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Park, Se Hyung. "Estrogen in ovarian cancer cell metastasis". Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/1287.
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Benign ovarian tumors and majority of epithelial ovarian cancers possess steroid receptors including estrogen receptors (ERs). However, the estrogen-ER signaling in ovarian carcinomas is not completely understood. Tumorigenesis is a multiple-step process involving dysregulated cell growth and metastasis. Tumor cells acquire the capacity of migration and invasion by temporal phenotypical and genotypical changes termed epithelial-mesenchymal transition (EMT). Considerable evidence implicates a mitogenic action of estrogen in early ovarian carcinogenesis. In contrast, its influence in the metastatic cascade of ovarian tumor cells remains obscure. In this study, I have focused on the role of 17β-estradiol (E2) in ovarian tumorigenesis. EMT related genes including E-cadherin, Snail, Slug, and Twist were examined. E2 treatment led to clear morphological changes and an enhanced cell migratory propensity. These morphologic and functional alterations were associated with changes in the abundance of EMT-related genes. Upon E2 stimulation, expression and promoter activity of the epithelial marker E-cadherin was strikingly suppressed, whereas EMT-associated transcription factors Snail and Slug were significantly up-regulated. This up-regulation was attributed to the increase in gene transcription activated by E2. Depletion of the endogenous Snail or Slug using small interfering RNA (siRNA) attenuated E2-mediated control in E-cadherin. In addition, the E2-induced cell migration was neutralized by Snail and Slug siRNAs, implying that both transcription factors are indispensable for the pro-metastatic actions of E2. Importantly, by using selective ER agonists as well as over-expression and siRNA approaches, it was identified that E2 triggered the metastatic behaviors exclusively through an ER⍺-dependent pathway. In contrast, overexpression of ERβ opposed the phenotypic changes and down-regulation of E-cadherin induced by ER⍺. In addition, microarray analysis was performed to characterize more putative downstream mediators of E2. Expression levels of 486 genes were found to be altered by at least 50% upon E2 treatment, and included several genes involved in oncogenesis, cell cycle control, apoptosis, signal transduction and the gene expression machinery. These candidate genes may be valuable for better delineating the ER pathways and functions. In summary, this study provides compelling arguments that estrogen can potentiate tumor progression by EMT induction, and highlight the crucial role of ER⍺ in ovarian tumorigenesis.
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Oosterhout, Anselmus Gerardus Maria van. "Small cell lung cancer and brain metastasis". Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=6643.
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Villafañe, Johann Sebastian Bergholz. "Role of P63 in cell migration and cancer metastasis". Thesis, Boston University, 2012. https://hdl.handle.net/2144/12282.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.The p53-related p63 protein is expressed as multiple isoforms involved in diverse biological functions, including cell proliferation, survival, apoptosis, differentiation, senescence, and aging. An inverse correlation between p63 expression and cancer progression in a variety of human cancers suggests that p63 functions as a metastasis suppressor. Here, we show that the predominant isoform of p63, ΔNp63α, plays a major role in inhibiting cell migration, invasion, and cancer metastasis by modulating Extracellular signal-regulated protein kinase 1 and 2 (Erk1/2) signaling. We profiled gene expression in human breast cancer Hs-578T cells stably expressing wild type ΔNp63α, or a mutant derivative defective in DNA binding or protein-protein interaction. We observed that wild type ΔNp63α, but not the mutant derivatives, up-regulated Mitogen-activated Protein (MAP) Kinase Phosphatase 3 (MKP3), a negative regulator of Erk1/2 signaling. Accordingly, exogenous ΔNp63α expression in breast cancer MDA-MB-231 cells up-regulated MKP3 expression, decreased nuclear levels of phosphorylated Erk1/2, and down-regulated Matrix Metalloprotease 1 and 9 (MMP1/9) expression. In addition, ΔNp63α inhibited cancer cell invasion, which was significantly rescued by disrupting MKP3 expression. Conversely, pan-p63 knockdown in mammary epithelial MCF-1OA and head and neck squamous cell carcinoma FaDu cells resulted in decreased MKP3 expression and concomitant higher levels of Erk1/2 phosphorylation, while Mek1/2 phosphorylation levels were not affected. Consistently, pan-p63 knockdown led to increased cell motility and invasion, which was reversed either by reintroduction of the ΔNp63α isoform alone, but not by other isoforms, or by expression of MKP3. Interestingly, p63 ablation-induced cell motility is dependent on Erk2, but not Erk1 expression. Moreover, we found that both p63 and MKP3 expression is usually decreased in invasive breast carcinoma, indicating a clinical correlation between p63 and MKP3 down-regulation and cancer progression. Finally, we found that reduced p63 expression in Her2/Neu-transformed MCF-1OA cells dramatically increased metastatic frequency to the lungs in a mouse model of breast cancer. Taken together, these results not only reveal a novel molecular pathway by which p63 plays an important pathological role in cancer metastasis, but also contribute to the design of therapeutic strategies in the treatment of cancer.
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Chan, Pui-man Poemen. "Micrometastases of esophageal cancer /". View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36404652.
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Shirure, Venktesh S. "Molecular Mechanisms of Circulating Tumor Cell Adhesion in Breast Cancer Metastasis". Ohio University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1357706517.
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Xing, Fei. "ROLE OF NOTCH SIGNALING IN BREAST CANCER METASTASIS". OpenSIUC, 2012. https://opensiuc.lib.siu.edu/dissertations/514.
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Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In the first part of this study, we aimed to define the mechanism of Notch ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch liagnds in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly up-regulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a ã-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be up-regulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma plays a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer. In the second part of this study, the role of Notch signaling in brain metastasis was investigated. Metastatic diseases are responsible for the majority of the deaths in breast cancer patients and the brain is one of the most common metastatic sites. The metastatic tumor in the brain profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the one year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumor cells in the brain highly expressed IL-1â which can "activate" astrocytes. This activation significantly augmented the expression of JAG1 in the reactive astrocytes, which in turn activated Notch signaling pathway of cancer stem-like cells (CSCs) upon direct interaction. We also found that the activated Notch signaling in CSCs up-regulated Sox2 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis growth in our animal model. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease
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Lomax-Browne, Hannah Jane. "Interactions between cancer cell glycans and endothelial cells during adhesion events in metastasis". Thesis, Oxford Brookes University, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501906.
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Metastasis, the process by which cancer spreads in the body, is a complex, multi-step cascade which is poorly understood and is the cause of death of most cancer patients. Aberrant glycosylation is an established characteristic of cancer cells and appears to have a role in metastatic mechanisms. The lectin from Helix pomatia, the Ron (Helix pomatia agglutinin, HPA), recognises aberrant glycans terminating in α-N-acetylgalactosamine (GalNAc). The presence of GalNAc-glycans on cancer cell surfaces, detected by HPA binding, is associated with metastasis and consequent poor survival.
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Marshall, John Francis. "The role of integrins in melanoma progression and metastasis". Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295235.
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Harihar, Sitaram. "The Role of Phosphoinositide Signaling in Breast Cancer Metastasis Suppressor 1-Mediated Metastasis Suppression of Human Breast Carcinoma Cells". DigitalCommons@USU, 2011. https://digitalcommons.usu.edu/etd/870.
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Breast cancer is the most common non-skin cancer in women and the second most common cause of cancer-related death in U.S. women. Despite numerous advances in treatment strategies against breast cancer, the presence of undetected distant metastasis of the primary tumor remains the main cause of mortality. Current screening and detection methods such as mammograms are simply not sensitive enough to detect formation of metastasis. Further, currently available therapies against metastatic breast cancer do not provide a complete cure for the disease. Thus, understanding the biology and molecular factors involved in cancer metastasis will help aid in preventing the onset of metastasis and discovering an effective treatment for this deadly disease. My research focused on understanding the mechanism of action of one such factor, breast cancer metastasis suppressor 1 (BRMS1), a suppressor gene found deleted in late stage breast cancers. The goal of my dissertation was to investigate the role of membrane signaling lipids phosphoinositides, specifically phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) in BRMS1-mediated metastasis suppression in MDA-MB-435 and MDA-MB-231 human breast carcinoma cells. My studies revealed BRMS1 selectively reduced receptor tyrosine kinases (RTK) and Gprotein coupled receptors (GPCR) expression and downstream signaling in human breast carcinoma cells. My observations are critical as many of these receptors are upregulated in metastatic breast cancer and PI(4,5)P2 is a critical constituent for mediating their downstream signaling events. Further, using immunoblotting studies, I uncovered a possible compensatory mechanism in tumor cells to overcome downregulation of PI(4,5)P2 by BRMS1 and maintain its downstream signaling. When studied for BRMS1 regulation of enzymes involved in PI(4,5)P2 synthesis, I showed BRMS1 completely inhibits phosphatidylinositol 4-phosphate 5-kinase β (PIP5Kβ) expression. Using overexpression studies, I showed PIP5Kβ to be the major contributor to the cellular PI(4,5)P2 pool required for agonist-induced intracellular calcium rise. Taken together, my dissertation research has identified some critical breast cancer markers and revealed signaling pathways altered by BRMS1 in human breast carcinoma cells that can be studied as potential therapeutic targets against breast cancer metastasis.
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Zhang, Hanshuo. "Large-scale identification of functional genes regulating cancer cell migration and metastasis using the self-assembled cell microarray". Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/49066.
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Metastasis is one of the critical hallmarks of malignancy tumor and the principal cause of death in patients with cancer. Cell migration is the basic and essential step in cancer metastasis process. To systematically investigate functional genes regulating cell migration and cancer metastasis on large scale, we developed a novel on-chip method, SAMcell (self-assembled cell microarray). This method was demonstrated to be particularly suitable for loss-of-function high-throughput screening because of its unique advantages. The first application of SAMcell was to screen human genome miRNAs, considering that more and more miRNAs had been proved to govern cancer metastasis. We found that over 20 % of miRNAs have migratory regulation activity in diverse cell types, indicating a general involvement of miRNAs in migratory regulation. Through triple-round screenings, we discovered miR-23b, which is down-regulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including cell motility, cell growth and cell survival. In parallel, the second application of SAMcell was to screen human genome kinase genes, considering that more and more kinase genes had become successful diagnostic marker or drug targets. We found over 11% migratory kinase genes, suggesting the important role of kinase group in metastasis regulation. Through both functional screening and bioinformatics analysis, we discovered and validated 6 prospective metastasis-related kinase genes, which can be new potential targets in cancer therapy. These findings allow the understanding of regulation mechanism in human cancer progression, especially metastasis and provide the new insight into the biological and therapeutical importance of miRNAs or kinases in cancer.
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Gronau, Julian Hendrik. "The role of Endo180 in prostate cancer cell migration and metastasis". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/27289.
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Expression of the transmembrane type I receptor Endo180 (CD280, MRC2, uPARAP) has been associated with fibrosis, breast cancer, glioma and head and neck cancer. In this thesis I have evaluated the role of Endo180 in prostate cancer pathology with a particular focus on its link to increased tumour cell migration and metastasis. The aims of my project were as follows: (a) to ascertain the co-evolution of Endo180, its interaction partners and domain function in silico; (b) to design a non-radioactive assay to enable the study of Endo180 phosphorylation in vitro; (c) to establish of a multi-cell line model as a clinically relevant experimental tool to investigate the relevance of Endo180 expression with prostate cancer progression; and (d) to conduct the first full clinicopathological evaluation of Endo180 in prostate cancer patients. The findings presented confirm that the MRC2 gene, which encodes Endo180, is conserved throughout all known vertebrate genomes and that functional amino acid residues within the receptor are conserved across a wide range of species. A putative urokinase-plasminogen activator uPA-binding motif located in the C-type lectin domain-4 (CTLD-4) of the receptor was present in all mammals but no other species. Three-dimensional modelling revealed that the motif is accessible for predicted high-affinity binding between the two molecules. To investigate the biological consequence of the interaction between Endo180 and uPA, site directed mutagenesis was used to generate Endo180 lacking uPA-binding capacity. 2-D SDS-PAGE, immunoprecipitation and band-shift assays failed to detect Endo180 phosphorylation in fibroblasts; a finding that may reflect redundancy of this post-translational modification in stromal versus epithelial cells. A high-throughput screening approach was taken to identify factors that promote epithelial-to-mesenchymal transition (EMT) like responses in prostate cell lines derived from normal prostate epithelium (RWPE-1), benign hyperplasia (RCN170, RCN165), primary prostate cancer (RC92a, RC58T) and secondary metastatic prostate cancer (LNCaP, DU145 and PC3). With the exception of LNCaP cells all lines expressed low to intermediate levels of Endo180. The Endo180-transcriptional regulatory factor, TGF-β1, increased Vimentin expression in RC92a cells. The invasive properties of this panel of cell lines were assessed using a modified organotypic invasion assay in the absence and presence of TGF-β1. Multiple tissue microarray analysis revealed an increase of 26% in the five-year survival rate of patients with negative Endo180 expression (p = 0.02) and 46% in patients with negative Endo180 expression and low Gleason grade (p = 0.015). This data is the first to confirm a major clinical impact of Endo180 expression in any disease state. Future work should now be focused on the mechanisms through which Endo180 can promote prostate cancer progression and its application as a biomarker. The mechanistic studies will benefit from the clinically relevant in vitro models established as part of this thesis; and will help pinpoint the precise molecular interactions that could be potential therapeutic targets.
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Rud-Majani, Zahra Erami. "Investigation of E-cadherin dynamics in cancer cell adhesion and metastasis". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5619/.
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E-cadherin is a cell adhesion protein required for epithelial tissue integrity. In many cancer cells mis-regulation of E-cadherin adhesions causes increased progression and invasion of cancer. Alteration in E-cadherin dynamics could therefore serve as an early molecular biomarker of metastasis. In this project, I used E-cadherin FRAP to asses real time dynamics of cadherin junctions in a pancreatic cancer mice model of in a variety of micro-environments. My data showed that p53 mutation drives metastasis through mobilizing E-cadherin in junctions. Also, I used FRAP as a pharmaco-dynamic marker to assess the effect of an anti-invasive drug (dasatinib) in pancreatic tumours in vivo. Moreover, my E-cadherin FRAP data along with cross-linking experiments and disruption of E-cadherin interactions by mutation provided a comprehensive framework for understanding E-cadherin dynamics at cell-cell. Here, I have identified four distinct populations of E-cadherin within regions of cell-cell contact and characterized the interactions governing their mobility using FRAP. These pancreatic cancer cells had the immobile fraction (Fi) of E-cadherin-GFP comprised adhesive and non-adhesive populations. The remaining mobile fraction (Fm) also comprised of non-adhesive and adhesive populations, one population moves at the rate of pure diffusion, and therefore represents free E-cadherin monomers. The other population moves more slowly, and represents E-cadherin monomers turning over within immobile complexes. Inclusion of E-cadherin into either adhesive population requires cis-, trans-, and actin interactions. The signaling pathways in cells dramatically affect the fractions of these cadherin components. I showed that understanding the dynamics of these four populations of E-cadherins could be used to design or interpretation of future pharmacological and genetic experiments to probe the function of E-cadherin in development, disease progression, and response to therapy.
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Tang, Yuanyuan. "Nitric Oxide/Peroxynitrite Imbalance Induces Adhesion of Cancer Cells to Lymphatic Endothelium - Clinical Implications for Cancer Metastasis". Ohio University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1439563414.
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Pardo, Pastor Carlos 1989. "Piezo ion channels in cancer cell mechanotransduction". Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664209.
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The mechanical dependence of transformation and metastasis is an emerging field, but the role of mechanosensitive channels has been largely omitted. This thesis focuses on the roles played by the mechanosensitive ion channels Piezo1 and Piezo2 in the transduction of mechanical stimuli (confinement, adhesion, substrate rigidity, adhesive ligand concentration) by cancer cells.
In a first chapter, we show that confinement triggers Piezo1-mediated calcium entry. This activates phosphodiesterase 1, reducing cAMP levels and, consequently, PKARac1 activity, relieving Myosin II from its inhibition. We also find a parallel, direct activation of Myosin II by confinement. As a combined result, cells stiffen and optimize their adhesion-free migration mode, usually responsible for in vivo migration during metastatic invasion. Piezo1 knockdown supresses confinement-induced calcium entry and impairs the underlying circuitry in ovarian epithelial (CHO) or melanoma (A375) cells. As a result, siPiezo1 cells show reduced migratory capacity under confinement.
In the second chapter, we discover an essential role for Piezo2 as a transducer of environmental mechanical cues into RhoA activation to modulate the mechanobiological responses of MDA-MB-231-BrM2 brain metastatic breast cancer cells. Piezo2 knockdown disturbs stress fibre formation, adhesion orientation, force transmission and nuclear accumulation of the malignant co-transcriptional activator YAP, and this is phenocopied by extracellular calcium suppression. Promoting Actin polymerization with jasplakinolide or by over-expressing constitutively active forms of Rho or mDia1 restores stress fibres and nuclear YAP accumulation. In addition, Piezo2 knockdown disrupts several pro-metastatic functions: cell proliferation, migration, invadopodia formation, extracellular matrix degradation, and secretion of SERPINB2, a protein needed for protecting invasive cells from brain parenchymal defence mechanisms.
The works presented in this thesis unveil important roles for Piezo channels as a first line of mechanical input detectors in distinct cells. These discoveries are relevant for several fields, e.g. cancer research, and highlight the importance of ion channels as transducers of environmental stimuli.La dependència mecànica de la transformació i la metàstasi és un camp d’estudi / de recerca emergent, però el paper que hi juguen els canals iònics mecanosensibles s’ha omès fins ara. Aquesta tesi se centra en els rols dels canals Piezo1 i Piezo2 en la transducció d’estímuls mecànics per cèl·lules canceroses, com ara confinament, adhesió, rigidesa del substrat, concentració de lligands adhesius. En un primer capítol, mostrem que el confinament dispara l’entrada de calci per mitjà de Piezo1. Això activa la fosfodiesterasa 1, que redueix els nivells d’AMPc i, en conseqüència, l’activitat PKARac1, que deixen d’inhibir Miosina II. També trobem una activació paral·lela de Miosina II directament per confinament. Com a resultat final, les cèl·lules guanyen rigidesa i optimitzen el seu mode migratori independent d’adhesions, que és el preponderant in vivo durant la invasió metastàtica. Reduir els nivells de Piezo1 suprimeix l’entrada de calci induïda per confinament i desactiva el circuit subjacent en cèl·lules ovàriques epitelials (CHO) i de melanoma (A375). Això minva la capacitat migratòria de les cèl·lules siPiezo1. En un segon capítol, descobrim un rol essencial per a Piezo2 com a activador de RhoA en resposta a estímuls mecànics. Això modula les respostes mecanobiològiques de les cèl·lules MDA-MB-231-BrM2, de càncer de mama metastàtic a cervell. La reducció dels nivells de Piezo2 destorba la formació de fibres d’estrès, l’orientació de les adhesions, la transmissió de forces i l’acumulació nuclear del regulador transcripcional prometastàtic YAP. Suprimir el calci extracel·lular fenocòpia aquests resultats. Promoure la polimerització d’Actina amb jasplaquinolida o mer mitjà de la sobreexpressió de formes constitutivament actives de RhoA o mDia1 restableix les fibres d’estrès i l’acumulació nuclear de YAP. A més, la reducció de Piezo2 suspèn diverses funcions prometastàtiques: proliferació cel·lular, migració, formació d’invadopodis, degradació de la matriu extracel·lular i secreció de SERPINB2, una proteïna necessària per protegir les cèl·lules invasores dels mecanismes de defensa del parènquima cerebral. Els treballs presentats en aquesta tesi desvelen rols importants pels canals Piezo com a una primera línia de detectors d’estímuls mecànics en diferents tipus cel·lulars. Aquests descobriments són rellevants per a diversos àmbits, com ara la recerca en càncer, i remarquen la importància dels canals iònics com a transductors d’estímuls ambientals.
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Douglas, Temple Anne. "Development of a Dielectrophoresis-Based Cancer-Cell Analysis Tool". Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/85239.
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One significant obstacle in cancer treatment is tumor heterogeneity. Different subpopulations within a tumor can respond differently to chemotherapy, resulting in resistance and recurrence. Addressing these differences while choosing a treatment modality could significantly improve chemotherapy outcomes. This work focuses on the development of a new modular device that leverages the unique advantages of a contactless dielectrophoresis, a method that uses applied electric fields in a microfluidic device to separate cells by biophysical phenotype. By optimizing force balancing between the dielectrophoretic force and the drag force on cells in the device, and by using cell-size pillars to maximize electric field gradients per volt applied while reducing cell-cell interactions,we demonstrate that it is possible to separate mouse ovarian surface epithelial (MOSE) cells at different stages while maintaining high viability. We also show other cell types to be separable with this device and develop an algorithm to rapidly analyze cell response to a variety of frequency/voltage/flow rate combinations. We also propose a microfluidic device downstream of the DEP chip that can be used to provide an integrated system for studying the subpopulations separated using dielectrophoresis by moving them into a culture chamber with hydrogel where they can be grown in 3D and characterized for a variety of parameters such as biophysical structure, metastatic capacity, and chemotherapy resistance.Ph. D.
Dielectrophoresis is a method by which cells are polarized in response to an electric field gradient. This work optimizes this technique so that it can be used to separate highly similar subpopulations of cancer cells in a microfluidic device. Computer code is also developed to automate data processing. A technique for analyzing these cell subpopulations is also proposed and some feasibility testing performed.
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Chan, Pui-man Poemen, i 陳培文. "Micrometastases of esophageal cancer". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B45012842.
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GEHLSEN, KURT RONALD. "IN VITRO AND IN VIVO STUDY OF MELANOMA TUMOR CELL INVASION AND METASTASIS". Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/188148.
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The correlation of information obtained from in vitro investigations and in vivo experiments has frequently evaded researchers, especially in the area of tumor cell invasion and metastasis. In order to better understand and associate in vitro tumor cell invasion through basement membranes with in vivo tumor metastasis in syngeneic animal models, and the subsequent modulation of these processes, the following studies have been undertaken. Malignant murine melanoma cell lines designated B16F1 and B16F10, syngeneic to the C57BL6 mouse, a melanotic variant of the Cloudman S-91 melanoma cell line (denoted Mel-11a) with the syngeneic host being the DBA/2J mouse, and a malignant human melanoma line referenced as A375P (parental) and A375M (metastatic) were used for this dissertation project. Tumor cells were labeled with either ¹⁴C-thymidine or ¹²⁵I-deoxyuridine using previously established protocols. Radiolabeled tumor cells were introduced into the Membrane Invasion Culture System (MICS) in vitro, a system developed in our lab, and concomitantly into the lateral tail vein by injection or intracutaneously into the appropriate syngeneic host in the presence or absence of such biological response modifying agents as [Nle⁴, D-Phe⁷]-MSH, and α-MSH. The superpotent analogue of α-MSH ([Nle⁴, D-Phe⁷] -MSH) showed a proliferative and survival enhancing effect on tumor metastasis in vivo with no effect on in vitro tumor cell invasion, with similar effects demonstrated by α-MSH. The effects of these melanotropins on spontaneous metastasis formation appears to be negligible. The A375M and A375P human melanoma cells parallel their metastatic profile in vitro when assayed in MICS. In concert with these studies, the development of a control cell line, comprised of neural crest-derived melanocytes, and the study of their subsequent invasiveness in vitro were pursued. The neural crest-derived melanocytes were unable to invade the basement membranes (BM); although co-culturing neural crest cells with B16F10 melanoma cells produced an effect such that the neural crest cells did significantly invade the BMs. These studies demonstrate the ability of the MICS in vitro invasion assay to discriminate between tumor cells with differing metastatic propensities and could possibly be used in future studies to predict the effectiveness of biological response modifying agents in vivo.
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Lakins, Matthew. "The role of stroma microenvironments in prostate cancer cell migration and metastasis". Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/3106/.
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Terminal prostate cancer is the result of metastatic spread of the tumour from the prostate and is the 2nd leading cause of cancer deaths in men. Although in vitro assays have been developed to screen for inhibitors of prostate cancer metastasis and cell migration, they routinely utilise 2- Demensional (2-D) culture of prostate cancer cell lines. Current assays do not simulate complexity of the in vivo human tumour microenvironment which contains a mixture of normal and transformed epithelial cells and stromal cells. Therefore there is a requirement to develop novel 3-D models to recapitulate the in vivo tumour microenvironment to understand tumour stroma function. Utilising a 3-D co-culture spheroid model incorporating primary human tumour stroma with prostate cancer cells we have shown that the stroma has a key role in prostate cancer epithelial cell migration and motility. By utilising 4-D two-photon imaging and gene expression analysis we have analysed the molecular mechanisms of stromal cell mediated prostate cancer cell migration, identifying genes that regulate the migration process. Analysis of human tumour stroma indicates a key role in the immune system in driving tumour stroma to express a lymphoid stromal phenotype that provides the microenvironment for active tumour cell migration. This offers an interesting dichotomy that the formation of lymphoid like stroma in aggressive tumours may paradoxically deliver help to drive the immune response to the tumour whilst simultaneously providing the microenvironment for tumour cell migration and metastasis. The molecular mechanism of prostate cancer cell migration and metastasis and stroma-epithelial cell interactions involves a complex balance between the adhesion molecule VCAM-1 and two counter ligands VLA-4 and SPARC, also known as osteonectin or BM-40. The utilisation of shRNA knockdown, Fc chimeric proteins and blocking antibodies, indicates a key role for stromal-epithelia adhesion and detachment dependent cell migration mediated by VCAM-1, VLA-4 and SPARC.
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Dye, Danielle E. "The role of MCAM in melanoma and metastasis". University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0207.
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[Truncated abstract] Melanoma cell adhesion molecule (MCAM) is highly expressed in more than 70% of metastatic melanoma and is correlated with invasive potential. However, the specific contribution MCAM makes to invasion and metastasis in melanoma is not clear. In this study, I have demonstrated that transfection of MCAM into MCAM-negative melanoma and CHO cells leads to changes in cell shape, and the modulation of cell-to-cell and cell-matrix interactions. MCAM positive cells were slower to spread on collagen type I, collagen type IV and laminin 1 than MCAM negative cells, although these differences were not apparent on vitronectin, fibronectin and laminin 10. In contrast, MCAM expression had little effect on cell adhesion to any of the matrices tested. MCAM positive (compared to negative) cells also showed morphological changes and a rearrangement of the actin cytoskeleton when plated on a matrix containing laminin 5. Taken together, these data suggest that MCAM expression modulates β1-integrinmediated spreading on matrix, but has little effect on αvβ3-mediated cell-matrix interactions. As this study provided little evidence to suggest that MCAM transfection altered β1 integrin expression levels on melanoma cells, it is proposed that a competitive interaction between the cytoplasmic domains of MCAM and β1 integrin may affect mature focal adhesion assembly. MCAM expression in melanoma cells was also associated with decreased cell movement over matrix into a scratch-wound site and an increased tendency to form cell cords on Matrigel. These two assays gauge the propensity of a cell to engage in cell-cell versus cell-matrix interactions, and suggest that MCAM positive cells favour cell-cell adhesion. Interestingly, MCAM transfection was also associated with an increased ability of melanoma cells to migrate through a basement membrane towards a chemoattractant. ... Analysis of the intracellular domain of MCAM revealed the presence of tyrosine and dileucine endocytosis signals. Interestingly, disruption of these two motifs did not seem to impair the internalization of MCAM from the cell surface. The di-leucine motif, however, was necessary for the recycling of MCAM back to the surface following endocytosis. Lastly, MCAM was found to exists as dimers within the cell membrane in the absence of ligand, although the exact location of the dimerization motif is not yet clearly defined. Collectively, findings from my study suggest: MCAM expression in melanoma cells facilitates cell-cell interactions, whilst concomitantly modulating cell-matrix interactions. MCAM transfection also leads to enhanced migration of melanoma cells through a basement membrane. Thus, MCAM expression may increase the ability of melanoma cells to migrate as a collective, a feature of highly invasive cancer. The intracellular domain of MCAM interacts with ApxL2, a novel member of the Shroom family of actin-binding proteins. It is likely that ApxL2 links a proportion of MCAM within the cell to the actin cytoskeleton, contributing to cell shape determination and other processes, such as migration. MCAM exists as dimers on the cell surface and is internalized at least partially by a clathrin-mediated mechanism.
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Millarte, Valentina [Verfasser]. "Signaling at the Golgi Apparatus During Cell Migration and Implication for Cancer Cell Metastasis / Valentina Millarte". Konstanz : Bibliothek der Universität Konstanz, 2015. http://d-nb.info/1080908919/34.
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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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Maeda, Ryo. "Circulating CD14+CD204+ Cells Predict Postoperative Recurrence in Non-Small-Cell Lung Cancer Patients". Kyoto University, 2016. http://hdl.handle.net/2433/215213.
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Hsu, Rich. "The role of toll-like receptor 4 (TLR4) in lipopolysaccaride (LPS) induced gastrointestinal cancer metastasis". Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=92293.
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There are emerging lines of evidence to suggest that infectious complications in gastrointestinal cancer patients undergoing curative resection may associate with cancer recurrence, but the exact mechanism is not well understood. Toll-like receptor 4 (TLR4) is the sole receptor for lipopolysaccharide (LPS), a gram-negative bacterial antigen involved in such infectious complications. Previously, TLR4 expression has been found on several cancer types including prostate and lung; in this study, we characterized TLR4 expression for several esophageal and colorectal cell lines, and evaluated the effects of LPS on tumor proliferation, tumor cytokine production, and tumor adhesion. Even though LPS has no direct impact on tumor proliferation, LPS stimulation increased IL-6 production in HKESC-2 esophageal cancer cells. LPS-TLR4 signaling through p38 MAP kinase was necessary for LPS induced cancer cell attachment to fibronectin, an important composition of liver extracellular matrix. LPS-treated colon cells also showed an increase adherence to liver sinusoids. Both inhibition of p38 map kinase and TLR4 antagonist significantly prevented LPS induced adhesion to fibronectin. This study has provided some of the mechanisms responsible for inflammation associated cancer recurrence in patients who undergo curative surgical resection. These data suggest that LPS-TLR4 signaling in gastrointestinal cancer cells increases their metastatic potential and TLR4 blockade may have a therapeutic value in the prevention of cancer metastasis.Des données récentes suggèrent que le développement de complications infectieuses à la suite d'une résection curative chez les patients atteints d'un cancer gastro-intestinal peut être associé à une récidive du cancer, cependant le mécanisme exact n'est pas bien compris. Toll-like receptor 4 (TLR4) est le seul récepteur connu pour le lipopolysaccharide (LPS), un antigène provenant des bactéries à Gram négatif impliquées dans de telles complications infectieuses. Précédemment, l'expression de TLR4 a été détectée pour plusieurs types de cancers incluant la prostate et le poumon. Dans le cadre de cette étude, nous avons caractérisé l'expression de TLR4 pour de multiples lignées cellulaires sophagiennes et colorectales, ainsi qu'évalué l'effet du LPS sur la prolifération tumorale, la production de cytokine tumorale, et l'adhésion tumorale. Malgré le fait que le LPS n'ait aucun effet sur la prolifération cellulaire tumorale, la stimulation par LPS augmente la production de IL-6 chez les cellules cancéreuses HKESC-2 provenant de l'sophage. Le signalement intracellulaire LPS-TLR4 par p38 MAP Kinase est nécessaire pour l'attachement à la fibronectin des cellules cancéreuses traitées avec LPS, une composante importante de la matrice extracellulaire hépatique. Les cellules provenant du colon traitées avec LPS ont démontrées une augmentation de leur adhésion aux sinusoïdes hépatiques. Cette étude a fournie quelques-uns des mécanismes responsables de la récurrence cancéreuse associée à l'inflammation chez les patients subissant une résection chirurgicale curative. Ces résultats suggèrent que la signalisation par LPS-TLR4 dans les cancers gastro-intestinaux augmente leur potentiel métastatique et que le blocage de TLR4 ait possiblement un effet thérapeutique dans la prévention des métastases cancéreuses.
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Wright, Adele Hart. "The role of integrins in the differential upregulation of tumor cell motility by endothelial extracellular matrix proteins". Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/17352.
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Liu, Tiffany. "The role of macrophage chemoattractant signaling in cancer cell migration, metastasis and neovascularization". Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p1476514.
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Heidemann, Franziska Verfasser], i Udo [Akademischer Betreuer] [Schumacher. "Selectins Mediate Small Cell Lung Cancer Systemic Metastasis / Franziska Heidemann. Betreuer: Udo Schumacher". Hamburg : Staats- und Universitätsbibliothek Hamburg, 2015. http://d-nb.info/1074642244/34.
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Graham, Alastair Noel John. "An investigation into the factors promoting metastasis in non-small cell lung cancer". Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326409.
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Alkishi, Ahmed. "Investigating the mechanisms of oral cancer cell binding to the endothelium during metastasis". Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/9642/.
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Barnes, James Matthew. "Influence of matrix and fluid microenvironments on cancer cell migration, survival, and metastasis". Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2818.
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Metastasis is the most common cause of lethality in patients with solid tumors. This complex cascade of events begins with invasion of local tissue by cancer cells of the primary tumor and eventually leads to dissemination of cancer cells through the bloodstream. In order to colonize a distant tissue, circulating cancer cells must first survive the physical stresses within the vasculature, and then traverse the endothelium, by a process called extravasation. After extravasation, colonized cancer cells face several additional challenges including proliferation in a nutrient-deprived microenvironment. Epithelial-mesenchymal transition (EMT) is a process by which cells lose their epithelial characteristics and gain a mesenchymal, often migratory phenotype. There is much evidence that EMT augments cancer cell invasion, however little is known about how EMT-like cells interact with their microenvironment during metastasis. We investigated the migratory behavior of EMT-like cancer cells on different basement membrane constituents as well as in the presence of other cell types. We showed that ZEB1, a driver of EMT, regulates pro-migratory genes, resulting in cells which must co-opt with their matrix and cellular surroundings to elicit invasive migration. Additionally, we show that RNAi-mediated knockdown of ZEB1 results in significantly reduced anchorage-independent growth as well as metastatic colonization in mice. Thus, ZEB1 and EMT-states may facilitate both extravasation and survival of cancer cells in vivo.
In experimental and clinical settings, metastasis is viewed as an inefficient process; of the many cancer cells which enter the bloodstream, very few go on to form secondary tumors. The events which contribute to this inefficiency are debated. A popular theory is that most cancer cells die in circulation, under hemodynamic shear forces. There is evidence, however, which challenges this paradigm. Direct analyses of the response of cancer cells to shear forces are lacking. Therefore, we designed an in vitro model of fluid shear stress, which allows high throughput analysis of various cell types. In a broad panel of cancer cell lines, derived from various tissues, we found a remarkably conserved inducible shear stress resistance response. This response was absent in normal epithelial cells or non-transformed cell lines. Mechanistically, this response requires extracellular calcium and actin polymerization. These studies revealed a novel mechanism which may be necessary for progressive metastasis, and has practical implications in the study of circulating tumor cells. To gain insight into the metastatic phenotype, we analyzed of a panel of cancer cell lines derived from metastatic passage in mice. We noticed that derivative cells were physically smaller than their respective parental cell lines. Reduced cell size was correlated with attenuated activation of the mTOR pathway, and an increase in autophagic flux. Autophagy allows cells to digest their own proteins and organelles, and thus benefits cells residing in a nutrient-depleted environment. Our data suggest that autophagic cells are selected for in the metastatic microenvironment Future directions aim to determine the role of autophagy in metastasis. Finally, we show that an aggressive subpopulation of prostate cancer cells exhibit stem cell-like features, which may be regulated by ZEB1. In sum, these studies provide mechanistic details underlying the interactions of cancer cells with matrix and fluid microenvironments, which in turn affect migration, survival, and metabolism during metastasis.
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Akunuru, Shailaja. "Regulation of cancer stem cell activity and epithelial mesenchymal transition by Rac1 in Human lung adenocarcinoma cells". University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314301864.
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Oh, Jaeho. "Cell adhesion chromatography system for biophysical to biochemical analysis of human colon cancer metastasis through the vasculature". Thesis, Georgia Institute of Technology, 2014. http://hdl.handle.net/1853/52307.
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Circulating cell adhesion amidst the high shear environment of the vasculature is central to several physiological and pathophysiological processes, including leukocyte recruitment to sites of inflammation, stem cell homing and cancer metastasis. This process is initiated by selectin-mediated adhesion, the molecular “brakes” that slow cells down relative to bulk fluid flow to facilitate cell-cell signaling and eventual firm cell adhesion. Selectin recognition therefore represents a critical step whereby therapeutic interventions aimed towards the interference of cell homing could be targeted. While the force dependency of these high kon and koff rate interactions has been well described, little understanding exists of the long time- and length-scale interactions of different cell subtypes that would best describe the functional capacity of different cell homing via selectins to systemic peripheral tissues. This limits the adequate description of sustained cell adhesion efficiencies in physiological conditions that predicates the effectiveness of cell homing as well as the design effective therapeutic interventions to selectively attenuate metastasis but not normal cell homing using such criteria. To address this issue, we developed a so-called “cell adhesion chromatography” system, a microfluidic-based device designed for use in conjunction with videomicroscopy for the interrogation of the adhesion behavior of cells over long time- and length-scales. In order to achieve uniform contact of a pulse cell suspension input into a selectin-functionalized parallel plate flow chamber, we designed a feature that enables complete cell settling to the chamber bottom based on Stoke’s flow predictions, increasing contact uniformity of the pulse cell input with the substrate upon entry into the main chromatography channel from ~50 to >95%. Using this configuration, residence time distributions for a pulse input of cells perfused at defined shear stresses were generated based on cell elution times from the cell adhesion chromatography system. Selectin-functionalized substrates delayed cell elution times relative to bovine serum albumin coated-substrates by orders of magnitude in a selectin concentration, shear and cation dependent fashion. Preliminary experiments were also performed to begin to define the differences in efficiencies of healthy (human monocyte) versus malignant (human colon carcinoma) cell adhesion to selectins in shear flow. Our results suggest significant differences in the functional capacity of healthy versus malignant cells to sustain adhesion in shear flow and that cell adhesion chromatography is a new tool that provides unique insight into the process of cell adhesion in fluid flow.
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Campbell, Thomas. "The role of voltage-gated sodium channels in non-small cell lung cancer". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-voltagegated-sodium-channels-in-nonsmall-cell-lung-cancer(a65f4c5e-b217-483b-91d3-bb669965eb03).html.
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Various ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, migration and invasion. Expression of functional voltage-gated sodium (Nav) channels is implicated in the metastatic potential of breast, prostate, colon, cervical and lung cancer cells. However, the cellular mechanisms that regulate Nav channel expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, the role of epidermal growth factor receptor (EGFR) signalling and Nav channels in non-small cell lung cancer (NSCLC) cell lines have been examined. It is shown that functional expression of Nav1.7 promotes invasion in strongly metastatic H460 NSCLC cells. However, in non-invasive A549 NSCLC cells, Nav1.7 is completely absent. Inhibition of Nav1.7 either pharmacologically by tetrodotoxin (TTX) or genetically by small interfering RNA (siRNA) reduces H460 cell invasion by up to 50%. Whilst EGFR signalling enhances proliferation, migration and invasion of H460 cells, EGFR-mediated upregulation of Nav1.7 specifically, is required to promote invasive behaviour in these cells. Examination of Nav1.7 expression at the mRNA, protein and functional levels further reveals that EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of Nav1.7 expression to promote cellular invasion in NSCLC. The role of Nav channels in promoting cancer cell invasion is also unclear. Therefore, the effect of Nav channel activity on two likely downstream contributors to cellular invasion, intracellular calcium concentration, [Ca2+]i, and intracellular pH, pHi, have been examined. It is shown that functional expression of Nav1.7 likely drives H460 NSCLC cell invasion via H+ efflux from the cell in an uncharacterised mechanism potentially involving NHE1, resulting in extracellular acidification of the perimembrane space. However, much more work is needed to understand this Na+-dependent invasive mechanism. Immunohistochemistry (IHC) of patient biopsies confirms the clinical relevance of Nav1.7 expression in NSCLC. Thus, Nav1.7 has significant potential as a novel target for therapeutic intervention, possibly in conjunction with existing EGFR inhibitors, and/or as a diagnostic/prognostic marker in NSCLC.
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Tabassum, Doris Priscilla. "Exploring Intra-tumor Cooperation in Metastasis and Drug Resistance using Heterogeneous Xenograft Models of Breast Cancer". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493472.
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Breast cancer is a highly heterogeneous disease, having not only several intrinsic sub-types but also significant sub-clonal heterogeneity within tumors. Intra-tumor heterogeneity can have profound impact on tumor evolution, disease progression and response to therapy. Furthermore, these phenomena can also be influenced by interactions of cancer cells with those of the microenvironment, thereby adding an extra layer of complexity to the study of tumor biology.
To investigate the impact of sub-clonal heterogeneity on tumor phenotypes, we developed a heterogeneous mouse xenograft model of breast cancer. Our model revealed that tumor growth can be driven by a minor clone, expressing IL11, in a non-cell autonomous fashion mediated through the microenvironment. We also found that non-cell autonomous driving and clonal interference stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions leading to new phenotypic traits.
Utilizing the same model, we identified cooperative interactions between IL11- and FIGF- expressing sub-clones that enhance the metastatic behavior of the tumor as a whole. We found that metastatic cooperation between these two populations result in larger and heterogeneous lung metastasis. Using expression profiles from primary tumors and corresponding metastatic lesions, we identified several key immune-regulatory and extracellular matrix (ECM) remodeling pathways that promote metastasis in our model system.
Lastly, we examined heterotypic interactions between tumor cells and cancer associated fibroblasts (CAFs) to understand the mechanism of resistance to lapatinib. Using a 3D co-culture model, we identified significant sub-type-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells induced by CAFs. We identified JAK2/STAT3 pathway and CAF-secreted hyaluronan as major factors contributing to CAF-mediated protection. We also found that close spatial proximity to CAFs impacts therapeutic responses by affecting proliferation rates of cancer cells.
In summary, we have used in vitro and in vivo models systems to identify key interactions within populations of tumors cells, as well as between tumor microenvironmental components and cancer cells, to identify mechanisms that influence tumorigenesis, metastasis and drug response. We believe that these findings will increase our understanding of breast cancer heterogeneity and enable us to design better therapeutic regimens to eradicate the disease.Medical Sciences
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Huisken-Hill, Alyse Lynn. "Influencing Pathways that Cause Metastasis and Stemness in Epithelial Ovarian Cancer". CSUSB ScholarWorks, 2016. https://scholarworks.lib.csusb.edu/etd/355.
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Ovarian cancer is the fifth leading cause of cancer death in women between the ages of 35 and 74. With 22 thousand new cases and 15 thousand deaths annually ovarian cancer is among the most deadly cancers with a death to incidence ratio of 68%. With 70% of cases High Grade Serous Ovarian Carcinoma (HGSOC) is the most common type of ovarian cancer and causes 90% of ovarian cancer deaths. 80% of patients have reoccurrence within five years and only 15-30% of patients with recurrent metastatic ovarian cancer respond to current therapies, chemotherapy and surgery. One reason for the high reoccurrence rate is thought to be linked to the heterogeneity of tumors: there is evidence that, among tumor cells, a subpopulation is cancer stem cells (CSCs). Since CSCs are frequently drug resistant, when the patient undergoes chemotherapy many of the cells may die but the CSCs are left behind and the tumors can therefore regrow. CSCs are also more likely to undergo epithelial-mesenchymal transition which gives these cells the ability to more readily migrate and invade through the extracellular matrix, leaving the primary tumor to form metastases. One key inducer of EMT and therefore possibly of metastasis of particular interest in this project is SNAI1 (Snail). It is therefore the goal of this project to understand the growth, makeup and metastatic ability of HGSOC cell lines to test possible strategies to decrease growth of cancer and prevent metastasis.
In this thesis project the phenotype, CSC population make up, and functionality of various HGSOC cell lines was examined. The cell lines assessed were A2780, Kuramochi, OVSAHO, COV318, SKOV3 and OVCAR8. A Snail knockdown OVCAR8 cell line was also assessed as described above and in a xenograft model. It was determined that the cell lines show varying phenotype from epithelial like to mesenchymal like morphology and the cell lines have varying concentrations of cancer stem cells. It was also determined that the CSC population of the HGSOC cell lines were positive for both epithelial and mesenchymal markers in the same cells. OVCAR8 stood out as a hybrid line with both epithelial and mesenchymal characteristics and was therefore chosen for the Snail knockdown model. In the Snail knockdown we observed that CSC markers were reduced, however no change between control and knockdown was seen in the in vitro functional experiments. There was a difference seen between Snail knockdown and control in the in vivo mouse xenograft model. Snail knockdown showed a trend for decreasing tumor burden in both primary and metastatic tumors and showed a significant decrease in growth of metastatic tumor at day 43. Based on these results Snail may be an important target for cancer therapy.
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Limestoll, Scott R. "Discrete Modeling of Cell Island Migration". Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228413862.
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Volakis, Leonithas I. "Evaluating Dynamic Changes in Cancer Cell Mechanics during Epithelial to Mesenchymal Transition". The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492739871307445.
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Molina, Delgado Angie. "Role of the microtubule-associated protein ATIP3 in cell migration and breast cancer metastasis". Phd thesis, Université René Descartes - Paris V, 2014. http://tel.archives-ouvertes.fr/tel-01068663.
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Breast cancer is the most common malignancy in women, affecting one out of eight women worldwide. Even if most of the breast tumors are efficiently treated using targeted therapies, there is still a heterogeneous breast cancer subpopulation known as "triple-negative", which is highly metastatic and, due to the absence of targeted therapies, of poor prognosis. The elucidation of the processes involved in tumor progression and metastasis remains an important challenge in the search for new therapies against this subtype of breast cancer. Previous results from the laboratory have shown that ATIP3, a major product of the candidate tumor suppressor gene MTUS1, is a microtubule associated protein (MAP), whose expression is decreased in 85% of high grade, 83% of triple negative and 62% of metastatic breast carcinomas. Re-expression of ATIP3 in breast cancer cells significantly reduces cell proliferation in vitro, and tumor growth in vivo. Based on these results, my PhD project aimed at evaluating the role of ATIP3 in tumor cell migration and cancer metastasis. In the first part of my thesis, I will present data showing that ATIP3 is a novel prognostic marker for breast cancer patients' survival and a new anti-metastatic molecule. By means of DNA microarray analysis, we showed that low ATIP3 expression levels correlate with reduced overall survival of metastatic breast cancer patients. Using an in vivo model for cancer metastasis, we then showed that re-expression of ATIP3 reduces metastatic progression and lowers the number and size of metastatic foci. At the functional level, ATIP3 reduces breast cancer cell migration by reducing cell velocity and directionality. At the molecular level we further showed, using nocodazole washout experiments and MT growing ends tracking, that ATIP3 slows MT regrowth and decreases MT dynamics. Altogether, these studies indicate that ATIP3 is a novel MT stabilizing protein that controls the ability of MT tips to reach the cell cortex during migration, a mechanism that may account for reduced cell migration and metastasis. In the second part of my thesis, I will present data investigating the mechanisms by which ATIP3 regulates MT dynamics. To this end, we searched for new ATIP3-interacting partners. Interestingly, EB1, the core component of plus-end tracking proteins, was found to interact with ATIP3 not at the growing end of the MTs (as most EB1-interacting proteins), but mostly in the cytosol and at the MT lattice. The identification of the EB1-interacting domain of ATIP3 (termed CN) and further characterization of deletion mutants revealed that ATIP3-EB1 interaction is involved in impaired accumulation of EB1 at the plus-end. Based on these results and on FRAP analysis of EB1-GFP fluorescence recovery, a model was proposed in which the interaction between ATIP3 and EB1 may slower EB1 turnover at the MT plus-end, possibly by limiting EB1 association with its recognition site. In line with this model, in ATIP3-depleted cells dynamic EB1 molecules are more prone to accumulate at the growing end to increase MT dynamics. Relevance of this model in human pathology was then tested by evaluating ATIP3-EB1 expression levels in breast tumors, indicating that combined relative expression levels of both proteins may be considered as a prognostic marker of patient survival. Finally, in a third part of my thesis, I will present some preliminary data showing that ATIP3 may interact with the depolymerizing kinesin MCAK and the tumor suppressor APC, both of which are also well-known partners of EB1. The characterization and the implication of these interactions on ATIP3 functions (MT dynamics for MCAK interaction and cell polarity for APC interaction) remains to be investigated.
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Munro, Catriona. "Novel target identification & characterisation of key cell motility regulators in lung cancer metastasis". Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24741.
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Lung cancer is the most common cancer killer worldwide. One of the major reasons for failing to cure this malignancy is the high rate of metastasis. Hence, understanding the mechanisms by which these cells metastasise is required to improve patients' survival. Using the non-small cell lung cancer cell line A549 we optimised a 3D Invasion assay to enable a robotised high-throughput siRNA screen of large gene libraries. Despite thorough optimisation a pilot screen for the Phosphatome highlighted multiple issues with our set-up. Further optimisation work was conducted to improve the resolving power of the assay. However, as no clear explanation for the poor reproducibility could be uncovered, work began on a potential modulator of cell motility identified during a previous motility screen of the kinome. Microtubule affinity regulating kinases 4 (MARK4) is one of four members of the MARK family. A previously performed kinome siRNA screen for modulators of cell migration revealed that depletion of MARK4 reduced A549 cell migration. We validated this observation and additionally found that MARK4 silencing inhibited cell invasion through 3D collagen matrices. MARK4 depletion markedly changed cell structure, as exemplified by an increase tubulin network area. Follow-on experiments revealed an altered speed of microtubule polymerisation in MARK4-silenced cells. We observed that MARK4 downregulation promoted resistance to the chemotherapeutic agents Paciltaxel and Cisplatin, an effect potentially linked to a reduced proliferation in MARK4-silenced cells. MARK4 overexpression in NSCLC cells increased cell motility but did not impact the cell area or resistance to chemotherapy. A targeted siRNA cell motility screen of a selection of proposed MARK4 interacting proteins enabled us to connect MARK4 with Protein Phosphatase 2A and GSK3. Although further investigation is required into the signalling pathways upstream and downstream of MARK4, this work identified novel functions for this kinase and highlighted potential mechanisms underlying its effects.
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Tavares, Nuno Tiago Fidalgo. "Radium-223 in metastatic prostate cancer: effects on metastasis microenvironment". Master's thesis, 2019. http://hdl.handle.net/10773/26898.
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Prostate cancer is the second most frequent neoplasia in males and the fifth cancer-related cause of death worldwide. Androgen deprivation therapy has been the gold standard treatment for advanced prostate cancer. However, in spite of this therapy being associated with the tumour’s remission, it is also associated with prostate cancer recurrence, which leads to a lethal stage of the disease named castration resistant prostate cancer. Despite the high mortality of this stage, nowadays there are some therapy options to manage it, raising survival and providing more life quality to the patients. One of these options is the Radium-223, an alpha particle emitter radiopharmaceutical that has a positive effect on the increasing of overall survival of patients, also lowering the risk of symptomatic skeletal events.
The main objectives of this experimental work were to optimize and characterize a three-dimensional cell culture model in two prostate cancer cell lines and then assess the effects of the Radium-223 on the model through molecular and cellular techniques.
In the first phase of the work, it was used the magnetic levitation method in order to form three-dimensional spheroids of PC3 and LnCap, using after the MTT assay to check the PC3 model’s influence on the cells metabolism, fluorescence microscopy and histochemical staining techniques to study spheroid structure and viability, immunocytochemistry for protein expression and flow cytometry to learn about the culture’s viability and cell death pathways. The effects of the Radium-223 were then studied by the SRB assay, to evaluate total protein content, by Alamar Blue, to study cell proliferation, and by May-Grünwald-Giemsa staining, to check cellular morphology post-irradiation.
The two different cell lines showed different types of three-dimensional structures in culture, and due to its more compact and spherical structure, it was decided to study the PC3 cell line in this experimental work. The PC3 structures displayed a spherical conformation and presented extensive necrotic and apoptotic zones, since the size of the spheroid was in the order of mm2. Besides, the spheroids also exhibited different expression in some key proteins when compared with control cells cultured in monolayer, an important fact when testing cancer therapeutics.
After the irradiation of the spheroids with Radium-223, all doses tested presented a decrease compared to the control whether it was in total protein content or cell proliferation. The results also showed that the Radium-223 treatment exhibited a lower efficacy in the spheroids when compared with monolayer cells, which can be due to the fact that the three-dimensional structures are closer to mimicking the in vivo scenario, and so the cytotoxicity of the Radium-223 is decreased. Also, as alpha particles have low penetration ranges and the spheroid has a large size, the radiopharmaceutical might not be properly entering the three-dimensional structure.
Thereby, with this work it was possible to conclude that, as expected, the Radium-223 acts differently when tested in monolayer and in three dimensional cultures, as shown by the primary results obtained. Thus, it is very important to evaluate this and, in the future, other drugs or radiopharmaceuticals, using in vitro three dimensional spheroids before passing to in vivo studies, as they can function as a bridge between the two and give more information than standard cell culture, better mimicking the tumor microenvironment.O cancro da próstata é a segunda neoplasia mais frequente em homens e a quinta causa de morte relacionada com cancro em todo o mundo. A terapia de privação de andrógenos tem sido o gold standard para o tratamento do cancro da próstata avançado, mas apesar desta terapia ser associada com a remissão do tumor, é também associada com a recorrência do cancro na próstata, que pode levar a um estádio mais avançado da doença designado cancro da próstata resistente à castração. Apesar deste ser ainda um estádio mortal da doença, hoje em dia existem algumas opções terapêuticas para aumentar a sobrevida e providenciar maior qualidade de vida aos doentes. Uma destas opções é o Rádio-223, um radiofármaco emissor de partículas alfa que tem um efeito positivo na taxa de sobrevivência dos doentes, e também na diminuição de eventos sintomáticos relacionados com o esqueleto. Sendo assim, os principais objetivos deste trabalho experimental foram a otimização e caracterização de um modelo celular em três dimensões de duas linhas celulares de cancro da próstata, e a avaliação dos efeitos do Rádio-223 no modelo tridimensional utilizando diversas técnicas de biologia molecular e celular. Na primeira fase do trabalho, utilizou-se o método de levitação magnética para a formação de esferóides tridimensionais de PC3 e LnCap, utilizando-se posteriormente o ensaio MTT para verificar a influência do modelo no metabolismo celular, microscopia de fluorescência e colorações histoquímicas para estudar a estrutura e viabilidade dos esferóides, imunocitoquímica para a expressão proteica e citometria de fluxo para avaliar a viabilidade e as vias de morte celular. Os efeitos do Rádio-223 foram estudados posteriormente pelo ensaio SRB, para avaliar o conteúdo proteico total, por Alamar Blue, para estudar a proliferação celular, e pela coloração May-Grünwald-Giemsa, para avaliação da morfologia celular pós-irradiação. As duas linhas celulares demonstraram formar diferentes tipos de estruturas tridimensionais em cultura, e por formarem estruturas mais compactas, decidiu-se estudar a linha celular PC3. As estruturas das células PC3 demonstraram ter uma conformação esférica e apresentaram extensas zonas necróticas e apoptóticas, visto que os esferóides possuíam dimensões na ordem dos mm2. Além disso, os esferóides exibiram diferenças na expressão de algumas proteínas chave quando comparadas com células controlo em monocamada, facto que deve também ser tido em conta no estudo de terapêuticas para o cancro com este tipo de modelos. Após a irradiação dos esferóides com Rádio-223, todas as doses testadas apresentaram uma diminuição comparadas com o controlo, quer em conteúdo proteico total ou proliferação celular. Os resultados mostraram também que o tratamento com Rádio-223 exibiu menor eficácia nos esferóides quando comparados com células em monocamada, o que se pode dever ao facto das estruturas tridimensionais serem modelos mais próximos do cenário in vivo, e, portanto, a citotoxicidade do Rádio-223 poderá ser diminuída. Além disso, como as partículas alfa têm baixo alcance de penetração e o esferóide tem um tamanho consideravelmente grande, o radiofármaco pode não penetrar com eficácia na estrutura tridimensional. Assim, com este estudo foi possível concluir que, como expectável, o Rádio-223 atua de forma diferente quando testado em monocamada e em culturas tridimensionais, e que é de grande importância avaliar este, e no futuro outros fármacos, com culturas em três dimensões, pois estas podem funcionar como uma “ponte” entre os estudos in vitro em monocamada e os estudos in vivo, melhor mimetizando o microambiente tumoral.
Mestrado em Biologia Molecular e Celular
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(11200086), Odalys Torres Luquis. "The Lymphatic System in Breast Cancer Metastasis". Thesis, 2021.
Znajdź pełny tekst źródłaStreszczenie:
The leading cause of breast cancer-associated death is metastasis. During metastasis, tumor cells metastasize from primary tumors to distant organs via the circulatory and lymphatic systems. However, in 80% of solid tumors, metastasis via the lymphatic system precedes metastasis via the vascular system. There is a lot of information about metastasis through the circulatory system. However, not much information is available about the tumor cell dissemination through the lymphatic system or the lymphatic microenvironment that aids in this process in breast cancer metastasis. In addition, the molecular properties of tumor cells as they exit the primary tumor into the afferent lymphatics en route to the sentinel lymph nodes (SLNs) are not yet known.This project aims to determine why and how tumor cells metastasize to the lymphatic system. The proposal is based on the hypothesis that active migration is needed for tumor cells to spread via the lymphatic vessels. Thus, finding and understanding the molecules that contribute to this can be a breakthrough for breast cancer metastasis therapy.
The goals of this thesis are to 1) Examine the molecular, genetic, and proteomic characteristics of circulatory tumor cells and compare these to the primary tumor and lung metastasis, 2) Examine the role of Toll-like receptors in tumor cell migration to the lymph node, and 3) Identify the difference in protein expression among two different types of breast cancer (Triple-Negative and Luminal A) and understand their aggressive biology.
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Lin, Hsin-Hsien, i 林信賢. "PLAU Promotes Cancer Cell Metastasis By Activating CDCP1". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/a7f9m9.
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Lin, Chia-Liang, i 林佳良. "Molecular mechanisms of the metastasis associated protein 2 in cell metastasis of human cervical cancer cells". Thesis, 2018. http://ndltd.ncl.edu.tw/handle/ubjswy.
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博士中山醫學大學
生化微生物免疫研究所
106
Metastasis Associated 1 Family Member 2 (MTA2) is a central components of the Mi-2/NuRD complex, which possesses both nucleosome remodeling and histone deacetylase activities. Recent studies have indicated that MTA2 was associated with cells proliferation and metastasis in many cancer cells. The present study investigated the effect of MTA2 knockdown in cell proliferation and metastasis of human cervical cancer cells and the specific mechanism. Herein, we showed that MTA2 expression was correlated significantly with tumor differentiation and Gleason''s grade in cervical cancer tissue. Lentivirus mediated short hairpin RNA (shRNA) was used to knockdown MTA2 expression in cervical cancer cell lines. In vitro migration and invasion assay demonstrated MTA2 depletion inhibited cells metastasis ability, but not affect of the cells proliferation. In addition, MTA2 knockdown decreased MMP-12 protein levels and increased KLK10 in cervical cancer cells, as determined by proteinase microarray analysis. Furthermore, western blot analysis indicated ASK1, MEK3/6, and p38 signaling pathways were activated, then induced p-YB1 (phosphorylated of Y box-binding protein 1) nuclear translocation, significantly inhibited AP-1 activity binding to the MMP-12 promoter, and trans-suppressed the expression of MMP-12. In vivo studies using tail intravenous injection in mice models indicated that MTA2 knockdown significantly inhibited metastasis to lung. In addtion, MTA2 depletion increased mirR-7 expression, which targets Sp1, by MicroRNA Sequencing analysis. Mechanistic investigations suggested that MTA2 knockdown inhibited Sp1 expression and interaction with the KLK10 5’-flank region via regulating miR-7 expression. Moreover, the protein levels of Sp1 were up-regulated and down-regulated of KLK10 after transfection with miR-7 inhibitor that reversed cell metastasis and invasion in cervical cancer cells. In conclusion, our findings suggest that MTA2 is important for tumor metastasis through knockdown of MTA2 will regulate p38/YB1/MMP-12 signaling pathway and induce miR-7 expression by targeting Sp1 mediated KLK10 expression.
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Zhang, Chentian. "Microfabricated systems for studying cancer metastasis". Thesis, 2016. https://hdl.handle.net/2144/14637.
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Cancer metastasis is the critical event leading to 90% of cancer related death. Although significant improvement in our understanding on cancer metastasis has been made through years of research, the fundamental mechanism behind this process is still not fully elucidated. For cancer researchers, the “gold standard” for metastasis studies has traditionally been the use of tissue culture and mouse models. Tissue culture offers the simplest system and ease of control but is not able to recapitulate many of the features found in an in vivo tumor microenvironment. On the other hand, mouse model systems offer the most sophisticated and physiologically relevant platforms for studying cancer. However, the lack of control over the in vivo environment in these mouse models and inherent discrepancies from human physiology make results from these models difficult to be translated to clinical trials.
The advancement in microfabrication techniques and cancer models developed based on these techniques has shown potential in addressing the gap between in vitro tissue culture and mouse models. Microscopic tumor microenvironments could be built in these in vitro systems to study behavior of human cancer cells. However, the expertise involved in and extra instrumentation needed for implementing these systems have prevented their widespread use by general cancer researchers.
In this dissertation, we developed two simple microfabricated systems and demonstrated their application in two aspects of cancer research. The first system is a microfabricated cell patterning stencil, where paracrine signaling can be established and its impact can be measured based on cell migration. Using this tool, we investigated the interaction between melanoma and microenvironmental cells from their common metastasis target organ. Through these simple patterning techniques, we observed significant effects that a given microenvironmental cell line had on the two different melanoma lines, as well as how melanoma affected different microenvironmental cell lines. The second system, a microfluidic device, is able to present individual soluble factors to cancer cells in order to test the response of cancer cells to these physiologically relevant factors. Through this stand-alone system, we found that breast cancer metastasis is influenced by the protein molecules secreted by themselves as well as the local glucose level.
Through these findings we believe that our microfabricated systems can benefit the general cancer research community in which a complicated problem can be broken down into manageable pieces and studied on a simple platform in a controlled way. Observation made through these systems can inspire general cancer researchers to form new hypotheses and eventually lead to new findings.2017-02-17T00:00:00Z
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Luga, Valbona. "Tumour-stroma Signalling in Cancer Cell Motility and Metastasis". Thesis, 2013. http://hdl.handle.net/1807/43634.
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The tumour-associated stroma, consisting of fibroblasts, inflammatory cells, vasculature and extracellular matrix proteins, plays a critical role in tumour growth, but how it regulates cancer cell migration and metastasis is poorly understood. The Wnt-planar cell polarity (PCP) pathway regulates convergent extension movements in vertebrate development. However, it is unclear whether this pathway also functions in cancer cell migration. In addition, the factors that mobilize long-range signalling of Wnt morphogens, which are tightly associated with the plasma membrane, have yet to be completely characterized. Here, I show that fibroblasts secrete membrane microvesicles of endocytic origin, termed exosomes, which promote tumour cell protrusive activity, motility and metastasis via the exosome component Cd81. In addition, I demonstrate that fibroblast exosomes activate autocrine Wnt-PCP signalling in breast cancer cells as detected by the association of Wnt with Fzd receptors and the asymmetric distribution of Fzd-Dvl and Vangl-Pk complexes in exosome-stimulated cancer cell protrusive structures. Moreover, I show that Pk expression in breast cancer cells is essential for fibroblast-stimulated cancer cell metastasis. Lastly, I reveal that trafficking in cancer cells promotes tethering of autocrine Wnt11 to fibroblast exosomes. These studies further our understanding of the role of the tumour-associated stroma in cancer metastasis and bring us closer to a more targeted approach for the treatment of cancer spread.
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Chang, Jeng-Shou, i 張正守. "The Role of GIT1 in lung cancer cell metastasis". Thesis, 2017. http://ndltd.ncl.edu.tw/handle/uu9epu.
Pełny tekst źródłaStreszczenie:
博士國立陽明大學
生化暨分子生物研究所
105
Lung cancer is the leading cause of cancer-related deaths worldwide and the prognosis of non-small-cell lung cancer (NSCLC) remains poor. Identification of novel prognostic markers and therapeutic targets are urgently needed. Here we identified G-protein-coupled receptor-kinase interacting protein 1 (GIT1) gene from 5,000 High-throughput antibodies library screening using tissue microarray (TMA) after comparing protein expression differences of five major human cancer primary tumors and normal adjacent tissues. The results were further confirmed by online microarray database analysis to show GIT1 as a prognosis predictor in NSCLC. GIT1 is participated in cell movement activation, which is a fundamental process during tissue development and cancer progression. GIT1/(PAK interacting exchange factor, PIX) forming a functional protein complex that contributes to (Ras-related C3 botulinum toxin suxstrate 1, Rac1)/(Cell division cycle 42, Cdc42) activation, resulting in increasing cell mobility. Although the importance of Rac1/Cdc42 activation is well documented in cancer aggressiveness, the clinical importance of GIT1 remains largely unknown. Here, we investigated the clinical significance of GIT1 expression in NSCLC and also verified the importance of GIT1-Rac1/Cdc42 axis in stimulating NSCLC cell mobility. The result indicated higher GIT1 expression patients had significantly poorer prognoses in disease-free survival (DFS) and overall survival (OS) compared with lower GIT1 expression patients. Higher GIT1 expression was an independent prognostic factor by multivariate analysis and associated with migration/invasion of NSCLC cells in transwell assay. In vivo studies indicated that GIT1 promotes metastasis of NSCLC cells. Finally, GIT1 was found to stimulate migration/invasion by altering the activity of Rac1/Cdc42 in NSCLC cells. Together, the GIT1 expression is associated with poor prognosis in patients with NSCLC. GIT1 is critical for the invasiveness of NSCLC cells through stimulating the activity of Rac1/Cdc42.
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Tan, Izza Maria Doreen A. "ADAMTS1 is a promoter of metastatic cell behaviour in mammary cancer cells". Thesis, 2014. http://hdl.handle.net/2440/87148.
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Metastatic disease is the primary cause of mortality in breast cancer. It is characterised by the dissemination of cancer cells from the primary site, infiltration into vessel networks and the establishment of new tumour growth in secondary tissues. Several events are required for metastasis to occur, including enhancement of cell-matrix adherence, augmented motility and invasiveness. The extracellular matrix (ECM) environment plays a vital role in the processes involved in metastatic progression and undergoes aberrant remodelling to permit and support the metastatic cascade. Metalloproteinases are a group of enzymes that play a major role in ECM remodelling. The ADAMTS metalloproteinase family has been implicated in the re-organisation of the tumour microenvironment associated with cancer development and metastatic disease progression. Of the 19 ADAMTS proteases, considerable attention has been devoted to the role of its first member ADAMTS1 in cancer metastasis. Both exogenous overexpression and upregulation of the endogenous ADAMTS1 gene have been strongly associated with metastatic disease in breast cancer. The MMTV-PyMT transgenic breast cancer model recapitulates in vivo metastasis and ablation of Adamts1 impeded the aggressive advancement and growth of pulmonary metastases. The signalling pathways and mechanistic events through which ADAMTS1 mediates its pro-metastatic effects are currently unknown. The aim of this present study is to therefore identify the causal events imposed by ADAMTS1 to promote breast cancer metastasis, with much focus on its role in matrix adhesion, cell migration and invasion. Using isolated primary mammary carcinoma cells PyMT/Adamts1⁺ʹ⁺, PyMT/Adamts1⁺ʹ⁻ and PyMT/Adamts1⁻ʹ⁻ mice, I performed real-time assessment of cell-matrix adhesion, motility and invasion and found diminished capacity of PyMT/Adamts1⁻ʹ⁻ cells to adhere to matrigel and migrate towards a chemoattractive environment. Consistent with the reciprocal approach, introduction of Adamts1 into the MCF10A breast cell line induced the inverse effect, promoting cell adhesion and motility in cells overexpressing Adamts1. Cell-matrix adhesion is a major cue for the determination of front-rear polarity necessary in cell migration and hence, the influence of ADAMTS1 on cell-matrix adhesion underpinned its effects on breast cancer cell migration. Breast cancer cell invasion was unaffected by loss or gain of Adamts1, suggesting a redundant role for ADAMTS1 in this process. To unravel the transcriptional differences and mechanistic pathways induced by ADAMTS1, microarray analysis was undertaken with PyMT/Adamts1⁺ʹ⁺ and PyMT/Adamts1⁻ʹ⁻ mammary tumours. Remarkably, only 2 differentially regulated genes were identified from our analysis. Further investigation of the most dysregulated gene, BC018473, revealed a non-homologous inheritance of this strain specific gene, which unfortunately prevented conclusions being drawn on the underlying genetic effects attributable to Adamts1 ablation. This study was the first to present a novel role for ADAMTS1 in the promotion of breast cancer cell adhesion to the ECM. This capacity to dynamically modulate adhesion through ADAMTS1 is important in cell migration and highlights a potential mechanism by which ADAMTS1 promotes breast cancer metastasis.Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2014
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Chen, Min-Wei, i 陳民瑋. "H3K9 Histone Methyltransferase G9a Promotes Cancer Cell Invasion and Metastasis". Thesis, 2010. http://ndltd.ncl.edu.tw/handle/23603814540857504865.
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博士國立臺灣大學
毒理學研究所
99
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression. In addition, G9a may also have functions in cancer cell motility, survival and angiogenic activity. Our results underscore the utility of developing G9a inhibitors as a potentially powerful therapeutic target. We also established the HTS platform for inhibitors against the G9a.
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Kung, Chang-I., i 龔倉義. "The Effects of Tanshinone IIA on Breast Cancer Cell Metastasis". Thesis, 2006. http://ndltd.ncl.edu.tw/handle/19403025722012435911.
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碩士國立陽明大學
解剖暨細胞生物學研究所
94
Recent studies have shown that Tanshinone IIA, a kind of lipid-soluble extract isolated from a traditional herb medicine, salvia miltiorrhiza BUNGE, exhibits a potent cytotoxicity and growth inhibition on various human carcinomas and ability to inhibit the growth of human carcinomas. NQO1 in normal cell contributes a function preventing from hurt of reactive quinone and maintain the antioxidant in normal cell, but in human cancer cell, it is over-expressed and contributes drug-resistant function. There are not many studies about the effect of Tanshinone IIA on human breast cancer. In this study, we investigate the cytotoxicity of Tanshinone IIA on human breast cancer cell line, the ability in inhibiting metastasis, and the decrease the expression of NQO1. The result shows that treatment of MDA-MB-435s cells with 25μM Tanshinone IIA increase the sub G0-G1 phase. After 48hour treatment of MDA-MB-435s cells with 25μM Tanshinone IIA, expression of the CD44 cleavage product decreases. After 48 hour treatment of MDA-MB-435s cells with 25μM Tanshinone IIA, expression of NQO1 decreases. The data also shows that the expression of standard form CD44 increases after treating MDA-MB-435S with 25μM Tanshinone IIA for 48 hour. According to this data, Tanshinone IIA has cytotoxicity to MDA-MB-435S cells, and Tanshinone IIA could decrease the cleavage of CD44 and the expression of NQO1. According to this study, we suggest that Tanshinone IIA has potential to treat human breast tumor, decrease the migration of breast cancer cell by inhibiting CD44 cleavage.
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Jiang, Zhe-Yu, i 江哲佑. "Identification of the factors that promote ovarian cancer cell metastasis". Thesis, 2016. http://ndltd.ncl.edu.tw/handle/89939179597039925212.
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碩士國立陽明大學
生命科學系暨基因體科學研究所
104
Ovarian cancer is the most lethal gynecologic malignancy. It not only is hard to be diagnosed at the early stages, but also comes along with a high recurrent rate as well as chemoresistance at the advanced stages even after surgical treatment. In order to improve the current treatment of ovarian cancer, I attempted to identify the important factors potentially involved in the progressions of metastasis and angiogenesis. Firstly, I designed an in vivo selection scheme using nude mice to select ovarian cancer cells tending to metastasis and recurrence. A2780 and SKOV3 were subjected by intraperitoneal injection to selection for three cycles and the corresponding A2780M3 and SKOV3M3 were obtained. In the cell-based experiments, A2780M3 exhibited the ability of proliferation under high cell density, whereas SKOV3M3 evolved the ability of anchorage-independent growth. The mRNA expression of EMT markers and the ability of migration were also altered in both cell lines. Furthermore, both A2780M3 and SKOV3M3 showed higher tumoral formation ability than their parental cells in boh intraperitoneal and subcutaneous xenografts in nude mice. In addition, immunohistochemical staining indicated that the tumors formed by A2780M3 have less apoptotic signal than those formed by A2780. These results concluded that A2780M3 is more malignant. Therefore, cDNA microarray was further used to differentiate the gene expression profile between A2780 and A2780M3. I then obtained three candidates, CYP1B1, LOX and SALL1, after genomic analysis of the microarray data. In the preliminary experiment, I found that higher CYP1B1 expression is correlated with TMS-mediated suppression of cell proliferation. Secondly, I also established a hypoxia model mimicked by DFO supplement, trying to identify the crucial factors involved in the angiogenesis process of ovarian cancer. I applied angiogenesis array to detect the changes of angiogenic factors in the conditioned media harvested from A2780, SKOV3 and OVCAR3 with or without DFO treatment. Following this, three angiogenic factors upregulated by HIF-1were selected, including VEGF, IL-6 and IL-8. Taken together, the results in my thesis allow me to find three candidate genes involved in ovarian cancer metastasis and three candidate genes involved in ovarian cancer angiogenesis. These candidate genes might play important roles in ovarian cancer progression.
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Wang, Chung Chiang, i 王重強. "The mechanism of penta-acetyl geniposide inhibits cancer cell metastasis". Thesis, 2002. http://ndltd.ncl.edu.tw/handle/64032358168912194288.
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碩士中山醫學大學
生物化學研究所
90
Penta-acetyl geniposide【(Ac)5GP】was a acetylated product from geniposide, a glycoside existing in Gardenia Fructus. Our previous studies have shown that (Ac)5GP is involved in the chemoprevention and induction of apoptosis of C6 glioma cells. In this study, we demonstrate that (Ac)5GP may inhibits the invasion of C6 glioma cells. Cancer cell invasion requires coordinated processes, such as changes in cell-matrix adhesion, degradation of the extracellular matrix, and cell migration. We found that (Ac)5GP inhibited motility and cell-matrix adhesion of C6 glioma significantly via Boyden chamber migration assay and cell-matrix attachment assay. Moreover, (Ac)5GP reduced expression of matrix metalloproteinase-2 and -9 via semi-RT-PCR and gelatin zymography. On the other hand, We found (Ac)5GP inhibited C6 glioma cells PI-3K protein expression and ERK1.2 phosphorylation. Furthermore, PI-3K and MEK phosphorylation inhibitors: Wortmannin and PD98059 inhibited MMP-2 and MMP-9 activity respectively. So, we suggested that (Ac)5GP may inhibits C6 glioma cells MMP-2 amd -9 activity by inhibiting PI-3K protein level and ERK1.2 phosphorylation.