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Smith, Neil Jonathan. "Extramural vascular invasion in colorectal cancer." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510379.
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Ünlü, Ali. "Mechanism of invasion by prostate cancer." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244438.
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Peng, Lu. "Multiscale mathematical modelling of cancer invasion." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/c0aec459-7953-4172-b1f9-5ad029aae9df.
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Invasion of the surrounding tissue is one of the hallmarks of cancer. Solid tumours have a reciprocal relationship with the surrounding microenvironment, a complex tissue composed of extracellular matrix and other multiple distinct cell types. Prote- olytic degradation and remodelling of the extracellular matrix is essential for cancer cells to be able to invade. Important matrix degrading enzymes include the matrix metalloproteases (MMP) and the urokinase plasminogen activator (uPA). This thesis has investigated the complex process of cancer growth and spread that occur across several different spatial scales, in order to gain a better understanding of the key processes involved during invasion. At first, we tested our modelling concept by applying a level-set method to a moving boundary problem. Later, a multi-scale mathematical model of cancer invasion was developed by coupling the urokinase plasminogen activation (uPA) system with a two-scale computational modelling technique. This approach allows us to investigate cancer invasion not only at the macroscopic tissue level, but also at the microscopic cellular level. Our computational simulation results demonstrate a range of heterogeneous dynamics which are qualitatively similar to the invasive growth patterns observed in a number of different types of cancer known as tumour infiltrative growth patterns (INF).
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Safuan, Sabreena. "Lymphovascular invasion in melanoma and breast cancer." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12771/.
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The theory of metastatic cascade suggests that vasculature plays a central role in the metastatic processes by being the major route of spreading. Two main circulatory systems in the body are responsible for cancer cell dissemination; the blood vascular system and the lymphatic system. However, comparing between these circulatory systems, much less is known about lymphatic vessels, with few studies being conducted about the initial steps of metastasis. In the first part of this project, a series of 202 formalin fixed paraffin embedded (FFPE) cutaneous melanoma sections were stained with D2-40, CD34 and CD68 to identify lymphatics, blood vessels and macrophages respectively, to examine vessel distribution and the involvement of inflammatory infiltrate in mediating vascular invasion (VI). Sections were also stained by conventional haematoxylin and eosin (H&E), to assess VI, and results compared against those obtained by immunohistochemistry (IHC) that allow discrimination of lymphatic and blood vessel invasion. It was found that lymphatics are mainly located at the peritumoural area of the tumour but intratumoural lymphatics are present and appeared to be functional based on the presence of tumour emboli in the vessels. In addition, vascular invasion in melanoma is mainly lymphatic vessel invasion with H&E assessment underestimating its incidence. Lymphatic vessel invasion were significantly associated with markers of aggressive disease which suggest their importance in melanoma. Lymphatic vessel invasion was also associated with a high macrophage count, suggesting a role for macrophage in mediating the process of metastatic via lymphatic vessels. In the second part of this project, the adhesion pattern of melanoma and breast cancer cell lines to blood and lymphatic endothelial cell models; large vessel versus microvessel and primary versus immortalised cells were compared. In addition, the effect of macrophage secreted cytokines; TNF-α and IL-1β, tumour conditioned media and macrophage conditioned media on the adhesive process were also studied. Both melanoma and breast cancer cells exhibited a higher level of adhesion to blood compared to the lymphatic endothelial cells. IL-1β stimulation of endothelial cells, tumour cells or both together showed a significant increased in the percentage of adhered tumour cells to the endothelial cell models with a higher increased to the lymphatic endothelial cells. A significant increased tumour cell adhesion was also observed with macrophage conditioned media and this effect seemed to be associated with the amount of IL-1β present. Interestingly, the increased adhesion effect observed with this supernatant was removed with the use of interleukin-1 converting enzyme (ICE) inhibitor. Expression of adhesion molecules; CLEVER-1, ICAM-1 and VCAM-1 were examined to study which adhesion molecules might regulate the process of tumour-endothelial interactions. Stimulation of endothelial cell models with IL-1β did not show any significant altered CLEVER-1 expression suggesting that although CLEVER-1 is an important lymphatic specific adhesion molecule, it may not be the principle regulator of tumour-endothelial interactions. This process may be regulated by ICAM-1 and VCAM-1 in which the expression increased significantly upon stimulation with IL-1β. In the third part of this study, the effect of TNF-α, IL-1β, tumour conditioned media and macrophage conditioned media stimulation on melanoma and breast cancer cell migration were investigated using wound healing assays. Following exposure to TNF-α and IL-1β, a significant increase in the percentage of wound closure was observed and the increase was higher in IL-1β stimulated cells. Similarly, when tumour cells were exposed to macrophage conditioned media, there was an increase in the percentage of wound closure compared to control cells. The effect of IL-1β and macrophage conditioned media on breast cancer cell migration across blood and lymphatic endothelial cells were also studied using Boyden chamber transmigration assay. Significant increased in tumour cells transmigration was observed with IL-1β stimulation, with similar affinity across both endothelial cell types. However, when cells were stimulated with macrophage supernatant from lipopolysaccharide (LPS) stimulated macrophages, an increase transmigratory effect was notably observed to the lymphatic endothelial cells. Interestingly, the increased adhesion effect was removed with the used of ICE inhibitors. The last part of this study dealt with IL-1β expression in breast tissue samples. 1511 early stage breast cancer tissue microarray samples were stained with commercially available IL-1β antibody to examine the association with lymphatic vessel invasion, clinicopathological variables and clinical outcome. High IL-1β expression in tumour cells was significantly associated with the absence of both intra-tumoural and peri-tumoural lymphatic vessel invasion. A significant association was also observed between low IL-1β expression in tumour cells with breast cancer specific survival and disease free interval. In conclusion, lymphatic vessels have been found to play a significant role in breast cancer and melanoma cells progression by being the major route for vascular dissemination. In the in-vitro settings, this study has shown that IL-1β, with macrophages as the main producer, could regulate tumour cell invasion especially to the lymphatic circulation. This project has yielded some important results towards understanding of the lymphatic vasculature and modulation of lymphatic vessel invasion. However, more studies are needed to enable translation of research into clinical management of cancer.
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Starobinska, Ella. "Matrix Degradation and Invasion in Breast Cancer." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/244788.
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In order to metastasize, cancer cells need to invade and degrade matrix. Previous research showed that Epidermal Growth Factor Receptor (EGFR) is an oncogene, a member of ErBb family, that is over-expressed in aggressive cancers. EGFR mediates cell survival, proliferation, and motility through different signaling pathways. Located on the basolateral membrane of the cell, EGFR can be either translocated to the nucleus, degraded by the lysosome or recycled. However, in cancerous cells, EGFR activity is altered by MUC1, which associates itself with EGFR. Research suggested that this pathway acts in a Met-dependent manner. We conducted matrix degradation and invasion assays to see whether MUC1/EGFR activity has affect on these processes. Matrix degradation assay showed that Muc1 and EGFR inhibit matrix degradation and PMIP promotes it. However, Muc1/EGFR regulated matrix degradation is not Met-dependant. Meanwhile, the transwell invasion assay provided variable and statistically insignificant results.
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Planchon, Damien. "Etude du rôle de la surexpression des flotillines dans l'invasion cellulaire." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT056.
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L’invasion cellulaire est un phénomène pendant lequel les cellules présentent des changements importants dans leur forme et acquièrent la capacité à dégrader les structures qui les entourent afin de migrer au sein d’un organisme. L’invasion est cruciale pour la stabilité physiologique d’un organisme car elle intervient à différentes étapes de notre vie notamment lors du développement embryonnaire ou pendant une réaction immunitaire. Cependant ce mécanisme est également majeur lors de la progression tumorale. Dans nos organismes, les cellules sont entourées par la matrice extracellulaire (MEC) qui doit être remodelée ou dégradée lors du processus d’invasion. Cette dégradation est réalisée par des structures cellulaires spécialisées, les invadopodes, qui sont des sites où sont libérés les protéines spécialisées dans la dégradation de la MEC, parmi lesquelles MT1-MMP joue un rôle prépondérant. Les capacités à envahir et à dégrader la MEC d’une cellule dépendent donc fortement de la libération de MT1-MMP aux sites de dégradation. Les mécanismes qui permettent le transport de MT1-MMP aux zones d’intérêts sont encore mal compris. Dans ce contexte, nous avons mis en évidence que les Flotillines sont d’importants régulateurs de l’adressage et la libération de MT1-MMP à ces sites de dégradations. Les Flotillines 1 et 2 sont des protéines ubiquitaires très conservées. La quantité de Flotillines est augmentée dans de nombreux cancers invasifs et ceci est considéré comme un marqueur de mauvais pronostic. Lors de mon projet, nous avons mis en évidence que l’augmentation de la quantité de Flotillines dans des cellules normales de différentes origines, est suffisante pour induire une forte invasion cellulaire in vivo et in vitro (respectivement dans des modèles de xénogreffes chez le poisson zèbre dans modèles de sphéroïdes 3D dans des matrices de collagènes). De même, la suppression des Flotillines dans des cellules cancéreuses est associée à une diminution de leurs capacités invasives in vivo et in vitro. Ces résultats s’expliquent par le fait que les Flotillines régulent le trafic intracellulaire de MT1-MMP et augmentent sa libération aux sites de dégradation favorisant ainsi l’invasion cellulaireTumor cell invasion and consecutive metastasis formation are the main cause of death in cancer patients. Invading tumor cells are surrounded by stroma and extracellular matrix (ECM) that is remodeled or degraded during the metastatic process. ECM degradation is mediated by specialized organelles called invadosomes. Their function strongly depends on matrix metalloproteinases (MMPs) that degrade ECM. Among all the MMPs, MT1-MMP plays a major role the invasive behavior of metastatic cells.Flotillin 1 and 2 are two ubiquitous and highly conserved membrane proteins that can assemble in large oligomers, known to participate in membrane proteins clustering and endocytosis. Flotillins are overexpressed in many invasive cancers and considered as markers of poor prognosis, results we confirmed using several sarcoma and carcinoma models. During my project we identified Flotillins as regulators of MT1-MMP trafficking and cell invasion.We used a dual reciprocal approach consisting of the overexpression of Flotillins in non tumoral cells and of down-regulation of Flotillins in metastatic cells. We showed that flotillins downregulation in invasive cancer cells dramatically inhibit their invasive properties as monitored in vitro using a 3D-collagen invasion assay and in vivo using zebrafish xenografts. Reciprocally, ectopic overexpression of Flotillins in non-tumoral cells is sufficient to induce their invasive behavior in vitro and in vivo. This increase of invasion is mainly due to a higher ability to degrade the matrix in a MT1-MMP-dependent manner. Finally, we showed that Flotillins are critical regulators of the trafficking and the release of MT1-MMP at the degradation site
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Woodward, Julia Keren Lynda. "Adhesion and invasion studies of uveal melanoma." Thesis, University of Sheffield, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251213.
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García, de Albéniz Xabier. "Mechanisms of invasion and metastasis in colorectal cancer." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/300900.
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We studied the mechanisms driving the metastatic spread in colorectal cancer (CRC), focusing in the MAPK pathway. We developed in vivo a highly metastatic cell line using a KRAS-mutated cell line (SW620) in an ortothopic xenograft mouse model and used both in vivo and in vitro experiments to evaluate the mechanisms of metastasis. We also used data from two large prospective cohorts of incident CRC to evaluate the association of an intronic variant of SMAD7 (rs4939827, 18q21) with the phenotype and molecular characterisitics of CRC.
In the first project, we inoculated SW620 luciferase-expressing cells into portal circulation of immunodeficient mice via intrasplenic injection followed by splenectomy, in order to isolate cell populations that target the liver. Comparative transcriptomic analysis identified 194 genes differentially expressed between the parental and the highly metastatic cell line. We found pathways of nitrogen metabolism, cell adhesion molecules and mitogen-activated protein kinases (MAPKs). Downregulation of ERK2 (but not of ERK1) in the highly metastatic cell line reverted its metastatic capacity to the liver, but not to the lung in our mice model. We thus hypothesized that the ability to metastasize the lung by the highly metastatic derivative had to be driven by other mechanism.
The expression of parathyroid hormone-like hormone (PTHLH) was upregulated in our highly metastatic derivative and was inversely correlated with the expression of MKK6. Downregulation of PHTLH in the highly metastatic derivative decreased its capacity to colonize the lung without decreasing its capacity to colonize the liver after intra portal inoculation. We evidenced that PTHLH induced apoptosis of human pulmonary endothelial cells via apoptosis-inducing factor mitochondrion-associated 1.
In the second project we evaluated the association of the SMAD7 intronic variant with tumor phenotype and several CRC molecular characteristics. We used 1509 CRC cases and 2307 age-matched controls nested within the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We randomly selected between one and three matched controls.
Among the 1509 cases with blood or buccal samples in this study, we were able to successfully obtain tissue suitable for molecular analyses in 658 cases. We genotyped rs4939827 (TaqMan) successfully in 98% of the samples in NHS and 99.6% of the samples in HPFS. The phenotipic features evaluated were: TNM stage, grade of differentiation, location of the primary tumor (colon vs. rectum) and age at diagnosis. The evaluated molecular characteristics were DNA methylation of RUNX3 and LINE-1 (long interspersed nucleotide element-1), CpG island methylator phenotype (CIMP), microsatellite instability, TP53 expression by immunohistochemistry and the mutational status of BRAF, KRAS and PIK3CA.
We found that the minor allele (G) in rs4939827 was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95% confidence interval (CI) 0.62-0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95% CI 0.93-1.23, P for heterogeneity = 1.2 x 10-4). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95% CI, 1.02-1.42).
In conclusion, we provide clinical and molecular evidence showing that ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver and reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. We also show that patients with the rs4939827 CRC-susceptibility locus diagnosed with CRC tend to develop tumors with greater invasiveness (as measured by the pT stage).Parte de esta investigación consiste en explorar los mecanismos involucrados en el patrón metastático de CCR. Asimismo usamos datos epidemiológicos donde evaluamos la asociación entre el polimorfismo intrónico de SMAD7 (rs4939827, 18q21) con el genotipo y características tumorales. En el primer proyecto usamos un modelo murino de metástasis hepáticas para crear un derivado celular con alto tropismo metastático a hígado y pulmón. Mediante análisis de expresión de genes usando chips de transcripción identificamos 194 genes diferencialmente expresados El análisis de muestras clínicas mostró que aquellos pacientes cuyo tumor presentaba bajos niveles de p38 sufrían una mayor frecuencia de metástasis al pulmón, pero no a otros órganos. Al tratar ratones que habían desarrollado metástasis hepáticas derivadas de la línea celular parental con un inhibidor específico de p38, vimos que se incrementaba la afinidad metastática al pulmón. Evidenciamos que p38, a través del silenciamiento de PTHLH, en el derivado celular altamente metastático disminuía su capacidad de colonizar el pulmón. Demostramos que PTHLH induce la apoptosis de células humanas de endotelio pulmonar a través del factor AIFM1, facilitando que las células metastáticas puedan extravasarse al pulmón. En el segundo proyecto evaluamos la asociación de un polimorfismo intrónico del gen SMAD7 con el fenotipo y varias características moleculares del tumor. Para ello empleamos 1509 casos de cáncer de colon y recto y 2307 controles emparejados anidados en las cohortes Nurses Health Study y Health Professionals Follow-up Study. Encontramos que el alelo de menor frecuencia de rs4939827 (G) se asociaba con un menor riesgo de desarrollar un CCR con un estadio pT1 o pT2 [razón de odds (OR) ajustada, 0.73; intervalo de confianza al 95\% (CI) 0.62-0.87] pero no con tumores con estadio pT3 o pT4 (OR ajustada, 1.07; 95\% CI 0.93-1.23, valor p de heterogeneidad = 1.2 x 10-4). La asociación entre el polimorfismo de rs4939827 y CCR también difería significativamente según la metilación de RUNX3 (valor p de heterogeneidad = 0.005). Entre aquellos pacientes diagnosticados con CCR, el alelo de menor frecuencia de rs4939827 (G) estaba significativamente asociado con peor supervivencia (hazards ratio, 1.20; 95\% CI, 1.02-1.42).
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Koo, V. S. W. "Bioimaging and quantitative analysis of bladder cancer invasion." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484961.
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TGF-beta1 is known to induce changes tumour morphology and motility which are associated with invasion and metastasis via the phenomenon of epithelial-mesenchymal transition (EMD. Although morphology and motility can be determined in vitro, tumour invasion and metastasis are best investigated in an animal model that can be monitored. The aim of this study was to quantify the effects ofTGF-bT;ta1 on AY-27 bladder tumour and to establish DsRed2 fluorescence monitoring in the AY-27/F344 Fisher rat bladder tumour model using IVIS®200 imaging system. Using cbnventional microscopic assessment, scratch wound and Matrigel assays, we showed that TGF-beta1 induces spindle-shape morphology and significantly increased the motility and invasion in AY-27 cells. Preliminary data showed decreased expression of cytokeratin 18 and polarised distribution of vimentin of TGF-beta1 treated cells, indicating the occurrence of EMT. We also developed the Spindle Index assay that objectively quantified morphology change; and invented a novel chemo-attractant based Koo Assay of Migration which quantified tumour motility. These novel assays concurred with the above reference assays and can serve as an adjunctive investigative tool. DsRed2 was transfected into AY-27 using Lipofectamine2000 and the fluorescent intensity and stability were quantified using IVIS®200 and phase-contrasUfluorescent microscopy. However. the DsRed2 fluorescence intensity was not bright or stable. In addition. the DsRed2 transfection has altered the. morphology and growth characteristics of the cell. Instead, we used tdTomato, a variant of DsRed, and found it superior to DsRed2 in the fluorescent intensity and stability and it did not alter the characteristics of AY-27 cells. We showed that fluorescence detection of SUbcutaneously injected AY-27/tdTomato in F344 rat was successful using IVIS®200. However. intravesical fluorescence detection was hampered due to the thick rat tissue overlying the bladder. We suggest that f1uorescently tagged bladder or other deep intra-abdominal tumour model in rats may not be suitable for monitoring using IVIS®200.
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Marchesin, Valentina. "Role of ARF6 in breast cancer cell invasion." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066297/document.
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La migration des cellules tumorales à travers la matrice extracellulaire dépend de l'activité d'une métalloprotéase matricielle, MT1-MMP, ancrée à la membrane plasmique. MT1-MMP accumule aux invadopodes, des protrusions membranaires à base d'actine responsables de la dégradation de la matrice. La petite protéine G ARF6 est impliquée dans la régulation du trafic membranaire et dans le remodelage du cytosquelette d'actine. Dans mon travail de thèse, j'ai montré qu'ARF6 et deux de ses protéines effectrices JIP3 et JIP4, sont nécessaires à l'exocytose de MT1-MMP au niveau des invadopodes et, par conséquent, à la capacité des cellules tumorales à remodeler la matrice extracellulaire et migrer à travers un environnement matriciel tridimensionnel. ARF6, à travers son interaction avec JIP3/4, contrôle négativement l'activité du complexe dynactine/dynéine, un moteur moléculaire qui se déplace en direction du bout (-) des microtubules, et donc la clairance des endosomes MT1-MMP à partir de la périphérie cellulaire. En plus dans des échantillons humaines ARF6 est accumulée au niveau de la membrane plasmique, avec MT1-MMP, dans un sous-groupe de carcinomes mammaires agressifs, en confirmant donc l'implication d'un axe ARF6-JIP3/JIP4-MT1-MMP dans le processus invasif du cancer du sein. Dans une deuxième étude, j'ai montré que l'hyperactivation d'ARF6 induit un réarrangement important du cytosquelette d'actine à la surface ventrale des cellules tumorales mammaires et contribue à l'activation et au ciblage de Rac1 au front cellulaire. Mon travail a permis d'identifier de nouveaux mécanismes moléculaires par lesquels ARF6 contribue au programme invasif des cellules tumorales mammairesThe ability of cancer cells to traffic through the extracellular matrix relies on the action of the membrane-anchored matrix metalloprotease MT1-MMP. MT1-MMP is exocytosed to invadopodia, the actin-based membrane protrusions responsible for matrix degradation. The small GTP-binding protein ARF6 is known to coordinate post-endocytic recycling and actin cytoskeletal organization at the plasma membrane and was shown to be up-regulated in breast cancer cells. In my PhD work I showed that ARF6 and two of its effectors JIP3 and JIP4 are required for MT1-MMP endosomes intracellular positioning and exocytosis at invadopodia and consequently for tumor cells ability to remodel the matrix and invade through a three-dimensional matrix environment. ARF6, through the interaction with JIP3/4, negatively controls the activity of the minus-end-directed microtubule motor dynactin/dynein, thus negatively regulating the clearance and inward movement of MT1-MMP endosomes from the cell periphery. In human samples ARF6 is accumulated at the plasma membrane, together with MT1-MMP, in a subset of highly aggressive breast carcinomas, thus corroborating the ARF6-JIP3/JIP4-MT1-MMP axis in breast cancer invasion. In a second study I addressed the contribution of ARF6 activation on actin cytoskeleton remodeling in breast cancer cells. ARF6 links epidermal growth factor receptor signaling to Rac1 activation and targeting to the leading edge where it activates the SCAR/WAVE complex and regulates ventral actin polymerization during lamellipodia extension. Collectively my work identifies novel molecular mechanisms through which ARF6 contributes to the invasive program of breast tumor cells
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Behmoaram, Emy. "Biological studies of fascin function in cancer cell invasion and cancer progression." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111596.
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The process of metastasis is initiated through the acquisition of inherent and autonomous motile and invasive properties by tumor cells. These phenomena are initiated through a balance between forward cancer cell membrane protrusion and tail retraction, and occur via cell cytoskeleton remodeling, actin reorganization, and coordinated focal adhesion assembly and disassembly events. Among the vast network of cytoskeletal proteins, the actin-bundling protein fascin plays a major function in cell cytoskeleton remodeling. It is a 55-kDa protein involved in the formation of filopodia and cell migration, and found to be upregulated in many cancers. We report herein key functions for fascin in the regulation of prostate and breast cancer progression. Fascin expression is upregulated in localized and hormone refractory prostate cancer, responsible for a more aggressive clinical course. In addition, functional dissection of fascin reveals a novel function in the regulation of focal adhesion turnover dynamics, by modulating the phosphorylation state of central focal adhesion proteins through a potential collaboration with the protein tyrosine phosphatase, PEST. Together, our data support the importance of fascin in cancer cell invasion and as a significant prognostic marker and a potential therapeutic target for aggressive cancers.
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Sin, Sai-lung Steven, and 冼世隆. "Chloride channel in glioma cell invasion." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41508555.
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Sin, Sai-lung Steven. "Chloride channel in glioma cell invasion." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41508555.
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周穎嫻 and Wing-han Vivian Chow. "Genes associated with invasion and metastasis of head and neck cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31222468.
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Turner, Stephen. "Mathematical modelling of cancer invasion and biological cell movement." Thesis, Heriot-Watt University, 2002. http://hdl.handle.net/10399/438.
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Neisen, Jessica. "Chemokine regulation of microenvironment-enhanced invasion in prostate cancer." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677956.
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The interaction between a tumour and the surrounding non-malignant stroma impacts on nearly every aspect of malignant progression. The heterogeneity of the tumour microenvironment (TME), however, makes mapping this interaction difficult. Each stromal population contributes to various functions and each tumour type has its own distinct pathway of interaction with different stromal populations. The majority of these interactions are mediated by soluble factors secreted into the TME. The aim of this study was to elucidate the role that IL-8 signalling may play in prostate tumour interaction with the TME and to determine the mechanism by which IL-8 signalling impacts on tumour-associated stromal cells to enhance tumourigenicity. IL-8 in the prostate TME is primarily derived from the tumour cells and bone-marrow derived myeloid cells are capable of responding to tumour-derived IL-8 via high levels of cell surface IL-8 receptors CXCR1 and CXCR2. Direct co-culture of the highly invasive prostate cancer cell line PC3 and a bone marrow-derived, macrophage representative line, THP-1 enhances invasion through Matrigel (2.4-fold, p=0.0098) and increases wound closure after 6 h (50.63% v 25.65% for PC3 cells alone; p=0.010B). Inhibition of IL-8 signalling by neutralizing antibody (i) or PEPducin inhibition of CXCR1 and CXCR2 (ii) inhibited macrophage-dependent invasion and wound closure: (i) 90% decrease in normalized invasion and 43% decrease in wound closure, p<0.001 and p=0.03 respectively relative to IgG and (ii) 38% reduction in wound closure, p=0.0002 compared to non-targeting peptides. Development of a stable PC3-based CXCL810w cell line, PC3-120p, confirmed these findings. PC3-120p cells were unable to initiate THP-1-potentiated motility and invasion, however, this response was rescued by addition of exogenous human CXCLB. Exogenous CXCLB was shown to up-regulate secretion of RTK-activating cytokines and growth factors from THP-1 cells. Addition of the RTK inhibitor cabozantinib (XL 184) but not crizotinib abrogated THP-1-dependent invasion and wound healing response of PC3 cells. Differential analysis of RTKs regulated by both cabozantinib and CXCLB neutralizing antibody in co-culture identify multiple RTKs as potential downstream regulators of CXCLB-dependent, monocyte-enhanced PC3 invasion. Together, this data supports the adjuvant targeting of molecules involved in tumour-stroma interactions to enhance the efficacy of prostate cancer treatment.
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Tod, Jo. "The role of Eps8 in regulating pancreatic cancer invasion." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/375024/.
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Paterson, Chay Giles Blair. "Minimal models of invasion and clonal selection in cancer." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28986.
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One of the defining features of cancer is cell migration: the tendency of malignant cells to become motile and move significant distances through intervening tissue. This is a necessary precondition for metastasis, the ability of cancers to spread, which once underway permits more rapid growth and complicates effective treatment. In addition, the emergence and development of cancer is currently believed to be an evolutionary process, in which the emergence of cancerous cell lines and the subsequent appearance of resistant clones is driven by selection. In this thesis we develop minimal models of the relationship between motility, growth, and evolution of cancer cells. These should be simple enough to be easily understood and analysed, but remain realistic in their biologically relevant assumptions. We utilise simple simulations of a population of individual cells in space to examine how changes in mechanical properties of invasive cells and their surroundings can affect the speed of cell migration. We similarly examine how differences in the speed of migration can affect the growth of tumours. From this we conclude that cells with a higher elastic stiffness experience stronger resistance to their movement through tissue, but this resistance is limited by the elasticity of the surrounding tissue. We also find that the growth rate of large lesions depends weakly on the migration speed of escaping cells, and has stronger and more complex dependencies on the rates of other stochastic processes in the model, namely the rate at which cells transition to being motile and the reverse rate at which cells cease to be motile. To examine how the rates of growth and evolution of an ensemble of cancerous lesions depends on their geometry and underlying fitness landscape, we develop an analytical framework in which the spatial structure is coarse grained and the cancer treated as a continuously growing system with stochastic migration events. Both the fully stochastic realisations of the system and deterministic population transport approaches are studied. Both approaches conclude that the whole ensemble can undergo migration-driven exponential growth regardless of the dependence of size on time of individual lesions, and that the relationship between growth rate and rate of migration is determined by the geometrical constraints of individual lesions. We also find that linear fitness landscapes result in faster-than-exponential growth of the ensemble, and we can determine the expected number of driver mutations present in several important cases of the model. Finally, we study data from a clinical study of the effectiveness of a new low-dose combined chemotherapy. This enables us to test some important hypotheses about the growth rate of pancreatic cancers and the speed with which evolution occurs in reality. We test a moderately successful simple model of the observed growth curves, and use it to infer how frequently drug resistant mutants appear in this clinical trial. We conclude that the main shortcomings of the model are the difficulty of avoiding over-interpretation in the face of noise and small datasets. Despite this, we find that the frequency of resistant mutants is far too high to be explained without resorting to novel mechanisms of cross-resistance to multiple drugs. We outline some speculative explanations and attempt to provide possible experimental tests.
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Esmaeili, Pourfarhangi Kamyar. "Effect of Extrinsic and Intrinsic Factors on Cancer Invasion." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/585155.
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Bioengineering;Ph.D.;
Metastasis is the leading cause of death among cancer patients. The metastatic cascade, during which cancer cells from the primary tumor reach a distant organ and form multiple secondary tumors, consists of a series of events starting with cancer cells invasion through the surrounding tissue of the primary tumor. Invading cells may perform proteolytic degradation of the surrounding extracellular matrix (ECM) and directed migration in order to disseminate through the tissue. Both of the mentioned processes are profoundly affected by several parameters originating from the tumor microenvironment (extrinsic) and tumor cells themselves (intrinsic). However, due to the complexity of the invasion process and heterogeneity of the tumor tissue, the exact effect of many of these parameters are yet to be elucidated. ECM proteolysis is widely performed by cancer cells to facilitate the invasion process through the dense and highly cross-linked tumor tissue. It has been shown in vivo that the proteolytic activity of the cancer cells correlates with the cross-linking level of their surrounding ECM. Therefore, the first part of this thesis seeks to understand how ECM cross-linking regulates cancer cells proteolytic activity. This chapter first quantitatively characterizes the correlation between ECM cross-linking and the dynamics of cancer cells proteolytic activity and then identifies ß1-integrin subunit as a master regulator of this process. Once cancer cells degrade their immediate ECM, they directionally migrate through it. Bundles of aligned collagen fibers and gradients of soluble growth factors are two well-known cues of directed migration that are abundantly present in tumor tissues stimulating contact guidance and chemotaxis, respectively. While such cues direct the cells towards a specific direction, they are also known to stimulate cell cycle progression. Moreover, due to the complexity of the tumor tissue, cells may be exposed to both cues simultaneously, and this co-stimulation may happen in the same or different directions. Hence, in the next two chapters of this thesis, the effect of cell cycle progression and contact guidance-chemotaxis dual-cue environments on directional migration of invading cells are assessed. First, we show that cell cycle progression affects contact guidance and not random motility of the cells. Next, we show how exposure of cancer cells to contact guidance-chemotaxis dual-cue environments can improve distinctive aspects of cancer invasion depending on the spatial conformation of the two cues. In this dissertation, we strive to achieve the defined milestones by developing novel mathematical and experimental models of cancer invasion as well as utilizing fluorescent time-lapse microscopy and automated image and signal processing techniques. The results of this study improve our knowledge about the role of the studied extrinsic and intrinsic cues in cancer invasion.
Temple University--Theses
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Atieh, Youmna Marie Lyne. "Interplay between cancer cells and cancer-associated fibroblasts in tumor invasion and metastasis formation." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066140/document.
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Les carcinomes sont des cancers touchant plusieurs organes du corps humain, notamment les seins, le pancréas, les poumons, l'intestin… et sont issus de la transformation de cellules épithéliales en cellules tumorales. Au cours du développement d'une tumeur, les cellules cancéreuses, contrairement aux cellules normales, acquièrent la capacité de se déplacer dans le corps humain, jusqu'à coloniser des organes voisins. Ces colonies sont appelées métastases. Le processus métastatique est responsable de 90% des décès dans le cadre des carcinomes. Ce processus n'est pas dû à l'action isolée des cellules cancéreuses mais est aussi le résultat d'une coopération entre la tumeur et son voisinage – le microenvironnement tumoral – favorisant la survie et la migration des cellules cancéreuses. Les fibroblastes sont une population cellulaire du microenvironnement tumoral. Il a été démontré que les fibroblastes sont activés à proximité des cellules cancéreuses ; on les qualifie de fibroblastes associés au cancer ou CAFs. Dans des tissus de patients, les tumeurs les plus agressives corrèlent avec un enrichissement en fibroblastes et une matrice plus dense. Mon projet de thèse illustre un nouveau mécanisme de coopération entre CAFs et cellules cancéreuses. Cibler l’action des fibroblastes pourrait ralentir la progression tumorale, voire bloquer la formation de métastasesCancer-associated fibroblasts (CAFs) are the most abundant cells of the tumor stroma. Their capacity to contract the matrix and induce invasion of cancer cells has been well-documented. However, it is not clear if CAFs remodel the matrix by other means (degradation, matrix deposition or stiffening). This project demonstrates that CAFs induce cancer cell invasion through assembly of FN into the matrix. CAFs assembled fibronectin (FN) mainly via integrin α5 but integrin αvβ3 was necessary for initial mechanosensing and fibrillar adhesion formation. In the absence of FN, contractility of the matrix by CAFs is preserved. When degradation is impaired, CAFs retain the capacity to induce invasion in a FN-dependent manner. In all cases, the levels of expression of integrin β3 and the amount of assembled FN was directly proportional to the invasion induced by fibroblast populations. Our results highlight FN assembly and integrin β3 as new hallmarks of CAFs. We also noticed that cancer cells migrate towards CAFs suggesting a possible chemotactic response. Using Dunn’s chemotaxis chamber, we found that cancer cells migrate along a gradient of CAF-conditioned media and a gradient of fibronectin. Finally, orthotopic injections of cancer cells and CAFs in the colon wall of mice revealed that CAFs stimulate metastasis of cancer cells to the liver. In conclusion, our data show that CAFs promote cancer cell invasion by depositing fibronectin that can guide cancer cells favoring metastasis formation
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Allen, Victoria. "Uncovering Pathways Regulating ILC Metastasis Through miRNA Expression Analysis and Generation of Novel Invasive ILC Models." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39616.
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Invasive lobular carcinoma (ILC) is the second most common form of breast cancer. ILC presents at later stages with many challenges, therefore improved diagnostic and therapeutic targets are needed. A microRNA (miRNA) genome analysis identified miR-23c and miR-23b-3p as possible regulators of ILC invasion due to their significantly increased expression in invasive compared to minimally invasive ILC cell lines. By decreasing the levels of miR-23c and miR-23b-3p using hairpin inhibitors, the invasive MDA-MB-330 cell line had significantly reduced invasion, while overexpressing these miRNAs using mimics in the minimally invasive MDA-MB-134VI cell line increased invasion. During the course of this study, it became apparent that limited tools exist for studying invasive ILC. Therefore, two more invasive ILC cell line models were created by isolating and expanding MDA-MB-134VI cells that had invaded through Matrigel® coated invasion chambers. This thesis has thus created new models of invasive ILC as well as identified miR-23c and miR-23b-3p as regulators of MDA-MB-330 and MDA-MB-134VI cell line invasion.
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Monteiro, Pedro. "Rôle des complexes WASH et exocyste dans l’invasion tumorale." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066291/document.
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La dissémination des cellules cancéreuses et la formation de métastases sont des étapes cruciales dans la progression tumorale et constituent une cause majeure des décès dus au cancer. La métalloprotéase transmembranaire MT1-MMP est un acteur clé impliqué dans le franchissement des barrières tissulaires et le remodelage de la matrice extracellulaire (ECM) par les cellules cancéreuses. MT1-MMP est présente dans des vésicules intracellulaires, appelées endosomes, via lesquels elle est adressée à la membrane plasmique (PM) afin d'y dégrader la ECM. Des travaux menés au laboratoire ont identifié le complexe exocyste (CE) comme un acteur important pour la formation d'invadopodes dans la lignée d'adénocarcinome mammaire MDA-MB-231. Ce complexe multiprotéique (Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 et Exo84) est impliqué dans l'arrimage des vésicules intracellulaires à la PM. Des cribles double-hybride ont identifiés la protéine WASH comme partenaire potentiel du CE (via les sous-unités Exo84 et Sec3). WASH est capable d'induire la polymérisation de l'actine en activant le complexe Arp2/3. In vitro, nous avons montré que les complexes WASH et exocyste interagissent physiquement et coordonnent le trafic intracellulaire et l'adressage de MT1-MMP à la PM. Ces résultats mettent en évidence une étroite collaboration entre le cytosquelette d'actine et les mécanismes d'exocytose lors des étapes précoces de dégradation de la ECM ainsi que dans l'invasion tumoraleCancer cell invasion is a prerequisite to tumor progression and metastasis. In order to disseminate, tumor cells must degrade and remodel the extracellular matrix (ECM) in a process that requires the trans-membrane matrix metalloproteinase MT1-MMP, which is a key component of the ECM remodeling apparatus of cancer cells. MT1-MMP overexpression in cancers is associated with increased invasion and metastasis. Many cellular proteins are involved in the transport and delivery of MT1-MMP-containing vesicles to the PM. Previous work from the laboratory identified the exocyst complex (EC) as a key component required for matrix proteolysis and invasion of cancer cells. This multiprotein complex (Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84) plays essential roles in docking secretory vesicles at the PM for exocytosis. To better characterize this complex, a yeast two-hybrid screen was performed, identifying the protein WASH as a potential partner of Exo84 and Sec3. WASH is a Nucleation Promoting Factor (NPF) able to activate the actin nucleating Arp2/3 complex. Results of the present study showed that WASH and the exocyst complexes interact and localize on MT1-MMP-positive endosomes in MDA-MB-231 breast cancer cells. This study highlight a direct implication of WASH and exocyst complex in ECM degradation by cancer cells through the docking and exocytosis of MT1-MMP-containing endosomes at the PM through connections between these compartments and the extracellular medium. This WASH- and exocyst-dependent MT1-MMP exocytosis mechanism is required for degradation of adjacent tissue by cancer cells during tumour cell invasion
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Hamyeh, Mohamed. "Régulation de l'agressivité tumorale mammaire par la protéine tyrosine phosphatase PTPL1/PTPN13." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT015/document.
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Le cancer du sein est un problème majeur de santé public dont l'incidence est en permanente augmentation. La mortalité est le plus souvent due aux métastases. Les études concernant PTPL1, la plus grande des tyrosines phosphatases cytoplasmiques, ont montré que PTPL1 présente les caractéristiques de suppresseur de tumeur. PTPL1 se trouve mutée dans plusieurs types de cancers et son expression est un marqueur de bon pronostique dans les tumeurs mammaires. Mon laboratoire a également montré que PTPL1 participe à l'effet pro-apoptotique des anti-oestrogènes dans les cellules tumorales hormono dépendantes en déphosphorylant IRSl, le substrat d'IGF1-receptor freinant ainsi la voie PI3K/AKT. PTPL1 régule également la croissance, l'invasion et l'adhésion dans les cellules cancéreuses mammaires peu agressives MCF7.Nous avons établi un modèle cellulaire de clones isogéniques capables d'exprimer PTPL1 ou ses mutants d'une manière inductible dans les cellules cancéreuses mammaires invasives MDA-MB-231. D’une part, nous avons montré un impact négatif de l'expression de PTPL1 sur le phénotype invasif de ces cellules. D'une manière intéressante, le mutant catalytiquement inactif a montré un comportement similaire à celui du contrôle de transfection. Ceci montre l'importance de l'activité catalytique de PTPL1 dans l'inhibition du phénotype agressif. Nous testons maintenant in vivo la tumorigenicité des clones chez les souris athymique.D'autre part, nous avons étudié par protéomique comparative (SILAC) la tyrosine phosphorylation globale des protéines cellulaires dans les cellules MCF-7 et MDA-MB-231 exprimant ou non PTPL1. Parmi les protéines identifiées nous retrouvons des acteurs des différentes voies de signalisations connues dans la littérature pour être impactées par PTPL1 , mais de manière remarquable plus du quart des protéines identifiées sont liées aux jonctions cellulaires ou à leur régulation. Nous avons donc étudié l'effet de la phosphatase sur les jonctions cellulaires et montré que la surexpression de PTPL1 favorise la formation d'agrégats cellulaire en culture 3D, augmente la stabilité des contacts cellulaire en vidéo-microscopie, relocalise la desmogléïne aux jonctions cellulaires et induit une réexpression de la E cadhérine aux niveau du contact cellule/cellule dans les cellules MDA-MB-231.Les jonctions et la polarité cellulaires sont très importantes en cancérologie en particulier dans le processus invasif qui est la première étape de la dissémination métastatique donc il serait maintenant important d'identifier les substrats directs de PTPL1 pour élucider la signalisation de PTPL1 vers les jonctions et proposer de nouvelles cibles thérapeutiqueThe regulation of breast tumor aggressiveness by Protein Tyrosine Phosphatase PTPL1/ PTPN13Breast cancer is a major problem for public health of which the incidence continues to increase. Its mortality is often linked to metastasis formation. Studies on PTPL1, the largest protein tyrosine phosphatase, have shown that it presents the characteristics of a tumor suppressor gene. PTPL1 is mutated in several types of cancers and its expression is associated with good prognostic in prostate and breast cancers. My team has shown that PTPL1 mediates the pro apoptotic effect of anti-estrogen in hormone-sensitive tumor cells by dephosphorylating IRS1, Insulin growth factor-1 receptor substrate, thus blocking PI3K/Akt pathway. In addition, PTPL1 regulates the growth, the invasion, and the adhesion of low aggressive breast tumor cells MCF-7.Our team established an isogenic cellular model capable of expressing PTPL1 or its mutants (phosphatase-dead and substrate-trapping mutants) in an inducible fashion in invasive cells. We showed that functional PTPL1 expression has a negative impact on cell aggressive phenotypes. Interestingly, the phosphatase-dead mutant exhibits the same behavior as the transfection control. This evidences that PTPL1 activity is crucial for the inhibition of aggressiveness. We are currently testing the clones tumorigenicity in athyemic mice.Furthermore, we conducted a comparative proteomic (SILAC) in order to study the global tyrosine phosphatome in MCF-7 and MDA-MB-231 cells with or without PTPL1. Our findings suggest that PTPL1 regulates the phosphorylation of proteins involved in different signaling pathways already described in the literature to be impacted by PTPL1. Remarkably, the quarter of proteins identified belong to cell junction structure or regulation. We then studied the impact of this phosphatase on cell junctions and showed that PTPL1 overexpression enhances cell aggregate formation in 3D culture, increases cell contact stability, relocates desmoglein to the cell junctions, and induces E-cadherin re-expression at the level of cell-cell contacts in MDA-MB-231 cells.Cell junctions and polarity are very important in oncology and particularly in the invasive process which is the first step in the metastatic dissemination. Our ongoing work focuses on identifying direct substrates for PTPL1 in order to elucidate the underlying PTPL1 signal leading to cell junctions and consequently propose a novel therapeutic targets
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Hatzikirou, Haralambos. "Lattice-gas cellular automata for the analysis of cancer invasion." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-21387.
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Cancer cells display characteristic traits acquired in a step-wise manner during carcinogenesis. Some of these traits are autonomous growth, induction of angiogenesis, invasion and metastasis. In this thesis, the focus is on one of the latest stages of tumor progression, tumor invasion. Tumor invasion emerges from the combined effect of tumor cell-cell and cell-microenvironment interactions, which can be studied with the help of mathematical analysis. Cellular automata (CA) can be viewed as simple models of self-organizing complex systems in which collective behavior can emerge out of an ensemble of many interacting "simple" components. In particular, we focus on an important class of CA, the so-called lattice-gas cellular automata (LGCA). In contrast to traditional CA, LGCA provide a straightforward and intuitive implementation of particle transport and interactions. Additionally, the structure of LGCA facilitates the mathematical analysis of their behavior. Here, the principal tools of mathematical analysis of LGCA are the mean-field approximation and the corresponding Lattice Boltzmann equation. The main objective of this thesis is to investigate important aspects of tumor invasion, under the microscope of mathematical modeling and analysis: Impact of the tumor environment: We introduce a LGCA as a microscopic model of tumor cell migration together with a mathematical description of different tumor environments. We study the impact of the various tumor environments (such as extracellular matrix) on tumor cell migration by estimating the tumor cell dispersion speed for a given environment. Effect of tumor cell proliferation and migration: We study the effect of tumor cell proliferation and migration on the tumor’s invasive behavior by developing a simplified LGCA model of tumor growth. In particular, we derive the corresponding macroscopic dynamics and we calculate the tumor’s invasion speed in terms of tumor cell proliferation and migration rates. Moreover, we calculate the width of the invasive zone, where the majority of mitotic activity is concentrated, and it is found to be proportional to the invasion speed. Mechanisms of tumor invasion emergence: We investigate the mechanisms for the emergence of tumor invasion in the course of cancer progression. We conclude that the response of a microscopic intracellular mechanism (migration/proliferation dichotomy) to oxygen shortage, i.e. hypoxia, maybe responsible for the transition from a benign (proliferative) to a malignant (invasive) tumor. Computing in vivo tumor invasion: Finally, we propose an evolutionary algorithm that estimates the parameters of a tumor growth LGCA model based on time-series of patient medical data (in particular Magnetic Resonance and Diffusion Tensor Imaging data). These parameters may allow to reproduce clinically relevant tumor growth scenarios for a specific patient, providing a prediction of the tumor growth at a later time stageKrebszellen zeigen charakteristische Merkmale, die sie in einem schrittweisen Vorgang während der Karzinogenese erworben haben. Einige dieser Merkmale sind autonomes Wachstum, die Induktion von Angiogenese, Invasion und Metastasis. Der Schwerpunkt dieser Arbeit liegt auf der Tumorinvasion, einer der letzten Phasen der Tumorprogression. Die Tumorinvasion ensteht aus der kombinierten Wirkung von den Wechselwirkungen Tumorzelle-Zelle und Zelle-Mikroumgebung, die mit die Hilfe von mathematischer Analyse untersucht werden können. Zelluläre Automaten (CA) können als einfache Modelle von selbst-organisierenden komplexen Systemen betrachtet werden, in denen kollektives Verhalten aus einer Kombination von vielen interagierenden "einfachen" Komponenten entstehen kann. Insbesondere konzentrieren wir uns auf eine wichtige CA-Klasse, die sogenannten Zelluläre Gitter-Gas Automaten (LGCA). Im Gegensatz zu traditionellen CA bieten LGCA eine einfache und intuitive Umsetzung der Teilchen und Wechselwirkungen. Zusätzlich erleichtert die Struktur der LGCA die mathematische Analyse ihres Verhaltens. Die wichtigsten Werkzeuge der mathematischen Analyse der LGCA sind hier die Mean-field Approximation und die entsprechende Lattice - Boltzmann - Gleichung. Das wichtigste Ziel dieser Arbeit ist es, wichtige Aspekte der Tumorinvasion unter dem Mikroskop der mathematischen Modellierung und Analyse zu erforschen: Auswirkungen der Tumorumgebung: Wir stellen einen LGCA als mikroskopisches Modell der Tumorzellen-Migration in Verbindung mit einer mathematischen Beschreibung der verschiedenen Tumorumgebungen vor. Wir untersuchen die Auswirkungen der verschiedenen Tumorumgebungen (z. B. extrazellulären Matrix) auf die Migration von Tumorzellen dürch Schätzung der Tumorzellen-Dispersionsgeschwindigkeit in einem gegebenen Umfeld. Wirkung von Tumor-Zellenproliferation und Migration: Wir untersuchen die Wirkung von Tumorzellenproliferation und Migration auf das invasive Verhalten der Tumorzellen durch die Entwicklung eines vereinfachten LGCA Tumorwachstumsmodells. Wir leiten die entsprechende makroskopische Dynamik und berechnen die Tumorinvasionsgeschwindigkeit im Hinblick auf die Tumorzellenproliferation- und Migrationswerte. Darüber hinaus berechnen wir die Breite der invasiven Zone, wo die Mehrheit der mitotischer Aktivität konzentriert ist, und es wird festgestellt, dass diese proportional zu den Invasionsgeschwindigkeit ist. Mechanismen der Tumorinvasion Entstehung: Wir untersuchen Mechanismen, die für die Entstehung von Tumorinvasion im Verlauf des Krebs zuständig sind. Wir kommen zu dem Schluss, dass die Reaktion eines mikroskopischen intrazellulären Mechanismus (Migration/Proliferation Dichotomie) zu Sauerstoffmangel, d.h. Hypoxie, möglicheweise für den Übergang von einem gutartigen (proliferative) zu einer bösartigen (invasive) Tumor verantwortlich ist. Berechnung der in-vivo Tumorinvasion: Schließlich schlagen wir einen evolutionären Algorithmus vor, der die Parameter eines LGCA Modells von Tumorwachstum auf der Grundlage von medizinischen Daten des Patienten für mehrere Zeitpunkte (insbesondere die Magnet-Resonanz-und Diffusion Tensor Imaging Daten) ermöglicht. Diese Parameter erlauben Szenarien für einen klinisch relevanten Tumorwachstum für einen bestimmten Patienten zu reproduzieren, die eine Vorhersage des Tumorwachstums zu einem späteren Zeitpunkt möglich machen
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Adoki, Samson. "Involvement of scribble protein in breast cancer invasion and metastasis." Thesis, University of Essex, 2016. http://repository.essex.ac.uk/17655/.
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A common feature of cancer cells is the loss of cell polarity. Scribble is a cell polarity protein with an unknown mechanism for its role in tumour suppression. Changes in the phosphorylation pattern of four serine sites at the C-terminal of scribble, implicate scribble in breast cancer invasion and metastasis. This was due to CD74 overexpression in lymph node metastatic triple negative breast cancers. Investigating how changes in serine phosphorylation status at these sites affect the regulation of invasion and metastasis in breast cancer was the focus of this study. These sites were mutated by site-directed mutagenesis to generate mutant scribble genes grouped into A-mutants and D-mutants, based on the amino acid change to the serine sites to mimic unphosphorylated and phosphorylated scribble, respectively. Widefield and confocal bioimaging of the expression and localization of these mutants in cell line HEK293T revealed good expression but varied localization to cytoskeletal elements, intercellular contact site, microtubules, centrosome and vesicles. Wound healing, MTT and flow cytometry assays were conducted on HEK293T transfected with these mutant genes to study how their expression affected cell migration, proliferation and the cell cycle, respectively. Notable differences emerged: 1.) A-mutants migrated more than D-mutants. 2.) D-mutants proliferated more than A-mutants and 3.) There were significantly more D-mutant expressing cells in the G2 phase of the cell cycle. Protein interaction study was also conducted. The binding partners of S[1306+1309]A and S[1306+1309]D mutants of scribble were captured and analysed by Co-IP and mass spectrometry. Bioinformatics analysis identified the pathways these binding proteins were significantly involved in: S[1306+1309]A binding partners were involved in cell migration via regulation of actin cytoskeleton pathway but contribute to intercellular adhesion via the tight junction pathway. S[1306+1309]D binding partners were involved in the TSH signalling and cell cycle pathways. The results show a significant possibility that unphosphorylated and phosphorylated hScrib support cell invasion and cell proliferation, respectively, and that these processes are antagonistic.
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Zeelenberg, Ingrid Saskia. "Chemokine receptor signals: role in migration, invasion and cancer metastasis." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/72874.
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Tang, Haoran. "Scar/WAVE complex suppresses cell invasion and cancer cell transformation." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3633/.
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The mechanisms by which cancer cells hijack the actin cytoskeleton to invade and disseminate to distant sites of metastasis remains one of the great frontiers in cancer research. Many actin-regulating proteins have been identified to be important in cancer cell invasion and metastasis. However the role of a major actin assembly promoting complex, Scar/WAVE regulatory complex (WRC) in cancer cell invasion is poorly understood. WRC has a well-known motility-promoting role in 2D planar cell migration, but a recent study on human epithelial cancers suggests WRC may be anti-invasive in vivo. To investigate the controversy, human epithelial cancer cells with reduced WRC expression were tested in multiple 3D cell motility assays. Interestingly, WRC demonstrates a robust anti-invasive role in these exciting experiments. To understand how loss of WRC promotes invasion, the molecular mechanism is investigated. N-WASP is the other major actin assembly promoting protein. Unlike WRC, N-WASP is interestingly not required for 2D planar cell migration, but is important for motility in 3D. The interplay of the two major actin assembly promoting proteins has not been explored in 3D cell motility. I report here that loss of WRC promotes hyper-activation of focal adhesion kinase that leads to N-WASP accumulation and activation at the invasive front. This chain of events results in enhanced invasion providing a molecular mechanism of WRC’s anti-invasive function.  In addition to this FAK-N-WASP core mechanism, I also identified a novel pro- invasive role of HSPC300 independently of WRC. Loss of WRC possibly releases free HSPC300 that could subsequently interact with and regulate N-WASP activation during invasion providing a potential direct molecular link between the two proteins. Furthermore, WRC also supresses focal adhesion kinase mediated cell transformation and tumour formation in vivo. In this thesis I therefore demonstrate novel anti-invasion and anti-tumourigenesis functions of WRC. I also show how a novel WRC binding protein, NHS, could negatively regulate WRC function.
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Thomas, Dustin G. "ROLE OF NON-MUSCLE MYOSIN IIB IN BREAST CANCER INVASION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1449156792.
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Bair, Elisabeth Laurine. "Cell-cell and cell-matrix interactions involved in cancer invasion." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280673.
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In order for a cancer to metastasize, it must first invade through the basement membrane that surrounds it, invade blood vessels and travel through the bloodstream to a new location where it extravasates the vessel and begins growing at the new site. The mechanisms by which a cancer becomes able to invade and metastasize are currently under intense study. Interactions of the cell with its environment via cell-cell contacts, extracellular matrix (ECM) interactions, and circulating proteins are thought to play a major role in signaling for these invasive processes to occur. Upregulation of proteolytic enzymes, such as the matrix metalloproteases, is suspected of being involved in the metastatic process. Cell-cell and cell-matrix contacts via integrins and cadherins are necessary for upregulation of the matrix metalloprotease matrilysin in oral squamous cell carcinoma. In an effort to identify the factors involved in upregulation of matrilysin expression detected in a co-culture of oral squamous cell carcinoma (SCC) cells and fibroblast cells, a coculture model designed to represent the actual tumor environment, we show that inhibition of beta1 integrin, E-cadherin, and N-cadherin with blocking antibodies thoroughly decreases the induction of matrilysin in the co-culture model. This demonstrates that interactions between cancer cells and normal cells surrounding them may allow for invasion and metastasis. The protein 90K may also play a role in the invasive process of prostate cancer. It functions as an immune modulator upregulating cytokines that induce MMPs and we show that it can induce matrilysin expression in prostate cancer cells. It also functions in cell aggregation, which can help cells survive during metastasis. For this reason, expression of 90K in prostate cancer, which we examined, may be indicative of aggressive disease, making 90K a potentially useful tumor marker. Cell-matrix contacts are also important for the transmembrane matrix metalloprotease MT1-MMP cleavage of laminin-10. We demonstrate that recombinant MT1-MMP is able to cleave human laminin-10 into four distinct products. This allows for prostate cancer cell migration on laminin-10 coated substrates, which can be inhibited with the addition of MT1-MMP antisense oligonucleotides. Ln-10 cleavage also occurs in vivo in human prostate tissue, indicating that this cell-matrix interaction has in vivo relevance in human prostate cancer.
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Chinigò, Giorgia. "TRP channels functional role in prostate cancer angiogenesis and invasion." Electronic Thesis or Diss., Université de Lille (2022-....), 2022. http://www.theses.fr/2022ULILS103.
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Le cancer de la prostate (CaP) est la deuxième cause de mortalité par cancer chez l'homme et sa lethalité est principalement due aux métastases. Il est donc essentiel de comprendre les mécanismes par lesquels les tumeurs se développent et comment les métastases peuvent se diffuser dans le corps. L'agressivité des tumeurs prostatiques est étroitement liée à la migration des cellules épithéliales et endothéliales (EC) provoquant l'invasion des tissus voisins ainsi que la vascularisation tumorale. Plusieurs canaux de la famille TRP (Transient Receptor Potential) sont dérégulés dans les cellules cancéreuses et ont été suggérés comme marqueurs pronostiques et diagnostiques ainsi que comme des cibles potentielles pour la thérapie du cancer. Dans cette thèse doctorale, j’ai établi le rôle de certains canaux TRP régulant la signature calcique des cellules endothéliales et cancéreuses de la prostate, en se concentrant en particulier sur les canaux qui affectent la migration, une étape clé commune dans la vascularisation et l'invasion tumorales.Nous avons etabli le profil complet d'expression de tous les TRP dans les EC normales et les EC dérivées de tumeurs de la prostate (PTEC), mammaires et rénales. Nous avons identifié trois gènes «associés à la prostate» dont l'expression est corrélée positivement dans les PTEC (TRPV2, TRPC3 et TRPA1). Parmi eux, TRPA1 joue un rôle essentiel dans la régulation de l'angiogenèse du CaP, favorisant la migration des PTEC, la formation du réseau vasculaire et l'angiogenèse par bourgeonnement in vitro et in vivo.En ce qui concerne la motilité des cellules cancéreuses d’origine épithéliale, je me suis concentrée sur TRPM8, canal pour lequel un rôle protecteur dans le CaP métastatique a été proposé via l’altération de la motilité cellulaire. Nous avons tout d’abord validé le rôle anti-métastatique de TRPM8 in vivo, montrant que la surexpression et l'activation de TRPM8 réduisent significativement la croissance tumorale et la dissémination des métastases dans un modèle murin de xénogreffe orthotopique de la prostate. De plus, en étudiant le mécanisme moléculaire sous-jacent à la fonction inhibitrice de TRPM8 sur la migration des cellules du CaP, nous avons constaté que TRPM8 inhibe la migration et l'adhésion des cellules du CaP indépendamment de sa fonction canalaire en piégeant au niveau intracellulaire la petite GTPase Rap1A sous sa forme inactive et en évitant ainsi sa activation sur la membrane plasmique. De plus, nous avons identifié et validé les résidus impliqués dans l'interaction entre TRPM8 et Rap1A: résidus E207 et Y240 dans la séquence de TRPM8 et Y32 dans celle de Rap1A. Nos données révèlent donc le rôle de TRPA1 et TRPM8 dans l'angiogenèse et l'invasion du CaP en affectant la migration cellulaire.Dans la lutte contre les métastases, le développement de systèmes de nano-administration efficaces est aussi crucial que l'identification de nouvelles cibles moléculaires. Dans ce contexte, une deuxième partie de ce projet de doctorat était axé sur l'étude des nanoparticules lipidiques en tant que systèmes d'administration de médicaments appropriés. En particulier, l'utilisation de nanoparticules lipidiques solides (SLN) et de quatsomes (QS) pour l'incorporation de colorants polyméthine (PMD) adaptés à des fins diagnostiques et thérapeutiques a été étudiée. Nous avons démontré que les nanoparticules lipidiques non seulement augmentent la solubilité de la PMD dans des conditions physiologiques, mais améliorent même leurs performances spectroscopiques, faisant des nanoparticules chargés de PMD des candidats potentiels et attrayants pour l'imagerie in vivo et/ou les applications PDT.Dans l'ensemble, cette thèse de doctorat propose les canaux TRP comme nouvelles cibles potentielles dans le traitement du CaP et, en même temps, les nanoparticules lipidiques comme nouveaux outils thérapeutiques pour améliorer l'administration de médicaments dans le traitement du cancerProstate cancer (PCa) is the second most lethal tumor among men and its mortality is mainly due to metastasis. Thus, it is critical to understand the mechanisms by which tumors grow and how metastases can diffuse throughout the body. Cell migration of both epithelial and endothelial cells (EC) is required for cancer cell invasion of neighboring tissues as well as for the formation of tumor vasculature. Several Transient Receptor Potential (TRP) channels are deregulated in cancer cells and have been suggested as valuable markers in predicting cancer progression as well as potential targets for pharmaceutical therapy. In the present Ph.D. thesis, I established the role of TRP channels regulating Ca2+ signature in PCa cells and vasculature focusing, in particular, on the channels that affect migration, a common key step in tumor vascularization and invasion.The role of TRP channels in prostatic angiogenesis was studied in prostate tumor-derived EC (PTEC): we fully profiled the expression of all TRPs in normal ECs and TECs derived from PCa, breast, and renal tumors. We identified three ‘prostate-associated’ genes whose expression appears selectively upregulated in PTECs: TRPV2, TRPC3, and TRPA1. Among them, TRPA1 seems to play a critical role in regulating PCa angiogenesis, promoting PTEC migration, vascular network formation, and angiogenic sprouting both in vitro and in vivo.As regards, instead, epithelial PCa cells' motility, emerging evidence indicates that TRPM8 may exert a protective role in metastatic PCa by impairing the motility of these cancer cells. Investigating the molecular mechanism underlying this biological effect, we found that, as previously described for ECs, TRPM8 inhibits PCa cell migration and adhesion independently from its channel function by intracellularly trapping the small GTPase Rap1A in its inactive form and thus avoiding its translocation and activation on the plasma membrane. Moreover, we identified and validated the residues involved in the interaction between TRPM8 and Rap1A: residues E207 and Y240 in the sequence of TRPM8 and Y32 in that of Rap1A.Our data shed new light on the roles played by TRPA1 and TRPM8 in prostate cancer angiogenesis and invasion by affecting cell migration of endothelial and epithelial cells, respectively.In the fight against metastasis, the development of efficient nanodelivery systems can be as crucial as the identification of new molecular targets in cancer therapy to fill the gap between “drug discovery” and “drug delivery” which is one of the most challenges in clinical perspectives. In this context, the second part of this Ph.D. project focused on the study of lipid nanoparticles as suitable drug delivery systems. In particular, the use of solid lipid nanoparticles (SLN) and quatsomes (QS) for the incorporation of polymethine dyes (PMD) suitable for both diagnostic and therapeutic purposes was investigated. We demonstrated that lipid nanocarriers not only increase the solubility of PMD in physiological conditions but even enhance their spectroscopic performances, making PMD-loaded nanocarriers potential and appealing candidates for in vivo imaging and/or PDT applications.Overall, the present Ph.D. thesis deepens our knowledge of the role of TRP channels in PCa progression, providing new insight into their possible use as new therapeutic targets in PCa treatment and, at the same time, proposes new therapeutic tools to improve drug delivery in cancer therapy
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Scott, Rebecca Wilson. "LIM kinase regulation of cell motility and invasion." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2247/.
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This thesis describes how both LIM Kinase 1 and LIM Kinase 2 are both important regulators of cell invasion. Chapter 3 presents data that shows that inhibition of LIMK function blocks the collective invasion of MDA MB 231 breast carcinoma cells in a three-dimensional matrix. Although LIMK was not required for cell motility in two dimensions, a novel role for LIMK in both extracellular matrix degradation and deformation activities was shown in three dimensions in Chapter 4. Consistent with matrix remodeling being a requirement for path generation by leading cells in collective invasion, LIMK activity was also shown to be required by leading cells in MDA MB 231 collective invasion. However, it was also discovered that LIMK activity was not required for path following MDA MB 231. The importance of Cofilin activity as a conduit of LIMK activity during invasion was investigated in Chapter 5, a well as potential novel protein interactions of Cofilin. The identification of novel substrates of LIMK was attempted in Chapter 6, leaving prospective routes of investigation to further elucidate the roles of LIMK1 and LIMK2 in cells. The main findings presented in this thesis reveal a requirement for LIMK activity in the path generation function of leading cells in collective invasion. Given that individual invading cells must generate their own paths, these results lend support to the continued development of LIMK inhibitors to counter tumor cell invasion and metastasis.
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MacArthur, Benjamin Daniel. "Mathematical modelling of malignant growth and invasion." Thesis, University of Southampton, 2002. https://eprints.soton.ac.uk/50611/.
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The work presented in this thesis is concerned with the growth and development of malignancy. Such development can be thought of in terms of cell proliferation and associated morphological developments as well as in terms of active migration of malignant cells. Consequently this thesis can broadly be divided into two parts, one concerning growth dynamics in tumours, and the other active invasion of tissue by the malignancy. The first part of this thesis is concerned with the development of growth induced stresses within a multi-cell tumour spheroid (MCS), and associated structural changes. In particular, the growth and development of necrotic regions within a MCS is studied. Traditionally necrotic regions are considered to arise from the accumulation of necrotic cell debris, and as such form under chemically adverse conditions e.g. in hypoxic or nutrient deficient regions. However, it has been observed that the connection between such conditions and necrosis formation is not so simple. In particular, necrosis formation can precede or follow hypoxia. Therefore, in this thesis we examine a novel mechanism for necrosis formation, by allowing necrotic regions to arise under conditions of adverse mechanical stress. We consequently develop a model for spheroid growth in which necrosis forms in areas of mechanical tension but does not assume this formation a priori, and show that under the right conditions such a spheroid will support necrosis formation pre-hypoxia. Models in which the MCS is composed of a viscous, an elastic, and a viscoelastic material are all considered, and it is concluded that both biologically and mathematically a tumour spheroid is best modelled as a viscoelastic medium. The second part of this thesis is concerned with active migration of cells across a substrate via haptotaxis, and the application of this motility mechanism to glioma invasion of the central nervous system. A novel model for receptor mediated haptotaxis is developed which allows adhesion, proteolysis of extra-cellular matrix (ECM) components and subsequent migration of a cell to be modelled in a biochemically accurate manner. This single cell framework is then used to derive an average cell continuum velocity and flux, and these in turn are used to examine cell population migration via receptor mediated haptotaxis. Under appropriate limits the model presented is shown to reduce to a well known class of models, and as such provides a sound biochemical basis for these previous modelling attempts. Invasion of glioma cells into the central nervous system is studied with particular attention being paid to the effects of glioma-host interactions in modulation of migration velocity and interface shape. It is concluded that, under certain circumstances, an up-regulation of pro-migratory ECM components by the brain can inhibit glioma migration by slowing cell migration speed, and by sharpening the glioma-host interface. The phenomena of interface sharpening is seen as important, since gliomas often show diffuse boarders which present problems for their surgical resection within reasonable limits. The model outlined therefore suggests potential avenues for pre-surgical treatment which may prove very fruitful.
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Zangari, Joséphine. "Contribution du transfert du miR-223-3p des neutrophiles aux cellules tumorales dans la progression du cancer du poumon." Thesis, Nice, 2016. http://www.theses.fr/2016NICE4040.
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Le cancer du poumon est la première cause de mortalité par cancer en France et dans le monde. Aujourd'hui, en France, la survie cinq ans après un diagnostic de cancer du poumon est de seulement 14%, ce qui en fait l'un des cancers les plus difficiles à soigner. La médecine personnalisée, notamment l’immunothérapie, est désormais l’approche privilégiée pour les cancers du poumon aux stades métastatiques. Au sein d’une tumeur, les cellules cancéreuses sont entourées par un microenvironnement inflammatoire riche en polymorphonucléaires neutrophiles (PMN). Alors qu’il est établi que la présence répétée de PMN est associée au développement des carcinomes, la contribution de l'interaction intratumorale des PMN avec les cellules cancéreuses dans la progression tumorale n’est pas claire. Pour cela nos objectifs ont été de : 1) décrypter les moyens de communication engagés entre les neutrophiles et les cellules tumorales (miARNs et microvésicules) et 2) la régulation de ces acteurs dans les cellules réceptrices, 3) démontrer leur rôle dans la progression et la dissémination tumorale. La plasticité tumorale et l’invasion font parties des caractéristiques les plus importantes de la progression du cancer. Ces travaux nous ont permis d’identifier un nouveau mécanisme d'acquisition transitoire du phénotype invasif via le transfert de miARNs extracellulaires dans les cellules tumorales. Nous avons pu observer que le miR-223-3p extracellulaire est transféré des PMN aux cellules tumorales pulmonaires via des exosomesLung cancer is the leading cause of cancer mortality in France and worldwide. Today in France, the overall five-year survival rate after diagnosis is only 14%, making it one of the most challenging cancers to treat. Personalized medicine is now the preferred approach for lung cancer for metastatic stage, including so-called immunotherapy. Within a tumor, cancer cells are surrounded by an inflammatory microenvironment rich in polymorphonuclear neutrophils (PMN). While it is established that the presence of PMN is associated with the development of carcinomas, the contribution of intratumoral PMN and their interaction with cancer cells in tumor progression is unclear. To explore these hypotheses, objectives of our study were: 1) to decrypt the communication between neutrophils and tumor cells (miRNAs and microvesicles) and 2) the regulation of these actors in the recipient cells, 3) to demonstrate their role in tumor progression and dissemination. Tumor plasticity and invasion are part of the most important features of cancer progression. This work has allowed us to identify a new mechanism of transient acquisition of phenotype by transfer of extracellular miRNA (ex-miRNA) into cancer cells with and, importantly, by letting the ex-miRNA decay. We observed that the ex-miR-223-3p is transferred from PMN to lung tumor cells via exosomes. This transfer is functional, as demonstrated by the occurrence of epithelial to mesenchymal transition (EMT) associated with an invasive phenotype and inhibition of one of its targets, FOXO1 transcription factor
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Perumpanani, Abbey John. "Malignant and morphogenetic waves." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318866.
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MacDonald, Patricia. "Defining functional domains within GPNMB important for breast cancer cell invasion." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96829.
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Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein that is commonly expressed in basal/triple-negative breast cancer. Our group discovered that GPNMB/OA is sufficient to enhance the migration and invasion of weakly metastatic murine breast cancer cells in vitro, and promotes the formation of bone and lung metastases in vivo. In this study, we sought to fully characterize the pro-invasive role of GPNMB/OA in human breast cancer cells by defining those motifs/domains within GPNMB/OA that are required to promote breast cancer cell invasion. In addition, we have sought the identity of putative GPNMB/OA interacting proteins that may be involved in promoting GPNMB/OA-mediated effects on breast cancer cell invasion and metastasis. To accomplish this, a panel of GPNMB/OA mutants were generated and expressed in the GPNMB/OA null BT-549 and MDA-MB-453 human breast cancer cells and subjected to in vitro invasion assays characterization. A candidate approach based on previous literature reports was used to facilitate the identification of GPNMB/OA protein binding partners in addition to attempting mass spectrometry analysis. Finally, a transgenic mouse model was created that expresses human GPNMB/OA under the control of the Mouse Mammary Tumor Virus (MMTV) promoter to further explore the role of GPNMB/OA on mammary gland development and tumorigenesis in vivo. Our results indicate that human GPNMB/OA is sufficient to induce enhanced invasion of BT549 breast cancer cells in vitro, which requires both the cytoplasmic tail and RGD recognition motif. Characterization of the MMTV-GPNMB/OA transgenic mice revealed that GPNMB/OA does not negatively affect normal mammary duct development in virgin females and no mammary tumors have developed to date. We conclude that GPNMB/OA is indeed capable of inducing invasion of breast cancer cells in vitro, which may require the participation of integrins and/or the residues/motifs within the cytoplasmic tail responsible for recruiting signalling molecules to this region of GPNMB/OA.Glycoprotein non-metastatic melanoma protein B (GPNMB), aussi connu sous le nom de Ostéoactivine (OA), est une protéine transmembranaire fréquemment exprimée dans les tumeurs mammaires appartement au sous-type triple négatif. Notre groupe a mis en évidence que l'expression de GPNMB/OA est suffisante pour accroître, in vitro, les capacités migratoires et invasives associées aux cellules murines de cancer du sein faiblement métastatiques. In vivo, l'expression de GPNMB/OA est caractérisée par une augmentation de la formation des métastases osseuses et pulmonaires. Dans cette étude, nous avons cherché à caractériser le rôle pro-invasif associé à l'expression de GPNMB/OA dans les cellules humaines de cancer du sein en identifiant les domaines ou motifs de GPNMB/OA impliqués dans le phénotype invasif des cellules de cancer du sein. D'une part, nous avons entrepris l'identification de protéines interagissant avec GPNMB/OA et qui pourraient participer aux phénotypes associés à l'expression de GPNMB/OA. Pour ce faire, nous avons généré une série de mutants pour la protéine GPNMB et nous les avons exprimées dans les lignées cellulaires BT-549 et MDA-MB-453, qui n'exprime normalement pas GPNMB/OA, que nous avons par la suite soumis à des essais d'invasion in vitro. D'autre part, une étude de la littérature scientifique, associée à une analyse par spectrométrie de masse, ont été utilisées pour identifier les protéines partenaires potentielles de GPNMB/OA. Finalement, nous avons généré une lignée de souris transgénique qui exprime la forme humaine de GPNMB/OA sous le contrôle du promoteur Mouse Mammary Tumor Virus (MMTV). Ce modèle murin a été utilisé pour étudier le rôle de GPNMB/OA sur le développement de la glande mammaire et sur la tumorigenèse in vivo. Ainsi, ces travaux ont démontré que la forme humaine de GPNMB/OA est suffisante pour induire une augmentation des propriétés invasives des cellules BT549 et que ce phénotype requiert à la fois la région cytoplasmique et le motif RGD de la protéine GPNMB/OA. La caractérisation, des souris transgéniques MMTV-GPNMB/OA a révélé, pour sa part, que GPNMB/OA n'interfère pas avec le développement normal des glandes mammaires chez les femelles vierges et aucune tumeur n'a été détectée à ce jour. L'ensemble de nos données démontre que GPNMB/OA est capable d'induire les propriétés invasives associées aux cellules de cancer du sein, et que ce phénotype requiert l'interaction du motif RGD de la protéine GPNMB avec les intégrines et/ou des résidus ou motifs présents dans la partie cytoplasmique de GPNMB/OA et qui pourraient induire le recrutement de molécule de signalisation dans cette région de GPNMB/OA.
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Qazi, Romena. "The role of the urokinase family in invasion by breast cancer." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266538.
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Ord, Jonathan J. "Microarray analysis of pathways involved in bladder cancer invasion and metastasis." Thesis, Queen Mary, University of London, 2008. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1571.
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Hypoxia-inducible genes have been linked to the aggressive phenotype of cancer. However, nearly all work on hypoxia-regulated genes has been conducted in vitro on cell lines. Here the hypoxia transcriptome in primary human bladder cancer was investigated using cIDNA microarrays to compare genes induced by hypoxia in vitro in bladder cancer cell line EJ28 with genes upregulated on an in vivo array of 39 bladder tumours (27 Ta/T1 12 T2-T4). mRNA array fold-changes were correlated with carbonic anhydrase IX (CA IX) staining and necrosis of tumours as surrogate markers of hypoxia. Of 6000 genes 32 were repeatedly hypoxia-inducible in vitro more than 2-fold, five of which were novel, including lactate transporter SLC16A3 and RNAse 4. Eight of 32 hypoxia-inducible genes in vitro were also upregulated on the vivo array. Vascular endothelial growth factor (VEGF) mRNA was upregulated 2-fold by hypoxia and 2 to 18-fold in 31/39 tumours. Also up regulated on both arrays was GLUT 1 mRNA, and fold changes on the in vivo genearray significantly correlated with CA IX staining of tumours (p=0.008). However Insulin-like growth factor binding protein 3 (IGFBP-3) mRNA was the most strongly differentially expressed gene in both arrays and its upregulation was confirmed in the urine of bladder cancer patients (n=157, p<0.01) and in cell line supernatants. Angiogenin was also upregulated in urine of bladder cancer patients. Selected genes upregulated by hypoxia (HIF la, HIF 2a, CA IX and NIP3) were studied by immunohistochemistry for their prognostic significance and association with necrosis in 98 cystectomy specimens. Normal human urothelial cells were also grown in culture and a hypoxia genearray profile compared with EJ28, peripheral blood monocytes and T-cells. This thesis studies the prevalence of hypoxia and necrosis in bladder cancer, its relationship with prognosis, genes associated with the hypoxic phenotype and hypoxia related molecular pathways.
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Harper, Kelly. "Autotaxin promotes cancer cell invasion via the lysophosphatidic acid receptor 4." Mémoire, Université de Sherbrooke, 2010. http://savoirs.usherbrooke.ca/handle/11143/4035.
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Tumor metastasis is a fundamental property of malignant cancer cells and the major cause of death in cancer patients. Recent studies indicate that tumor cell invasion and metastasis may be initiated by the formation of the actin-rich cell protrusions with ECM degradation activity, invadopodia. However, despite extensive research on the biology of invadopodia, very little is known about their specific inducers during tumor progression. Autotaxin (ATX) is a secreted lysophospholipase whose expression levels within tumors correlates strongly with their aggressiveness and invasiveness. ATX produces lyosophosphatidic acid (LPA), a phospholipid with known tumor promoting functions that acts through the G-protein coupled receptors, LPA[subscript 1-6] . Recently, overexpression of ATX and LPA receptors (LPA[subscript 1-3]) has been linked to increased tumor invasion and metastasis in vivo , however, the role of other LPA receptors (LPA[subscript 4-6]) as well as the exact mechanisms by which ATX induces tumor metastasis remain poorly characterized. In order to determine the involvement of ATX and LPA in invadopodia production, we used the fibrosarcoma HT-1080 cells stably transfected with ATX or shRNA targeting ATX in fluorescent matrix degradation assays. Our results demonstrate that ATX is implicated in the production of invadopodia resulting in an increase in both their formation and function. Using LPC or LPA, the substrate and product of ATX, we further show that invadopodia production is dependent on the production of LPA from LPC. Among the LPA receptors, LPA 4 has the highest expression in HT1080 cells. Using LPA[subscript 4] shRNA as well as agonists and inhibitors of the cAMP pathway, we provide evidence that LPA[subscript 4] signaling through the cAMP-EPAC-Rap1 axis, regulates invadopodia formation downstream of ATX. Furthermore, inhibition of Rac1, a known effector of Rap1 and invadopodia formation, abolished EPAC-induced invadopodia production, suggesting downstream participation of Rac1. Finally, results using LPA[subscript 4] shRNA support the requirement of this receptor for in vitro cell invasion and in vivo metastasis formation. Our results suggest that ATX through LPA[subscript 4] is a strong inducer of invadopodia formation that correlates with the ability of the cells to invade and metastasize. This study also revealed an unexpected signaling pathway for cell invasion involving LPA[subscript 4]-driven cAMP production and subsequent activation of the EPAC-Rap1-Rac1 axis.
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Sells, Earlphia. "Role of Tissue Kallikrein-Related Peptidase 6 in Colon Cancer Invasion." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/605219.
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Growing evidence indicates that serine proteases known as kallikreins are associated with malignancy and may have potential diagnostic/prognostic applications in cancer. Kallikreins are the largest group of serine proteases. Kallikrein enzymes are often involved in proteolytic cascades through their function in degradation of extracellular matrix proteins and promotion of angiogenesis. Kallikrein 6 (KLK6) is a member of the family of fifteen highly conserved secreted trypsin- or chemotrypsin-like serine proteases. Over-expression of KLK6 has been observed in different pathophysiological states such as neurodegenerative diseases, inflammation and various cancers, including colorectal cancer. In Chapter 3 we elucidated the miRNA-based mechanism of regulation of invasion in metastatic colorectal cancer over-expressing KLK6. We developed HCT116 colon stable isogenic cell lines with knockdown of KLK6 expression using short-hairpin interference RNA (shKLK6 clones). The shKLK6 clones had decreased expression and secretion of KLK6 protein with a minimal effect on cell growth and viability in cell culture. SCID mice injected with shKLK6-3 clone 3 cells exhibited a statistically significant increase in the survival rates (P=0.005), decrease in the incidence of distant metastases and a shift in the location of the metastatic foci closer to the cell's injection site. Levels of KLK6 protein secreted into the bloodstream were significantly lower in animals injected with shKLK6-3 clone 3 compared to HCT116 control clone 1 (P < 0.04). Through bioinformatics analyses we identified and validated three miRNAs, which are important in post-translational modification of bioactive proteins, proliferation, migration and p38 MAPK signaling pathway. In Chapter 4 we developed Caco-2 colon stable isogenic cell lines with expressing enzymatically active or mutant KLK6 protein (Caco-2 stable clones). We employed these cell lines to investigate the importance of KLK6 enzymatic activity of initiation of cell invasion using in vitro and in vivo models.
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Zheng, Yun, Jinjun Guo, Jin Zhou, Jinjian Lu, Qi Chen, Cui Zhang, Chen Qing, H. Philip Koeffler, and Yunguang Tong. "FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion." BioMed Central Ltd, 2015. http://hdl.handle.net/10150/610293.
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BACKGROUND: Metastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments. METHODS: Illumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer. RESULTS: Analyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ~ 0.89, p = 2.1E-226 ~ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the −600 to −300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the −391 to −385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR < 0.05) differentially expressed between WT and PTTG1−/− HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1. CONCLUSIONS: PTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.
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Adams, Matthew. "The expression and distribution of Tenascin C in breast cancer invasion." Thesis, University of Leicester, 2002. http://hdl.handle.net/2381/29410.
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Tenascin C (TNC) is an extracellular matrix protein that is expressed at low levels in normal adult tissue but is highly expressed around breast cancers. TNC exists as multiple isoforms generated through alternative splicing. Isoform expression in benign and malignant breast disease was investigated.;Significant differences in TNC isoform profile were identified. Whilst all tissues expressed the fully truncated TNC, expression of two additional isoforms was significantly associated with the invasive phenotype (p<0.001). A subset of pre-invasive carcinomas also expressed these additional isoforms. Furthermore, expression correlated with the presence of additional protein isoforms in stroma, where they were produced by stromal fibroblasts in malignant tissue, and both periductal fibroblasts and residual myoepithelial cells in ductal carcinoma in-situ (DCIS).;In-vitro experiments indicated growth factor specific induction of TNC. Epidermal growth factor induced expression of higher molecular weight TNC isoforms but initial investigations with transforming growth factor beta1 had no effect.;Two highly invasive breast cancer cell lines (MDA-MB 231 and MDA-MB 468) were found to produce TNC in contrast to tumour cells with a lower invasive capacity (MCF7 and T47D). TNC altered cell morphology and increased migration in cell lines MCF7, T47D and MDA-MB 468, but not MDA-MB 231. Effects on migration via alteration in fibroblast function was also seen in cell lines MCF7, T47D, and MDA-MB 468 , but not cell line MDA-MB 231. This indicates cell type specific direct and indirect effects of TNC on migration.;TNC had no effect on proliferation, or on the expression of a range of matrix metalloproteinases associated with breast carcinoma.;Primary tissue analysis demonstrates for the first time that specific TNC isoforms are expressed in invasive breast carcinomas and that these isoforms are identified in a subset of DCIS. These isoforms may predict invasion and thus provide, appropriate targets for therapeutic intervention.
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Truong, Danh, Julieann Puleo, Alison Llave, Ghassan Mouneimne, Roger D. Kamm, and Mehdi Nikkhah. "Breast Cancer Cell Invasion into a Three Dimensional Tumor-Stroma Microenvironment." NATURE PUBLISHING GROUP, 2016. http://hdl.handle.net/10150/621806.
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In this study, to model 3D chemotactic tumor-stroma invasion in vitro, we developed an innovative microfluidic chip allowing side-by-side positioning of 3D hydrogel-based matrices. We were able to (1) create a dual matrix architecture that extended in a continuous manner, thus allowing invasion from one 3D matrix to another, and (2) establish distinct regions of tumor and stroma cell/ECM compositions, with a clearly demarcated tumor invasion front, thus allowing us to quantitatively analyze progression of cancer cells into the stroma at a tissue or single-cell level. We showed significantly enhanced cancer cell invasion in response to a transient gradient of epidermal growth factor (EGF). 3D tracking at the single-cell level displayed increased migration speed and persistence. Subsequently, we analyzed changes in expression of EGF receptors, cell aspect ratio, and protrusive activity. These findings show the unique ability of our model to quantitatively analyze 3D chemotactic invasion, both globally by tracking the progression of the invasion front, and at the single-cell level by examining changes in cellular behavior and morphology using high-resolution imaging. Taken together, we have shown a novel model recapitulating 3D tumor-stroma interactions for studies of real-time cell invasion and morphological changes within a single platform.
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Shimizu, Yosuke. "SPA-1 controls the invasion and metastasis of human prostate cancer." Kyoto University, 2011. http://hdl.handle.net/2433/147332.
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Fite, Kristen. "Dysregulation of Phospholipase D (PLD) isoforms increases breast cancer cell invasion." Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright149557402792618.
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Chow, Wing-han Vivian. "Genes associated with invasion and metastasis of head and neck cancer /." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B22142526.
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Hoque, Apu E. (Ehsanul). "Migration and invasion pattern analysis of oral cancer cells in vitro." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220239.
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Abstract Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but relatively little is known about its role in cancer. In this study, the function of Dsg3 was investigated in oral squamous cell carcinoma (SCC) cell lines in vitro using locally established human leiomyoma tumor microenvironment (TME) matrices. Since Dsg3 has been identified as a key regulator in cell adhesion, we hypothesized that it may play a role in oral SCC cells adhesion and motility. Thus, one aim of the study was to explore this hypothesis by both gain and loss of function methods in four human buccal mucosa SCC SqCC/Y1 cell lines: transduction of vector control (Ct), full-length (FL) or two different C-terminally truncated Dsg3 mutants (Δ238 and Δ560). Live cell imaging was performed for 2D migration and 3D sandwich, alongside other assays. In 3D sandwich, we tested the effects of the monoclonal antibody, AK23, targeting the extracellular domain of Dsg3 in SqCC/Y1 cells. Our results showed that loss of Dsg3 disrupted cell adhesion and protein expression. In 2D assays, FL and Dsg3 mutants migrated faster with higher accumulated distances than Ct. In contrast with 2D, mutants showed accelerated invasion over the Ct in 3D models. The AK23 antibody inhibited only the invasion of FL cells. The TME in vivo consists of cellular and matrix elements playing a leading role in carcinoma progression. To study carcinoma cells invasion in vitro, mouse Matrigel® and rat type 1 collagen are the most commonly used matrices in 3D models. Since they are non-human in origin, they do not perfectly mimic human TME. To address this, we have developed a solid organotypic myoma disc model derived from human uterus leiomyoma tumor. Here, we introduce a novel Myogel, prepared from leiomyoma similar to Matrigel®. We validated Myogel for cell-TME interactions in 3D models, using SqCC/Y1 and HSC-3 cell lines. Compared with Matrigel® and type I collagen, oral SCC cell lines invaded more efficiently in Myogel containing matrices. This study describes promising 3D models using human TME mimicking Myogel which is suitable to analyze oral SCC cells both in carcinoma monocultures and in co-cultures, such as with TME fibroblasts. We also introduce a possible novel therapeutic target against Dsg3 to suppress cancer cell invasionTiivistelmä Desmogleiini 3 (Dsg3) on desmosomien adheesioreseptori, jonka merkityksestä syövässä tiedetään vähän. Koska Dsg3 on tärkeä epiteelisolujen välisissä liitoksissa, oletimme sillä olevan vaikutusta myös suun karsinoomasolujen tarttumisessa ja niiden liikkuvuudessa. Testasimme hypoteesiamme muuttamalla Dsg3:n toimintaa ihmisen posken karsinoomasolulinjassa SqCC/Y1, josta oli aiemmin valmistettu neljä erilaista muunnosta: tyhjän vektorin sisältävä kontrollisolulinja (Ct), kokopitkää Dsg3 tuottava solulinja (FL), sekä kaksi Dsg3 C-päästä lyhennettyä mutanttisolulinjaa (Δ238 ja Δ560). Immunofluoresenssi-menetelmää käyttäen analysoimme solulinjoissamme solujen välisiä liitoksia. Lisäksi mittasimme solujen liikkeitä 2D-migraatio- ja 3D-sandwich-kokeissa. Testasimme myös Dsg3:n solunulkoista osaa tunnistavan monoklonaalisen vasta-aineen (AK23) vaikutusta solujen invaasioon. Osoitimme, että Dsg3:n rakenteen muuttaminen ja toiminnan estyminen häiritsi solujen tarttumista. 2D-kokeissa sekä FL että mutanttilinjat (Δ238 ja Δ560) migroivat kontrollisoluja nopeammin ja pidemmälle, mutta 3D-kokeissa vain mutanttilinjat invasoituivat kontrollisoluja tehokkaammin. AK23-vasta-aine esti vain FL-solujen invaasiota. Syöpäsolujen 3D-invaasiota mittaavissa kokeissa käytetään yleensä hiiren kasvaimesta valmistettua kaupallista Matrigeeliä® tai rotan kudoksista eristettyä tyypin I kollageenia. Tutkimusryhmämme on jo aiemmin kehittänyt organotyyppisen myoomamallin, jossa valmistamme myoomakudosnapit ihmisen kohdun leiomyoomakasvaimista. Tässä työssä valmistimme leiomyoomasta Myogeelia, vertasimme sitä Matrigeeliin®, sekä tutkimme tarkemmin Myogeeli-valmisteen soveltuvuutta 3D-tutkimuksiin. Totesimme, että kielen (HSC-3) ja posken (SqCC/Y1) karsinoomasolut invasoituivat tehokkaimmin Myogeeli-pitoisissa matrikseissa kuin Matrigeeliä® tai kollageeniä sisältävissä kasvatusalustoissa. Tutkimustulostemme perusteella Myogeeli-pohjaiset 3D-mallit soveltuvat hyvin sekä syöpäsolulinjojen invaasiotutkimuksiin että yhteisviljelmiin, joissa syöpäsoluja viljellään yhdessä syöpäkasvaimen ympärillä olevien solujen, kuten fibroblastien, kanssa
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Lam, Hoyin. "3D co-culture spheroid drug screening platform for pancreatic cancer invasion." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/3d-coculture-spheroid-drug-screening-platform-for-pancreatic-cancer-invasion(5fb01f64-2526-46c7-b171-933a4ec066d2).html.
Full textAbstract:
Pancreatic ductal adenocarcinoma (PDAC) is the 5th most common cause of death by cancer in the UK, accounting for 5% of all cancer deaths in the UK. Only 8% of the PDAC patients from all stages combined, survives for 5 years or longer. Late stage diagnosis combined with early cancer cell dissemination and poor response to current available treatments highlights the need for novel therapeutics tackling tumour growth and invasion. Previously, it has been shown that cellular plasticity during disease progression and the tumour stroma could contribute to cancer metastasis and resistance to therapy. Furthermore, progression in genetic sub-type classification of PDAC has shown differences in patient survival and response to treatment. However, PDAC cell plasticity and morphology in the presence of matrix has not been extensively addressed nor linked with sub-types thus far. Moreover, while 3D models are increasingly applied in order to mimic in vivo conditions more closely, the majority of current screening assays do not include components of the stroma and are based mainly on cell viability. In addition, well established genetic engineered mouse models (GEMM) and patient derived xenograft (PDX) are not cost effective or widely accessible for screening purposes. Understanding the behavioural characteristics and drug responses of PDAC cells with models mimicking the in vivo microenvironment is pivotal in developing novel therapies. To address the need for invasion models that can be used for screening, I have first investigated PDAC cell behaviour with the 2.5D model in vitro and selected a representative cell line for screening. Subsequently, I have developed and optimised a 3D co-culture spheroid screening platform to assess compounds for inhibition of PDAC invasion in the presence of pancreatic stellate cells. A select drug library with 99 FDA approved compounds was probed for potential drug repurposing for PDAC invasion and selected for further validation. Together these experiments will provide us novel insight into the invasive behaviour of pancreatic cancer cells and identify potential novel molecular targets against PDAC cell invasion.
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Gillespie, H. C. "The role of the adhesion molecule CD44 in tumour invasion." Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390886.
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Gibson, D. S. "The role of the cysteine proteinase cathepsins in astrocytoma invasion." Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368776.
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Zhou, Chun, and 周純. "Effect of FTY720 on the growth and invasion ability of androgenindependent prostate cancer cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31685742.
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