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1
Migliozzi, Matthew. "Investigating the anti-metastatic activity of semaphorin-3F." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12162.
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Thesis (M.A.)--Boston UniversityMetastasis is the leading cause of cancer-related deaths. Although there are many factors that promote and facilitate invasive tumors—angiogenesis and lymphangiogenesis provide a means by which invasive tumor cells can spread to distant organs. Semaphorins (SEMAs) were originally discovered for their role in axon guidance during development, however, SEMAs are now known for their anti-metastatic potential. SEMA3F is a 95-kDA protein that induces both anti-angiogenic and anti-lymphangiogenic effects by binding its receptor, Neuropilin 2 (NRP2). SEMA3F-induced signaling via NRP2/plexinA1 complexes inhibits RhoA and results in f-actin depolymerization. SEMA3F may also inhibit angiogenic and lymphangiogenic signaling by competitive inhibition of VEGF-C and VEGF-A binding to NRP2. In this study we have purified SEMA3F protein for use in several in vitro and in vivo studies. Endothelial cell spheroids were unable to produce sprouts during an in vitro spheroid sprouting assay when treated with SEMA3F. In addition, treatment with SEMA3F induced f-actin depolymerization and cell collapse during in vitro endothelial cell collapse assays. A375SM human melanoma cells were injected in nude mice and treated with SEMA3F purified protein. The resultant tumors showed decreased intra- and peri-tumoral lymphatic and vascular densities. Tumors in SEMA3F treated mice were also found to be more necrotic than those of the control. In a second study, slow release osmotic pumps containing SEMA3F protein were implanted in Nrp2+/LacZ heterozygous mice prior to the injection of B16F10 mouse melanoma cells. These mice exhibited decreased tumor volumes indicating SEMA3F may inhibit tumorigenesis. These results indicate the potential of SEMA3F as an anti-metastatic/anti-tumorigenic therapeutic.
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Rowling, Emily. "Pre-clinical evaluation of novel anti-metastatic targets." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/preclinical-evaluation-of-novel-antimetastatic-targets(caa9ab41-c054-4559-b575-3fd8974005a7).html.
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Background: Radiotherapy is used in the treatment of over 50% of cancer patients and bar surgery, is the most effective cancer intervention. However, in the clinic secondary malignancies have been observed following radiotherapy and in vitro increased cell migration and invasion have been seen following radiation. The Src/FAK signalling pathway is known to play an important role in the metastatic phenotype through its involvement in cell adhesion, migration and invasion and we have previously demonstrated that radiotherapy can activate this pathway along with the phosphoinositide 3-kinase (PI3K) pathway, also associated with tumour metastases and an aggressive phenotype. Using pharmacological inhibitors, we have investigated combination approaches to evaluate whether Src and PI3K targeting is beneficial in a radiotherapy context, especially focusing on metastatic phenotype. We wished to relate pathway activation to cellular phenotype and increase understanding of the metastatic cascade, the processes involved and the signalling pathways taking the lead. Method: Using thyroid carcinoma cell lines FTC133 and 8505c the effects of Src inhibition using AZD0530, FAK inhibition using FAKi and PI3K inhibition using GDC-0941 were studied. The effects of radiotherapy alone, and in combination with the above inhibitors, were also studied. In vitro MTT, apoptosis and clonogenic assays were used to assess cell proliferation and cell survival and scratch assays, cell adhesion and cell spreading assays were used to assess the effects of the drugs on metastatic characteristics. In vivo tumour growth, survival and ex vivo clonogenics were used to measure the effects of AZD0530 and GDC-0941. Western blotting, immunofluorescence and immunohistochemistry was used to observe the effects on pathway activation and protein localisation. Results: Src and FAK inhibition reduced metastatic characteristics of thyroid carcinoma cell lines in vitro such as cell spreading and migration. FAK inhibition showed a greater effect on cell survival by MTT, clonogenic and apoptosis. In the thyroid carcinoma cell lines radiotherapy enhanced the metastatic phenotype. This was seen by enhanced activation of the Src and PI3K pathways, increased migration and invasion in vitro and enhanced tumour metastasis in vivo. By combining Src inhibition with radiation a reduction in metastatic characteristics was observed and by combining PI3K inhibition with radiotherapy radiosensitivity could be improved. With the triple combination of Src and PI3K inhibition with radiotherapy a significant reduction in cell survival was demonstrated in vitro compared to radiation alone and either inhibitor combined with radiation, with a corresponding significant reduction in tumour growth being observed in vivo. With the combination of Src and PI3K inhibition significant reductions in metastatic characteristics were also observed both in vitro and in vivo seen by a reduction in cell migration and tumour metastasis. Finally combined inhibition of the Src and PI3K pathway reduced the radiation enhanced activation of several pathways in vivo including Src and PI3K.Conclusions: Together these results suggest that the Src and PI3K pathways play a role in radiation enhanced metastatic characteristics in thyroid carcinoma and through combined inhibition of the pathway the negative effects of radiation, enhanced migration and invasion, can be inhibited and the cells can be made more radiosensitive. Full characterisation of the pathways involved in radiation induced motility and radioresistance will provide further rationale for combination therapies and provide potential for application of these therapies in the clinic.
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Dyer, Hayder. "Development of and its peptide derivatives as potential anti-angiogenic and anti-metastatic." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534745.
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Menhofer, Magdalena H. "Characterization of the myxobacterial compound Chondramide as novel anti-angiogenic and anti-metastatic agent." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-167962.
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Sharma, Ankur. "Development of nanoparticulate drug delivery systems for anti-metastatic Ran GTPase therapeutics." Thesis, Ulster University, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725342.
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Sawan, Ali Sadek. "Tumour suppressor and anti-metastatic gene expression in human breast cancer : an immunohistochemical study." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239797.
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Schmitt, Florian [Verfasser], and Rainer [Akademischer Betreuer] Schobert. "New Microtubule-destabilizing Agents : Optimization of their Anti-angiogenic, Vascular-disruptive, and Anti-metastatic Activity / Florian Schmitt ; Betreuer: Rainer Schobert." Bayreuth : Universität Bayreuth, 2018. http://d-nb.info/1178526321/34.
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Menhofer, Magdalena H. [Verfasser], and Stefan [Akademischer Betreuer] Zahler. "Characterization of the myxobacterial compound Chondramide as novel anti-angiogenic and anti-metastatic agent / Magdalena H. Menhofer. Betreuer: Stefan Zahler." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1049647912/34.
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Kubisch, Rebekka. "Mechanism of cancer evading metronomic chemotherapy and action of Archazolid as an anti-metastatic drug." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-158654.
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In the present study the mechanisms leading to acquired chemoresistance, as well as new
treatment strategies implying the prevention evading of tumor cells were addressed.
Resistance formation is one of the major hurdles in cancer therapy. Metronomic antiangiogenic
treatment of xenografted prostate cancer tumors in mice with cyclophosphamide
(CPA) results in the appearance of resistant tumors. To investigate the complex molecular
changes occurring during resistance formation, a comprehensive gene expression analysis of
the resistant tumors in vivo was performed. A multitude of differentially expressed genes,
e.g. PAS domain containing protein 1 (PASD1), annexin A3 (ANXA3), neurotensin (NTS) or
plasminogen activator tissue (PLAT), were observed, when comparing resistant to in vivo
passaged tumor samples. Moreover, tumor cells from in vivo and in vitro conditions showed
a significant difference in target gene expression. For clarification of the mechanisms leading to the survival of tumor cells during maintained anti-angiogenic CPA therapy the
differentially expressed genes were assigned to functional pathways like: axon guidance, steroid biosynthesis and complement and coagulation cascades. As blood flow might play a crucial role during maintained anti-angiogenic therapy, further analysis was focused on the genes grouped in complement and coagulation cascades. pregulation of anti-coagulatory ANXA3 and PLAT and downregulation of SERPIN A1 and other SERPIN-family members was shown by qPCR analysis. In contrast coagulation factor F3 was upregulated, accompanied by the expression of an altered gene product. Taken together, a potential role of anticoagulation as a resistance mechanism for anti-angiogenic CPA therapy could be described.
Furthermore, the role of archazolid, a novel myxobacterial V-ATPase inhibitor in cancer
treatment and in particular its action on the secreted cellular proteome was evaluated. As
extracellular protein secretion may have an impact on invasive properties of tumor cells, the
changes of the secretome profile of highly migratory urinary bladder carcinoma cells upon
archazolid treatment were analyzed. An induced secretion of prometastatic lysosomal
proteins such as the cathepsin family was observed. Interestingly, intracellular cathepsin B
activity however strongly decreases and mature cathepsin B protein diminishes. It could be
shown that archazolid inhibits the mannose-6-phosphate receptor mediated trafficking of
procathepsin B from the trans-Golgi network to prelysosomal compartments, leading to an
impaired cathepsin B maturation process. This results in an unnatural secretion of the inactive proenzyme and a dramatic decrease in intracellular cathepsin B activity.
Importantly, also in vivo an archazolid induced reduction of cathepsin B activity was proven
and archazolid treatment resulted in a reduced formation of distant metastases in the lungs.
In summary these results indicate that archazolid in addition to its known anti-migratory
properties might exert an anti-metastatic effect by reducing the activity of pro metastatic
proteases like cathepsin B.
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Stoiber, Katharina [Verfasser], and Angelika [Akademischer Betreuer] Vollmar. "The myxobacterial acetyl-CoA carboxylase inhibitor Soraphen A as a novel anti-metastatic and anti-proliferative agent / Katharina Stoiber ; Betreuer: Angelika Vollmar." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1127528025/34.
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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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Jacquelot, Nicolas. "Impact du système immunitaire dans le mélanome métastatique : étude de son rôle pronostique et prédictif." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS142.
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Le mélanome métastatique reste un enjeu majeur de santé publique. Les avancées fulgurantes de ces dernières années ont permis d’améliorer la prise en charge thérapeutique, notamment avec l’arrivée des anticorps bloquant ou agonistiques ciblant les molécules de co-inhibition ou de co-stimulation. Cependant, certains patients sont réfractaires à tout traitement. Il est donc nécessaire de mettre en évidence l’importance de certains paramètres immunologiques permettant d’améliorer le suivi des patients de stade III à haut risque de récidive. De plus, il est primordial de découvrir des marqueurs prédictifs associés à la réponse à ces différents traitements immunomodulateurs. Nous avons identifié une association entre une fréquence élevée de CD45RA+CD4+ et de CD3-CD56- au sein des métastases ganglionnaires avec la survenue d’une récidive anticipée.Une forte expression de NKG2D à la surface des lymphocytes T CD8+, une faible proportion de Tregs ou une faible expression de PD-L1 à la surface des T circulants sont associées à une meilleure survie. Aussi, la mise en place d’un test in-vitro étudiant les réactivités fonctionnelles des lymphocytes infiltrant les tumeurs a permis de dégager l’importance de l’expression de CD95/Fas sur les T CD4+ circulants et de CD137/4-1BB sur les T CD8+ circulants dans la prédiction de la réponse à l’ipilimumab (anti-CTLA-4) et à la combinaison ipilimumab + nivolumab (anti-PD-1). Par ailleurs, le pattern d’expression des récepteurs de chimiokines à la surface des lymphocytes T périphériques permet de détecter les localisations métastatiques de mélanome. Cette étude a révélé également l’importance biologique de l’axe CCR9/CCL25 dans l’immunosurveillance naturelle anti-tumoraleMetastatic melanoma (MM) is an unmet medical need. The development of immune checkpoint blockers (ICB) improved patient’s clinical outcomes. However, some patients still do not respond to these therapies. To adress these issues, we must find some immunological parameters which predict the relapse of high risk resected stage III melanoma patients. Moreover, it is an urgent need to identify some predicting parameters to these ICB. In our studies, high frequencies of CD45RA+CD4+ and CD3-CD56- in metastatic lymph nodes are associated with a short relapse-free survival. Higher expression of NKG2D on CD8 T cells, low Tregs and low PD-L1 expression on circulating T cells are associated with a prolonged overall survival.Furthermore, we designed an in-vitro test to assess intratumor lymphocytes reactivities to ICB and cytokines (IL-2 and IFNα2a). Low expression of CD95/Fas on CD4+ circulating T cells and high expression of CD137/4-1BB on circulating CD8+ T cells are associated with the response to ipilimumab (anti-CTLA-4) and to the combination ipilimumab + nivolumab (anti-PD-1), respectively. In addition, the chemokine receptor pattern expressed at the surface of circulating lymphocytes could predict the metastatic spreading of melanoma. In this last study, we demonstrated the critical role of CCR9/CCL25 pathway in the natural anti-cancer immune surveillance
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Kubisch, Rebekka [Verfasser], and Ernst [Akademischer Betreuer] Wagner. "Mechanism of cancer evading metronomic chemotherapy and action of Archazolid as an anti-metastatic drug / Rebekka Kubisch. Betreuer: Ernst Wagner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1037311507/34.
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Vinayan, Anup. "Targeted anti-angiogenic therapy in metastatic renal cell carcinoma and methodological improvements in assessment of therapeutic response with imaging biomarkers." Thesis, University of Hertfordshire, 2018. http://hdl.handle.net/2299/20960.
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Background: Drugs targeting angiogenic pathway remain the mainstay of treatment for metastatic renal cell carcinoma (mRCC). Tyrosine Kinase Inhibitors (TKI) as Sunitinib, Pazopanib as single agents and humanised monoclonal antibody bevacizumab (Bev) in combination with Interferon- α2a (IFN) have established as the first-line therapy for mRCC. Despite improvements in treatment, there are multiple questions which remain unanswered. In the combination of Bev and IFN, the respective role of each drug and whether any additional anti-angiogenic activity is gained by adding IFN to Bev remains unknown. As the clinical benefit obtained with these cytostatic agents does not always correlate with the conventional response assessment techniques as RECIST, it is necessary to reconsider the methods by which we assess benefit from these therapies. In this thesis, I report three studies aiming to answer these questions. Methods: With the clinical trial reported here, I explore whether Bev induced changes in vascular parameters measured by Dynamic Contrast Enhanced MRI (DCE-MRI) is significantly enhanced by the addition of IFN. In a phase II, randomised, open labelled, multicentre trial, treatment naïve mRCC patients were randomised to receive Bev on its own or in combination with a low dose (3MU) or standard dose (9MU) IFN. DCE-MRI was used to assess the changes in vascularity with the primary endpoint being, changes in transfer coefficient (Ktrans) after six weeks of treatment. I also report two retrospective imaging-based studies, using contrast-enhanced CT scans, performed to improve the methodology of response assessment for these antiangiogenic therapeutics. Here I explore the use of a) combining changes in size and arterial phase contrast enhancement measured using CT scan and b) changes in CT texture as methods of therapeutic response assessment in mRCC patients treated with TKI. Results: With the phase 2 clinical trial, we faced significant difficulty in recruitment as a result of restrictions in access to treatment in NHS, other competing studies and restrictions proposed by the DCE-MRI inclusion criteria. With slow recruitment, an unplanned analysis was performed after 21 patients were recruited. Analysis of primary endpoint showed no trend in the difference between arms with no correlation found between change in Ktrans and addition of IFN to bevacizumab. Effect size analysis performed due to the small numbers recruited failed to show any significance in the observed difference in Ktrans. Change in Ktrans and Kep may identify a group of patients likely to have PFS > 6 months, but this observation needs to evaluation in a larger sample size. Measuring size and change in arterial phase enhancement retrospectively using CT, a new criterion "modified" Choi, which prerequisite a combination of a decrease in arterial phase density by 15% and a decrease in size by 10% for response was proposed. Response assessment was measured with RECIST, Choi and modified Choi individually in 20 evaluable patients retrospectively and clinical benefit compared with Kaplan-Meier statistics and Log-Rank test. Response assessment as defined by the modified Choi criteria successfully identified patients who received clinical benefit from the treatment. Time to progression (TTP) was 448 days for the partial response and 89 days for stable disease as per the new criteria which were statistically significant with a p-value of 0.002. The second retrospective analysis explored the textural changes in enhanced CT scan. Performed in collaboration with researchers from Brighton University who developed the software algorithm used to assess changes in entropy and uniformity, 87 metastases from 39 patients with mRCC were analysed at baseline and after two cycles of TKI treatment. Textural parameters and response assessment criteria were correlated with TTP. After two cycles of TKI, the decrease in tumour entropy was 3%-45%, and increase in uniformity was 5%-21%. At a threshold change of -2% with uniformity, on a coarse scale of 2.5, the textural change was able to separate responders from non-responders. With Kaplan-Meier analysis comparing all four criteria, the percentage change in uniformity was statistically more significant than for RECIST, Choi, and Modified Choi criteria. Cox regression analysis showed that texture uniformity was an independent predictor of time to progression. Discussion: With the studies reported here, I was able to demonstrate the importance of improving the methodology in assessment of therapeutic response to targeted anti-angiogenic therapy in metastatic renal cell carcinoma. Even though the clinical trial, terminated early due to slow recruitment, did not reach its primary endpoint, changes in other vascular parameters as Kep combined with changes Ktrans showed tendency towards identifying a group of patients who derived clinical benefit of >6months with these therapies. This is particularly exciting as given the vascular stabilisation effect proposed for bevacizumab, the effusion parameter Kep may be a better tool in assessing response rather than Ktrans and warrants further assessment in a larger cohort. Modified choi criterion and textural analysis are two important methodological improvements in response assessment of cytostatic anti-angiogenic therapy. In the analyses reported here, both techniques have shown superiority over RECIST in response assessment and differentiating mRCC patients who is likely to gain clinical benefit by TKI therapy. Validation of these criteria on a larger patient cohort is important. As these criterions are assessed on standard enhanced CT scans, incorporating these criteria, especially modified choi criterion, as part of standard CT assessment could be performed and will provide a real world validation. Retrospective assessment using larger cohort of patients from previous phase 3 trials or inclusion of these parameters prospectively in phase 3 trials would also help us in evaluating these modalities further.
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Frölich, Matthias Frank [Verfasser], and Andreas [Akademischer Betreuer] Jung. "The polymorphic DNA marker rs849142 predicts skin toxicity in anti-EGFR treatment of metastatic colorectal cancer / Matthias Frank Frölich ; Betreuer: Andreas Jung." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1170582745/34.
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Robador, Arteta Jose Ramon [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Crosstalk between melanoma cells and the blood-brain barrier: Impact on coagulation and brain metastasis to identify new anti-metastatic targets / Jose Ramon Robador Arteta ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1201551145/34.
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Sevrain, Charlotte. "Synthèse d'inhibiteurs du canal potassique SK3 - composés à visée antimétastatique et vectorisation d'ARN interférents." Phd thesis, Université de Bretagne occidentale - Brest, 2013. http://tel.archives-ouvertes.fr/tel-01065085.
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L'apparition de métastases est souvent le signe d'un mauvais pronostic vital pour les personnes atteintes d'un cancer. Ce processus de formation de métastase est un phénomène complexe dans lequel la migration cellulaire est un facteur clé.De récentes études ont montré que le canal SK3 (canal potassique de faible conductance dont l'activité dépend de la concentration cytosolique en calcium) était exprimé dans des cellules cancéreuses à fort pouvoir métastatique et leur conférait des capacités de migration accrues. Cette protéine constitue donc une nouvelle cible thérapeutique très intéressante pour agir sur la dissémination de cellules cancéreuses.Les objectifs de ces travaux de thèse ont permis de mettre en oeuvre deux stratégies visant à inhiber l'activité de ce canal potassique SK3.L'édelfosine, un glycérolipide à tête phosphocholine, a rapidement été reconnue comme étant un inhibiteur efficace de l'activité de ce canal. Cependant les effets secondaires induits par cette molécule ont conduit à rechercher des analogues moins toxiques et tout aussi efficaces. Des études structures-activité menées au sein du laboratoire ont permis de développer un nouveau glycérolipide à tête lactose, l'ohmline. Dans le but de compléter cette étude, nous avons réalisé la synthèse de glyco-glycérolipides et de glycophospho-glycérolipides et avons montré leur capacité à inhiber la protéine SK3 et à réduire la migration cellulaire SK3 dépendante.Une seconde stratégie vise à l'utilisation possible d'ARN interférents pour bloquer l'expression de la protéine SK3. Dans ce but, nous nous sommes intéressés à la synthèse et à l'incorporation, dans des formulations de lipides cationiques utilisés pour la transfection, de lipides neutres portant des motifs anisamides, ligands spécifiques des récepteurs sigma surexprimés dans des lignées cellulaires de tumeurs exprimant SK3. La synthèse de lipophosphoramides comportant un motif anisamide est présentée suivie de leur utilisation dans des expériences de transfection modèles (vectorisation d'ADN plasmidique) afin d'évaluer l'efficacité du ciblage engendré par le motif anisamide.
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Vinholes, Jeferson Jose Fonseca. "Effects of bone metastases on bone metabolism : implications for assessment of response to bisphosphonates and systemic anti-cancer therapy." Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264749.
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Nonomura, Yumi. "Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225479.
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Fregni, Giulia. "The role of human Natural Killer cells (NK) in anti-tumour immune responses." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T068/document.
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Les cellules Natural Killer (NK) sont des effecteurs cytotoxiques impliqués dans la réponse immune contre les infections et les tumeurs. Pendant ma thèse j’ai étudié la fonctionnalité des cellules NK humaines en réponse à des lignées cellulaires de carcinome rénal à cellules claires (RCC) et de mélanome métastatique, deux tumeurs immunogènes. Nos résultats montrent que certaines mutations de VHL augmentent la susceptibilité des lignées RCC à la lyse NK. La perte de fonction de VHL corrèle avec une expression membranaire diminuée des molécules HLA-I par les lignées RCC mutées pour VHL. Chez les patients atteints de mélanome métastatique de stade IV, nous avons décrit un phénotype particulier des NK sanguines (NKp46dim/NKG2Adim) qui leur confère une forte activité antitumorale. Après traitement des patients par chimiothérapie, la fonctionnalité NK était réduite et le phénotype modifié. Pour étudier les cellules NK infiltrant les mélanomes, nous avons mis au point des conditions expérimentales pour caractériser les cellules NK de ganglions métastatiques de patients de stade III. Nos résultats préliminaires montrent que, par rapport aux ganglions sains, les NK des ganglions métastatiques présentent un phénotype altéré et un potentiel fonctionnel diminué. Nos résultats suggèrent que d’une part l’immunogénicité dépendante des oncogènes et d’autre part les altérations NK induites par la tumeur et/ou par la chimiothérapie sont des facteurs importants à considérer dans le choix des protocoles d’immunothérapie basés sur les cellules NKNatural Killer cells are cytotoxic lymphocytes involved in the immune response against tumours and infections. We investigated the NK-mediated functions in response to clear-cell renal cell carcinoma (RCC) and metastatic melanoma, two human immunogenic tumours. We showed that certain VHL mutations increased RCC cell susceptibility to NK lysis. VHL loss of function correlated with lower expression levels of membrane HLA-I molecules on VHL-mutated RCC and a decreased triggering of inhibitory NK receptors compared to RCC with a functional VHL. In stage IV melanoma patients, we showed that blood NK cells displayed a unique NKp46dim/NKG2Adim phenotype and high lytic potential towards melanoma cells. Following chemotherapy, NK cell function was reduced and the phenotype modulated. To study melanoma-infiltrating NK cells, we have set up experimental conditions to characterise NK cells in metastatic LNs from stage III melanoma patients. Our preliminary data show that, compared to normal LNs, NK cells from metastatic LNs are altered. Our findings suggest that oncogenic-dependent immunogenicity, tumour-associated NK alterations and chemotherapy are important factors that must be taken into account in the choice of immunotherapeutic protocols based on NK cells
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Devaud, Christel. "Etude in vivo du potentiel anti-tumoral des lymphocytes Tγδ Vδ2 négatifs humains dans un modèle murin." Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21684/document.
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Les lymphocytes T ?d seraient des effecteurs essentiels dans la réponse immunitaire aux stress induits notamment par les infections et la tumorigénèse. Plusieurs arguments dont leur localisation intra-épithéliale mais aussi leurs capacités effectrices multiples et rapides les caractérisent comme des acteurs primordiaux dans l’immunité anti-tumorale. Mon projet de thèse consistait à examiner le potentiel anti-tumoral des lymphocytes T ?d humains, Vd2 négatifs (neg), dans un contexte in vivo, grâce à l’utilisation d’un modèle murin. Des études antérieures menées au laboratoire démontraient une expansion de lymphocytes T Vd2neg dans la circulation sanguine de transplantés rénaux développant une infection à cytomégalovirus (CMV). Des clones T Vd2neg, isolés de ces patients, présentaient une forte réactivité in vitro contre des cellules infectées par le CMV mais aussi contre des cellules tumorales notamment d’origine colique (comme la lignée HT29). Un ligand commun induit par l’infection à CMV et la transformation tumorale, reconnu par les clones T Vd2neg serait à l’origine de cette double réactivité. La première partie de mon projet s’est concentrée sur l’étude du potentiel anti-tumoral de ces clones T Vd2neg in vivo, qui comprenait leur capacité à atteindre des cellules tumorales d’origines coliques (HT29) et à les lyser. Dans un modèle de xénogreffe dans des souris immunodéficientes, nous avons démontré que les clones TVd2neg, injectés dans le péritoine (i.p) pouvaient retarder la croissance de tumeurs solides HT29 sous-cutanées. D’après nos résultats, cette inhibition du développement tumoral proviendrait d’une action précoce et spécifique des cellules T Vd2neg et impliquerait le récepteur à chimiokine CCR3. Nos données suggèrent donc que des lymphocytes T Vd2neg, réactifs contre le CMV, pourraient migrer in vivo jusqu’au site d’injection des cellules tumorales et inhiber la croissance de la tumeur probablement grâce à leur acticité cytolytique. La deuxième partie de mon projet de thèse proposait d’approfondir l’étude du rôle des lymphocytes T Vd2neg contre les tumeurs coliques. Ainsi nous avons testé, in vivo, l’implication de lymphocytes T Vd1+ humains, une population représentative des épithéliums intestinaux, dans le cancer métastatique colorectal (CMC). Nous avons développé un modèle d’implantation orthotopique de cellules tumorales HT29 dans des souris immunodéficientes, qui mime le développement du CMC chez l’homme. Des tumeurs primaires intra-caecales et des métastases pulmonaires et hépatiques se développent chez les souris. De plus, nous avons pu suivre leur croissance grâce à l’introduction de la luciférase dans les HT29 et à une technique d’imagerie in vivo en bioluminescence. Nos résultats montrent qu’un traitement continu des souris par des injections de lignée T Vd1+ en i.p inhibe le développement des tumeurs primaires et retarde l’apparition des métastases à distance. Ces données soutiennent l’implication des lymphocytes T Vd2neg dans le contrôle des CMC. De façon intéressante, elles mettent en avant une implication anti-métastatique des cellules T Vd2neg. L’ensemble de nos travaux souligne le rôle des cellules T Vd2neg dans la réponse immunitaire contre les cancers colorectaux et étaye leur potentiel d’action lors de la progression des tumeurs vers des métastases, ouvrant ainsi des perspectives pour l’utilisation de ces cellules dans les thérapies des CMCGamma delta (?d) T lymphocytes contribute to host immune competence uniquely especially during stress immune responses to infections and tumors. Because ?d T cells colonize epithelial surfaces, where they can exert rapid and pleiotropic effector functions, they are critical protagonists in anti-cancer response. During my Phd project we explored the anti-tumor potential of Vd2 negatives (neg) ?d T lymphocytes, in vivo using a mouse xenograft tumor model. A few years ago, studies in our laboratory showed an increase of peripheral blood Vd2neg ?d T lymphocytes in allograft recipients infected by cytomegalovirus (CMV). Interestingly, Vd2neg ?d T clones isolated from these patients showed a cytotoxic activity against CMV infected fibroblast in vitro. Moreover, they were able to kill colon cancer cells (HT29) in vitro, in contrast to normal epithelial cells. Cancer cell- as well as CMV infected cell- killing involved T cell receptor (TCR) engagement, independently of major histocompatibility complex (CMH) recognition, probably with a common ligand. The first part of my Phd project was undertaken to evaluate the in vivo tumor reactivity of anti-CMV Vd2neg clones, including their ability to inhibit tumor growth as well as their migratory potential toward colon cancer cells. In immunodeficient mice, we showed that systemic intraperitoneal (i.p) injections with human Vd2neg clones inhibited the growth of HT29 hypodermal tumors xenografts. Furthermore, our results demonstrated that Vd2neg T cells had an early and specific anti-tumor effect, and that such activity could be hampered in vivo using an anti-CCR3 antibody. Our study suggest that Vd2neg T cells with an anti-viral potential are able to reach a tumor site in vivo, and inhibit tumoral growth exercising a cytolytic activity. The second part of my Phd project proposed to get further insights on the role of Vd2neg T cells in the immune surveillance against colon cancer. To this aim, we tested, the involvement of human Vd1+ T lymphocytes, a substantial fraction of T cells in intestinal epithelia, in limiting tumor spread in vivo, using a mouse model of colorectal carcinoma (CRC). We sat up a physiological mouse model of CRC by orthotopic microinjection of HT29 colon cell, which mimics the natural history of human CRC. Indeed, primary colic tumors and pulmonary and hepatic distant metastases grew in mice. Furthermore, bioluminescence imaging was used to follow the outcome of luciferase expressing cancer cells. We showed that systemic treatment with human Vd1+ T lymphocytes could inhibit the growth of intracaecal HT29 tumors and led a substantial reduction of distant metastases. Our results are the first arguing for a crucial role of ?d T cells against CRC, specially in preventing the dissemination of colon cancer cells. Taken together, our results underline the role of of ?d T cells in theimmune response against colorectal cancer. Our findings put forward Vd2neg T cells as attractive candidates for novel anti-tumor immunotherapy protocols
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Chao, Wei, and 趙葳. "The anti–inflammatory and anti–cancer metastatic studies of 3,4-dihydroxybenzalacetone." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/xnyssr.
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Moreira, Ana Rita Sampaio. "Anti-PD-1 Immunotherapy in Advanced Metastatic Melanoma." Master's thesis, 2019. http://hdl.handle.net/10316/88302.
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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de FarmáciaA imunoterapia com inibidores do checkpoint imunitário, como os fármacos anti-PD-1, é uma área em crescente desenvolvimento devido à sua eficácia terapêutica e às vantagens no tratamento do melanoma metastático avançado. De facto, a imunoterapia tem sido alvo de vários estudos recentes em diversos tipos de cancro, nomeadamente no melanoma, uma ameaça crescente a nível mundial. As taxas de incidência do melanoma estão a aumentar: em 2018 na Europa, foi considerado o quinto e oitavo cancro com maior número de novos casos estimados entre mulheres e homens, respetivamente, constituindo uma ameaça à saúde em todo o mundo. A contribuir para a incidência crescente deste cancro estão as alterações climáticas, em particular o aquecimento global do século passado, que veio aumentar a tendência para passar mais tempo ao ar livre e, consequentemente, a exposição à luz solar e radiação ultravioleta. De entre os fatores de risco mais relevantes para o melanoma, o aumento da radiação ultravioleta devido à destruição da camada do ozono constitui um dos principais responsáveis pelo número crescente de novos casos. Os agentes anti-PD-1, tais como o Nivolumab e o Pembrolizumab, permitem um tratamento mais eficaz, aumentando a duração das respostas à terapia e prolongando a sobrevida do paciente. No entanto, estudos recentes de segurança e tolerabilidade afirmaram que, embora estes fármacos apresentem menos efeitos adversos e toxicidade, podem ser responsáveis por eventos adversos específicos mediados por autoimunidade. No geral, a imunoterapia com agentes anti-PD-1 representa uma área altamente promissora no tratamento de alguns tipos de cancro, tal como o melanoma.
Immunotherapy with immune checkpoint inhibitors, such as anti-PD-1 drugs, is an area in increasing development for its efficacy and advantages in the treatment of advanced metastatic melanoma. In fact, immunotherapy has been the target of several and recent studies in different types of cancer, namely in melanoma, a globally growing threat. The incident rates for melanoma are increasing: in 2018 in Europe, it was the fifth and eighth cancer with more estimated new cases among females and males, respectively, posing a major health threat worldwide. Contributing to the increasing incidence of this cancer is climate change, particularly global warming of the past century, which has increased the tendency to spend more time outdoors and, consequently, the exposure to sunlight and ultraviolet radiation. Among the most relevant risk factors for melanoma, the increase in ultraviolet radiation due to ozone layer depletion is one of the main factors responsible for the incidence of new cases. Anti-PD-1 agents like Nivolumab and Pembrolizumab allow a more effective treatment, increasing the duration of the responses to the therapy and prolonging the survival of the patient. However, recent studies about safety and tolerability have stated that, although these drugs present less adverse effects and toxicity, those may lead to specific autoimmune-mediated adverse events. Overall, immunotherapy with anti-PD-1 agents represents a highly promising area in the treatment of some types of cancer such as melanoma.
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Chang, Chi-Wu, and 張集武. "Anti-metastatic Activity of Epigallocatechingallate in Human Uveal Melanoma Cells." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/14955297848362536440.
Full textAbstract:
博士中山醫學大學
醫學研究所
103
Epigallocatechingallate (EGCG), the major polyphenol in green tea, has been shown to downregulate matrix metalloproteinase-2 (MMP-2) in many cancer cell types. However, the effect of EGCG on the migration and expression of MMP-2 of uveal melanoma cells has not been reported. We studied this effect and relevant signaling pathways in a human uveal melanoma cell line M17. MTT study revealed that EGCG did not affect the cell viability of M17 cells up to 100 μM. Wound-healing assay showed that EGCG significantly reduced the migration ability of cells in a dose-dependent manner from 20 to 100 μM. Gelatin zymography showed that secreted MMP-2 activity was inhibited dose-dependently by EGCG, whereas the MMP-2 expression at protein and mRNA levels were not affected as determined by Western blot and RT-PCR. EGCG significantly increased the expressions of MMP-2 endogenous inhibitors (TIMP-2 and RECK) in M17 cells. Western blot analysis of MAPK signal pathways showed that EGCG significantly decreased phosphorylated ERK1/2 levels, but not p38 and JNK levels, in melanoma cells. ERK1/2 inhibitors also reduced the migration and activity of MMP-2 in M17 cells. The present study suggested EGCG at nontoxic levels could inhibit migration of melanoma cells via downregulation of activities of secreted MMP-2 through the inhibition of the ERK1/2 phosphorylation. Therefore, EGCG may be a promising agent to be explored for the prevention of metastasis of uveal melanoma.
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Huang, Yi-Ting, and 黃依婷. "Anti-metastatic activity of Antrodia camphoratain human breast cancer cells." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/62728621889203479957.
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碩士中國醫藥大學
營養學系碩士班
97
Antrodia camphorata (AC) is well- known in Tiawan as a traditional Chinese medicine. It has been shown to exhibit anti-inflammatory, antioxidation and anticancer properties. According to the previous data, AC-10 induced apoptosis in human breast cancer cells (MDA-MB-231). Breast cancer is a common cancer in women. In this study, we investigate anti-metastatic activity of AC-10. Degradation of extracellular matrix is crucial for malignant tumor development and metastasis. Treatment with AC-10 is effective in suppressing cancer cell migration and invasion. These effects were associated with a reduced protein expression of MMP-9, MMP-2, uPA, uPAR and VEGF together with an enhanced expression of TIMP-1, TIMP-2 and PAI-1. AC-10 decreased activities of MMP-9 and uPA, but not effect of MMP-2. Further studies showed that AC-10 regulated MMP-9 production via MAPK signaling pathway, as evidenced by the findings that AC-10 inhibited the phosphorylation of ERK1/2, P38 and JNK1/2. Additionally, pretreatment of MDA-MB-231 cancer cells with 10 and 30 μM of U0126, a specific ERK inhibitor, and SB203850, a specific P38 inhibitor and SP600125, a specific JNK inhibitr resulted in a reduced activities of MMP-9. And AC-10 inhibited NF-kB transcriptional activity. These results suggested that AC-10 could reduce the invasion and migration via MAPK and NF-kB signaling pathways in MDA-MB-231 human breast cancer cells, and may use AC-10 as an anti-invasive agent in the prevention and treatment of breast cancer.
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Fu, You-Sheng, and 傅宥勝. "Assessment of Anti-metastatic Potential of Fungal Compounds in Cell Model." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/26853128001200196855.
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碩士東海大學
食品科學系
104
Breast cancer is the most prevalent female tumor which causes 460,000 annual deaths. Most of the fatality does not come from breast cancer in its primary site, but rather from the metastasis malignancy. Bone is the major metastasis site of breast cancer,and bone metastasis, which arises mainly by osteoclasts,accounts for over 30% among all secondary tumor cases of breast cancer. Antrodiacinnamomea and Hericiumerinaceusare rich sources of several classes of bioactive compounds. NB-AB, an antroquinonol derivative, was purified from Antrodiacinnamomea,andNB-EA, an erinacine purified from Hericiumerinaceus,both possess anticancer activities and were employed in this study. NB-EA and NB-AB significantly inhibited the differentiation of Raw 264.7 to osteoclast, possibly through MAPK pathway, either in normal differentiation media or in medium supplemented with conditioned media from the culture media of breast cancer cells. Furthermore,NB-EA and NB-ABalso suppressed matrix metalloproteinase 9 (MMP 9) activity and the migration of MDA-MB-231 cells, which might be related to the inactivation of Erk and JNK.In this study, we have demonstrated the anti-metastatic potential and underlying mechanisms of NB-EA and NB-AB in an in vitro cell model.
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Chang, Chong-keng, and 張宗鏗. "Functional domains of RECK protein that mediate its anti-metastatic activity." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/pj8967.
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碩士國立中山大學
生物醫學科學研究所
95
RECK(reversion-inducing cysteine-rich protein with Kazal motifs) encodes a membrane-anchored glycoprotein of about 110 kDa with multiple epidermal growth factor-like repeat, four N-glycosylation sites and three Kazal-like domains. RECK functions as a tumor suppressor gene which may inhibit the release and activation of MMP-2 and MMP-9. Previous studies indicated that RECK-mediated suppression of tumor cell invasion is regulated by glycosylation of RECK in human tumor cell lines. However, the anti-cancer action of other functional domains of RECK have not been studied. In the study, We investigated the effects of different functional domains of RECK protein on the invasion of tumor cell lines and on the activation of matrix metalloproteinase. We constructed bacterial expression vector and secretory mammalian expression vector which could produce full-length, Kazal-like motifs 1~3, Kazal-like motifs 2~3 and CKM5 polypeptides. Recombinant proteins were purified and used for treatment of human lung cancer cell lines. We found that treatment of K23 and RECK recombinant proteins resulted in suppression of invasive ability and MMP activity. Moreover,K23 and RECK proteins were found to inhibit the secretion of matrix metallo- protease-9 (MMP-9). K23 also formed a complex with MMP-9 and inhibited its proteolytic activity noncompetitively. Experimental metastasis assay revealed that there were fewer tumor nodule formation in the lungs injected with A549 cells stably expressing K23 than control vector. Thus, these findings indicate that the K23 domain of RECK functions as an inhibitor of tumor invasion and metastasis.
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Mabasa, Rixile Forever. "Evaluation of ricinus communis semi-purified extracts' potential as anti-metastatic agents using metastatic breast cancer (MCF-7) cancer cells." Thesis, 2017. http://hdl.handle.net/10386/1974.
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Thesis (MSc. (Biochemistry)) -- University of Limpopo, 2017The malignancy of cancer cells is responsible for the high death rate in patients diagnosed with metastatic cancers. Medicinal plants represent a reservoir of bioactive compounds that can be useful in the management of cancer. In this study, semi-purified extracts of Ricinus communis leaves were evaluated for their potential to serve as an anti-metastatic agent by using in vitro assays that tested their effects on a number of processes related to metastasis. The exhaustive extraction procedure was employed to generate the crude acetone extracts of R. communis leaves. The crude extracts were then subjected to solvent-solvent fractionation to yield six semi-purified extracts (n-butanol, Chloroform, Ethyl-acetate, n-hexane, Methanol + H2O and H2O). Thin layer chromatography (TLC) was done to determine the phytochemical composition of the semi-purified extracts as well as their antioxidant potential. Non-polar fractions showed to have a diverse mixture of phytochemicals with, however, very limited antioxidant activity. On the other hand, polar fractions showed to have phytochemical compounds with strong antioxidant potential. TLC guided the selection of n-hexane and n-butanol as fractions of great phytochemical diversity and antioxidant activity, respectively. The selected fractions were then assessed for their effect on the viability of normal fibroblasts (BUD-8) and breast (MCF-7) cancer cells using the MTT assay. The n-butanol fraction was shown to significantly decrease the viability of BUD-8 at concentrations above 200 µg/ml. The n-hexane fraction, however, showed to significantly affect the viability of the cells even at lower concentrations. On the positive side, the reduced viability of BUD-8 cells after exposure to both fractions was followed by an increase in cell proliferation after 24 hours suggesting that the extracts exhibited cytostatic rather than cytotoxic effects. Treatment of MCF-7 cells with different concentrations (100-500 µg/ml) of the fractions showed a dose- and time-dependant decrease in cell viability. Hoechst stain also confirmed the non-toxicity of the fractions to MCF-7 cells at 100 and 200 µg/ml. The fractions also showed to possess free radical scavenging activities by reducing the amount of intracellular ROS as demonstrated by the DCFH-DA fluorescent assay. Fluorescence intensity was strongly reduced in cells treated with the fractions and elevated in H2O2-treated and untreated MCF-7 cells. The effect of the fractions on metastasis was assessed by determining their effects on MCF-7 cell migration, attachment and invasiveness using wound healing assay, adhesion assay and Boyden chamber invasion assay, respectively. The wound healing assay showed the fractions to have strong inhibitory activities on the migration of MCF-7 cells. The xii ability of the cells to attach to cell culture treated plates was also greatly reduced in cells treated with the fractions. The n-butanol fraction was demonstrated to exhibit a time- and dose-dependent inhibition on MCF-7 cell invasion by reducing the cells’ capability to penetrate through the matrigel matrix to the bottom of the porous membrane. Gelatin-zymography was done to assess the effect of the n-butanol fraction on activity of MMP-2 and MMP-9. The fraction showed to completely inhibit the gelatinolytic activity of MMP-2 and no band corresponding to the molecular weight of MMP-9 was observed, suggesting that MCF-7 cells produce undetectable levels of MMP-9. The n-butanol fraction further showed to down-regulate the expression of a range of proteins such as MMP-9, uPA, VEGF, TGF-β1 implicated in metastasis and angiogenesis determined using the human angiogenesis antibody array kit. This study demonstrated that the fractions of R. communis extracts have the ability to inhibit major processes of the metastatic cascade by down-regulating the expression of proteins relevant to metastasis. Thus, the fractions can be considered as potential anti-metastatic agents functional in the regulation and/or treatment of malignant of cancers.
National Research Foundation (NRF)
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Shiao, Cheng-Kai, and 蕭承愷. "The Anti-metastatic Effect of Glabridin in NCI-H460 Lung Cancer Cells." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/52687014841490844293.
Full textAbstract:
碩士中華醫事科技大學
生物科技系暨生物醫學研究所
103
Glabridin, isolated from Glycyrrhiza uralensis Linn., is a naturally occurring flavonoids in licorice. Some reports demonstrated that glabridin had various anti-carcinogenic properties. First, the result demonstrated glabridin could inhibit the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay, Boyden chamber invasion/migration assay, and wound healing assay. Data also showed glabridin could inhibit the enzyme activities and messenger RNA levels of matrix metalloproteinase-2/9 (MMP-2/MMP-9) and u-PA by gelatin zymography assay、casein-plasminogen assay and RT-PCR assay.
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Xia, Ci-Chan, and 夏慈禪. "The Anti-metastatic Effects of Inoscavin A on Lung Cancer Cell Lines." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/62qze4.
Full textAbstract:
碩士中國醫藥大學
中國藥學暨中藥資源學系碩士班
102
Lung cancer is the leading cause of cancer mortality, and metastasis is a primary cause of cancer death. Inoscavin A is a new compound isolated from a medicinal mushroom Inonotus sanghuang. In this study, we first observed that inoscavin A exerted a dose-dependent inhibitory effect on adhesion, migration, and invasion of the highly metastatic A549 and LLC lung cancer cell lines in the absence of cytotoxicity. These effects were associated with a decreased protein expression of MMP-2 and MMP-9 together with an increased expression of TIMP-1 and PAI-1. Inoscavin A also inhibited the enzymatic activity level of uPA and MMP-9. Moreover, we demonstrated that treatment with inoscavin A reduced phosphorylation of FAK. Further studies showed that inoscavin A repressed the activation of MAPK and PI3K/Akt/mTOR signaling pathway, as evidenced by inhibited the phosphorylation of ERK1/2, JNK1/2, p38, PI3K, AKT, mTOR, p70S6K and 4EBP1. In addition, the treatment of A549 cells with inhibitor specific for PI3K /AKT (LY294002), ERK1/2 (PD98059), JNK1/2 (SP600125), p38(SB203580) and mTOR (rapamycin) decreased the expression of MMP-2 and MMP-9. Taken together, these results suggested that inoscavin A inhibits cell adhesion, migration and invasion by reducing uPA, MMP-2 and MMP-9 activation through the suppression of the FAK, mainly mediated by inhibition of MAPK and PI3K/Akt/mTOR signaling pathways. Additionally, induction of TIMP-1 and PAI-1 expression is at least partially involved in the inhibition of MMP-9 and uPA activation by inoscavin A. These findings identify inoscavin A as a promising novel therapeutic agent for lung cancer.
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Fu, Chih-Wei, and 傅志偉. "Nature-inspired anti-cancer and anti-metastatic agents: Design, synthesis and biological validation in vitro and in vivo." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/4m29z2.
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博士國立中央大學
化學學系
104
Topic Ⅰ：Synthesis of core structure of one, two and many nitrogen atoms containing heterocycle with four indole derivatives as anti-cancer agents Our previous developed tetraindole compounds, found that SK228 has a promising anti-cancer activity at the nanomolar range (J. Med. Chem. 2012, 55, 1583-1592). However, SK228 showed poor solubility and was toxic to the mice, our attempt is to improve these drawbacks in this study. During optimization of reaction conditions, we synthesized a series of new tetraindole entities (compounds 2-17) containing a pyridine core at either 2, 5 position or 2, 6 position under I2/EtOH and CAN/ACN in reflux conditions, respectively. The results show that a potent candidate, 14 (FCW81) with a core structure of pyridine at 2,5 positions, has an optimum antiproliferative activity against human triple negative breast cancer (MDA-MB-231) cell, with similar anticancer potency compared to that of SK228. FCW81 induces DNA damage, G2/M arrest and apoptosis. Furthermore, FCW81 also significantly inhibited tumor growth in a xenograft human breast cancer mice model with apparent reduction of side effects. In summary, FCW81 has the potential to serve as an anticancer agent for the treatment of human breast cancers, especially in triple negative breast cancer. A series of new tetraindole entities containing many nitrogen atoms heterocycle core was synthesized. Compound 24 had anticancer activity against triple negative breast cancer MDA-MB-231 and colon cancer SW480 cell lines with IC50 value 0.37 and 1.08 μM, respectively. The relative biological and animal studies are under progress. Topic Ⅱ：Synthesis of lithocholic acid derivatives with different types of N3 linkers as sialyltransferase inhibitors and anti-metastatic agents Recently, aberrant sialylation is found to be related to cancer metastasis. Our lab developed some sialyltransferase inhibitors, such as litho-O-Asp, AL10 and KS034, but they possessed moderate anti-migration inhibition in cellular level. This study focuses on developing the lithocholic acid derivatives to enhance the anti-migration activity with significant inhibition and selectivity of sialyltransferase. The first generation of lithocholic acid derivatives was synthesized, 15 compounds (Ⅱ-2aA-2eA, Ⅱ-3aB-3eB and Ⅱ-4aC-4eC), containing the NBD, p-nitrobenzoyl or coumarin moieties with different length of azide linkers. We observed that lithocholic acid derivatives with NBD moiety have similar sialyltranferase inhibition in comparison to those of AL10 and KS034. Significantly, FCW34 and FCW66 had 2- or 3- folds anti-migration activity more than those of AL10 and KS034. Surprisingly, FCW34 meaningfully suppressed tumor growth and metastasis in a xenograft human breast cancer mice model. In summary, FCW34 had the potential to serve as an anti-metastasis agent for the treatment of human breast cancer with the unique inhibitory selectivity toward α(2,3)-N and α(2,6)-N sialyltransferases. The second generation of lithocholic acid derivatives focuses on modification of lithocholic acid at C3 position, such as amino acid side chain and aromatic entities. The results showed that FCW393 and FCW551 had similar sialyltranferase inhibition in comparison to FCW34. Surprisingly, those FCW393 and FCW551 had 4- or 8- folds anti-migration activity more than that of FCW34. And FCW393 could effectively inhibited tumor growth and metastasis in a xenograft human breast cancer mice model. In summary, FCW393 display the potential to serve as an anti-metastasis agent for the treatment of human breast cancer with the unique inhibitory selectivity toward α(2,6)-N sialyltransferase.
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Chen, Yang-Yu, and 陳姎愉. "Anti-metastatic activity of Rheum palmatum L. extracts in human oral cancer cells." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/80955195691202903870.
Full textAbstract:
碩士中山醫學大學
口腔醫學研究所
103
The incidence and mortality of oral cancer in Taiwan have been increased during the last decade, which could be mainly resulted from the difficulty in treatment related to metastasis. Rheum palmatum L, a traditional Chinese herbal medicine, has well effect of curing laxative; simulate the circulation of blood, stops bleeding, antitumor and anti-bacterial. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidase, are able to degrade the extracellular matrix which play critical roles in angiogenesis, cell growth, invasion and metastasis of cancer cells. Several studies demonstrated that the components of Rheum palmatum L induce apotosis in different human cancer cell lines as well as inhibit the ability of invasion and migration in human colorectal cancer cells. However, the effect of Rheum palmatum L on metastasis of oral cancer has yet to be fully clarified. Here, we investigated the anti-invasive activity of Rheum palmatum L on a human oral cancer cell line (SCC-9) in vitro and its underlying mechanisms. This study demonstrates that Rheum palmatum L extract. has no cytotoxicity at the range of 0~20 μg/mL in SCC-9 oral cancer cell line. According to western blot and zymography assays, an increase of Rheum palmatum L concentration effectively reduced the secretion and the protein expression of MMP-2. Furthermore, the expression of MMP-2 mRNA is substantially reduced by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR analysis . On the other hand, Rheum palmatum L extract. could inhibit the ability of invasion and migration in SCC-9 cell line via extracellular signal-regulated kinase (ERK) 1/2 signal pathway；moreover, could exert a considerable synergistic inhibition effect by treatment with the inhibitor of ERK U0126 and PD98059. Taken together, Rheum palmatum L extract. may provide a novel anti-metastasis agent in the treatment of oral cancer.
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Huang, Sheng-Kai, and 黃聖凱. "Anti-metastatic effect of acridone alkaloids from twigs of Severinia buxifolia in NSCLC." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/j7eah7.
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碩士高雄醫學大學
天然藥物研究所碩士班
106
Lung cancer is one of the most common cancer worldwide which is by far the leading cause of cancer death because of its rapid metastasis and poor prognosis. The incidence of lung cancer about 80% diagnosed with non-small lung cancer (NSCLC). Therefore, developing novel anti-cancer drugs to treat with NSCLC is indispensable. Serverinia buxifolia, a common folk medicine used in Southeast Asia, which displays many pharmacological activities such as anti-malaria, anti-rheumatism, and anti-nociceptive. Acridone alkaloids [atalaphyllidine (Sbs-A), atalaphyllinine (Sbs-B), N-methylseverifoline (Sbs-E), N-methylatalaphylline (Sbs-I), 5-hydroxy-N-methylseverifoline (Sbs-J), glycocitrine (Sbs-K), severifoline (Sbs-S)] isolated from S. buxifolia were examined for their anti-cancer activity in the A549 NSCLC cell line. By cytotoxicity and cell metastatic tests, we found Sbs-A, Sbs-B, and Sbs-J has a better inhibitory effect. By reporter and Western blot assays, we found Sbs-A at 10 μM concentration could significantly inhibit HIF-1α transactive activity and protein levels. Sbs-A effect on HIF-1α mRNA and protein stability have been ruled out, and we found Sbs-A inhibit protein synthesis via inhibition of 5’UTR of HIF-1α, which controls the translation efficiency of HIF-1α. Sbs-A inhibited HIF-1α protein synthesis and downregulated its target genes twist, c-Myc, Sox2, and CA9 protein expression might involve in acridone alkaloids inhibit lung cancer metastasis. Our study suggests that Sbs-A might have development potential to inhibit lung cancer metastasis via inhibition of HIF-1α protein synthesis.
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Yen, Chih-Yung, and 嚴智勇. "The anti-metastatic effects of Ellagic acid in Human lung carcinoma A549 cells." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/10515450764665479813.
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碩士中國醫藥大學
中國藥學暨中藥資源學系碩士班
99
Metastasis in cancer patients is often fatal cancer caused by one of the reasons. Metastasis of cancer cells involve multiple processes and various cytophysiological changes, including changing adhesion capability between cells and extracellular matrix (ECM) and damaging intercellular interaction. Degradation of the ECM of the basement membrane was caused by proteinases such as matrix metalloproteinases (MMPs). Among the MMPs family, MMP-2 and MMP-9 play a critical role in tumor invasion and metastasis, therefore, the inhibition of cell migration or invasion mediated by MMP-2 and MMP-9 could be a preventive way of cancer metastasis. Ellagic acid (EA), an antioxidant, is a phenolic compound presenting in fruits (raspberries, blueberries, strawberries) and walnuts. However, the mechanism of EA on the anti-metastasis is still unclear. In this study, EA was used to evaluate growth inhibition, the inhibitory effects of EA on the growth of tumor cells were determined by MTT assay. EA showed an inhibit ory effect on cell migration and invasion by transwell chamber assay. we found that EA can reduce the MMP-2 and urokinase-plasminogen activator (u-PA) activity by zymography and Western-blot. EA also induced the endogenous inhibitor, tissue inhibitors of metalloproteinases (TIMPs) by Western-blot. These findings suggest that EA has potential as an antimetastatic agent.
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Chen, Yu-Ling, and 陳玉聆. "Effects on Cell Growth and Expression of Anti-metastatic Gene Drg 1 by Apigenin and Butyrate in Human Metastatic Colorectal Carcinoma Cell LoVo." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/14760677857910965608.
Full textAbstract:
碩士實踐大學
食品營養研究所
92
Apigenin, a common plant flavonoid, has been reported as a chemopreventive agent possesses anti-oxidative and anti-carcinogenic properties. Butyrate, a short-chain fatty acid produced by microbial fermentation of fiber in the colonic lumen, has been shown to modulate proliferation and differentiation of colon cancer cell line. Drg 1 was first identified upon induction of differentiation in colon carcinoma cells. Recent studies hypothesize that drg 1 might act as a metastatic suppressor gene in colon carcinoma cell line. Based on above hypothesis, the aim of our study was to determine the effect of apigenin and butyrate on growth and metastatic ability of colorectal carcinoma cells. LoVo cells treated with various concentration of apigenin or butyrate were conducted. MTT assay was used to evaluate the growth inhibitory activity of drugs treated. mRNA expression patterns were examined by RT-PCR. Dose- and time-dependent inhibition of growth was observed in colon carcinoma cells treated with either apigenin or butyrate. Expression of drg 1 was up-regulated upon 20 M of apigenin or 2 mM of butyrate treatment . Especially, co-treatment with apigenin and butyrate further enhanced expression of drg 1 in LoVo cells. Our results suggest that inhibition of growth and metastaic ability of LoVo cells treated with apigenin or butyrate may be partially mediated via regulation of the expression of drg 1.
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Cheng-Chi, Yang, and 楊呈琦. "To study the anti-metastatic effects of clarithromycin on non-small lung cancer cells." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/84901574780516346840.
Full textAbstract:
碩士國立中興大學
生命科學系
93
Abstract Clarithromycin is a new 14-member macrolide antibiotic, it has been used as anti-inflammatory drug to treat diffuse panbronchiolitis and to restraining Helicobacter Pylori since 1990. Clinically mainly in long term-low dose; in 1997, Yasunami indicated that clarithromycin is a potent angiogenesis inhibitor for anti-tumor activity, the research later indicated clarithromycin can suppress tumor-associated growth factor expression by tumor, such as TNF-α and IL-6, result in suppressed tumor growth and metastasis, but its detail mechanism is unclear. And in our study, clarithromycin can not obviously suppress the proliferation of non-small-cell lung cancer (NSCLC) cell line, CL1-5, but remarkably decreases the invasion ability of CL1-5. Metastasis means that the malignant cancer cell moves from original position to the second place. Metastasis contains several important stages; including cell migration, invasion, and angiogenesis. Tumor macrophage infiltrating can promote metastasis, it is a normal immune response, but in tumor infiltrating process macrophages can secrete many kinds of inflammatory factors, such as TNF-α, that increases the IL-8 expression and angiogenesis of tumor, makes malignly to tumor and negatively to patient prognosis. In this study, we used the CL1-5/macrophage co-culture system to promote angiogenesis and metastasis of tumor, and then treated with clarithromycin. Furthermore, microarray analysis is used to find out the effect of clarithromycin on interaction between macrophage-CL1-5. And confirm the difference of gene expression probably by quantitative real-time RT-PCR, we confirmed several genes by quantitative real-time RT-PCR, the genes that could be increased by macrophage co-cultured and decreased by clarithromycin include PlGF, DnaJ, and JunB, and other genes that could be decreased by macrophage co-cultured and increased by clarithromycin include profilin 2, INF-PK, and archain-1. PlGF is a VEGF family protein, can promote angiogenesis; JunB is a subunit of AP-1 that is an important transcription increasing expression factor of IL-8; DnaJ and profilin 2 may be involved in cell migration. Both are highly expressed in cell with strongly invasion and migration activity. In addition, previous study indicated that clarithromycin has inhibitor activity on IL-8 produced by inflammatory cells. IL-8 is an important angiogenesis factor, and it was highly expressed under macrophage co-culture condition, suggest that clarithromycin suppress tumor angiogenesis and metastasis through its inhibitor activity of IL-8. The results of quantitative real-time RT-PCR indicated that IL-8 mRNA expression in CL1-5 was reduced under treatment with clarithromycin, and the IL-8 mRNA expression in macrophage co-culture induced CL1-5 is less reduced under treatment with clarithromycin; furthermore, the result of luciferase reporter gene assay indicated that IL-8 promoter activity is upregulated by macrophage co-culture and down-regulated by treatment with clarithromycin. It is reporter that IL-8 is regulated by NF-κB pathway, when the inhibitor of NF-κB, IκBα was phosphorylated, NF-κB would translocate into nucleus and bind to IL-8 promoter. In this study, western blotting was used to analyze NF-κB translocation, the result indicated that NF-κB translocation activity is upregulated by macrophage co-culture and down-regulated by treatment with clarithromycin, but in macrophage co-culture induced CL1-5 NF-κB translocation activity had not significantly suppressed under treatment with clarithromycin, and the phosphorylated IκBα analyzed by western blotting had the same trend. We think that clarithromycin inhibits the secretion of IL-8 through other pathway, such as AP-1 pathway. In microarray analysis, we could modified the gene variation and putatively influenced signal transduction pathway under treatment with clarithromycin; clarithromycin inhibits tumor angiogenesis and metastasis also through NF-κB pathway, and the NF-κB pathway is generally regulated by TNF-α and IL-1α, whether is clarithromycin begins to influence or there is further characterization of pathway identified will be in progress in the future.
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Shieh, Sing-Ying, and 謝幸英. "Expression of the anti metastatic nm23-H1 gene is regulated by the thyroid hormone." Thesis, 1998. http://ndltd.ncl.edu.tw/handle/04685389385994335481.
Full textAbstract:
碩士長庚大學
基礎醫學研究所
86
Abstract Tumor metastasis remains the leading cause of death for patients with 11 malignant neoplasms. Its processes are inversely related to the level of Nm23 protein expression in human breast carcinoma, melanoma and hepatoma. Thyroid hormones (T3/T4) regulate growth, development, differentiation and metabolic processes. Recent studies indicate that these effects are mediated by the interaction of T3 with the ligand-dependent transcription factors-thyroid hormone receptors (TRs). In addition, the gene regulating activity of TRs depends not only on T3 but also on the specific DNA sequences in the promoter regions of T3 target genes, known as the thyroid hormone response elements (TREs). To understand the effect of tumor metastasis by T3, I studied the regulation of Nm23-H1 protein. T3 inhibited the expression of Nm23-H1 protein in epidermal carcinoma, choriocarcinoma, breast carcinoma, and hepatoma cell lines by using Western blot analysis. Isogenic HepG2 cell lines that overexpress either wild-type TRa1 (HepG2-Wt) or mutant TRa1 (HepG2-Mt) as well as parental HepG2 (HepG2-P) cells were used to study the expression of Nm23-H1 protein. Its expression was inversely correlated with that of TRa1 but not with mutant TRa1. This suggests that the expression of nm23-H1 is regulated by T3. In addition, T3 enhanced the invasive ability about 4-folds in the HepG2-Wt but not in the HepG2- Mt or HepG2-P. It suggests that a negative TRE is possibly in the 5'- flanking region of the nm23-H1 gene. A serious of 5' deletions was generated to analysis the function of the promoter. Three regions, -584/-521, -471/-437, and -392/-337 possibly contained negative TREs. The retnoid X receptor (RXR) and N-CoR were enhanced the repression ability exerted by T3 in two regions -597/-302 and -471/-437. In addition, the repression ability required DNA binding domain (aa 102 to 170) of TRb1 in two fragments, - 584/-302 and -471/-437. Finally, the TRa1 and TRb1 bound to the -392/-333 region, however, only TRb1 bound to the -489/-433 fragment by electrophoresis mobility shift assay. In summary, the expression of Nm23-H1 protein was inhibited by the binding of liganded-TR to the -471/-437 and -392/-337 promoter regions, and thus enhanced the invasive ability of cells.
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Tsai, Pei-Chien, and 蔡沛倩. "Anti-metastatic mechanism of ovatodiolide and cardiotoxin III in MDA-MB-231 breast cancer cells." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/69877866081639953068.
Full textAbstract:
碩士高雄醫學大學
醫藥暨應用化學研究所
100
One: Cancer metastasis is a primary cause of cancer death. Ovatodiolide, a bioactive cembrane-type diterpenoid isolated from Anisomeles indica (L.) Kuntze (Labiatae), has been shown to inhibit the growth and proliferation of cancer cells. However, the anti-metastatic effects of ovatodiolide on highly metastatic human breast cancer MDA-MB-231 cells remain unclear. In this study, we first noted that ovatodiolide inhibited MDA-MB-231 cell migration and invasion by wound-healing assay and Boyden chamber assay. Western blot, gelatin zymography and reversed transcription-PCR analysis showed that ovatodiolide significantly and selectively suppressed the expression, activation, and mRNA of matrix metalloproteinase-9 (MMP-9) in a concentration-dependent manner. Ovatodiolide significantly decreased the nuclear level of nuclear factor kappaB (NF-κB), increased inhibitor of kappaBα (IκBα) through preventing phosphorylation of upstream signal IκB kinase (IKK). Pretreatment with a specific NF-κB inhibitor (PDTC) and an IκB protease inhibitor (TPCK) also reduced MMP-9 activity, cell migration and cell invasion. Moreover, ovatodiolide can suppress activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase and Akt, while it did not affect phosphorylation of extracellular signal regulating kinases (ERK)1/2. Additionally, the treatment of inhibitors specific for PI3K (wortmannin), JNK (SP600125) or p38 MAPK (SB203580) to MDA-MB-231 cells could result in a reduced activation of MMP-9, concomitantly with a marked inhibition on cell migration and invasion. Taken together, these results demonstrate that ovatodiolide inhibits the metastatic ability of MDA-MB-231 cells by reducing MMP-9 activity through suppressing JNK, p38 MAPK and PI3K/Akt signaling pathways and inhibiting NF-κB activity. These results are the first to reveal the function of ovatodiolide in tumor metastasis and its underlying molecular mechanism, thus suggesting ovatodiolide to be a promising antimetastatic agent. Two: Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis in various tumors. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CTX III on cell metastasis. CTX III inhibited the EGF-induced activation of matrix metalloproteinase-9 (MMP-9), and further suppressed cell invasion and migration without obvious cellular cytotoxicity. CTX III suppressed EGF-induced nuclear factor- kappaB (NF-κB) nuclear translocation and also abrogated the EGF-induced phosphorylation of EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular regulated kinase (ERK)1/2. In addition, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an up-stream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by EGF. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of ERK1/2 and PI3K/Akt, suggesting that ERK1/2 and PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CTX III inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt, ERK1/2, and NF-κB signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CTX III as a potent anti-metastatic agent in MDA-MB-231 cells.
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Omar, Aadilah. "Application of anti-LRP/LR specific antibodies on neoplastic cell lines for metastatic cancer treatment." Thesis, 2012. http://hdl.handle.net/10539/11891.
Full textAbstract:
The 37kDa/67kDa laminin receptor (LRP/LR) is thought to play a major role in the
adhesion to laminin and consequently invasion resulting in the metastasis of tumor
cells. This receptor is reported to be over-expressed in several neoplastic cell lines
and is believed to increase tumor aggressiveness. This research aims at determining
whether the application of anti-LRP/LR specific antibody (IgG1-iS18) on neoplastic
cell lines would result in a decrease in invasion and adhesion. All neoplastic cell lines
had significantly increased cell surface LRP/LR levels compared to NIH/3T3 cells,
with the most notable increase seen in SW480 cells (10.98%). Due to a positive
correlation between the cell surface LRP/LR levels and invasion potential we propose
that an increased LRP/LR level correlates to an increased ability to invade. A
significantly decreased adhesion potential was noted in all neoplastic cell lines except
the non-invasive MCF-7 cell line, upon application of IgG1-iS18, 21% decrease in
HT-1080 cells, 14% in HeLa, 20% in LNCaP, 48% and 74% in A549 and SW480
cells, respectively. Incubation with the anti-LRP/LR antibody IgG1-iS18 resulted in a
significant reduction of the invasive potential of HT-1080 (44%), A549 (33%), HeLa
(69%), SW480 (91%) and LNCaP cells (38%). Furthermore, a high Pearson’s
correlation coefficient between adhesion potential and invasive potential was seen,
confirming that adhesion is indeed a pre-requisite for invasion. The significant
reduction in invasion and adhesion of HT-1080, A549, HeLa, SW480 and LNCaP
cells upon application of the IgG1-iS18 antibody suggests that this macromolecule
might act as a promising therapeutic tool for the treatment of various metastatic
cancer types.
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Duarte, Raquel Sofia Cruz 1992. "Role of PLCy1 in the resistance mechanism to Anti-EGFR therapy in metastatic colorectal cancer." Master's thesis, 2017. http://hdl.handle.net/10451/33228.
Full textAbstract:
Tese de Mestrado, Oncobiologia, Universidade de Lisboa, Faculdade de Medicina, 2017Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Cetuximab (Cetx) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), which was recently approved for the treatment of metastatic colorectal cancer (mCRC). However, Cetx effectiveness is only about 20% due to the existence of multiple resistance mechanisms downstream of EGFR. KRAS mutations are recognized as a predictor of resistance to anti-EGFR treatment, nevertheless, 54% of wild-type KRAS patients still do not respond to this therapy. Therefore, there is a clear need for new biomarkers capable of accurately predict response to therapy. PLCγ1 is activated by direct binding and phosphorylation by EGFR and has been implicated in oncogenic signaling downstream of this receptor. PLCγ1 catalyzes the hydrolysis of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), involved in diverse cellular processes, such as cell proliferation, differentiation and motility. In this thesis, we investigate the contribution of PLCγ1 for the resistance mechanism to Cetuximab, in an in vitro and a clinical approach. Overall, our results show that PLCγ1 is highly expressed in Cetuximab-resistant colon cancer cell lines. PLCγ1 knockdown in resistant cell lines (CACO-2 and HT-29) was able to sensitize them to Cetx. Furthermore, PLCγ1 overexpression in the most sensitive cell line (SW48) confers increased Cetuximab resistance. Additionally, SW48 cell line that was continuously exposed to Cetx for five months shows a slightly increase in PLCγ1 expression when compared with parental control. Finally, immunohistochemical analysis of PLCγ1 in human CRC samples shows an association between increased PLCγ1 expression and poor progression-free survival of patients under Cetx treatment. Taking together, our results show a correlation between PLCγ1 expression levels and Cetuximab resistance, suggesting that PLCγ1 could be a predictive biomarker of EGFR resistance, helping selecting patients more likely to respond to this therapy.
O cancro colo-rectal é o terceiro cancro mais incidente a nível mundial, com a quarta maior taxa de mortalidade. A elevada mortalidade associada a este tipo de cancro é essencialmente devida à acrescida dificuldade no tratamento da doença metastática. Nos últimos anos, o desenvolvimento e utilização de novos fármacos, como os anticorpos monoclonais dirigidos contra o recetor do fator de crescimento epidérmico (EGFR), têm aumentado a eficácia das terapêuticas convencionais em tumores metastáticos. No entanto, existe ainda um grande número de doentes que não responde a estas terapêuticas ou que acaba por desenvolver resistência às mesmas, após um período inicial de tratamento. Dado este cenário, torna-se cada vez mais urgente a procura de novos biomarcadores, mais sensíveis e específicos, que possam indicar com maior clareza quais os pacientes que beneficiam destas terapêuticas. O EGFR está implicado no desenvolvimento e progressão de múltiplos tumores, nomeadamente nos casos de cancro colo-rectal. A ativação deste recetor conduz à ativação de várias vias de sinalização celulares implicadas no controlo da sobrevivência celular, progressão do ciclo celular, angiogénese, migração e invasão/metastização. O Cetuximab (Cetx) é um anticorpo monoclonal direcionado especificamente contra o EGFR, que se liga à sua porção extracelular com uma afinidade superior à dos seus ligandos endógenos. Desta forma, o Cetx bloqueia a ligação dos ligandos ao EGFR, impedindo a ativação do recetor, o que se traduz na inibição das vias intracelulares e dos processos por elas regulados. Além disso, o Cetx induz a internalização do EGFR levando à diminuição dos recetores disponíveis na superfície celular. Finalmente, o Cetx permite ainda o reconhecimento das células tumorais pelas células efetoras imunitárias citotóxicas, desencadeando o processo de citotoxicidade mediada por células dependentes de anticorpo. Infelizmente, apenas um pequeno número de pacientes responde eficazmente a esta terapêutica. Mutações ativadoras no gene KRAS, que codifica para uma proteína a jusante na via de sinalização do EGFR, estão já identificadas como fortes indicadores de resistência ao Cetuximab, uma vez que ativam constitutivamente as vias intracelulares, de forma independente do recetor. Ainda assim, 54% dos doentes que não apresentam mutações neste gene desenvolvem resistência (intrínseca ou adquirida) a esta terapêutica. A ativação constitutiva de outros efetores intracelulares, tais como BRAF, PI3K e PLCγ, pode também constituir um mecanismo de resistência à terapia anti-EGFR, sendo que a PLCγ nunca foi anteriormente estudada neste contexto. Existem duas isoformas da PLCγ, a PLCγ1 e a PLCγ2, sendo que a primeira é amplamente expressa, estando presente em quase todos os tecidos, e a segunda é expressa essencialmente em células do sistema imune. Ambas as PLCγ são diretamente ativadas por recetores do tipo tirosina cinase, dos quais fazem parte o EGFR, e, quando ativas, são responsáveis pela conversão do fosfolípido de membrana fosfatidilinositol 4,5-bifosfato (PIP2) em dois mensageiros secundários, o diacilglicerol (DAG) e o inositol trifosfato (IP3). Estes mensageiros secundários são essenciais para a regulação de múltiplos processos celulares como proliferação, diferenciação, migração e angiogénese. Diversos estudos demonstraram que a PLCγ1 possui um papel importante no desenvolvimento e progressão tumoral, nomeadamente ao nível da migração celular. Neste sentido, o knockdown da expressão da PLCγ1 numa linha celular de carcinoma mamário (MDA-MB-231) inibiu o desenvolvimento de metástases pulmonares em modelo animal de ratinho. Por outro lado, a sobre-expressão de PLCγ1 foi observada em diversos tipos de tumores, incluindo colo-rectais, quando comparados com tecidos normais adjacentes, e foi associada a um pior prognostico e a um risco aumentado de desenvolvimento de metástases à distancia. Para além deste facto, mutações no gene PLCG1 foram recentemente associadas com o desenvolvimento de angiossarcomas e linfomas cutâneos de células T. Finalmente, apesar de pouco estudada no contexto de resistência à terapêutica, mutações no gene da PLCG2 (isoforma maioritariamente expressa em células hematopoiéticas) foram associadas ao mecanismo de resistência ao Ibrutinib, um inibidor da tirosina cinase de Bruton, no tratamento de leucemia linfocítica crónica. Tendo em conta o papel da PLCγ1 na regulação de processos celulares como a migração, invasão e progressão tumoral, e a sua estreita relação com o recetor EGFR, o principal objetivo deste trabalho é explorar a hipótese do envolvimento da PLCγ1 no mecanismo de resistência à terapêutica anti-EGFR. Para testar esta hipótese começou-se por avaliar a resposta de um painel de cinco linhas celulares de cancro colo-rectal (todas KRAS wild-type) ao tratamento com Cetuximab e correlacionar essa resposta com o nível de expressão da PLCγ1. Os nossos resultados mostram que os níveis de expressão da PLCγ1 estão aumentados nas linhas celulares mais resistentes ao Cetuximab, quando comparados com os níveis de expressão das linhas mais sensíveis. De seguida, foi realizada a sobre--expressão da PLCγ1 na linha mais sensível (SW48), enquanto que na linha mais resistente (CACO-2) foi realizado o knockdown da expressão da PLCγ1. O Knockdown da expressão da PLCγ1 na linha CACO-2 permitiu sensibilizá-la de forma significativa (p=0,0289) ao tratamento com Cetx. Por outro lado, a sobre-expressão da PLCγ1 na linha SW48 fez com que esta aumentasse a resistência ao tratamento com Cetuximab. A sobre-expressão de um mutante PLCγ1 constitutivamente ativo na sua função lipase (ΔSA), não mostrou diferenças na resposta ao Cetuximab quando comparada com o controlo. Estes resultados indicam um possível mecanismo de resistência independente da função lipase da PLCγ1. Simultaneamente, uma linha celular com sensibilidade intermedia ao Cetx (HT-29) mas com mutação ativadora do gene BRAF, foi também selecionada para se realizar o knockdown da expressão da PLCγ1. Mais uma vez, o knockdown da expressão da PLCγ1 permitiu também aumentar a sensibilidade das células ao Cetx (p=0,0222), mesmo na presença de uma mutação ativadora no gene do BRAF (V600E). Por fim, a linha SW48 foi também continuamente exposta a elevadas concentrações de Cetuximab por um período de cinco meses, a fim de avaliar um possível envolvimento da PLCγ1 na resistência adquirida ao Cetx. Neste caso, foi possível ver um aumento de expressão da PLCγ1, comparativamente com as células parentais não tratadas. De uma forma geral, os nossos resultados sugerem que o aumento da expressão desta proteína poderá estar associado não só a um mecanismo de resistência inato ao tratamento, mas também a um mecanismo adaptativo de resistência ao Cetx. Por fim, a expressão da PLCγ1 foi avaliada num grupo retrospetivo de amostras (n=25) de casos de carcinoma colo-rectal, provenientes do serviço de anatomia patológica do Hospital de Santa Maria. Estas amostras correspondem a amostras de tumores primários de doentes tratados com Cetuximab em contexto da doença metastática. A expressão da PLCγ1 foi avaliada por imunohistoquímica e os resultados foram analisados por um médico patologista, que realizou um score de intensidades de marcação. A elevada expressão da PLCγ1 foi significativamente associada (p=0,0460) a uma diminuição no tempo de sobrevivência livre de progressão, em doentes sob tratamento com Cetx. Observou-se também uma tendência entre maiores níveis de expressão de PLCγ1 e uma diminuição da sobrevivência global, sem, no entanto, existir significância estatística. Em conclusão, os resultados obtidos neste trabalho sugerem uma associação negativa entre os níveis de expressão da PLCγ1 e a resposta ao Cetuximab. Esta relação foi observada nos estudos in vitro e na avaliação de amostras de pacientes. O aumento da expressão da PLCγ1 pode também estar associado ao desenvolvimento de resistência adquirida ao Cetuximab. Demonstrar o envolvimento da PLCγ1 em mecanismos de resistência ao Cetuximab, e possivelmente a outras terapias anti-EGFR, poderá ter um grande impacto clínico no tratamento do cancro colo-rectal metastático, não só como potencial biomarcador preditivo de resposta à terapêutica, mas também como um possível novo alvo terapêutico.
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wang, Hsiao-Chieh, and 王曉潔. "In vitro anti-metastatic effects of hispolon on liver cancer cell line, SK-Hep-1 cell." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/08352912796774236036.
Full textAbstract:
碩士中國醫藥大學
中國藥學研究所
96
Metastasis is one of the major causes of cancer-associated mortality, and a large number of cancerous cells have the ability to secret matrix metalloproteinases (MMPs). Among them, MMP 2 and MMP 9, an extracellular matrix enzyme, is a key enzyme for cancerous cells to invade distant tissue from in-situ tissue. Many literatures showed that Phellinus linteus (PI) inhibited the cancer proliferation and metastasis. Hispolon was a highly antioxidant compound in PI and it possessed the effect of apoptosis on human epidermoid KB cells. However, the mechanism is still unclear on metastasis. In this study, we examined the effects of hispolon on invasion、migration、adhesion、MMP activity and protein expression on highly metastastic hepatocarcinoma. The effect of Hispolon was evalvated on invasion、migration and adhesion in SK-Hep-1 by Transwell chamber. The extracellular MMP 2, 9 activity and intracellular protein expression was used by gelatin zymography and Western blotting. We found that hispolon inhibited cell migration and invasion about 49% and 56% at 5 μg/ml, and inhibited about 63% and 62% at 10 μg/ml. Hispolon could not inhibit cell adhesion, significantly. Also, we found that Hispolon inhibited MMP 2, 9 activities after 24hr in a dose-dependent manner. The results demonstrated that the antimetastatic mechanisms of hispolon might be inhibit of MMP-2, 9 activities and enhance the TIMP 1, 2 expressions and inhibit of FAK and p-FAK expressions.
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Su, Po-Jung, and 蘇柏榮. "Comparison of efficacy between second line anti-androgen drugs for metastatic castration-resistent prostate cancer patients." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/mq9vtm.
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Li, Kai-chun, and 李凱君. "Blocking the Interaction between Pericellular Fibronectin Matrix and DPP IV as a Potential Anti-metastatic Strategy." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/2s85a7.
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TSAI, YI-TA, and 蔡易達. "The molecular mechanisms of Sorafenib and GW5074 anti-cancer combination therapy in metastatic renal cell carcinoma." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/51617077893198827872.
Full textAbstract:
博士國防醫學院
醫學科學研究所
105
Mitochondria are the powerhouses of cells and targets of cancer therapeutics. The unique role of Raf proteins in the mitochondria provides a strong rationale to target mitochondrial Raf proteins. However, Raf inhibitor monotherapy induces serine 338 phosphorylation of C-Raf (pC-RafS338) subsequent to mitochondrial translocation and impedes therapy. Currently, no selective mitochondrial targeted cancer therapeutics is available. This study identified a unique combination therapy of Raf inhibitors, sorafenib and GW5074, and targeted mitochondrial function instead of the canonical Raf signalling pathway, irrespective of upstream Ras and Raf mutation status. The GW5074 was bound to C-Raf and induced C-Raf conformation change, which enhanced sorafenib binding. This drug-target interaction facilitated the S308 phosphorylation of DAPK (pDAPKS308) translocation from the mitochondria to the cytoplasm, causing mitochondrial dysfunction and ROS generation. ROS facilitated PP2A dephosphorylation of DAPK at serine 308, disassembled the C-Raf and DAPK complex in the cytoplasm, and induced profound cancer cells necroptosis.
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Li, Cho-Han, and 李卓涵. "Studies on Curcumin and its analogs on anti-metastatic activities of human fibrosarcoma cells (HT-1080)." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/00651349802485252607.
Full textAbstract:
碩士臺北醫學大學
生藥學研究所
97
Curcumin, a yellowish pigment existed in turmeric plant has been shown to exhibit numerous biological properties, such as anti-inflammation, antioxidation, anti-invasion, and antimetastatic activity. Chemical modifications of curcumin have been studied intensively in an attempt to find an analog with similar but enhanced biological activities of curcumin. In literatures, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) played important roles in cancer cell invasion by hydrolysing extracellular matrix (ECM). In this study, curcumin and 23 novel analogs were used to screen for inhibition of matrix metalloproteinase-9 (MMP-9) activities, protein and gene expression of highly metastatic HT-1080 human fibrosarcoma cells to explore the mechanisms of action. All tested compounds, except analog 24 and analog 31 at concentration of 2.5 μM showed no cytotoxic activities at 5 μM. The analog 2 (six methoxy substitutes in phenyl groups) and analog 7 (three hydroxyl and one methoxyl substitutes in phenyl groups) showed higher MMP-9 inhibitory activities than curcumin did at 5 μM in gelatin zymography analysis. We comparatively examined the influence of analog 2, 7, 24 (three hydroxyl substitutes in phenyl groups), and 31(two hydroxyl and two methoxyl substitutes in phenyl groups) on the expression of MMP-9 of HT-1080 cells at concentration of 2.5 μM. Analog 2, 7, 24 and 31 suppressed the gene expression of MMP-9 as the results of RT-PCR assay and Western blot assay, and decreased their corresponding activities in HT-1080 cells revealed by gelatin zymography assay, MMP-9 activity ELISA and fibrin zymography assay which resulted in inhibition of HT-1080 cell invasion and migration differentially. All in all, analog 2 and 7 showed higher anti-metastatic activities than analog 24 and analog 31 did. Heme oxygenase 1(HO-1), a stress-responsive enzyme, which was found to correlate with production of reactive oxygen species (ROS), suggesting a causative relationship on MMP inhibition. Therefore, the effect of curcumin and analog 2, 7, 24 and 31 on HO-1 protein expression were also studied. Interestingly, exposure to curcumin, analog 2 and 31 treatment maximally induce HO-1 protein expression in HT-1080 cells, however, analog 7 and 24 were less apparently. These data suggested that the inhibitory effects of curcumin and analog 2, 7, 24 and 31 on MMP-9 gene expression and uPA activity was closely related to tumor invasion and migration in vitro. Furthermore, analog 2 showed highly MMP-9 inhibitory activity which possibly involved mechanisms related to its ability to induce HO-1 to suppress PMA-induced ROS, which can activate MMP-9 gene expression. In summary, these data demonstrated that analog 2, 7, 24 and 31 show higher anti-metastasis potency than curcumin by the differentially down-regulation of MMP-9 and uPA.
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Lin, Jen-Jie, and 林振頡. "Investigation of anti-tumor and anti-metastatic activties of 11-epi-sinulariolide acetate from the cultured soft coral Sinularia flexibilis on hepatoma cells." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/9b3885.
Full textAbstract:
博士國立屏東科技大學
獸醫學系所
105
The natural compounds from soft corals have been increasingly used for antitumor and other therapeutic purposes. 11-epi-sinulariolide acetate (terms: 11-epi-SA in this paper), an active compound isolated from the cultured soft coral Sinularia flexibilis was examined for the potential anti-tumor effect on four hepatocellular carcinoma cells (HCC). In the present study, HA22T cells showed more cytotoxic effect upon 11-epi-SA treatment as investigation the cell viability using MTT assay. Protein profiling of 11-epi-SA-treated HA22T cells revealed profound protein alterations related to stress response and protein synthesis and folding, suggesting that mitochondria and endoplasmic reticulum (ER) play a role in 11-epi-SA -initiated apoptosis. 11-epi-SA leads to the activation of caspase-dependent apoptotic cell death suggesting that mitochondrial-related apoptosis genes were involved in the cell programmed death. The unfolded protein response (UPR) signaling pathways-related proteins are also activated upon 11-epi-SA treatment and these changes were accompanied by increased expression of GADD153/CHOP, a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. However, the anti-migration and invasion effects and molecular mechanism of 11-epi-SA on hepatocellular carcinoma remain poorly understood. In this study, first discovered that 11-epi-SA provided a concentration-dependent inhibitory effect on the migration of human hepatocellular carcinoma HA22T cells by trans-well migration and invasion assays. Furthermore, after treatment with 11-epi-SA for 24 hours, there was suppressed the protein levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA) in HA22T cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and metalloproteinase-2 (TIMP-2) were increased in a concentration-dependent manner. Further investigation revealed that 11-epi-SA suppressed the phosphorylation of ERK1/2 and p38MAPK. 11-epi-SA also suppressed the expression of the phosphorylation of FAK/PI3K/AKT/mTOR pathways. In the present study, we investigated the anti-migration and invasion effects and underlying mechanisms of 11-epi-SA in HA22T cells.
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"Investigation of the anti-tumor and anti-metastasis effects of selected Chinese medicines in metastatic breast cancer, and the combined use with zoledronate." 2013. http://library.cuhk.edu.hk/record=b5884437.
Full textAbstract:
Luo, Kewang.Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 278-305).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
48
Chin-Shiu, Huang. "The anti-metastatic efficacy and mechanisms of lycopene in hepatocarcinoma cells both in vitro and in vivo." 2006. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0005-1608200622092200.
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Hsieh, Shu-Ching, and 謝淑卿. "Study the anti-metastatic molecular mechanism of a combination of metformin and sorafenib in human hepatocellular carcinoma." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/83913697460484992491.
Full textAbstract:
博士中山醫學大學
醫學研究所
103
Metformin has been shown to exert anti-cancer activities in several cancer cells and animal models. However, the molecular mechanisms of its anti-metastatic activities remain poorly understood and warrant further investigation. The aims of this study were to evaluate the ability of Metformin to inhibit the migration and invasion of hepatocellular carcinoma (HCC) and identify its effects on signaling pathways. Our data indicated that Metformin inhibits the migration and invasion of human HCC cells. Metformin was also found to significantly inhibit the expression and secretion of MMP-9 and uPA in HCC cells, and suppress the phosphorylation of ERK1/2 and JNK1/2. A treatment with an ERK1/2 inhibitor (PD98059) or JNK1/2 inhibitor (SP600125) enhanced the inhibitory effects of Metformin on the migration and invasion of HCC cells. Moreover, the Metformin-induced inhibition of MMP-9 and uPA promoter activity also blocked the nuclear translocation of NF-κB and its binding to the MMP-9 and uPA promoters, and these suppressive effects were further enhanced by PD98059 or SP600125. Moreover, Metformin markedly enhanced the anti-metastatic effects of Sorafenib. In conclusion, Metformin inhibited the migration and invasion of HCC cells by suppressing the ERK/JNK-mediated NF-kB-dependent pathway, and thereby reducing uPA and MMP-9 expressions. Additionally, a combination treatment with Metformin and Sorafenib yielded synergistic inhibitory effects in suppressing cell migration and invasion of HCC cells. These findings provide insight into the molecular mechanisms involved in the anti-metastatic effects of Metformin, as well as its ability to enhance the chemosensitivity of Sorafenib on HCC cells.
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Lin, Chin-Chung, and 林進忠. "Leaderl,an anti-metastatic constituent from the solid-state cultured mycelium of Antrodia cinnamomea and its mechanism." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/52146873350143390554.
Full textAbstract:
碩士中華科技大學
健康科技研究所在職專班
103
Antrodia cinnamomea (Syn. Antrodia camphorata or Taiwanofungus camphorata) is a precious and unique edible fungus originated from the forest of Taiwan. In this study, an anti-metastatic compound, 2,3,5-trimethoxy-4-cresol (LE01) was isolated from the solid-state cultured mycelium of A. cinnamomea. According to the results obtained from cell wound healing, cell migration and invasion assays, LE01 suppressed effectively on movement, migration and invasion of lung cancer cell lines at the dosage in different concentrations (0、5、10、20、40 μM) without toxicity on A549 cells. Furthermore, LE01 reduced major protein expressions of MMP-2, MMP-9, Akt until 52%、35% and 300%, respectively. In addition, TIMP-1 protein expression, which is known to regulate cell adhesion, migration and invasion, was also enhanced over 40% by LE01 at the dosage of 40 μM. Therefore, these results were showed that LE01 suppressed effectively on movement, migration and invasion of lung cancer cells, and achieved the effect of anti-cancer metastasis.