known interacting partner of uPAR, increased uPAR association with A6 integrin and enhanced production of A6p. Analysis of tissue obtained from human prostate tumors confirmed uPAR and A6 integrin expression in invasive disease. Taken together the results demonstrate a novel and dynamic role for uPAR regulation of integrin dependent adhesion through lateral interaction.Using the known conformation sensitivity of integrin function to I determined if engagement of the extracellular domain by antibodies inhibited integrin cleavage and the extravasation step of metastasis. Both endogenous and inducible levels of A6p were inhibited by engaging the extracellular domain of A6 with monoclonal antibody J8H. J8H inhibited tumor cell invasion through Matrigel. A SCID mouse model of extravasation and bone metastasis produced detectable, progressive osteolytic lesions within three weeks of intracardiac injections. Injection of tumor cells, pre-treated with J8H, delayed the appearance of metastases. Validation of the A6 cleavage effect on extravasation was confirmed through a genetic approach using tumor cells transfected with uncleavable A6 integrin. Uncleavable A6 integrin significantly delayed the onset and progression of osseous metastases out to 6 weeks post injection. The results suggest that A6 integrin cleavage permits extravasation of human prostate cancer cells from circulation to bone and can be manipulated to prevent metastasis.
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Garcia, Emilien. "Rôle de la tyrosine kinase SYK dans la régulation du processus métastatique du mélanome." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4154/document.
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La progression tumorale en cancer métastatique implique la perte de fonctions oncosuppressives, comme c'est le cas dans le mélanome. Une migration cellulaire aberrante est caractéristique de la progression du mélanome. SYK (Spleen tyrosine kinase) est une tyrosine kinase cytoplasmique impliquée dans la suppression tumorale du cancer du sein et du mélanome. Dans la peau, SYK est exprimée dans les mélanocytes mais est fréquemment réprimée épigénétiquement dans le mélanome. Nous avions pu montré que cette perte était associée à un échappement de la sénescence. Qu'elle puisse réguler la migration des cellules tumorales et la formation des métastases reste peu connu. Dans mes travaux j'ai utilisé des approches gain et perte de fonction pour analyser l'effet de SYK sur les mélanomes humains et murins. Respectivement, la réexpression et l'extinction de SYK diminue et augmente la migration, l'invasion et les métastases des cellules de mélanome. L'extinction de SYK induit notamment un phénotype et une signature mésenchymateuse. Notre étude dévoile ce rôle pour SYK dans la répression d'une adhérence dépendante des intégrines, points de tractions et plateforme de signalisation de la migration, et souligne l'importance la perte de SYK dans la formation de métastases. Pour clarifier le rôle de SYK dans la progression du mélanome, j'ai généré un modèle murin de KO conditionnel de SYK spécifique des mélanocytes concomitants à une perte de Pten et de l'activation de BrafV600E. Des résultats préliminaires suggèrent que la perte de SYK n'accélère pas la formation de mélanome dans ce contexte mutationnel mais mène à une invasion plus profonde des cellules tumorales dans le dermeThe progression of tumors to metastatic disease involves the loss of metastatic suppressor functions, as it is the case in melanoma. Thus, aberrant cell migration is a key feature of melanoma progression, and is required for metastasis. SYK (Spleen tyrosine kinase) is a cytoplasmic tyrosine kinase that has been implicated in tumor suppression of breast cancer and melanoma. In skin cells, SYK is found expressed in melanocytes but SYK is frequently downregulated in melanoma by epigenetic silencing. We showed previously that its loss has been associated with senescence escape. Whether it also regulates tumor cell migration and subsequent metastasis remains poorly understood. In this work we used gain- and loss-of-function approaches to analyze SYK’s effects on metastatic abilities of human and murine melanoma cells. Respectively, the reexpression or knockdown of SYK results in decreased or increased migration, invasion and metastasis of melanoma cells. Notably, SYK knockdown cells displayed a mesenchymal-like phenotype with upregulation of mesenchymal markers. Our study unveils a novel role for SYK in suppressing integrin-mediated adhesion, both a points of traction and a signaling platform during cell migration, and outlines the importance of SYK inactivation in acquisition of a metastatic phenotype. To clarify the role of SYK in melanoma formation and progression, we have generated a conditional Syk KO mouse model in melanoma based on melanocyte-specific Pten loss and BrafV600E activating mutation. Preliminary results suggest that Syk loss does not accelerate Pten/Braf-driven melanoma formation but leads to deep invasion of Braf/Pten tumor cells into the dermis
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Pischedda, F. "THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/363912.
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Negr1 is a member of IgLON adhesion protein family but its functions are largely unknown. In our previous work ((Pischedda et al. 2014), APPENDIX I) we identified Negr1 as a developmentally regulated synaptic protein. Thus we examined the consequences of Negr1 acute down regulation. Strikingly, we found that Negr1 ablation impairs neuronal maturation in vitro. In this project we demonstrated thanks to complementary biochemical and imaging approaches that Negr1 organizes trans-synaptic heterodimer and influences neurites outgrowth via MAPK signaling. In detail, we demonstrated that ectopic Negr1 is sufficient to improve neurite arborization and to rescue the morphological phenotype observed in Negr1 silenced cells. This function is dependent on the activation of MAPK pathway through tyrosine kinase receptors. In fact, we found that Negr1 physically and functionally interacts with FGFR2, modulates FGFR2 response to FGF and consequently influences MAPK pathway. FGFR2 pathway plays an important role during brain development. Not surprisingly, our investigation of the radial migration of newly generated cortical neurons revealed that Negr1- FGFR2 cross-talk controls cortical organization in vivo. Noteworthy, mutations in NEGR1 and FGFR2 genes have been recently identified as ASD candidates. Autism spectrum disorder (ASD) affects 0.9% of children and it is recognized as the most genetic of all developmental neuropsychiatric syndromes. Connectivity dysfunctions have been suggested as causative alterations in ASD. Given the functional, physical and genetic correlation among Negr1 and FGFR2 and the impact of Negr1 on neuron morphology and migration, Negr1-FGFR2 molecular cross talk might arise as a key mechanism during CNS development.
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Xiong, Siyuan. "The role of Activin B and TGFb1 in regulating endometrial cancer cell adhesion and migration." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58581.
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Endometrial cancer is the fourth most common female cancer and the most common gynecological malignancy. Although it comprises only ~10% of all endometrial cancers, the serous histological subtype accounts for ~40% of deaths due to its aggressive behavior and propensity to metastasize. Moreover, the number of endometrial cancer related deaths keeps rising, which can be attributed to the increased incidence of advanced-stage tumor and high risk histologies. Histopathological studies suggest that in non-endometrioid endometrial cancers (type II, mostly serous), elevated expression of activin/inhibin βB subunit is associated with reduced survival and TGFβ signalings are closely associated with the neoplastic transformation of human endometrium and the initiation of invasion of endometrial cancer. However, little is known about the specific roles and mechanisms of activin B (βB dimer) and TGFβ1 in type II endometrial cancer cell progression. We hypothesized that integrin αvβ3, E-cadherin, and PTEN play critical roles in activin B or TGFβ1 induced endometria cancer cell adhesion or migration. Type II endometrial cancer cell lines KLE, HEC-1B and HEC-50 were used as study models. Cancer cell adhesion was assessed by extracellular matrix coated 96 well adhesion assays. Cancer cell migration or invasiveness was assessed by transwell assays without or with coated matrigel following exposure to recombinant human activin B or TGFβ1. Small interfering RNA (siRNA)-mediated knockdown or vector-mediated overexpression approaches were used to investigate the molecular determinants of activin B or TGFβ1-mediated functions. In summary, our results demonstrate that SMAD-mediated integrin β3 up-regulation by activin B promotes type II endometrial cancer cell adhesion and migration while ERK1/2-SNAIL-mediated E-cadherin down-regulation by activin B plays important roles in cancer migration. Moreover, TGFβ1 induces type II endometrial cancer cell migration via ERK1/2 mediated-up-regulation of integrin αvβ3. TGFβ1 also promotes cancer cell migration by down-regulating PTEN via both SMAD-dependent and independent pathways. Our findings provide important insights into the molecular mechanisms underlying the effects of activin and TGFβ on endometrial cancer cell migration and suggest novel therapeutic targets for treating type II endometrial cancer.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
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Dawson, Cassandra. "Investigating the role of protein tyrosine phosphatase alpha in focal adhesion dynamics and cell migration." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62137.
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Cell migration is an important phenomenon in many physiological and pathological processes such as wound healing, embryogenesis, and cancer cell metastasis. Integrins bind components of the extracellular matrix and initiate a cascade of intracellular signaling changes that regulate focal adhesion dynamics and reorganization of the actin cytoskeleton. Focal adhesions are multiprotein complexes that are continuously assembled, remodeled, and disassembled to enable cell migration. Protein tyrosine phosphatase alpha (PTPα) is a receptor-like transmembrane protein that is involved in integrin signaling. In response to integrin stimulation, PTPα mediates Src activation through dephosphorylation of the inhibitory phosphosite of Src. This leads to formation of the Src-FAK complex which in turn phosphorylates PTPα at the Tyr789 site. PTPα-Tyr789 phosphorylation has been demonstrated to be an important event in coordinating focal adhesion formation, cytoskeletal rearrangement, and cell migration. Mouse embryonic fibroblasts (MEFs) lacking PTPα expression or expressing an unphosphorylatable mutant (Y789F) PTPα exhibit impaired focal adhesion formation and cell migration. In this study, I investigated the focal adhesion dynamics and cell migration capabilities of newly generated lines of wild-type and PTPα-deficient MEFs. Although these newly generated cells did not fully recapitulate the previously reported PTPα-dependent focal adhesion dynamics and cell migration defects, I observed that cells lacking PTPα expression exhibited defects in cell polarity and directionality, mechanisms that coordinate migration. My findings suggest that alterations to key signaling components or pathways in these cells may be responsible for coordinating focal adhesion dynamics and cell migration irrespective of PTPα expression.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Smith, Liisa Sundberg Taylor Joan M. "A role for focal adhesion kinase in vascular smooth muscle cell proliferation, migration and differentiation." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1258.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology and Laboratory Medicine." Discipline: Pathology and Laboratory Medicine; Department/School: Medicine.
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Bola, Becky Melanie. "The role of Kinesin-1 and Rab Proteins in cell migration and focal adhesion dynamics." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491863.
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In this project, the role that kinesin-1, its cargoes and the Rab family proteins in migration and focal adhesion dynamics has been investigated. When considering cell movement, the majority of studies have focussed on commonly studied themes such as cell polarity, Rho GTPases and the role of specific integrins and substrates. This project is novel in many respects, including the approaches taken.
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Rioja, Ana Ysabel. "Cell Adhesion and Migration on NDGA Cross-Linked Fibrillar Collagen Matrices for Tendon Tissue Engineering." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4214.
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Tendons, essential tissues that connect muscles to bones, are susceptible to rupture/degeneration due to their continuous use for enabling movement. Often surgical intervention is required to repair the tendon; relieving the pain and fixing the limited mobility that occurs from the damage. Unfortunately, post-surgery immobilization techniques required to restore tendon properties frequently lead to scar formation and reduced tendon range of motion. Our ultimate goal is to create an optimal tendon prosthetic that can stabilize the damaged muscle-bone connection and then be remodeled by resident cells from the surrounding tissues over time to ensure long-term function. To achieve this, we must first understand how cells respond to and interact with candidate replacement materials.
The most abundant extracellular matrix (ECM) protein found in the body, collagen, is chosen as the replacement material because it makes up the majority of tendon dry mass and it can be remodeled by cell-based homeostatic processes. Previous studies found that Di-catechol nordihydroguaiaretic acid (NDGA) cross-linked fibers have greater mechanical strength than native tendons; and for this reason this biomaterial could be used for tendon replacement.
This work focuses on investigating the behavior of fibroblasts on NDGA cross-linked and uncross-linked collagen samples to determine if cross-linking disrupts the cell binding sites affecting cell spreading, attachment, and migration. The in-vitro platform was designed by plasma treating 25 mm diameter cover slips that were exposed to 3-aminopropyl-trimetoxysilane/toluene and glutaraldehyde/ethanol solutions. The collagen solution was then dispensed onto the glutaraldehyde-coated cover slip and incubated for fibrillar collagen matrix formation. The collagen matrices were submerged in NDGA cross-linking solution for 24 hours to ensure the surface was completely cross-linked. Collagen films were made by allowing the uncross-linked gels to dry overnight before and after NDGA treatment, resulting in a more compacted structure.
A spinning disk device was employed to quantify the ability of cells to remain attached to the collagen samples when exposed to hydrodynamic forces. To avoid any cell-cell interaction and focus on cell-surface interactions, 50-100 cells/mm2 were seeded carefully on each sample. Temporal studies demonstrated that cell adhesion strength and spreading area reached steady-state by 4 hr. Adhesion and spreading studies along with migration experiments demonstrated that NDGA treatment affects cellular behavior on films, partially reducing adhesion strength, migration, and spreading area. However, on the cross-linked gels which are less dense, the only change in cell behavior observed was in migration speed.
We hypothesize that these differences are due to the collapsing of the collagen films. This compaction suggests a less open organization and could be allowing the collagen fibers to form more inter-chain bonds as well as bonds with the small NDGA cross-linker; while NDGA treatment of the fully hydrated gels may rely more on NDGA polymerization to span the greater distance between collagen fibrils. From these results, we can determine that the chemical/physical masking of the adhesion sites by NDGA on collagen films affects cellular behavior more than the masking that occurs in the cross-linked gels. Although this study shows an effect in cell behavior on the cross-linked films, it also demonstrates that cells can adhere and migrate to this NDGA biomaterial supporting the idea that this biomaterial can be utilized for tendon replacement.
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Infante, Elvira. "Role of Rap and Rho GTPases in T-acute lymphoblastic leukaemia cell adhesion and migration." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/role-of-rap-and-rho-gtpases-in-tacute-lymphoblastic-leukaemia-cell-adhesion-and-migration(e1c1aff6-96a7-4dc6-9ee5-355bb41b01ee).html.
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T-acute lymphoblastic leukaemia (T-ALL) is a common childhood cancer. Multiple genetic mutations have been identified in T-ALL patients. The most common is the mutation of the NOTCH 1 oncogene occurring in more than 50% of patients. Poor prognosis has often been shown to correlate with the migration and accumulation of T-ALL cells in the tissues. Rap and Rho family GTPases play key roles in T cell adhesion and migration and are often involved in cancer progression. Most of these proteins are post-translationally isoprenylated to facilitate their anchorage to membranes, where they function to stimulate signal transduction processes. In the first part of these studies, statins were used to reduce prenylation of GTPases, and to investigate whether the resulting alteration of GTPase membrane targeting affects T-ALL cell migration. Statins inhibited adhesion, chemotaxis and transendothelial migration of T-ALL cell lines. A similar effect was observed with geranylgeranyl transferase inhibitors and siRNA depletion of Raplb but not Rap la, RhoA, Racl, Rac2 and Cdc42. These results suggest that statins and Raplb depletion could be used to reduce tissue invasion in T-ALL. In contrast to other Rho family proteins, the atypical Rho GTPases RhoU and RhoV are not prenylated but undergo palmitoylation for membrane targeting. They are expressed at higher levels in primary T-ALL samples compared to primary T cells, and RhoU expression was shown to be unregulated by Notch 1. In the second part of these studies downregulation of RhoU and Notch 1 by siRNA reduced adhesion and migration of T-ALL cell lines. Interestingly, similar functional effects were observed upon siRNA depletion of RhoV. RhoU and RhoV partially co-localized and moved dynamically between endosomes and the plasma membrane, suggesting they act together to regulate membrane trafficking. These results indicate that RhoU and RhoV could contribute to T-ALL invasion by regulating T-ALL cell adhesion and migration.
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Tanizaki, Hideaki. "Rho-mDia1 pathway is required for adhesion, migration, and T cell stimulation in dendritic cells." Kyoto University, 2011. http://hdl.handle.net/2433/142071.
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Abedi, Syeda Husna Bano. "Mechanisms of migration of vascular smooth muscle and endothelial cells : role of the focal adhesion kinase pathway." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286793.
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Kerjouan, Adèle. "Décodage des fonctions spatio-temporelles de la signalisation Src impliqué dans la migration et l'invasion par une approche optogénétique." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV040.
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Les cellules détectent et intègrent une multitude de signaux d'instruction provenant de leur microenvironnement via un ensemble de récepteurs transmembranaires. Ces informations sont ensuite collectées au niveau des nœuds de signalisation intracellulaires pour être ensuite dispersées en cascades de signalisation afin de déterminer la destinée cellulaire. La manière dont un nœud de signalisation peut interpréter plusieurs stimuli et transmettre de manière spatio-temporelle les informations appropriées restent incomprises. Le proto-oncogène c-Src est une tyrosine kinase pléiotrope, un nœud signalisation essentiel au pilotage de nombreux processus cellulaires, tels que la migration, l'invasion, la dégradation et la division cellulaire. Nous avons développé une approche synthétique pour explorer la relation entre la structure de la SRC et la multiplicité des processus cellulaires qu’elle régule. Notre approche a abouti au découplage des différents modules composant la protéine SRC afin de comprendre l’impact de chacun d’eux sur son activité dans l’espace et dans le temps. Notre approche pour contrôler plusieurs états de la conformation SRC était la conception d’un OptoSrc capable à la fois de former des oligomères et d’être recruté à la membrane plasmique. Pour ce faire, nous avons modifié la structure de la SRC afin qu'elle soit potentiellement active dans le noir et nous l'avons fusionnée avec le CRY2 sensible à la lumière. La stimulation lumineuse induit l'hétérodimérisation CRY2 avec un CIBN ancré à la membrane plasmique et son homo-oligomérisation et déclenche une relocalisation de l’OptoSrc à la membrane plasmique ou son oligomérisation. Ce double système a permis de générer deux types de mobilitéz différentes au sein des adhérences focales à deux destins différents, la formation de lamellipodes dans un cas et la formation d’invadosomes dans l’autreCells sense and integrate a multitude of instructional signals from their microenvironment through a diverse set of transmembrane receptors. This information is then collected at intracellular signaling nodes to later disperse down signaling cascades to drive cell fate. How one signaling node can interpret multiple stimuli and spatio-temporally transmit the appropriate information remains poorly understood. The proto-oncogene c-Src is a pleiotropic tyrosine kinase, is one such node essential for driving many cellular processes, such as migration, invasion, degradation, and cell division. We developed a synthetic approach to explore the relationship between SRC structure and the multiplicity of cellular processes it regulates. Our approach resulted in the decoupling of the different modules composing SRC protein to understand how each of them impacts its activity in space and time. Our approach to control multiple state of SRC conformation was the design of an OptoSrc both capable of forming oligomers and to be recruited at the plasma membrane. To do so, we modified SRC structure to be potentially active in the dark and fused it with light sensitive CRY2. Light stimulation induces CRY2 hetero-dimerization with a CIBN anchored at the plasma membrane and its homo-oligomerisation triggering relocalization of OptoSrc at the plasma and/or its oligomerization. This system generated two different type of mobility of OptoSrc inside focal adhesion inducing two different adhesion fates, the formation of invadosome in one case and the formation of lamellipodia on the other
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Hamadi, Abdelkader. "Rôle de FAK (Focal Adhesion Kinase) dans le turnover des points d’adhérence durant la migration cellulaire." Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/public/theses_doctorat/2008/HAMADI_Abdelkader_2008.pdf.
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Ng, Lui, and 吳磊. "Actopaxin: a novel regulator of cell migration and invasion in human hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47752610.
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Invasion and metastasis are the major causes of treatment failure and high mortality rate in hepatocellular carcinoma (HCC) patients. Cell motility is crucial to tumor invasion and metastasis, requiring the ability of tumor cells to interact with extracellular matrix, which is regulated by integrins and integrin-associated molecules at the focal adhesions. Recent studies have demonstrated the role of β1 integrin (CD29) overexpression in HCC and its correlation with cancer cell invasiveness and metastastic potential, as well as its protective role against cancer cells against chemotherapeutic drug-induced apoptosis, yet the mechanism is not fully known. Focal adhesion proteins serve as binding platforms for additional cytoskeletal and signaling molecules in the CD29 signaling pathway. Recently, Actopaxin has been demonstrated to form complex with numerous molecules at the focal adhesions, including ILK, which interacts with the cytoplasmic tail of CD29. Through these interactions, Actopaxin has been shown to regulate different cellular events, including cell survival, spreading and cell migration. In this study, the role of Actopaxin in HCC was investigated. In particular, its role in the regulation of tumor invasion and metastasis of HCC cells was demonstrated.
This study showed that Actopaxin expression was overexpressed in HCC specimens when compared with the adjacent non-tumorous liver, and that its overexpression positively correlated with tumor size, stage and metastasis in HCC specimens. Actopaxin expression was also correlated with the metastatic potential in HCC cell-lines. Functional studies established that overexpression of Actopaxin conferred invasive phenotypes in primary, non-metastatic HCC cells, whereas down-regulation of Actopaxin could revert the invasive phenotypes and metastatic potential of metastatic HCC cells in vitro and in vivo. Suppression of Actopaxin expression was associated with reduced expression of ILK, PINCH, Paxillin and cdc42, whereas expressions of E-cadherin, β-catenin and GSK3β were induced, indicative of a less invasive and invasive phenotype. Conversely, overexpression of Actopaxin in primary, non-metastasis HCC cells accordingly up-regulated the expression of ILK, PINCH, Paxillin and cdc42, and down-regulation of of E-cadherin, β-catenin and GSK3β, suggestive of an enhanced invasive phenotype. The expression of Actopaxin was found to be correlated with CD29 level, indicating that Actopaxin is a CD29-associated protein and involved in CD29-regulated signaling. Finally, Actopaxin down-regulation enhanced chemosensitivity of of HCC cells towards chemotherapeutic treatment. Treatment with Oxaliplatin was enhanced in Actopaxin-deficient HCC cells, which showed a stronger inhibitory effect on cell proliferation and cell cycle progression, accompanied with induction on apoptosis. The enhanced chemosensitivity effect was a collective result of suppression of Survivin protein, β-catenin and mTOR pathways; and up-regulation of p53.
To conclude, this study demonstrated for the first time that Actopaxin is involved in HCC invasion, metastasis and chemosensitization, providing the basis to further investigate the potential role of this protein or its downstream effectors as a therapeutic target for inhibiting the development of metastasis and enhancing chemotherapy efficacy to combat HCC, and perhaps other invasive cancers.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy
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Comber, Kate. "Investigation into the molecular mechanisms governing Drosophila embryonic hemocyte migration in vivo." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606669.
Full textAbstract:
Accumulating evidence highlights the importance of studying the migration of cells within the context of their natural environment as manipulating the substrate on which a cell is migrating can have a dramatic impact on the mode/mechanisms employed by cells during migration. Central to this phenomenon is the requirement of adhesion to the ECM in order to gain traction during migration. Integrins constitute the main family of cell receptors involved in mediating cell-ECM interactions during motility. Whilst traditionally two-dimensional cell culture studies have placed emphasis on the importance of these receptors for spreading and migration, it has become evident that within more confined environments these receptors, at least for some cell types, are less crucial. In this research we utilise Drosophila embryonic hemocytes as an in vivo model for cell migration. We show that whilst hemocytes migrate within confined environments in vivo, these cells depend on integrins for powering both developmental and inflammatory migrations. Given the close association between these receptors and the actin cytoskeleton we were surprised to discover that removal of the main β integrin subunit, Myospheroid, did not affect cell spreading in vivo and had only a small impact on lamellipodial structure and dynamics. Furthermore we discovered that, in contrast to other cell types previously analysed, removal of this integrin subunit in hemocytes was not accompanied by an increase in the rate of actin retrograde flow within the protrusions, which we believe could reflect abrogation of a positive feedback between Rho, ROCK and Myosin II contraction. Instead, we discover a key role for integrins in regulating the microtubule cytoskeleton, in the maintenance of a polarised microtubule bundle, termed a ‘microtubule-arm’. Although the molecular mechanisms by which this stabilisation is coordinated have yet to be identified, this provides important insight into the co-regulation of adhesion and microtubule cytoskeleton important for the migratory behaviour of these cells. Cell migration reflects the complex and integrated regulation of the actin cytoskeleton by diverse families of actin regulatory proteins. Using hemocytes as a model system, we also explore the regulatory interactions between two main actin regulatory proteins, Diaphanous and Enabled, in vivo. Whilst the function of these proteins in the formation of filopodial protrusions is overlapping, recent research has highlighted the ability of these proteins to regulate the activity of one another. We find that co-expression of Enabled in hemocytes is able to rescue the morphological and migratory defects resulting from overexpression of active Diaphanous. Thus, data here presents Enabled as a negative regulator of Diaphanous, which may play an important role in the migration of hemocytes in vivo.
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Sroka, Thomas Charles. "Synthetic Peptide Ligand Mimetics and Tumor Cell Motility." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1325%5F1%5Fm.pdf&type=application/pdf.
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Birner, Ulrieke. "Cell adhesion molecule mechanisms for neutrophil and monocyte migration to joints of rats with adjuvant arthritis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0017/MQ49315.pdf.
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Hur, Sung-Sik. "Roles of 3D traction forces in migration and focal adhesion dynamics of bovine aortic endothelial cells." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3259061.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 11, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 77-79).
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Strugnell, Scott Stuart. "The role of tyrosine phosphorylated caveolin-1 in regulating focal adhesion dynamics and cancer cell migration." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/15218.
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Caveolin-1 (Cav1) is a conditional tumor suppressor whose expression is associated with a poor prognosis for many human cancer types. Cavi is a Src kinase substrate phosphorylated on tyrosine-14 (pYl4Cavl) that interacts with integrin and has been localized to focal adhesions (FAs). We undertook to study the role of pYl4Cavl in FA dynamics and tumor cell migration. Using FRAP analysis, we showed that pYl4Cavl phosphorylation and stabilization of FA kinase (FAK)-GFP in FAs occurs via a process that requires Rho/ROCK and Src signalling. In Cavi expressing MDA-231 breast carcinoma cells, pYl4Cavl was enriched in purified pseudopodial fractions while in low Cav1-expressing MDA-435 tumor cells, transfected Cav1, but not the Y1 4F mutant of Cay 1 -mRFP, was recruited to actin-rich
protrusions. In MDA-435 tumor cells, transfected Cav1 and the phosphomimetic Cav1
mutant, Cav1Y14D, were found in close proximity to FA-associated proteins. The
recruitment of either Cavl or Cav1Y14D to FAs was associated with increased cell
migration. The positively charged Cav1Y14R mutant was not as closly associated with FA
associated proteins, and increased cell spreading and stress fiber formation. The spatial association of pYl4Cavl with FAs may therefore regulate FA signaling and dynamics.
The Mgat5 gene encodes the Golgi N-acetylglucosaminyltransferase-V that generates B1,6 branched N-glycans that bind galectin-3 at the cell surface forming a lattice domain. We found that the Mgat5/galectin lattice acts together with pYl4Cavl to stabilize FAK in FAs, thereby enhancing FA disassembly and de novo formation leading to the activation of
directional tumor cell migration. Our data therefore argue that local interactions between the Mgat5/galectin lattice, Rho/ROCK and Src signalling and downstream phosphorylation of pY14Cav1 at FA sites promote tumor cell migration by regulating local FA dynamics in protrusive domains of tumor cells.
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Essex, Rachel R. "Determining the Effects of CD151 and β1 on Tumor Cell Adhesion and Migration." UKnowledge, 2015. http://uknowledge.uky.edu/cme_etds/56.
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Previous studies have shown that the upregulation of CD151 and β1 is associated with poor prognosis in many cancers such as breast cancer. Studies have provided evidence that these proteins are associated with the adhesion and migration of tumor cells. In this study, a microfluidic flow chamber was utilized to determine how CD151 and β1 affected the firm and initial adhesion of metastatic breast cancer cells to a planar endothelial monolayer under shear stress. This system mimicked the adhesion of metastatic breast cancer cells to the endothelial cells of the circulatory system. CD151 and β1 increased the firm adhesion of metastatic breast cancer cells onto an endothelial monolayer when subjected to high shear stresses. CD151 and β1 increased the initial adhesion of metastatic breast cancer cells onto an endothelial monolayer. A transwell assay was utilized to determine how CD151 and β1 affected random migration through different matrixes and random transendothelial migration. CD151 and β1 decreased the random migration of metastatic breast cancer cells through matrices. Additionally, background information is provided related to the metastatic cascade, how it can be modeled with microfluidics, and how CD151 and β1 have been known to effect cancer and metastasis.
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Hamadi, Abdelkader Rondé Philippe. "Rôle de FAK (Focal Adhesion Kinase) dans le turnover des points d'adhérence durant la migration cellulaire." Strasbourg : Université Louis Pasteur, 2008. http://eprints-scd-ulp.u-strasbg.fr:8080/1011/01/HAMADI_Abdelkader3_2008.pdf.
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Hoover, Ashtyn. "The Role of Small GTPase RhoG in Focal Adhesion Dynamics and Contractility." University of Toledo / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1556712457014336.
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