Rozprawy doktorskie na temat „Tumour metastasis”
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1
Clark, S. R. "The investigation of tumour metastasis". Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370241.
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Knight, C. Rosamund L. "Transglutaminase activity, tumour growth and metastasis". Thesis, Nottingham Trent University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278115.
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Hand, D. "The importance of transglutaminase in tumour growth and metastasis". Thesis, Nottingham Trent University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382575.
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Chen, Dongsheng. "Transcriptional regulation of the p9Ka gene in metastatic and non-metastatic rat mammary epithelial cells". Thesis, University of Liverpool, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266488.
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Li, Chao. "Investigation of the influence of tissue factor on tumour metastasis". Thesis, University of Hull, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441584.
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Royston, Daniel John. "The role of LYVE-1 in tumour metastasis and inflammation". Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558401.
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The lymphatic metastasis of tumours to lymph nodes (LN) is a frequent event in many cancers and heralds a poor clinical outcome. Comparison of lymphatic endothelial cells (LECS) from metastasizing murine T-241/VEGF-C fibrosarcomas and normal dermis revealed a tumour-specific LEC profile, characterized by the elevated expression of functionally significant molecules such as endothelial specific adhesion molecule (ESAM) and the TGF-~ coreceptor endoglin (CD105). Moreover, similar induction of ESAM and endoglin by human tumour Iymphatics was seen to dramatically correlate with LN metastasis. To further investigate interactions between tumour cells and Iymphatics, the role of lymphatic endothelial hyaluronan receptor LYVE-1 in LN metastasis was investigated. Using LYVE-1 mAbs and LYVE-1-1- mice, it was shown that a deficiency or perturbation of LYVE-1 expressed by tumour Iymphatics potentiated the lymphatic spread of spontaneously metastasizing T-241/VEGF-C fibrosarcomas and induced de novo metastasis by indolent parental T-241 tumours. Subsequent in vitro experiments using mAbs suggested that LYVE-1 exerts a blocking or 'gatekeeper' function, preventing pro-metastatic tumour cell-LEC interactions. Although largely restricted to the Iymphatics, LYVE-1 is also expressed in murine lung by type I alveolar epithelial cells (AECs). Using a bleomycin model of lung inflammation it was shown that LYVE-1-1- mice are unable to clear infiltrating leukocytes following acute lung injury. Furthermore, in vivo and in vitro experiments using blocking mAb reveal a critical role for LYVE-1 in the transepithelial migration of leukocytes across the alveolar epithelium, an essential step in the resolution of acute lung inflammation. These findings identify a specific role for LYVE-1 in cancer metastasis and the resolution of acute inflammation in the lung.
7
Texler, Michael Lutz. "Aetiology of tumour cell movement during laparoscopic surgery : patterns of movement and influencing factors". Title page, table of contents and abstract only, 1999. http://web4.library.adelaide.edu.au/theses/09MD/09mdt355.pdf.
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Accompanying CD-ROM contains image files and software. Bibliography: leaves 259-286. Explores the factors affecting the movement of tumour cells from a primary malignancy across the peritoneal cavity to the port-site following laparoscopic intervention. Filter methods and radio-labelled tumour cells provided the most useful way of following cell movement. Concludes spread of tumour cells to the port-site is more likely in the presence of disseminated disease, as well as with inappropriate surgical technique. Metastasis may be reduced by the use of intraperitoneal lavage and appropriate surgical technique.
8
Jack, A. S. "A study of the factors which affect the growth of tumour cells at distant sites". Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381493.
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Lundberg, Owe. "Laparoscopy and tumour growth : a clinical and experimental study". Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-227.
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10
Balathasan, Lukxmi. "Characterising the role of circulating immune cells in brain metastasis". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e7620d30-7e4a-468b-b819-db4cf27eaef6.
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Brain metastasis is a frequent occurrence in cancer patients and carries a high mortality rate. The incidence of brain metastasis is on the rise, highlighting the need for improved therapeutic intervention. Immune cells have been shown to promote disseminated tumour cells to colonise the lung and liver. Therefore, we aim to determine whether immune cells also facilitate brain metastasis by describing the host immune response to tumour cells attached to the brain vasculature. We developed a model of brain metastasis by using ultrasound guidance to perform intracardiac injection of tumour cells. Using this method, we identified highly and weakly brain metastatic cell lines. To understand how cancer cells develop into brain metastases, we analysed brains harvested 4 h- 14 d after tumour injections. At 4 h after intracardiac injection, only cell lines that developed into brain metastases were found adhered to the brain vasculature in high numbers. A small number of arrested tumour cells clustered with CD45⁺ immune cells. These tumour-CD45 clusters persisted over time whilst the frequency of solitary tumour cells declined. Tumour-associated CD45⁺ immune cells were identified to be Ly6G⁺Gr-1⁺CD11c⁻ myeloid cells. Considerably more tumour-CD45⁺ immune cell clusters were found within the brain vasculature when tumour cells were injected into mice bearing a primary tumour. Increased tumour-CD45⁺ immune cells clusters correlated with an increased number of brain metastases in the same group of mice. We also found a positive association between increased tumour-immune clusters and levels of tumour and host derived G-CSF. To establish a causal relationship between tumour cell-CD45 clusters and metastases, we developed an experimental setup for transcranial imaging. Our results suggest that tumour recruited immune cells may promote tumour cell colonisation of the brain and provides a framework for further investigation.
11
Abu-Izneid, Tareq, i n/a. "The Synthesis and Evaluation of Functionalised Carbohydrates as Probes of Tumour Metastasis". Griffith University. Institute for Glycomics, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20061019.111424.
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Sialyltransferases, CMP-sialic acid synthetases and CMP-sialic acid transport proteins play a crucial role in the construction of cell surface glycoconjugates. These proteins also have a pivotal role to play in a number of diseases, including cancer. The sialyltransferase enzymes are responsible for transfering sialic acids from the donor substrate (CMP-sialic acid) to growing cell surface glycoconjugate chains within the Golgi apparatus. The CMP-sialic acid synthetase enzymes are responsible for the synthesis of the CMP-sialic acid, the donor substrate of the sialyltransferases in the nucleus, while the CMP-sialic acid transport proteins are responsible for transporting CMP-sialic acid from the Cytosol to the Golgi apparatus. When these proteins function in an abnormal way, hypersialylation results, leading to an increased level of sialylation on the cell surface. This increased level of sialylation aids in the detachment of primary tumour cells due to an increase in the level of overall negative charge, causing repulsion between the cancer cells. Therefore, the sialyltransferase enzymes, CMP-sialic acid synthetases and CMP-sialic acid transport proteins are intimately involved in the metastatic cascade associated with cancer. Chapter 1 provides a general introduction of cancer metastasis, discussing the roles of three target proteins (CMP-sialic acid synthetases, CMP-sialic acid transport proteins and sialyltransferases), as well as discussing their substrate specificities, with an emphasis on their involvements in cancer metastasis. The Chapter concludes with an overview of the types of compounds intended to be utilised as probes or inhibitors of these proteins. Chapter 2 describes the general approach towards the synthesis of CMP-Neu5Ac mimetics with a sulfur linkage in the presence of a phosphate group in the general structure 38. The precursor phosphoramidite derivative 45 was prepared and isolated in a good yield using Py.TFA. Unfortunately, the target compound 38 could not be prepared. Chapter 3 describes an alternative strategy wherein S-linked sialylnucleoside mimetics, of the general structure 39, with a sulfur linkage, but no phosphate group, between the sialylmimetic and the ribose moiety in the base is targeted. A series of these S-linked sialylnucleoside mimetics were successfully prepared. Cytidine, uridine, adenosine and 5-fluorouridine nucleosides were used to create a library of different nucleosides and with structural variability also present in the sialylmimetic portion. This small 'library' of 15 compounds was designed to shed light on the interaction of these compounds with the binding sites of the sialyltranferase, CMP-sialic acid synthetase and/or CM-sialic acid transport protein. Approaches towards the synthesis of O-linked sialylnucleoside mimetics of the general structure 40 are described in Chapter 4. Several methodologies are reported, as well as protecting group manipulations, for successful preparation of these sialylnucleoside mimetics. Cytidine and uridine were employed as the nucleosides, thus allowing a direct comparison between the O- and S-linked sialylnucleoside mimetics in biological evaluation. It appears from these synthetic investigations that gaining access into the O-linked series is not as straightforward as for the S-linked series, with alternative protecting group strategies required for the different nucleosides. The biological evaluation of some of the compounds reported in Chapters 3 and 4 is detailed in Chapter 5. The sialylnucleoside mimetics were evaluated, by 1H NMR spectroscopy, for their ability to inhibit CMP-KDN synthetase. In addition, an initial 1H NMR spectroscopic-based assay was investigated for inhibition studies of α(2,6)sialyltranferase in the absence of potential inhibitors. The final chapter (Chapter 6) brings together full experimental details in support of the compounds described in the preceding Chapters.
12
Nixdorf, Sheri Clinical School Prince of Wales Hospital Faculty of Medicine UNSW. "Studies of tumour and metastasis suppressor genes in colorectal and bladder cancer". Awarded by:University of New South Wales. Clinical School - Prince of Wales Hospital, 2009. http://handle.unsw.edu.au/1959.4/44541.
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Together, colorectal (CRC) and bladder cancer (BlCa) are responsible for a large percentage of cancer related morbidity and mortality in Western society. A dramatic reduction in patient survival occurs as these cancers progress towards invasive and metastatic disease, from a five year survival rate of about 90% for localised disease to approximately 5-10% for advanced disease involving distant metastasis. A greater understanding of disease progression will lead to enhanced screening, diagnostic and treatment strategies, in turn providing an improved prognosis for the patient. The purpose of this study was to expand the current molecular knowledge of CRC and BlCa by elucidating the role of Mxi1 mutations and MTSS1 expression in CRC and BlCa respectively, and to examine the diagnostic potential of these genes. The Mxi1 coding region for 41 tumours, collected by the South Western Sydney Colorectal Cancer Tumour Bank from 2000-2001, was screened for mutations using Dideoxy Fingerprinting (ddF) and sequencing. Sequence alterations were detected in 34% of tumours. Three different polymorphisms and three mutations were detected. One mutation could possibly affect the tumour suppressor function of Mxi1. The presence of a gene mutation did not correlate to any clinical characteristics and is therefore not a suitable diagnostic marker. Microsatellite instability (MSI) status however, significantly correlated with tumour grade. Expression levels of MTSS1 and an associated gene, MTSS2, were examined in 16 BlCa cell lines, 9 clonally-derived BlCa sublines, and 30 transitional cell carcinomas (TCCs) collected by the Heinrich-Heine University from 1993-2000. Variable gene expression was observed in BlCa cell lines and tumour samples. No significant correlation of MTSS expression and invasive ability was observed for the cell lines or tumour samples. Further studies eliminated promoter methylation and p53 functional status as mechanisms involved in MTSS1 and MTSS2 down-regulation. Functional studies performed on stable MTSS1-expressing BlCa lines found that although migration was increased, cells displayed reduced anchorage-independent growth. The invasive ability of these cells was unchanged confirming that expression does not correlate with invasive ability. These data support the role of MTSS1 as a tumour suppressor and not as a metastasis suppressor gene. Although MTSS1 may not be useful in predicting more invasive disease, its role as a tumour suppressor in cancer may be useful.
13
Rmali, Khaled Ali Ramadan. "Tumour-associated angiogenesis in the development and metastasis of human colorectal cancer". Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/54099/.
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The study has further shown that IL-1[Special character omitted] is a potential regulator of TEM-8 expression in tumours and that IL-1[Special character omitted] significantly induced the formation of capillary-like tubules from the HECV cells, accompanied by an increase in TEM-8 expression. Where as, elimination of TEM-8 by way of ribozyme transgene significantly decreased the formation of capillary-like tubules and the mobility of HECV cells. Moreover we have demonstrated that the vW domain together with trans-membrane domain of TEM-8 are the structural domain that are responsible for the tubule forming action of TEM-8, using expression construct in varying cell lines.
14
Albon, Jacob George. "Developing and using atomic force microscopy to investigate mechanisms of tumour metastasis". Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/7815/.
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Mortality in breast cancer is increasingly linked to metastasis to bone, which is currently incurable and the mechanisms involved in this process are not fully understood. By using atomic force microscopy to extract the mechanical and adhesive properties of metastatic breast cancer cells under near physiological conditions the aim of the work presented in this thesis is to develop the methods used to extract these properties as well as enhance understanding of tumour metastasis. The biomechanical properties of three human breast cell lines with varying metastatic potential have been investigated through atomic force microscopy based indentation, using three separate analytical models. The indentation studies were used to reveal mechanical properties of living cells which can be attributed to cellular structures such as the cytoskeleton, cell membrane, cytoplasm and numerous intracellular organelles. This is the first study to compare three contact mechanical models on these cells. The results demonstrate that benign MCF-10A breast cells are less deformable than the invasive MCF-7 and metastatic MDA-MB-231 breast cancer cell lines. Force maps have also revealed elastic heterogeneity across the cell surface of all three cell lines which appears to correlate with intracellular structures. The results demonstrate that whole cell mapping has the potential to investigate cell mechanics using a variety of approaches. The biomechanical properties of sub-populations of the MDA-MB-231 cell line were also investigated. Sub-populations of cancer cells which were shown to display 'stem-cell-like' properties and 'normal' cancer cells which did not were identified using a number of in vitro techniques and selected for AFM indentation experiments via fluorescence microscopy. The results indicated no significant difference between the measured mechanical properties of the 'stem-like' and 'normal' cancer cells. Adhesive interactions between metastatic MDA-MB-231 cells and 'osteoblast-like' Saos-2 cells were then characterised using an AFM based single cell force spectroscopy (SCFS) protocol. The detachment force required to separate the two cell types was measured for untreated, zoledronic acid treated and anti-N-cadherin treated cells. The results showed that both treatments significantly reduced the detachment force. This result is important in understanding the mechanisms by which adjuvant zoledronic acid therapy may reduce bone resorption and metastases in patients with advanced breast cancer.
15
Abu-Izneid, Tareq. "The Synthesis and Evaluation of Functionalised Carbohydrates as Probes of Tumour Metastasis". Thesis, Griffith University, 2005. http://hdl.handle.net/10072/367269.
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Sialyltransferases, CMP-sialic acid synthetases and CMP-sialic acid transport proteins play a crucial role in the construction of cell surface glycoconjugates. These proteins also have a pivotal role to play in a number of diseases, including cancer. The sialyltransferase enzymes are responsible for transfering sialic acids from the donor substrate (CMP-sialic acid) to growing cell surface glycoconjugate chains within the Golgi apparatus. The CMP-sialic acid synthetase enzymes are responsible for the synthesis of the CMP-sialic acid, the donor substrate of the sialyltransferases in the nucleus, while the CMP-sialic acid transport proteins are responsible for transporting CMP-sialic acid from the Cytosol to the Golgi apparatus. When these proteins function in an abnormal way, hypersialylation results, leading to an increased level of sialylation on the cell surface. This increased level of sialylation aids in the detachment of primary tumour cells due to an increase in the level of overall negative charge, causing repulsion between the cancer cells. Therefore, the sialyltransferase enzymes, CMP-sialic acid synthetases and CMP-sialic acid transport proteins are intimately involved in the metastatic cascade associated with cancer. Chapter 1 provides a general introduction of cancer metastasis, discussing the roles of three target proteins (CMP-sialic acid synthetases, CMP-sialic acid transport proteins and sialyltransferases), as well as discussing their substrate specificities, with an emphasis on their involvements in cancer metastasis. The Chapter concludes with an overview of the types of compounds intended to be utilised as probes or inhibitors of these proteins. Chapter 2 describes the general approach towards the synthesis of CMP-Neu5Ac mimetics with a sulfur linkage in the presence of a phosphate group in the general structure 38. The precursor phosphoramidite derivative 45 was prepared and isolated in a good yield using Py.TFA. Unfortunately, the target compound 38 could not be prepared. Chapter 3 describes an alternative strategy wherein S-linked sialylnucleoside mimetics, of the general structure 39, with a sulfur linkage, but no phosphate group, between the sialylmimetic and the ribose moiety in the base is targeted. A series of these S-linked sialylnucleoside mimetics were successfully prepared. Cytidine, uridine, adenosine and 5-fluorouridine nucleosides were used to create a library of different nucleosides and with structural variability also present in the sialylmimetic portion. This small 'library' of 15 compounds was designed to shed light on the interaction of these compounds with the binding sites of the sialyltranferase, CMP-sialic acid synthetase and/or CM-sialic acid transport protein. Approaches towards the synthesis of O-linked sialylnucleoside mimetics of the general structure 40 are described in Chapter 4. Several methodologies are reported, as well as protecting group manipulations, for successful preparation of these sialylnucleoside mimetics. Cytidine and uridine were employed as the nucleosides, thus allowing a direct comparison between the O- and S-linked sialylnucleoside mimetics in biological evaluation. It appears from these synthetic investigations that gaining access into the O-linked series is not as straightforward as for the S-linked series, with alternative protecting group strategies required for the different nucleosides. The biological evaluation of some of the compounds reported in Chapters 3 and 4 is detailed in Chapter 5. The sialylnucleoside mimetics were evaluated, by 1H NMR spectroscopy, for their ability to inhibit CMP-KDN synthetase. In addition, an initial 1H NMR spectroscopic-based assay was investigated for inhibition studies of ?(2,6)sialyltranferase in the absence of potential inhibitors. The final chapter (Chapter 6) brings together full experimental details in support of the compounds described in the preceding Chapters.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Institute for Glycomics
Full Text
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Homer, Jarrod James. "Studies on angiogenesis in head and neck squamous cell carcinoma". Thesis, University of Hull, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342866.
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Leber, Thomas Matthias. "Regulation of MMP-9 in human ovarian cancer". Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298185.
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Psaila, Bethan. "Interactions between megakaryocytes and tumour cells in the bone marrow vascular stem cell niche promote tumour growth and metastasis". Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/5945.
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Specialized bone marrow microenvironments (vascular and osteoblastic 'niches') regulate normal haematopoietic stem/progenitor cells. Recently, the vascular niche has also been implicated as an area for preferential engraftment of malignant cells. The cellular and molecular factors that regulate the vascular niche and, in particular, the role of megakaryocytes are poorly understood. The aim of my work was to investigate the role of megakaryocytes in homing and engraftment of malignant cells to the bone marrow vascular niche using mouse models. C57Bl/6 wild-type and megakaryocyte-deficient, thrombopoietin (TPO)-/- mice were injected with B16 melanoma or EL4 lymphoma cell lines and the megakaryocyte-vascular niche investigated by immunohistochemistry, confocal microscopy, in vitro culture, co-cultures and gene expression by RT-PCR. In wild-type mice injected with B16 melanoma, platelet size and megakaryocyte numbers significantly increased (P<0.02). B16 tumour cells were found to produce the thrombopoietic factors VEGF, SCF and IL11. Bone marrow sinusoids were almost universally surrounded by one of more megakaryocytes tightly abutting the vascular endothelium, forming the megakaryocyte-vascular niche. Metastatic B16 cells were observed in close association with megakaryocytes in the vascular niche, consistent with this being a port of entry to the bone marrow. In TPO-/- mice, tumour growth and metastasis was markedly retarded and no tumour cells were seen in the bone marrow, suggesting that megakaryocytes play a functional role in metastasis. In TPO-/- bone marrow, vessels were more tortuous and larger in diameter (P=0.01); and expression of PF4, TSP1, VEGF and TGFβ was 70%- 90% lower, suggesting that a major proportion of angiogenic regulatory factors is producted by megakaryocytes in the bone marrow in wild-type mice. Furthermore, in wild-type mice, expression of VEGF and TGFβ significantly increased during tumour growth and metastasis while PF4 expression decreased (P<0.05). Megakaryocyte-conditioned medium (MCM) enhanced the proliferation rate of B16 cells (P<0.001) and also was highly chemotactic for B16 cells (P<0.001), an effect mediated by pertussis toxin-sensitive Gi-protein receptors and reduced in the absence of TSP1. Co-culture with B16 cells increased megakaryocyte expression of VEGF, TGFβ and TSP1 and decreased PF4, consistent with the in vivo observations, while cocultured B16 cells displayed increased expression of VEGF and TGFβ and adhesion integrins. Moreover, pretreating B16 cells with MCM prior to tail vein injection enhanced metastatic engraftment. To investigate the role of megakaryocytes in human malignancy, trephine bone marrow biopsies from patients with metastatic carcinoma were examined. Increased megakaryocyte numbers and abnormal megakaryocyte clustering were observed in the majority of patients, suggesting that megakaryocyte-tumour interactions may also occur in the setting of human metastatic disease. In conclusion, my findings suggest that megakaryocytes contribute to the integrity and function of the bone marrow vascular niche and that cellular/molecular cross talk between megakaryocytes and tumour cells may promote metastasis. Targeting these interactions may be useful as adjunctive therapy in metastatic disease.
19
Gardner, M. J. "Adhesion molecules in the interactions of ovarian tumour cells and mesothelial cells". Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336754.
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Billström, Anita. "The significance of urokinase-type plasminogen activator (u-PA) in tumour growth and linomide-induced upregulation of u-PA's endogenous inhibitor PAI-2". Lund : Research Laboratory, Dept. of Obstetrics and Gynaecology, Lund University Hospital, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39751812.html.
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Pu, J. "Electrical signals control the establishment of cell polarity, tumour metastasis and wound healing". Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590979.
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Endogenous direct-current electric fields (EFs) play significant roles in biological and pathological processes. In this thesis I will discuss how an applied EF affects cell polarity, tumour metastasis, wound healing and provide some insights to the underlying molecular mechanisms. Directional cell migration requires proper cell polarization. The redistribution of the Golgi apparatus is a critical event in cellular polarisation. Direct current EFs as low as 0.3 V/cm induces Golgi polarization and directed cell migration. The Golgi polarizes at the same time as cells change morphology and migrate directionally in response to an electric field. Golgi polarization in turn significantly reinforces and maintains optimal electrotaxis. PKC/PI3K-GSK-3β signalling is required to promote Golgi polarization and control the direction of cell protrusion. Development of breast cancer is accompanied by electrical depolarization of the tumour epithelial cells. Applied electric fields indeed induce increased speed and directional migration of the highly metastatic cancer cells. EFs enhanced directional migration depends on EGFR/ErbB1 expression levels. Inhibition of ErbB1 activity completely abolished the directional response of tumour cells to an electric field. EFs could be the earliest signal epithelia receive to initiate directional migration and healing. Using a single cell model and a monolayer wound healing model in vitro, we found that a physiological EF overrides other guidance cues. When wound healing required cells to move towards the anode, they failed to do so. By contrast they were repelled and the wound opened up. This suggests that endogenous EFs may play much more important roles in re-epithelialization in wound healing.
22
Al-Mulla, Fahd. "Genetic aberrations associated with metastasis in colorectal cancer : an insight into tumour heterogeneity". Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300772.
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Oates, Adam John. "The identification of metastasis-related gene products in a rodent mammary tumour model". Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283448.
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Durkan, Garrett Christopher. "Matrix metalloproteinase-1 and -9 and tissue inhibitor of metalloproteinase-1 in bladder cancer : pathophysiological significance and relationship to epidermal growth factor receptor expression". Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369832.
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Speakman, H. "Metastasis of the LMC1̲ rodent tumour and the response to treatment with cyclophosphamide in combination with surgery". Thesis, University of Leeds, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378851.
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Vallejo, Espi Maria de Lourdes. "Characterization of the mechanisms by which Carbonic Anhydrase IX facilitates tumour growth and metastasis". Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/52795.
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The presence of hypoxic microenvironments in solid tumours is a marker of poor prognosis in numerous cancer types, including breast cancer; the second leading cause of cancer-related death.
Hypoxia results in an adaptive response in tumour cells through the activation of the transcription factor Hypoxia Inducible Factor-1α (HIF-1α), which stimulates the expression of a large number of genes that contribute to tumour progression. One of the most prominently activated genes is Carbonic Anhydrase IX (CAIX), which facilitates the acidification of the extracellular space and cell invasion by producing protons. Moreover, it assists in keeping the intracellular space neutral through the generation of bicarbonate, which is shuttled into the cytoplasm by bicarbonate transporters, ultimately favouring cell survival. CAIX facilitates breast tumour growth and metastasis; however the exact mechanism remains unknown. The overexpression of CAIX in hypoxic solid tumours, its limited expression in normal tissue and the presence of an extracellular catalytic domain makes this protein an excellent therapeutic target.
The intent of this thesis was to unveil the mechanisms by which CAIX facilitates tumour progression, and to characterize novel small molecule inhibitors and antibodies targeting CAIX.
It was found that the intracellular (IC) domain of CAIX regulates its catalytic activity, which is required for cell survival, cell invasion and metastasis. The extracellular proteoglycan-like (PG-like) domain of CAIX does not regulate CAIX catalytic activity; however it does modulate cell migration, invasion and metastasis. I identified a role of CAIX in promoting tumour cell invasion through interaction with membrane-bound matrix metalloprotease-14 (MMP-14) and localization in invadopodia. The IC domain of CAIX mediates this interaction and CAIX enzymatic activity appears to regulate the ability of MMP-14 to degrade type I collagen during cell invasion.
From the pool of anti-CAIX inhibitors and antibodies characterized in this thesis, the inhibitor U-104 was excellent at blocking CAIX enzymatic activity and has entered phase I clinical trials. Likewise, anti-CAIX antibody MM-26 blocked 50% of CAIX activity and induced cell death in vitro.
The work described here provides new insight into the mechanism of CAIX-mediated tumour invasion and metastasis and has identified two new therapeutic strategies for targeting CAIX.Medicine, Faculty of
Biochemistry and Molecular Biology, Department of
Graduate
27
Taniguchi, Tadaaki. "Investigation of the mechanism of enhancement of invasion and tumour growth by tissue factor in human cancer". Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325327.
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Hall, Debbie M. S. "Investigation of the role of N-acetylgalactosylated glycoconjugates in cancer metastasis using the lectin from Helix pomatia (the Roman snail)". Thesis, Oxford Brookes University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367328.
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Nduka, Charles. "Operative dissemination of cancer : the impact of microenvironmental manipulation on post-operative tumour growth". Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391634.
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30
Holzapfel, Boris Michael. "Tissue engineering of a morphologically and functionally intact humanized bone organ for bone metastasis research". Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/84810/18/84810%28thesis%29.pdf.
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The aim of this thesis was to establish an individualized, patient-specific diagnostic and therapeutic preclinical disease model for bone metastasis research. Tissue engineering of humanized bone within mice allowed the development of a humanized immune system in the host animal. This novel platform makes it possible to analyze the growth of human cancer cells in human bone in the presence of human immune cells.
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Nouhi, Zaynab. "Prolactin plays a dual role in breast cancer : promoting formation of breast tumour while inhibiting its metastasis". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97983.
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Prolactin is a key mammary gland differentiation factor. However, the contribution of prolactin (PRL) to breast carcinogenesis is less clear. Accumulating evidences indicate that in established breast carcinomas autocrine/paracrine PRL can enhance growth/viability of breast cancer cells. Still, it is not known whether the ascribed pro-oncogenic activity of PRL describes fully the role of PRL in regulating breast carcinogenesis. On the other hand a critical role for Ras-Erk1/2 and TGF-beta (Transforming Growth Factor beta) pathway in breast cancer progression has already been established. Our results indicate that blocking PRL signal leads to activation of Ras-Erk1/2 pathway and TGF-beta pathway, two key pathways contributing to breast cancer metastasis. I showed that modulation of PRL signaling in breast cancer cells alters their morphogenic program. My results highlight a critical role for PRL in regulating epithelial plasticity and implicate PRL as invasive suppressor hormone in breast cancer cells.
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Elsharif, Amal A. M. "Functional Investigation of Dual αvβ3 and αllbβ3 Integrin Inhibition in Haematological and Solid Tumour Models". Thesis, University of Bradford, 2018. http://hdl.handle.net/10454/16883.
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Invasion and metastasis of cancer is the leading cause of increased mortality. In addition, haematological malignancies (leukaemia and lymphoma) are a significant cause of morbidity and mortality in both children and adults. Therefore, new treatments which will inhibit cancer progression are required. Integrin adhesion receptors, particularly the RGD-binding integrin subfamily comprising αvβ3, αvβ5, αvβ6, αvβ8, αllbβ3, α5β1, α8β1 and αvβ1 are related to progress and spread of cancer and poor prognosis. Because of the importance of integrin biology in the regulation of cancer dissemination, the integrin receptors are being utilised as targets to regulate cancer progression. The goal of this study was to develop a dual αvβ3/ αIIbβ3 expressing model for testing integrin antagonists. Expression of αv, αIIb, and β3 integrin subunits was characterised using immunofluorescence and flow cytometry in a panel of cell lines. After characterising the expression of αv, αIIb and β3 integrin subunits in inducible and natural expression models (K562 and MCF-7 cells respectively), functional tests for cellular adhesion, detachment and migration were determined. Phorbol 12-myristate 13-acetate (PMA)-treated K562 cells showed increased adhesion on fibrinogen compared to untreated cells. Adhesion of cancer cells (K562 ± PMA and MCF-7) to fibrinogen was inhibited and detachment was induced by the known β3 antagonists, cRGDfV and GR104453.
Migration of cancer cells (K562 without PMA and MCF-7) was inhibited by combination of the known β3 antagonists. A panel of 12 novel small molecules developed in the ICT was investigated for cytotoxicity and activity in the validated function assays. ICT9055 was the most potent antagonist in inhibition of cell adhesion, migration, and inducing cell detachment. The data presented in this thesis had selected models and assays for evaluating small molecule integrin antagonists and identified ICT9055 as a promising molecule to develop for further preclinical evaluation.The Libyan Embassy; Omer Al Mukhtar University, Faculty of Medical Technology, Derna, Libya.
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Zraikat, Manar Saleh Ali. "Development of in vitro models of invasion for the pharmacological investigation of small molecule inhibitors of tumour progression : development and validation of a 3-dimensional tumour spheroid invasion model to evaluate the pharmacological effects of novel small molecule β3 integrin antagonists". Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/7511.
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Tumour dissemination is a major reason for failure of therapy for many tumour types therefore there is a requirement for novel targets & therapies. The αIIbβ3 and αvβ3 integrins have been demonstrated to have significant involvement at many stages of the tumour dissemination process including, tumour cell adhesion, migration, metastasis and angiogenesis, and thus the β3 integrins are a potential target for therapeutic antagonism with small molecules. Because of the clear interaction between the different integrin types, targeting integrins as a therapeutic strategy requires targeting more than one integrin type. Consequently, the ICT is developing a group of novel new αIIbβ3 and αvβ3 integrin dual antagonists. One of the main challenges is having a relevant, validated experimental model that expresses these integrins. The aim of the work presented here is to develop and validate an in vitro αIIbβ3 and αvβ3 integrin expressing assay of tumour cell invasion. The spheroid invasion assay has the advantage over standard monolayer transwell chamber invasion assays of being a 3-dimensional assay, and thus mimics better the cell-cell interactions and architecture that are present in a tumour compared to the monolayer-based assay. A panel of human cancer cell lines known to express one of the molecular targets of interest, αvβ3 integrin was evaluated for the ability to form spheroids and to invade through collagen matrices. One glioma cell line, U87-MG, demonstrated consistent spheroid formation and invasion and was thus selected for further studies. Optimum conditions were established for use of U87-MG in the invasion assay, and the assay was validated using a known inhibitor of invasion, LiCl and known β3 antagonist, cRGDfV. Subsequently a group of novel small molecule β3 antagonists were evaluated at nontoxic concentrations using the assay. Both LiCl and cRGDfV inhibited spheroid invasion through the gel in a dose-dependent manner, thus validating the assay. Furthermore, when the novel small molecule β3 antagonists were evaluated using the model, a dose and time dependent reduction in U87-MG spheroids invasion in collagen was observed. In further work initial steps were taken to construct a cell line which expresses both αIIbβ3 and αvβ3 integrin to use in the model to assess for dual integrin antagonism. In conclusion, this work has established a validated assay which has been utilised for some compounds to evaluate a group of novel small molecule β3 integrin antagonists with encouraging results.
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Pittman, Kenneth Brian. "The development and evaluation of molecular biological techniques to detect solid tumour cells in peripheral blood /". Title page, table of contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09MD/09mdp689.pdf.
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Jassim, Amir. "Involvement of the matrix proteins SPARC and osteopontin in the dynamic interaction between tumour and host cells". Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/13399.
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Osteoblasts are highly active cells that are responsible for secreting bone forming components such as collagen type I and matricellular proteins that mediate collagen deposition and mineralisation. SPARC and osteopontin are matricellular proteins that are involved in bone regulation and cell-matrix interactions and are also upregulated in metastatic disease. Secretion of these proteins results in changes to the stromal environment that includes cell migration, angiogenesis, matrix degradation, matrix deposition, bone mineralisation and bone resorption. Signalling pathways not only lead to the expression of target proteins, but also have immediate early effects, for example, on cell adhesion. We asked if the ERK 1 and 2 module of the MAPK pathway was involved in the intracellular trafficking of SPARC and Osteopontin. Membrane trafficking is an essential process that ensures newly synthesised proteins pass from their site of synthesis to the extracellular environment. Using an inhibitor of ERK 1 and 2 activation (U0126), as well as siRNA directed against ERK 1 or 2 individually, a change in intracellular localisation of SPARC and osteopontin was observed in cells treated with U0126 and siRNA against ERK 2 alone, likely in or around the Golgi apparatus. Consistent with the observation above, analysis of protein secretion showed that there was a reduction of total protein secreted (30% reduction) when ERK 1 and 2 activation was prevented together or knock down of ERK 2 alone. A mechanism is proposed where ERK 2 is likely activating a substrate that is allowing SPARC and osteopontin to continue along the secretory pathway. This directly implicates ERK 2 as an important regulator of matricellular protein secretion in osteoblasts. In cancer, Ras mutations can lead to permanent activation of the MAPK pathway leading to cancer cell proliferation and survival, however, we propose another mechanism important in metastasis whereby ERK 2 activation is manipulated to facilitate secretion of matricellular proteins which can then mediate changes to the stromal environment that allow the tumour to metastasise successfully.
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Elkashef, Sara M. "Pharmacological evaluation of novel polysialyltransferase inhibitors as anti-metastatic agents and development of analytical methods for assessment of polysialylation inhibition : in vitro assessment of the effects of novel polysialyltransferase inhibitors on tumour cell function and development of quantitative HPLC-based methods for evaluation of novel polysialyltransferase inhibitors". Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14123.
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Polysialic acid (polySia) is a carbohydrate polymer highly expressed during embryonic development but rarely expressed during postnatal development. Two polysialyltransferase (polyST) enzymes are responsible for the synthesis of polySia: ST8SiaII and ST8SiaIV. During oncogenesis polySia is re-expressed and it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis. PolySia expression is strongly associated with poor clinical prognosis and correlates with aggressive and invasive disease in neuroblastoma and many other tumours. PolyST inhibition thus presents a novel, selective and largely unexplored therapeutic opportunity to reduce tumour dissemination. Progress towards development of polyST inhibitors has been limited by lack of an efficient technique for quantitative assessment of enzyme activity. We have validated a highly sensitive cell-based and cell-free high throughput HPLC-based inhibition assays. Using isogenic cell lines (C6-STX: polySia+/ST8SiaII+ and C6-WT: polySia-/ST8SiaII-) and naturally polySia expressing human neuroblastoma cells (SH-SY5Y), a set of ST8SiaII inhibitors designed and synthesised in house were evaluated for their ability to reduce polySia expression and to modulate cell migration in vitro. We have identified CMP-sialic acid precursors, including ICT-3176, which reduced polySia expression and tumour cell migration by up to 70%. These effects were only found in cell lines expressing ST8SiaII and polySia. Furthermore, we have investigated the possible additive anti-migratory effect of combining polyST inhibition with the inhibition of certain signalling pathways that have been previously suggested to be modulated by polySia expression. Out of these combinations it was found that combining ST8SiaII and C-MET/ALK inhibition had a synergistic effect on inhibiting cancer cell migration. Additionally, the effect of polySia expression on cancer cell behaviour under hypoxic conditions was examined, where it was found that polySia expression enhanced cell migration and survival and inhibits cell adhesion. In summary, polyST inhibitors which dramatically decrease cell migration in vitro through modulation of polySia assembly were identified, using optimised cell-free and cell-based assays. Initial investigations into the role of polySia in hypoxia were also accomplished. This work paves the way for development of a novel therapeutic for the treatment of neuroblastoma.
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Phipps, Laura Ellen. "Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:93198943-a7fa-4b30-aaed-c92d7e0a4ba6.
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Due to its selectivity in killing cancer cells, Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has provided a potential new agent for cancer treatment. However, despite promising pre-clinical results, it appears that TRAIL therapies will be most effective when used in combination with a sensitizing agent. In light of previous evidence suggesting that cell adhesion could influence sensitivity to Tumour necrosis factor family ligands, this thesis presents a study of the effects of disrupting matrix adhesion on the sensitivity of human MDA-MB-231 breast and 1205Lu melanoma cell lines to TRAIL-induced apoptosis. This was investigated using a number of models including i) culturing cells on normal and low attachment plates; ii) disrupting the transcription of genes involved in cell attachment and spreading in MDA-MB-231 cells using shRNA to Myocardin-related transcription factors-A and B (MRTF-A/B); iii) disrupting the integrin signalling pathway using inhibitors or siRNA to β integrin subunits, talin, integrin-linked kinase (ILK), focal adhesion kinase (FAK) and SRC. With the exception of ILK depletion, disruption of cell adhesion and spreading in all models resulted in sensitisation to TRAIL-induced apoptosis. Cells under these conditions also showed alterations in death receptor signalling and amplification of intrinsic apoptosis pathway signalling through caspase-9. Both MRTF-A/B depleted cells and those treated with the SRC family kinase inhibitor PP2 showed alterations in signalling through ERK1/2. When investigated in an experimental model of metastasis in mice, FAK and SRC inhibitors increased the clearance of MDA-MB-231 cells from the mouse lung when used in combination with recombinant human TRAIL therapy. By utilizing these models, the work in this thesis has shown that disrupting cell adhesion could provide a new combination strategy to sensitise tumour cells to TRAIL therapy.
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Recalde-Percaz, Leire. "Neuropilin 2 role in the regulation of disseminated tumour cells dormancy and metastasis in breast and head and neck cancer". Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/672374.
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Metastases are considered the last stage of tumour progression and the main cause of death associated to solid tumours. There are no effective treatments for metastasis which remain non- curable with more than 90% of patients dying from metastatic disease. They derive from disseminated tumour cells (DTCs) that can remain occult in a dormant state while adapting to the new microenvironment. By mechanisms that are still unclear, dormant DTCs can re-activate and become proliferative giving rise to metastatic outgrowth. Therefore, understanding the mechanisms by which metastases are formed is essential to face one of the most important problems in clinical oncology. Metastasis development depends on DTCs survival in circulation as well as on their ability to colonize new microenvironments. Therefore, we propose that the tumour microenvironment regulates the fate and survival of DTCs in secondary organs, hence regulating metastases.
This project has been developed in order to decipher the role of the nervous system in breast cancer (BrCa) and head and neck cancer (HNSCC) progression and metastasis. Particularly, we have investigated whether the neurogene neuropilin 2 (NRP2) has a crucial role in regulating DTCs biology and in remodelling the metastatic niche generating a favourable microenvironment for the survival and proliferation of the DTCs, all stimulating metastasis. As classical partners of NRPs, we have also studied the effect of class 3 semaphorins (SEMA3s) and their receptors, plexins (PLXNs), on tumour cells biology.
On one hand, we have shown that SEMA3F has an anti-tumour effect in vivo increasing quiescence markers expression and inducing a switch in primary tumours behaviour to a more dormant phenotype. We have also shown that it diminishes cell dissemination to secondary organs, which makes SEMA3F a potential good prognosis factor in BrCa and HNSCC. On the other hand, our results suggest that PLXNA2 inhibits tumour growth as well as prevents cell migration and invasion while it might modulate cell stemness. Moreover, we have also found that PLXNA3 might restrain tumour growth in oestrogen receptor (ER)-positive breast tumours and that the oestrogen signalling up- regulates PLXNA3 expression, associating PLXNA3 with longer dormancy periods of ER-positive breast tumours.
Finally, we have mainly focused on deciphering the role of NRP2 in regulating DTCs biology and lung metastases. Here, we have shown that NRP2 positively regulates BrCa and HNSCC cells proliferation, adhesion, migration, invasion and survival in vitro and in vivo. NRP2 deletion clearly inhibits tumour growth in vivo as well as decreases the number and size of lung metastases. Moreover, NRP2 is essential for lung DTCs proliferative phenotype, hence promoting lung metastases growth in vivo. Highlighting the role of the microenvironment, we have shown that the lung microenvironment up- regulates NRP2 expression partly by macrophages and fibroblasts-derived TGFβ1. Altogether, this thesis contributes to a better understanding of DTCs biology describing TGFβ1-NRP2 axis as a dormancy inhibitor pathway, promoting DTCs re-awakening and lung metastases development. The negative correlation of NRP2 expression with metastasis free survival in BrCa and HNSCC patients’ and our results emphasizing the metastatic role of NRP2, suggest that NRP2 could be a bad prognosis biomarker and a good target to design new drugs against metastasis.Les metàstasis, principal causa de mortalitat associada a tumors sòlids que provoquen la mort de més del 90% dels pacients, no disposen d’un tractament efectiu. Les metàstasis deriven de cèl·lules tumorals disseminades (CTDs) que escapen del tumor primari i, després d’un període d’adaptació al nou microambient, proliferen donant lloc a la metàstasi. Durant aquest període d’adaptació, les CTDs entren en un estat de latència que es caracteritza per una parada del cicle cel·lular, fet que les fa invisibles davant de les teràpies actuals. Mitjançant mecanismes parcialment desconeguts, les CTDs es reactiven i proliferen generant la metàstasi. Per tant, és imprescindible millorar el coneixement sobre la biologia de les CTDs per fer front a un dels principals problemes de l’oncologia clínica actual. Per tal que es generi una metàstasi, es requereix la supervivència de les CTDs tant en circulació com al nou microambient que colonitzaran. Tenint tot això en compte, proposem que el microambient tumoral influencia el fenotip i la supervivència de les CTDs, regulant així la formació de metàstasis. Aquesta tesi ha tingut com a objectiu l’estudi de la influència de factors neuronals en el desenvolupament del tumor i la metàstasi als càncers de mama i de cap i coll. Concretament, hem estudiat el paper de la Neuropilina 2 (NRP2) en la regulació de la biologia i supervivència de les CTDs, així com en la modulació del microambient tumoral, afavorint la formació de metàstasis. Així mateix, hem analitzat l’efecte i la contribució de les semaforines de classe 3 (SEMA3s) i els seus receptors, les plexines (PLXNs), als càncers de mama i de cap i coll. D’una banda, hem posat de manifest la funció anti-tumoral de la SEMA3F en augmentar l’expressió de marcadors de latència, a més de reduir la disseminació tumoral i d’induir fenotips menys proliferatius a les CTDs in vivo. D’altra banda, els nostres resultats suggereixen que la PLXNA2 semblaria inhibir el creixement de tumors de mama receptor d’estrogen (ER)-negatius, disminuint la migració i invasió cel·lular. Altrament, l’expressió de la PLXNA3 està regulada per la via dels estrògens, associant la seva expressió als períodes de latència més perllongats en tumors de mama ER-positius. Finalment, el nostre estudi s’ha centrat a determinar la funció de la NRP2 a les CTDs i al desenvolupament de metàstasis al pulmó. En concret, hem demostrat la relació de l’expressió de NRP2 amb una major proliferació, adhesió, migració, invasió i supervivència cel·lular in vitro i in vivo. En concordança, hem mostrat que la inhibició de NRP2 redueix tant el creixement del tumor primari com la formació de metàstasis als pulmons in vivo. Finalment, destacant el paper del microambient tumoral als pulmons, hem vist que el TGFβ1 secretat pels macròfags i fibroblasts pulmonars augmenta l’expressió de NRP2 a les cèl·lules tumorals. En definitiva, aquesta tesi contribueix a un major coneixement de les CTDs descrivint l’eix TGFβ1- NRP2 com a inhibidor de la latència cel·lular i promotor de les metàstasis pulmonars. Tenint en compte la correlació de l’expressió de NRP2 en pacients de càncer de mama i de cap i coll amb una major incidència de metàstasis, definim la NRP2 com a marcador de mala prognosi contra la qual generar possibles noves eines terapèutiques per a millorar els tractaments de la malaltia metastàtica
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Toh, Alan Kie Leong. "Functional roles of EMP-associated targets in breast cancer models". Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/207818/1/Alan%20Kie%20Leong_Toh_Thesis.pdf.
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Epithelial mesenchymal plasticity in cancer generally refers to the ability of a cancer cell to transform into a different cell form, which facilitates the metastatic spread of a cancer. This thesis explores the roles of four cancer-associated genes that affect the transition of the cell state during cancer metastasis, and includes extensive research on two of the four gene targets, namely TRIM28 and TGFBI. The effects of these genes in breast cancer systems indicated great potential for improving therapeutic responses towards cancer drugs, which would alleviate the suffering of breast cancer patients.
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Ham, Sunyoung. "The role of breast cancer derived-exosomes in the tumour micro-environment". Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/208432/1/Sunyoung_Ham_Thesis.pdf.
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The findings in this thesis demonstrate that cancer-derived exosomes play a critical role in the tumour microenvironment, which greatly expands our understanding of the mechanisms underlying cancer progression and metastasis. This research provides novel approaches at allowing improved utilisation of cancer-derived exosomes as diagnostic biomarker tools or for therapeutic interventions for cancer treatment.
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Grawenda, Anna Maria. "The identification and analysis of molecular biomarkers in the p53 tumour suppressor pathway that affect cancer progression in humans". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:5a76b7ca-22f6-4f49-b715-5ad43f916984.
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The tumour suppressor p53 is at the centre of the signalling pathway that controls cellular processes crucial in tumourogenesis, cancer progression and tumour clearance. Alterations in the p53 pathway that lead to cancer progression can be good candidates for molecular biomarkers that would assist in the identification of patients with different prognoses, but also serve as good predictors of appropriate targeted therapies. Patient cohorts and cancer cell panels are utilised to seek associations with the attenuation of the p53 pathway and cancer progression. Firstly, the alternatively spliced transcript of the p53 inhibitor HDMX, which is frequently found in tumours with poor prognosis, is studied. The high ratio of the alternatively spliced HDMX-S transcript over the full-length HDMX-FL transcript (HDMX-S/FL) is demonstrated to associate with p53 pathway attenuation in cancer cells and breast carcinomas, and with faster metastatic progression of osteosarcoma and breast cancer patients. Secondly, inherited polymorphism in the HDMX gene is investigated and demonstrated as a unique and highly reproducible eQTL, which identifies patients with different prognoses for metastatic disease in breast cancer and melanoma cohorts. Lastly, a screening approach to identify novel inherited polymorphisms in the p53 pathway genes that associate with metastatic progression of melanoma is developed and implemented, and subsequently in silico and in vitro functional analyses are performed to investigate a mechanism behind the FOXO3 SNP, identified as the strongest candidate, whereby the experimental evidence demonstrate that the causal SNP in the FOXO3 haplotype is controlled by the GATA3 transcription factor. Together, the work presented in this thesis provides strong support for the role of the p53 pathway in the metastatic progression of cancer, and suggests that molecular biomarkers that can detect changes in the activity of p53 pathway genes could offer a robust set of biomarkers for cancer progression applicable to different types of cancer.
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Hassan, Sara. "Epithelial-mesenchymal plasticity in circulating tumour cells from patients with metastatic cancers and PDX models". Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/228621/8/Sara_Hassan_Thesis.pdf.
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There is growing concern about the relevance of epithelial mesenchymal plasticity (EMP) status of primary tumours in influencing their metastatic potential. Circulating tumour cells (CTCs) provide a window into the metastatic process, and molecular characterisation of CTCs could lead to better understanding of the mechanisms involved in the metastatic cascade. This thesis is an investigation of molecular characteristics of EMP in tumours and CTCs using patient-derived xenograft models and patient blood samples. The CTC heterogeneity observed emphasises the complexity in CTC isolation and classification and supports the increasingly recognised importance of the epithelial-mesenchymal hybrid state in cancer progression and metastasis.
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Brown, David Norman. "Application of phylogenetic inference methods to quantify intra-tumour heterogeneity and evolution of breast cancers". Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/260251.
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Cancer related mortality is almost always due to metastatic dissemination of the primary disease. While research into the biological mechanisms that drive the metastatic cascade continues to unravel its molecular underpinnings, progress in our understanding of biological phenomena such as tumour heterogeneity and its relevance to the origins of distant recurrence or the emergence of resistance to therapy has been limited.In parallel to major breakthroughs in the development of high throughput molecular techniques, researchers have begun to utilise next generation sequencing to explore the relationship between primary and matched metastatic tumours in diverse types of neoplasia. Despite small cohort sizes and often, a limited number of matched metastases for each patient, pioneering studies have uncovered hitherto unknown biological processes such as the occurrence of organ specific metastatic lineages, polyclonal seeding and homing of metastatic cells to the primary tumour bed. While yet other studies continue to highlight the potential of genomic analyses, at the time this thesis was started, an in-depth knowledge of disease progression and metastatic dissemination was currently lacking in breast cancers.Herein, we employed phylogenetic inference methods to investigate intra-tumour heterogeneity and evolution of breast cancers. A combination of whole exome sequencing, custom ultra-deep resequencing and copy number profiling were applied to primary tumours and their associated metastases from ten autopsied breast cancer patients. Two modes of metastatic progression were observed. In the majority of cases, all distant metastases clustered on a branch separate from their primary lesion. Clonal frequency analysis of somatic mutations showed that the metastases had a monoclonal origin and descended from a common metastatic precursor. Alternatively, the primary tumour was clustered alongside metastases with early branches leading to distant organs. This dichotomy coincided with the clinical history of the patients whereby multiple seeding events from the primary tumour alongside cascading metastasis-to-metastasis disseminations occurred in treatment naïve de novo metastatic patients, whereas descent from a common metastatic precursor was observed in patients who underwent primary surgery followed by systemic treatment. The data also showed that a distant metastasis can be horizontally cross-seeded and finally revealed a correlation between the extent of somatic point mutations private to the distant lesions and patient overall survival. In an unrelated dataset of relapsed breast cancer patients with matched primary and distant lesions profiled using whole genome sequencing, the landscape of somatic alterations confirmed the time dependency of copy number aberrations implying that cancer phylogenies can be dated using a molecular clock.The work presented here harnesses the strength of high throughput genomic techniques and state of the art phylogenetic tools to tell the evolutionary history of breast cancers. Our results show that the linear and parallel models of metastatic dissemination which have been held as near doctrines for many years are overstated point of views of cancer progression. Beyond the biological insights, these results suggest that surgical excision of the primary tumour in de novo metastatic breast cancers might reduce dissemination in selected cases hence providing a potential biological rationale for this practice. Similarly, there is no strong evidence of benefit in overall survival from surgical resection of oligo-metastases in breast cancer. From our analyses, metastatic lesions constitute an additional source of seeding and heterogeneity in advanced breast cancer. The data presented here is too small to derive practice-changing evidence, but supports the concept that resecting isolated metastases may be of clinical benefit in oligo-metastatic breast cancer patients. In both cases, results from larger prospective studies are warranted.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
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Luco, Aimee-Lee. "Vitamin D strongly influences skeletal metastasis development in breast cancer: comparison of systemic vitamin D deficiency versus local ablation of CYP27B1 in breast tumour cells". Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121223.
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Vitamin D is very well known for its classical role in the maintenance of calcium and phosphorus homeostasis as well as in the prevention of rickets. More recent findings of its ability to inhibit cell proliferation, induce apoptosis, induce differentiation, inhibit angiogenesis, and modulate the immune system have made it a current topic of intense research, particularly in the field of cancer research. We used a murine model of breast cancer metastasis to bone to investigate the effect of vitamin D deficiency on the growth of breast cancer tumour cells within bone. We also established that these breast cancer tumour cells express the enzyme CYP27B1 (1α-hydroxylase) which is able to convert the inactive vitamin D precursor 25-hydroxyvitamin D (25(OH)D) to the active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D). We next examined the effect of the local activation of vitamin D by tumoral CYP27B1 on the growth of these tumour cells within bone. Although we did not see a significant difference in the growth of breast cancer tumour cells in the bones of vitamin D deficient mice as compared to vitamin D sufficient mice, we have demonstrated that breast cancer tumour cells that do not express CYP27B1 grow much more aggressively within bone than breast cancer tumour cells which express CYP27B1. This suggests a very important role for the local activation of vitamin D by extra-renal CYP27B1 on the growth of breast cancer tumour cells within the bone microenvironment. These findings suggest a potential use for 25(OH)D as a treatment for breast cancer metastasis to bone either alone or in combination.La vitamine D est bien connue pour son rôle dans le maintien des concentrations de calcium et du phosphore dans la circulation ainsi que dans la prévention du rachitisme. La découverte plus récente de sa capacité d'inhiber la prolifération cellulaire, induire leur différentiation ainsi que l'apoptose cellulaire, inhiber l'angiogenèse, et moduler le système immunitaire rend son étude un sujet de recherche très intéressant surtout dans le domaine de la recherche sur le cancer. Nous avons étudié l'effet de la carence en vitamine D sur la croissance tumorale dans un modèle murin de métastases osseuses du cancer du sein. Nous avons aussi établi que ces cellules expriment l'enzyme CYP27B1 (1α-hydroxylase) et sont donc capables d'activer la vitamine D en son métabolite actif la 1,25-dihydroxyvitamine D (1,25(OH)2D) à partir du métabolite inactif, la 25-hydroxyvitamine D (25(OH)D). Nous avons ensuite examiné l'effet de l'activation locale de la vitamine D par les cellules tumorales dérivées du sein sur la croissance de ces cellules dans le microenvironnement osseux. Nous n'avons constaté aucune différence significative entre la croissance des cellules tumorales du cancer du sein dans l'os chez les souris carencées en vitamine D en comparaison aux souris non carencées en vitamine D. Cependant, nous avons démontré que les cellules tumorales du cancer du sein qui expriment le CYP27B1 croissent beaucoup moins vite dans l'os que les cellules tumorales qui n'expriment pas le CYP27B1. Ces résultats suggèrent un rôle très important de l'activation extra-rénale de la vitamine D par les cellules tumorales du cancer du sein pour inhiber la croissance de ces cellules dans l'os. En conclusion, ces travaux indiquent que le précurseur inactif 25(OH)D pourrait être utilisé seul ou en combinaison pour le traitement des métastases osseuses du cancer du sein.
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Al, Saihati Hajir. "SIP1/ZEB2-induced epithelial mesenchymal transition promotes metastasis and alters chemokine (C-C motif) ligand 5 expression to modulate the tumour microenvironment in colorectal cancer". Thesis, University of Southampton, 2016. https://eprints.soton.ac.uk/417395/.
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Epithelial mesenchymal transition (EMT) is a critical trans-differentiation program driving cancer metastasis. Patients showing signs of invasive cancer or the presence of distant metastasis have a poor prognosis. Another well-known feature of decreased cancer-associated survival is the lack of anti-cancer immune responses. Thus I hypothesized that the EMT and anti-tumor response could be linked via altered secretion of soluble factors by metastatic cells. Colorectal cancer (CRC) cell lines and SIP1-inducible DLD cells were grown in DMEM. The induction of the SIP1 gene was carried out using doxycycline for 3 days. The EMT status of the CRC cell lines were assessed by preforming western blotting, immunofluorescence and RT-PCR for EMT biomarkers. Cytokine/chemokine expression in SIP1 inducible DLD cells was analyzed using commercially-available antibody arrays. Validation of the selected chemokine (CCL5) was carried out using sandwich ELISA as well as RT-PCR, with the CCL5 expression level analysed in a panel of CRC cell lines using the same techniques. The CCL5 promoter was then cloned into pGL3. The mechanism of action of ZEB1/2 on the CCL5 promoter was studied by luciferace assay and chromatin immunoprecipitation (ChIP). CCL5 coding region was cloned into pcDNA3.1 and stably transfected into DLD-1 cells. DLD-1 cells over-expressing CCL5/RANTES were injected orthotopically into SCID mice, and metastasis was investigated by immunohistochemistry (IHC). The relationship between infiltrating T lymphocytes (TILs) and the expression of both CCL5/RANTES and SIP1 was studied in 75 CRC patients by IHC and tissue micrroarray. The results of evaluating EMT status categorised 13 CRC cell lines as epithelial, intermediate epithelial, intermediate mesechymal and mesenchymal. Cytokine/chemokine antibody arrays showed a significant increase in CCL5/RANTES in induced DLD-SIP1 cells. ELISA, multiplex assays and RT-PCR confirmed the increased secretion of CCL5/RANTES in the induced DLDSIP1 cells. The CRC cell line panel showed that the average level of secreted CCL5/RANTES from mesenchymal CRC cells was significantly more than in epithelial cells (639.7 ± 175 vs 107.6 ± 30 pg/ml, respectively; p=0.0075). mRNA expression profiling confirmed this finding from the CRC panel. Promoter studies showed that ZEB1/2 bind to CCL5 promoter, thus activating CCL5 gene expression. No metastatic spread for of DLD-1 cells overexpressing CCL5/RANTES was observed when orthotopically injected into SCID mice. Our data shows that CCL5/RANTES is up-regulated by EMT-inducing transcription factor SIP1, and mesenchymal (metastatic) CRC cells secrete significantly more CCL5/RANTES compared to epithelial (non-metastatic) cells. Furthermore, abundant secretion of CCL5/RANTES might be a crucial regulator of immune infiltration in CRC, but not a direct inducer of metastasis, and that needs to be futher investigated. Inhibiting CCL5 activity in metastatic CRC may have a therapeutic potential.
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Lai, Andrew. "Towards the development of novel bispecific antibodies to inhibit key cell surface receptors integral for the growth and migration of tumour cells". Thesis, Queensland University of Technology, 2016. https://eprints.qut.edu.au/101339/1/Andrew_Lai_Thesis.pdf.
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This project describes the development of antibody fragments against key cell surface receptors as potential metastatic breast cancer therapeutics. As a product of an iterative screening process, an antibody fragment candidate was demonstrated to be functionally active in the inhibition of cancer cell growth and migration. This study provides a promising platform for further development of the characterised antibody fragment with the goal of generating an effective treatment for the inhibition of cancer cell survival and metastasis.
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Minutentag, Iael Weissberg. "Identificação de alterações no transcritoma associadas à progressão metastática em adenocarcinoma de reto". Botucatu, 2019. http://hdl.handle.net/11449/180847.
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Orientador: Sandra Aparecida Drigo LindeResumo: Introdução: Apesar dos avanços no tratamento, cerca da metade dos pacientes com câncer de reto (CR) desenvolverá metástase à distância. No entanto, as vias biológicas envolvidas na progressão do câncer não são totalmente conhecidas. Neste estudo, investigamos os perfis moleculares e imunológicos em adenocarcinomas de reto relacionados à progressão metastática visando identificar biomarcadores moleculares e/ou alvos terapêuticos. Pacientes e Métodos: O transcritoma de 15 tecidos de CR metastático (M) e não-metastático (NM) pré-tratamento e de duas amostras de tecido de reto normais foi avaliado utilizando a plataforma Clariom D. Os genes foram considerados diferencialmente expressos quando a alteração de expressão era maior que 2 vezes e o valor de p <0,05 e detectados com o pacote limma. As funções moleculares e vias biológicas foram determinadas com a ferramenta Enricher. Os achados foram validados utilizando dados do TCGA e o perfil imunológico determinado com o algorótimo xCell. Resultados: A comparação entre os grupos M e NM revelou 52 genes diferencialmente expressos, sendo 27 regulados positivamente e 25 regulados negativamente. O gene ANLN foi detectado com o maior valor de fold change nos tumores metastáticos. Além disso, expressão aumentada de ANLN foi associada com menor sobrevida em pacientes com CR. A via do fator de crescimento endotelial vascular (VEGF) foi detectada como alterada nos tumores M. Validação dos resultados com dados do TCGA confirmou o gene ANLN co... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Introduction: Despite advances in treatment, about half of patients with rectal cancer (RC) will develop distant metastasis. However, the biological pathways underpinning the cancer progression are not fully understood. In this study, we sought to identify molecular and immunological profiles in rectal adenocarcinomas related to metastatic progression aiming to identify molecular biomarkers and/or therapeutic targets. Patients and Methods: Transcriptome analysis of 15 pre-treatment metastatic (M) and non-metastatic (NM) rectal cancer tissues and two normal rectal tissue samples was evaluated using Clariom D platform. Genes were considered differentially expressed when presenting 2-fold change and p<0.05 and were obtained with limma package . Molecular function and biological pathways with the Enricher package. Our findings were validated from the TCGA database and the immunological profile was determined using the xCell algorithm. Results: The comparison of M with NM groups revealed 52 differentially expressed genes, being 27 up-regulated and 25 down-regulated. ANLN gene was detected as the top gene upregulated in M tumours. Additionally, ANLN overexpression was associated with shorter survival in RC patients. Vascular endothelial growth factor (VEGF) pathway was detected as altered in M tumours. Cross-study validation with TCGA dataset confirmed ANLN gene as associated with M tumours. Furthermore, KIF14, XRCC2 and GPX3 genes, which have important carcinogenesis functions, we... (Complete abstract click electronic access below)
Mestre
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Tomasin, Rebeka 1985. "Estudo da evolução tumoral, caquexia e metástase em diferentes modelos animais in vivo e in vitro = Tumour growth, cachexia and metastasis in vivo and in vitro". [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317753.
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Orientador: Maria Cristina Cintra Gomes MarcondesTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-26T00:25:10Z (GMT). No. of bitstreams: 1 Tomasin_Rebeka_D.pdf: 4368331 bytes, checksum: 33a1f49902e0d1a423b1a4b7ebe757e9 (MD5) Previous issue date: 2014
Resumo: Câncer é um nome genérico para um grupo de mais de cem doenças que compartilham algumas características. Talvez a característica mais marcante das neoplasias malignas seja a rápida proliferação de células anormais para além de suas fronteiras usuais, invasão de tecidos adjacentes e finalmente dispersão para órgãos distantes. Anualmente, cerca de oito milhões de pessoas morrem devido ao câncer e outros doze milhões de novos casos são diagnosticados. Dentre os eventos associados à progressão neoplásica, destacam-se as metástases e a caquexia. Metástases são tumores em sítios secundários, sendo responsáveis por cerca de 90% do total de mortes por câncer. Já a caquexia, uma síndrome paraneoplásica, é caracterizada por extensa espoliação de gordura e massa magra, fadiga e alterações metabólicas, prejudicando a qualidade de vida e a sobrevida de cerca de 50-85% dos pacientes, dependendo do tipo de tumor. Com relação às terapias, o grande desafio ainda é combater o tumor sem prejudicar o hospedeiro, o que acredita-se ser possível através de terapias-alvo para genes específicos e/ou tratamentos coadjuvantes, incluindo aqueles que empregam suplementação e/ou drogas derivadas de produtos naturais, que muitas vezes tem menor efeito tóxico ao hospedeiro. Desse modo, este trabalho teve dois objetivos: (1) avaliar a ação da administração oral de Aloe vera e mel sobre o tecido tumoral e o hospedeiro portador de carcinosarcoma de Walker 256; e (2) identificação de genes supressores de metástase através de screen funcional in vivo empregando-se biblioteca de shRNA em modelo de câncer de mama triplo negativo. Em relação ao primeiro objetivo, os resultados sugerem que a associação entre Aloe vera e mel pode modular a proteólise e o estresse oxidativo de maneira diferencial preservando o hospedeiro em detrimento do tecido tumoral. Ainda, o tratamento com Aloe vera e mel parece ser capaz de diminuir a propensão metastática das células tumorais in vivo, através de aumento na expressão de caderina-E e redução na expressão de caderina-N, bem como inibição da angiogênese. Outros experimentos sugerem que os efeitos antitumorais observados in vivo estão, em parte, relacionados à ação imunomodulatória de alguns componentes da Aloe vera. Com relação ao segundo objetivo, foram identificados dezenas de candidatos a genes supressores de metástase. Dentre esses genes, que estão sendo validados, Mnat1, Snd1, Cul5, Gabbr1, Rorb, Adk, Ccnd3, Gdnf, Nr1d1, Ptprs e Ltah4 são os genes-candidatos de maior confiabilidade por cumprirem um ou mais dos seguintes requisitos: (a) diminuição significativa do nível de DNA e RNA em canceres de mama humanos agressivos, sendo assim relacionados à pior prognostico, (b) papel biológico sugestivo, (c) fenótipo marcante durante o screen ou ainda (d) decréscimo significativo na expressão em linhagens de câncer de mama mais agressivas
Abstract: Cancer is a generic name for a group of over a hundred diseases which share some features. The most remarkable feature in cancer disease is the fast proliferation of abnormal cells beyond their usual boundaries, invasion of surrounding tissues and finally spread to distant organs. Every year, cancer is responsible for over eight million deaths and twelve million new cases are diagnosed. Among all the events associated with the neoplastic progression, metastasis and cachexia are major issues. Metastases, which are tumours growing in secondary sites, account for 90% of all cancer deaths. Cachexia, a paraneoplastic syndrome, is characterized by severe fat and lean mass waste, fatigue and metabolic alterations, jeopardizing the quality of life and reducing the survival of about 50-85% of the cancer patients, depending on the tumour type. Regarding to the therapies, the biggest challenge is still fighting the tumour without harming the host, which is believed to be possible by targeted therapies to specific genes and/or adjuvant treatments, including supplementation and drugs derived from natural compounds, which usually have lower side effects in the host. Knowing these points, this work had two aims: (1) evaluate the effects of Aloe vera and honey in both tumour and host tissues in Walker 256-tumour bearing rats; and, (2) identification of metastasis suppressor genes using a functional in vivo shRNA screen in a triple negative breast cancer syngeneic model. Regarding to the first aim, the results suggested that the combination of Aloe vera and honey selectively modulate proteolysis and oxidative stress, damaging the tumour tissue while protected the host. Moreover, the Aloe vera and honey treatment apparently decreases the metastatic potential in vivo, by simultaneous increase in E-cadherin and decrease in N-cadherin expression, while decreased tumour vascularization. Finally, our results suggested the antitumoral effects observed in vivo are, at least partially, related to the immunomodulatory activity of some Aloe vera¿s compounds. Regarding to the second aim, dozens of putative metastasis suppressor genes were identified. High confidence candidates, which would be further analysed are Mnat1, Snd1, Cul5, Gabbr1, Rorb, Adk, Ccnd3, Gdnf, Nr1d1, Ptprs e Ltah4. Their selection was based on meeting the following requirements: (a) significant decrease at DNA or RNA level in highly aggressive human breast cancer carcinomas and thus, worse prognosis, (b) suggestive biological role, (c) occurrence of a remarkable phenotype during the screen, and (d) significant decrease in expression in more aggressive cancer cell lines
Doutorado
Biologia Celular
Doutora em Biologia Celular e Estrutural
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Mallet, Daniel Gordon. "Mathematical Modelling of the Role of Haptotaxis in Tumour Growth and Invasion". Queensland University of Technology, 2004. http://eprints.qut.edu.au/15941/.
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In this thesis, a number of mathematical models of haptotactic cell migration are developed. The modelling of haptotaxis is presented in two distinct parts - the first comprises an investigation of haptotaxis in pre-necrotic avascular tumours, while the second consists of the modelling of adhesion-mediated haptotactic cell migration within tissue, with particular attention paid to the biological appropriateness of the description of cell-extracellular matrix adhesion. A model is developed that describes the effects of passive and haptotactic migration on the cellular dynamics and growth of pre-necrotic avascular tumours. The model includes a description of the extracellular matrix and its effect on cell migration. Questions are posed as to which cell types act as a source of the extracellular matrix, and the model is used to simulate the possible effects of different matrix sources. Simulations in one-dimensional and spherically symmetric geometry are presented, displaying familiar results such as three-phase tumour growth and tumours comprising a rim of proliferating cells surrounding a non-proliferating region. Novel effects are also described such as cell population splitting and tumour shrinkage due to haptotaxis and appropriate extracellular matrix construction. The avascular tumour model is then extended to describe the internalisation of labelled cells and inert microspheres within multicell tumour spheroids. A novel model of adhesion-receptor mediated haptotactic cell migration is presented and specific applications of the model to tumour invasion processes are discussed. This model includes a more biologically realistic description of cell adhesion than has been considered in previous models of cell population haptotaxis. Through assumptions of fast kinetics, the model is simplified with the identification of relationships between the simplified model and previous models of haptotaxis. Further simpli.cations to the model are made and travelling wave solutions of the original model are then investigated. It is noted that the generic numerical solution routine NAG D03PCF is not always appropriate for the solution of the model, and can produce oscillatory and inaccurate solutions. For this reason, a control volume numerical solver with .ux limiting is developed to provide a better method of solving the cell migration models.
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Krishnan, Jaya. "The role of vascular endothelial growth factor receptor 3, and its ligands vascular endothelial growth factor C and vascular endothelial growth factor D in tumour metastasis and haematopoeisis". Thesis, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270576.
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