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1
Sarvi, Sana. "Small cell lung cancer and cancer stem cell-like cells." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9542.
Testo completoAbstract (sommario):
Small cell lung cancer (SCLC) is a highly aggressive malignancy with extreme mortality and morbidity. Although initially chemo- and radio-sensitive, almost inevitable recurrence and resistance occurs. SCLC patients often present with metastases, making surgery not feasible. Current therapies, rationally designed on underlying pathogenesis, produce in vitro results, however, these have failed to translate into satisfactory clinical outcomes. Recently, research into cancer stem cells (CSCs) has gained momentum and form an attractive target for novel therapies. Based on this concept, CSCs are the cause of neoplastic tissue development that are inherently resistant to chemotherapy, explaining why conventional therapies can shrink the tumour but are unable to eliminate the tumour completely, leading to eventual recurrence. Here I demonstrate that SCLC H345 and H69 cell lines contain a subset of cells expressing CD133, a known CSC marker. CD133+ SCLC sub-population maintained their stem cell-like phenotype over a prolonged period of culture, differentiated in appropriate conditions and expressed the embryonic stem cell marker Oct-4 indicating their stem-like phenotype. Additionally, these cells displayed augmented clonogenic efficacy, were chemoresistant and tumorigenic in vivo, distinct from the CD133- cells. Thus, the SCLC CD133 expressing cells fulfil most criteria of CSClike definition. The molecular mechanisms associated with CD133+ SCLC chemoresistance and growth is unknown. Up-regulated Akt activity, a known promoter of resistance with survival advantage, was observed in CD133+ SCLC cells. Likewise, these cells demonstrated elevated expression of Bcl-2, an anti-apoptotic protein compared to their negative counterpart explaining CD133+ cell chemoresistance phenotype. Additionally, CD133+ cells revealed greater expression of neuropeptide receptors, gastrin releasing peptide (GRP) and V1A receptors compared to the CD133- cells. Addition of exogenous GRP and arginine vasopressin (AVP) to CD133+ SCLC cells promoted their clonogenic growth in semi-solid medium, illustrating for the first time neuropeptide dependent growth of these cells. A novel peptide (peptide-1) was designed based on the known structure of the substance P analogues that have shown benefit in animal models and in early clinical trials. This compound inhibited the growth of SCLC cells in in vitro with improved potency and stability compared to previous analogues and reduced tumorigenicity in vivo. Interestingly, peptide-1 was more effective in CD133+ cells due to increased expression of neuropeptide receptors on these cells. In conclusion, my results show that SCLC cells retain a sub-population of cells that demonstrate CSC-like phenotype. Preferential activation of Akt and Bcl-2 survival pathways and enhanced expression of neuropeptide receptors contribute to CD133+ SCLC chemoresistance and growth. Therefore, it can be proposed that CD133+ cells are the possible cause of SCLC development, treatment resistance and disease recurrence. Despite being chemoresistant, CD133+ cells demonstrated sensitivity to peptide-1. The identification of such new analogue that demonstrates efficacy towards resistant CD133+ SCLC cells is a very exciting step forward in the identification of a potential new therapy for resistant disease.
2
Fruka, Tayra. "An evaluation of cancer biomarkers in normal ovarian epithelial cells and ovarian cancer cell lines." University of the Western Cape, 2019. http://hdl.handle.net/11394/6920.
Testo completoAbstract (sommario):
Philosophiae Doctor - PhD<br>Introduction: Globally, there are over 190,000 new reported cases of ovarian cancers per annum. This comprises 3% to 4% of all cancers in women. Ovarian cancer is one of the leading causes of deaths in women. Ovarian cancer is the second most diagnosed gynaecological malignancy and over all the fifth cause leading to death among all types of cancer in the UK in 2004. More than 70% of epithelial ovarian cancers are diagnosed at an advanced stage. Consequently, the prognosis is poor and the mortality rate high. Thus, the survival rate is affected by how far the disease has progressed or spread. A dire need exists to identify ovarian cancer biomarkers, which could be used as good indicators of expression in ovarian cancer cells in vitro
Aim: The aim of this study was to analyse selected cancer biomarkers, which are currently under intense investigation for their suitability to diagnose epithelial ovarian cancer at an early stage. These biomarkers were analysed in terms of their in vitro expression in normal epithelial cells and ovarian cancer cell lines, which allows for their genomic and proteomic classification. The expression analysis of each biomarker is related to the malignancy of a tumour and, therefore, advocates its use for potential future improvement of sensitive tumour markers.
Methods: The primary human ovarian surface epithelial cell line (HOSEpiC), SKOV-3 cells and the OAW42 human epithelial ovarian tumour cell lines were used to evaluate the selected cancer biomarkers. Cells were cultured using appropriate media and supplements, and real-time quantitative polymerase chain reaction (RT-PCR) utilized to validate expression levels of the following genes: HDAC1, HDAC2, HDCA3, HDAC5, HDAC6, HDAC7, HDAC8, LPAR1, LPAR2, MUC16 and FOSL1, against normal housekeeping genes GAPDH and HPRT. In addition, immunocytochemistry was also used in the validation process of the aforementioned genes.
Significance: ovarian cancer cells express gene signatures, which pose significant challenges for cancer drug development, therapeutics, prevention and management. The present study is an effort to explore ovarian cancer biomarkers to provide a better diagnostic method that may offer translational therapeutic possibilities to increase five- year survival rate.
Results: HDAC5, HDAC6, LPAR1, LPAR2 and MUC16 expressed distinctively in ovarian cancers matched to other tissues or cancer types have already been identified by RT-QPCR and confirmed by immunocytochemistry and efforts to generate monoclonal antibodies to the other six genes (HDAC1, HDAC2, HDAC3, HDAC7, HDAC8 and FOSL1) encoded proteins are underway.
Conclusions: here we provide strong evidence suggesting that HDAC5, HDAC6, LPAR1, LPAR2, except MUC16 are up regulated in ovarian cancer. These data were confirmed by examining Human Protein Atlas (HPA) databases, in addition to protein expression of HDAC5, HDAC6, LPAR1, LPAR2 and MUC16 in cells cytoplasm. For future prospective, using other techniques that assess the variant expression that could explain the release of these gene candidates into the circulation with serum tumour markers, and protein expression will be strengthened.
3
Sasaki, Naoya. "Alpha-fetoprotein-producing pancreatic cancer cells possess cancer stem cell characteristics." Kyoto University, 2012. http://hdl.handle.net/2433/157414.
Testo completo
4
Wong, Kit-man Sunny, and 王傑民. "Isolation and characterization of cancer stem cells in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47250665.
Testo completoAbstract (sommario):
Tumor heterogeneity has long been observed and recognized as a challenge to
cancer therapy. The cancer stem cell (CSC) model is one of the hypotheses
proposed to explain such a phenomenon. A specific cancer stem cell marker has
not been determined for non-small cell lung cancers (NSCLC), preventing the
definitive evaluation of whether the biology of NSCLC is governed by the CSC
model. This study aimed to analyze the expression of candidate CSC markers and
using the identified putative marker, to isolate CSC and determine the
applicability of the CSC model in NSCLC.
The expression or activities of four putative stem cell markers, CD24, CD44,
CD133 and aldehyde dehydrogenase 1 (ALDH1) were measured by flow
cytometry in eight NSCLC cell lines before and after chemotherapy for 24 hours.
Markers with increased expression after treatment were considered potential CSC
markers and used for isolating tumor cell subpopulations from the untreated cell
lines by fluorescence-activated cell sorting (FACS). Confirmatory analyses using
widely acceptable methodology were performed to test for CSC properties in the marker+ and marker- subpopulations. Isolated subpopulations were further
characterized by functional and phenotypic studies.
Flow cytometry showed amongst the 4 markers, only ALDH1 expression was
significantly enhanced by chemotherapeutic treatment, suggesting ALDH1 could
be a CSC marker. Untreated ALDH1+ cells formed significantly more and larger
cell spheres in non-adherent, serum-free conditions than ALDH1- cells. Likewise,
higher in vitro tumorigenic ability was observed in ALDH1+ subset using colony
formation assay. Furthermore, a higher resistance to cytotoxic drugs was observed
in ALDH1+ compared to ALDH1- cells. In vivo studies also showed ALDH1+ cells
showed higher tumorigenicity than ALDH1- cells; as few as 2,500 ALDH1+ cells
formed tumor in SCID mice which were serially transplantable to 2nd and 3rd
recipients, while no tumor was formed from ALDH- cells with even ten times the
number of cells. Also, expression analysis revealed higher expression of the
pluripotency genes, OCT4, NANOG, BMI1 and SOX9, in ALDH1+ cells. In view
of previous studies reporting CD44 as a CSC marker in lung cancer, double
marker selection of putative CSC was performed to compare ALDH1+CD44+ and
ALDH1-CD44+ subpopulations. Results of the spheroid body formation assay and
cisplatin treatment experiments revealed the ALDH1+CD44+ subpopulation
possessed higher self-renewal ability and chemo-resistance. Cell migration and
invasion assays showed differences between the ALDH1+CD44+ and ALDH1-
CD44+ subpopulations. The significance of these observations require further
investigation.
In conclusion, the result showed that ALDH1 could be a marker for NSCLC stem
cells as evidenced by enhanced self-renewal and differentiation abilities in
ALDH1+ subpopulation. Furthermore, this study observed the presence of at least
two potential stem cell subpopulations in NSCLC cells with differential selfrenewal,
chemotherapy resistance and cell mobility properties. Further
investigations are required to validate these observations and to investigate the
underlying mechanisms. Better understanding of these issues would help to solve
the challenges brought by tumor heterogeneity in lung cancer therapy.<br>published_or_final_version<br>Pathology<br>Master<br>Master of Philosophy
5
Liu, Qing. "Curcumin induces cell inhibition in breast cancer cells." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38688608.
Testo completo
6
Liu, Qing, and 劉晴. "Curcumin induces cell inhibition in breast cancer cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38688608.
Testo completo
7
Oshima, Nobu. "Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors." Kyoto University, 2014. http://hdl.handle.net/2433/192147.
Testo completoAbstract (sommario):
Oshima N, Yamada Y, Nagayama S, Kawada K, Hasegawa S, et al. (2014) Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors. PLoS ONE 9(7): e101735. doi:10.1371/journal.pone.0101735<br>Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(医学)<br>甲第18547号<br>医博第3940号<br>新制||医||1006(附属図書館)<br>31447<br>京都大学大学院医学研究科医学専攻<br>(主査)教授 千葉 勉, 教授 野田 亮, 教授 武藤 学<br>学位規則第4条第1項該当
8
Coulson-Gilmer, Camilla Lucette. "Cancer stem cells and chemoresistance in ovarian cancer." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/18470/.
Testo completoAbstract (sommario):
The high mortality rate associated with epithelial ovarian cancer (EOC) is due to its insidious onset, leading to late diagnosis as well as eventual development of chemoresistance in the majority of patients. Cancer stem-like cells (CSCs) are thought to contribute to development of multi-drug resistant (MDR) tumours partly through their high level of ABC-transporter expression, which enables them to survive chemotherapy. ABC-transporter (MRP1, MRP2, BCRP, Pgp) and putative CSC-marker (ALDH1A1, CD44) expression was therefore evaluated by immunohistochemistry in a paraffin-embedded cohort of 57 high-grade EOC tumours. Typically 9-12% of cells in tumours expressed CD44 / ALDH1A1. These may represent a population enriched for CSCs. ABC-transporters were expressed in 10- 43% of cells on average. Using Spearman rank test, there was no correlation between CSC- marker and ABC-transporter expression, however correlation was observed between many of the ABC-transporters, suggesting existence of highly drug-resistant populations within tumours. Expression of CA125 (a glycoprotein expressed by EOC cells and used clinically to detect EOC relapse) and EpCAM (a cell adhesion molecule expressed by EOC cells) was also investigated. Interestingly, patient tumours with the highest level of EpCAM had longer overall survival by Kaplan-Meier analysis. In addition, increased expression of MRP1 and CD44 predicted poorer patient outcome by Cox regression analysis. In vitro functional assays were also used to identify CSCs. Cells derived from ascites samples had a mean colony-forming efficiency (CFE) or 6.3%, and in unsorted tumours this was 11.4%. Cancer cells were then isolated from primary ascites and tumour samples (using CA125 and EpCAM). On average, self-renewing assays revealed a 2.2-2.4-fold increase in CFE for CA125 or EpCAM positive sorted cells compared to CA125 or EpCAM negative cells. Future studies could characterise these self-renewing populations, which may lead to identification of novel CSC targets for use in EOC treatment.
9
Choi, Mi-Yon. "P53 mediated cell motility in H1299 lung cancer cells." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/109.
Testo completoAbstract (sommario):
Studies have shown that gain-of- function mutant p53, AKT, and NFκB promote invasion and metastasis in tumor cells. Signals transduced by AKT and p53 are integrated via negative feedback between the two pathways. Tumor derived p53 was also indicated to induce NFκB gene expression. Due to the close relationship between p53/AKT and p53/NFκB, we hypothesized that AKT and NFκB can enhance motility in cells expressing mutant p53. Effects on cell motility were determined by scratch assays. CXCL5- chemokine is also known to induce cell motility. We hypothesized that enhanced cell motility by AKT and NFκB is mediated, in part, by CXCL5. CXCL5 expression levels in the presence and absence of inhibitors were determined by qRT-PCR. We also hypothesized that gain-of-function mutant p53 contributes to the activation of AKT. The effect of mutant p53 on AKT phosphorylation was investigated with a Ponasterone A- inducible mutant cell line (H1299/R175H) and vector control. These results indicated that AKT and NFκB enhance motility in cells expressing mutant p53 and this enhanced motility is, in part, mediated by CXCL5. However, AKT phosphorylation was independent of mutant p53.
10
Kapeleris, Joanna C. "Circulating tumour cells in non-small cell lung cancer." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/228607/1/Joanna_Kapeleris_Thesis.pdf.
Testo completoAbstract (sommario):
Circulating tumour cells (CTCs) have the potential to transform the management of patients with non-small cell lung cancer (NSCLC). The applications of CTCs can identify clinically actionable targets to predict treatment response and to better understand metastasis. CTCs isolated using microfluidics can be used as prognostic indicators of NSCLC as well as characterizing for markers of immunotherapy (PD-L1), molecular targets (ALK, EGFR). Short term cultures were successfully expanded in 9/70 NSCLC patients and cultured for up to 3 months. Optimization of this novel CTC culture model provides opportunity to identify new therapeutics for NSCLC patients in a precision medicine approach.
11
Sherwood, Benedict T. "Radiosensitivity in bladder cancer cells." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29874.
Testo completoAbstract (sommario):
Potentially curative treatment options for patients with organ-confined transitional cell carcinoma (TCC) of the bladder (T1-4a/N0/M0) are radical cystectomy or radiotherapy (RT)-based 'bladder-preserving' regimens. A substantial number of patients who receive RT fail to respond (approximately 50%). Consequently, a greater understanding of the mechanisms of radioresistence is required, together with predictive information regarding the response of tumours to RT. Hypoxia and intrinsic cellular Radiosensitivity (IRS) are examined here, a factors that may influence the outcome of RT.;An immunohistochemical assay using hypoxia-related carbonic anhydrase IX (CA IX) was undertaken to determine the prognostic significance of hypoxia in bladder tumours treated with RT. A modified version of the alkaline comet assay (ACA) was used to examine differences in IRS between cells derived from TCC specimens. Nuclear factors that influence comet formation (and therefore radiosensitivity) were also examined, such as DNA double strand break (DSB) rates and differences in nuclear matrix protein (NMP) composition.;CA IX immunostaining did not provide prognostic information with respect to response to radical RT. ACA analysis indicated a wide range of responses between tumours. In TCC cell lines, DSB rates are not demonstrably different in cells of differentiated radiosensitivity, however, comparative analysis of nuclear proteins identified differences in their constitutive NMPs and repair enzymes.;These results do not provide evidence that hypoxia influences outcome after RT, but support the contention that ICR is important in dictating the response of bladder tumours to RT. Furthermore, in bladder cancer cell lines of differing radiosensitivity, differences in NMP and repair enzymes are identified. Further work is required to determine whether these are of prognostic importance.
12
Chan, Ching Wan. "Apoptosis in breast cancer cells." Thesis, University of Bristol, 2004. http://hdl.handle.net/1983/8971525c-0de9-4e21-9677-ab73d61ae65c.
Testo completo
13
Dai, Prè Elena <1990>. "ELECTRICAL CHARACTERIZATION OF CANCER CELLS." Master's Degree Thesis, Università Ca' Foscari Venezia, 2015. http://hdl.handle.net/10579/6321.
Testo completoAbstract (sommario):
In this work, the impedance of different cancer cell lines was measured using a lab-on-chip device developed by imec (interuniversity electronics center) in Leuven, Belgium.
The motivation of this thesis is the detection of circulating tumour cells (CTCs) from cancer metastatic patients. Currently CTC detection is challenging because of the low abundance and phenotype similarity with white blood cells. Imec is developing a proprietary transistor-embedded device for massively parallel on-chip single cell characterization in the European project MIRACLE (Magnetic Isolation and moleculaR Analysis of single CircuLating and disseminated tumor cElls on chip).
This chip is composed of thousands of measurement units for electrical impedance spectroscopy.
The first step of this work was measuring the impedance of different ionic strength solutions, in order to validate the equivalent circuit theoretical model, previously developed using the software Matlab and some literature data.
The second step was measuring the impedance of different cancer cell lines. A positive correlation between the cell membrane capacitance and the cell malignancy was seen. This was attributed to some changes, which happen during the cancerization process, such as cellular membrane and tight junctions destruction, which lead to an increased permeability and membrane potential reduction. These results agrees with some literature.
The last step was measuring the electrical impedance of cell membrane after incubation with a drug, named Paclitaxel, which acts specifically on cell microtubes, connected to the cell membrane. Treating the cells with drug is responsible of a variation of cell membrane impedance, which may be use as a criterion to differentiate different cancer cell lines. However, further work is necessary.
14
Kadaba, Raghunandan. "Desmoplastic stromal cells modulate tumour cell behaviour in pancreatic cancer." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8825.
Testo completoAbstract (sommario):
Pancreatic ductal adenocarcinoma (PDAC) is characterised by an intense desmoplastic stromal response that can comprise 60 to 80% of tumour volume and has been implicated to be a factor in promoting tumour invasiveness and the poor prognosis associated with this cancer type. It is now well established that pancreatic stellate cells, which are vitamin A storing cells found in the periacinar spaces of the stroma in the normal gland, are primarily responsible for this desmoplastic reaction. Studying the interaction between stellate cells and cancer cells could provide for a better understanding of the disease process. During the evolution of PDAC, the stromal proportion increases from 4% in the normal gland to up to 80%. We hypothesised that there is an optimal proportion of stellate cells and cancer cells that modulates tumour behaviour and we attempted to dissect out this probable ‘tipping point’ for stromal composition upon cancer cell behaviour using a well-established in vitro organotypic culture model of pancreatic cancer. The cancer cell-stromal cell interaction led to extra-cellular matrix contraction and stiffening; and an increase in cancer cell number. The stromal stellate cells conferred a pro-survival and pro-invasive effect on cancer cells which was most pronounced at a stellate cell proportion of 0.66-0.83. The expression of key molecules involved in EMT and metastasis such as E-Cadherin and β-catenin showed a reduction and this was found to be most significant again at a stellate cell proportion of 0.66-0.83. Stellate cells altered the genetic profile of cancer cells leading to differential expression of genes involved in key cellular pathways such as cell-cycle and proliferation, cell movement and death, cell-cell signalling, and inflammatory response. qRT-PCR confirmed the differential expression of the top differentially expressed genes and protein validation by immunofluorescence staining using PIGR as a candidate molecule confirmed the experimental findings in human PDAC specimens. This study demonstrates that the progressive accumulation of desmoplastic stromal cells has a tumour progressive (pro-survival, pro-invasive) effect on cancer cells in addition to stiffening (contraction) of the extracellular matrix (maximum effect when the stromal cell proportion is 60-80%). This is mediated through a number of signalling cascades and molecular targets. Dampening this tumour-promoting interaction between cancer and stromal cells by ‘multi-targeting’ agents may allow traditional chemo- and/or radiotherapy to be effective.
15
Wang, Wei. "Modulation of immune cell responses by small cell lung cancer cells." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/modulation-of-immune-cell-responses-by-small-cell-lung-cancer-cells(7bdc85c2-acd8-4f13-9d2b-e2ce07d1567b).html.
Testo completoAbstract (sommario):
Small Cell Lung Cancer (SCLC) accounts for 15-20% of all lung cancers and kills at least one person every 2 hours in the UK. There is no effective treatment and overall 2-year survival is less than 5%. Patients with SCLC have poorly understood local and systemic immune defects. Previous studies have shown several important defects in cell-mediated immune responses in patients with SCLC. A better understanding of interactions between SCLC tumour cells and immune cells may lead to the development of novel therapeutic approaches. There is increasing recognition that immunological biomarkers may add to traditional histological analyses and can be exploited in the management of multiple epithelial malignancies. There are currently no such markers used in the management of SCLC. In my PhD project, I have shown that cell lines from different SCLC patients have differential immunosuppressive capabilities. These properties are mediated by the secretion of differing levels of soluble molecules that can suppress the mixed leukocyte reaction (MLR) and CD4+ T cell proliferation, induce IL-10 secretion and differentiation of functional CD4+CD25+CD127+FoxP3+Helios- regulatory T cells (Tregs) from naïve CD4+ T cells. IL-15 is secreted by SCLC cells in culture in proportion to their immunosuppressive capability. Its in vivo relevance is supported by its presence in tumour biopsy samples. The suppressive effect on CD4+ T cell proliferation and the induction of Treg cell population was not affected by blocking IL-10 or TGF-β signalling but was partially reversed by blocking IL-15 activity. Therefore, IL-15 is one, though not the only, soluble molecule produced by SCLC cells to mediate immune suppression by inducing increased population of Treg cells. This may represent a mechanism by which SCLC cells can suppress the immune response. In addition, SCLC cells supressed TNF-α release from monocytes in response to LPS stimulation, down-regulated expression of CD16 and CD86 and upregulated expression of CD163 and CD206 on monocyte-derived macrophages (MDMs) upon activation. This M2-like phenotype poralization was associated with decreased TNF-α and IL-6 production and increased IL-10 secretion. These effects were abrogated by blocking the signalling of bombesin-like peptides (BLPs) that are neuropeptides produced by SCLC cells using a GRP receptor (GRP-R) antagonist. Therefore, the polarization of macrophages to an M2-like phenotype by SCLC cell-derived BLPs may represent another mechanism by which SCLC tumours suppress the immune response. Finally, SCLC tumour biopsies were shown to be infiltrated with various mononuclear immune cells and Treg cells. CD45 and FoxP3 were used as paninflammatory cell and Treg cell markers respectively. An elevated CD45+ infiltrate was predictive of prolonged survival in SCLC independent of age, sex, stage or treatment strategy. An elevated FoxP3+/CD45+ ratio was predictive of a significantly worse prognosis. This study identifies potential mechanisms by which SCLC tumour cells may downregulate local and systemic immune response, and also identifies an independent prognostic marker to predict patient survival in SCLC. Further, IL- 15 and BLPs are potential novel therapeutic targets in SCLC.
16
Grero, Dhanya. "Cytotoxicity of Vγ9Vδ2 T cells towards Colon Cancer Cells". Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-230976.
Testo completoAbstract (sommario):
Immunotherapies for cancer are widely studied at present. We are currently studying a specific form of “Vγ9Vδ2 T cells” found in the peripheral blood of healthy donors that can be used for the killing of HT-29 colon cancer cells. In order to determine the cytotoxicity of effectors, Vγ9Vδ2 T cells towards target cells, HT-29, it is important to first evaluate the absolute number of Vγ9Vδ2 T cells in a mixed cell population, and next to determine the phenotypic characterization, their activity and cytotoxicity in the presence of target cells. A flow cytometry and bead based assay was developed to evaluate the absolute number of Vγ9Vδ2 T cells in a mixed cell population. Peripheral Blood Mononuclear Cells (PBMCs) were surface stained with monoclonal antibodies (MoAbs) conjugated to fluorochromes that are cross reactive to cell surface markers such as CD3 (T Lymphocytes), γδ2 and were mixed with fluorophore beads. In these assays, no washes and centrifugation steps were performed after the cell surface staining and bead addition. The absolute cell counts were evaluated based on referencing a known concentration of beads. In addition, quantification assays were also performed to measure the cell and bead loss on surface staining that included washes and centrifugation steps and thus found a higher percentage loss of cells than beads. Immunophenotyping assays with four color staining were performed to monitor the phenotypic differentiation of effector cells based on cell surface markers CD27 and CD45RA. Only the naïve (CD27+CDRA+) and terminally differentiated effector memory (CD27-CD45RA+) were identified on the assays performed using Vγ9Vδ2 T cells of different donors. A flow cytometry based cytotoxicity (FCC) assay was completed to monitor the effector cell activity (CD69+) in the presence and absence of target cells and also the cytotoxicity was measured based on % specific lysis of target cells at four different effector to target (E:T) cell ratios. Only preliminary data were obtained for the FCC assay and the development is still in progress.
17
Fung, Kwong-lam, and 馮廣林. "Chemoresistance induced by mesenchymal stromal cells on cancer cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205639.
Testo completoAbstract (sommario):
Human mesenchymal stromal cells (hMSCs) are part of bone marrow micro-environment that supports hematopoiesis. However, hMSCs also enhance tumor progression and survival when they become part of the cancer micro-environment. I aimed to investigate the interaction between hMSCs and cancer cells during chemotherapy.
Firstly, I studied the interaction between hMSCs and T-lineage acute lymphoblastic leukemia (T-ALL) cells under pegylated arginase I (BCT-100) treatment. Three T-ALL cell lines were sensitive to BCT-100 but not hMSCs. Conversely, hMSCs could partly protect all T-ALL cell lines from BCT-100 induced cell death under transwell co-culture condition. Concerning the possible mechanism, the intermediate metabolite L-ornithine could not rescue most T-ALL cells from BCT-100 treatment. But the downstream L-arginine precursor, L-citrulline could partly rescue all T-ALL cells from BCT-100 treatment. Ornithine transcarbamylase (OTC) converts L-ornithine into L-citrulline. OTC expression level in hMSCs remained relatively high during BCT-100 treatment but OTC expressions in T-ALL cell lines declined drastically. It suggested that hMSCs may protect T-ALL cells against BCT-100 treatment by having sustained OTC expression. Suppression of hMSCs by vincristine (VCR) disrupted the protective effect of hMSCs to most T-ALL cells during BCT-100 treatment. This suggests that by transiently suppressing hMSCs, we may abolish the protective effect of hMSCs to T-ALL cells during BCT-100 treatment.
Then I studied the interaction between hMSCs and neuroblastoma under cisplatin treatment. Two neuroblastoma cell lines were used for both of them are cisplatin sensitive while hMSCs are cisplatin resistant. hMSCs could partly protect neuroblastoma cells from cisplatin induced cytotoxicity. On the other hand, exogenous IL-6 but not IL-8 could also partly rescue them from cisplatin induced cytotoxicity. IL-6 activated STAT3 phosphorylation dose-dependently and enhanced expression of detoxifying enzyme (glutathione S-transferase π, GST-π) in neuroblastoma. Such effect could be counteracted by anti-IL-6R neutralizing antibody tocilizumab (TCZ). However, TCZ failed to suppress hMSCs’ protection to neuroblastoma during cisplatin treatment. This suggests involvement of multiple factors. Up-regulation of serum GST-πin some hTertMSCs/neuroblastoma co-engrafted SCID mice compared to neuroblastoma engrafted mice provided a clue that GST-π might be a possible stromal-protection factor. Caffeic acid phenethyl ester (CAPE) is a known GST inhibitor after tyrosinase activation. Neuroblastoma cells expressed tyrosinase and CAPE enhanced cisplatin cytotoxicity on them, with or without hMSCs. Paradoxically, CAPE enhanced GST-πexpression with or without cisplatin treatment in neuroblastoma suggesting possible negative feedback to GST-π inhibition. However, such additive effect of CAPE to cisplatin cytotoxicity was not observed in vivo. Further delineation of the in vivo study design may help to verify the additive effect of CAPE to cisplatin cytotoxicity in vivo.
Finally, I studied the effect of apoptotic cancer cells (AC) on the immune function of hMSCs. hMSCs could phagocytose apoptotic neuroblastoma cells with respective up-regulation of many immune-mediators including two highly-expressed cytokines IL-6 and IL-8. Up-regulation of these immune-mediators may enhance immune cells chemotaxis. Further detailed investigation on the effect of AC-engulfed hMSCs to other immune cells will help us to understand the dynamic interaction between cancer cells and stromal cells during chemotherapy.<br>published_or_final_version<br>Paediatrics and Adolescent Medicine<br>Doctoral<br>Doctor of Philosophy
18
Sterrenberg, Jason Neville. "Molecular chaperone expression and function in breast cancer and breast cancer stem cells." Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1016238.
Testo completoAbstract (sommario):
The Cancer Stem Cell (CSC) theory suggests that cancers arise from and are maintained by a subpopulation of cancer cells with stem cell properties. Molecular chaperones are key components of cellular regulation. The overexpression of chaperones has become synonymous with cancer cells with chaperones being recognized as bona fide anti-cancer drug targets. Although chaperone activity has been characterized in cancer cells, very little is known about the cellular functions of chaperones in cancer stem cells. We set out to compare the expression of selected molecular chaperones in non-stem cancer cell and cancer stem cell enriched populations isolated from breast cancer lines, in order to identify chaperones differentially expressed between the two populations for further biological characterization. In order to isolate breast cancer stem cells from the MCF-7 and MDA-MB-231 breast cancer cell lines, three cancer stem cell isolation and identification techniques were utilized based on (1) cell surface marker expression (CD44+/CD24- and CD44+/CD24-/EpCAM+ phenotypes), (2) aldehyde dehydrogenase enzyme activity (ALDHHi) and (3) ability to grow in anchorage-independent conditions. The MDA-MB-231 and MCF-7 breast cancer cell lines displayed CD44+/CD24- cell populations with the MCF-7 cell line additionally displaying a large CD44+/CD24-/EpCAM+ population. Although both cell lines showed similar ALDHHi populations, they differed substantially with respect to anchorage-independent growth. MCF-7 cells were able to form anchorage-independent colonies while the MDA-MB-231 cell line was not. Anchorage-independent MCF-7 cells showed enrichment in CD44+/CD24- and CD44+/CD24-/EpCAM+ cells compared to adherent MCF-7 cells, and were selected for gene expression studies. Gene expression studies identified 22 genes as being down-regulated at the mRNA level in the anchorage-independent MCF-7 cells, while only 2 genes (BAG1 and DNAJC12) were up-regulated. The down-regulation of selected chaperones in anchorage independent MCF-7 cells was confirmed at the protein level for selected chaperones, including DNAJB6, a type II DNAJ protein shown to be involved in the regulation of Wnt signaling. In order to characterize the effect of DNAJB6 expression on BCSCs we developed a pCMV mammalian expression plasmid for both DNAJB6 isoforms (DNAJB6L and DNAJB6S). We successfully constructed mutants of the conserved histidine-proline-aspartic acid (HPD) motif of the J domain of DNAJB6S and DNAJB6L. These constructs will allow the analysis of the role of DNAJB6 in cancer stem cell function. To the best of our knowledge, this is the first report to focus on the comparative expression of molecular chaperones in normal and cancer stem cell enriched breast cancer populations.
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Hosseini, Shirazi Seyed Farshad. "Cell cycle dependency of cisplatin cytotoxicity on ovarian cancer cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/NQ36776.pdf.
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20
Qi, Yue. "Roles of ADAM12 in triple-negative breast cancer: regulation of cancer stem cells." Diss., Kansas State University, 2016. http://hdl.handle.net/2097/35780.
Testo completoAbstract (sommario):
Doctor of Philosophy<br>Biochemistry and Molecular Biophysics Interdepartmental Program<br>Anna Zolkiewska<br>ADAM12 (A Disintegrin and Metalloprotease 12) is a cell surface protease, which is deregulated in many human diseases. High expression of ADAM12 in triple-negative breast cancers (lacking estrogen receptor, progesterone receptor, and HER2 expression) is associated with poor patient prognosis. My dissertation focused on the understanding of the biological functions of ADAM12 in triple-negative breast cancers. I found that ADAM12 is significantly upregulated in the claudin-low molecular subtype of breast cancer. Claudin-low tumors are typically triple-negative and are enriched in cancer stem cells. Here, I demonstrated that the loss of ADAM12 expression not only decreased the number of cancer stem-like cells in vitro but also significantly compromised the tumor-initiating capabilities of breast cancer cells in vivo. This is the first evidence showing that ADAM12 might regulate the cancer stem cell-like phenotype in triple-negative breast cancers. I also discovered a novel mechanism of ADAM12-regulated signaling by transforming growth factor β (TGFβ) through modulation of TGFBR1 mRNA expression in breast cancer cells. Lastly, I characterized the effects of six different somatic mutations in the ADAM12 gene found in human breast cancers on the intracellular trafficking, post-translational processing, and function of ADAM12 protein. Collectively, the findings of this study support the notion that ADAM12 with catalytically active metalloprotease domain is required for the progression of triple-negative breast cancers.
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Fancher, Karen. "Transcriptional Alterations during Mammary Tumor Progression in Mice and Humans." Fogler Library, University of Maine, 2008. http://www.library.umaine.edu/theses/pdf/FancherK2008.pdf.
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22
Tang, Yuanyuan. "Nitric Oxide/Peroxynitrite Imbalance Induces Adhesion of Cancer Cells to Lymphatic Endothelium - Clinical Implications for Cancer Metastasis." Ohio University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1439563414.
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23
Murray, Nicholas. "Costimulation of T cells and its role in T cell recognition of malignant colorectal cells in vitro." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301247.
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24
SCIANO', Fabio. "Development of natural and synthetic compounds as kinase inhibitors targeting cancer cells and cancer stem cells." Doctoral thesis, Università degli Studi di Palermo, 2023. https://hdl.handle.net/10447/580156.
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25
Wright, Nicola. "Role of cancer stem cells in breast and prostate cancer." Thesis, Sheffield Hallam University, 2016. http://shura.shu.ac.uk/17363/.
Testo completoAbstract (sommario):
Cancer stem cells (CSC) are thought to be responsible for the initiation, propagation and tumour re-occurrence. CSC have been identified in most solid and haematological cancers and account for ~1% of the total cell population. Culturing cancer cell lines in monolayers enriches for the most dominant subpopulation which in most cases does not represent the slow dividing CSC population. We investigated the expression of CSC markers in 2D vs. 3D cell culture with the aim of identifying CSC-like cells via a nanog-reporter cell line and enable the subsequent targeting of these cells with CSC-targeting agents. SUM159 and MCF7 cell lines cultured in 3D cell culture significantly enriched for the CD44+/CD24- breast cancer stem cell phenotype when compared against 2D cell culture (p < 0.05 and 0.001 respectively) and also enriched for expression of CD181 (p < 0.05 and 0.001 respectively). However, this method did not enrich for the prostate CSC with the CD44+/CD133+ phenotype in PC3, DU145 and LNCAP cells. Using reporter cell lines to further identify the CSC population in SUM159 cell line that express GFP in response to Nanog (NRE-GFP), found that these cells were GFP+ve in the absence of Nanog protein. As these reporters were selected based on GFP that was supposedly Nanog driven other mechanistic studies were examined to determine how GFP is expressed in the NRE-GFP and control cell line. It was found that GFP could be induced in apoptosis, CSC enriching medium, hypoxia and by inhibiting the proteasome in the absence of Nanog protein. It was concluded that reporter cell lines that respond to a response element may not identify the CSC population as other factors can induce GFP expression. Compounds related to Withaferin A have been proposed to specifically target CSCs. Prostate and breast cancer cell lines cultured in 2D and 3D were treated with a novel withanolide derivative (LG-02) and Withanilode E to determine if these compounds were more effective at inducing cell cycle arrest and apoptosis using flow cytometry and microscopy. It was determined that LG-02 and WE primary mode of action is cell cycle inhibition and both compounds are more potent cell cycle inhibitors than Withaferin A. G1 phase accumulation was observed in the SUM159, PC3 and LNCAP cell lines and G2/M phase accumulation in the DU145 cell line. Cell cycle arrest was inconclusive in the MCF7 cell line. An apoptotic morphology was only significantly induced at higher concentrations in MCF7, PC3, DU145 and LNCAP. Withanolide derivatives also target the androgen response pathway, demonstrated by a decrease in PSA and androgen receptor in prostate cancer cell lines. LG-02 slowed growth of breast cancer cell lines cultured in 3D and inhibited spheroid formation of prostate cancer cell lines, however the androgen-dependent cell line LNCAP was consistently able to form 3D colonies, most likely via pAkt activation. We conclude that 3D cell culture does enrich for the CSC population in breast cancer cell lines but using a reporter cell line expressing GFP under the control of a NRE is not a suitable model for identifying the CSC population for subsequent drug treatment. In addition, Withanolide derivatives have potential anti-tumour activity and may represent a novel class of anti-androgenic agents.
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Gomes, Cátia Sofia Vicente. "Cues for cancer stem cells origin." Master's thesis, Faculdade de Ciências e Tecnologia, 2012. http://hdl.handle.net/10362/12439.
Testo completoAbstract (sommario):
Dissertação para obtenção do Grau de Mestre em
Genética Molecular e Biomedicina<br>Neural stem/progenitor cells (NSPC) can differentiate into neurons and glial cells in the central nervous system. Interestingly, NSPC biology is being applied to the study of human brain tumours, since these cells share some common features with glioma cells. However, it is not known the developmental stage with more similarities to glioma cells, or the most susceptible to malignant transformation.
We aimed to identify the stage(s) in the NSPC differentiation process towards astrocytes where cells acquire phenotype characteristics comparable to glioma cells.
NSPC that were obtained from E15 mouse brain, were grew as neurospheres (NS) and induced to astroglial differentiation until 7 days in vitro (DIV). After the cellular characterization of NS and differentiating cells, tumour-related factors were evaluated and their behavior compared to the one of GL261 mouse glioma cells.
Astroglial differentiation led to a decrease in progenitor cells, as expected. Multidrug resistance-associated protein 1 expression decreased and autophagy marker increased with differentiation. The vascular endothelial growth factor (VEGF), matrix metalloproteinases and S100B protein increased until 2/3 DIV, while the 1 DIV cells showed the highest migratory potential towards the chemotactic VEGF or GL261-conditioned media.
Comparison of data with glioma cells characteristics point to the first and second days of NSPC differentiation to astrocytes as the stages closing matching GL261 cells, and likely the most vulnerable to malignancy transformation.
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Sehl, Mary Elizabeth. "Stochastic dynamics of cancer stem cells." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=2023755671&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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28
Mesenhöller, Maike. "Endogenous photosensitisation of pancreatic cancer cells." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343044.
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29
Beatty, John David. "Characterisation of Bladder Cancer Dentritic Cells." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487987.
Testo completoAbstract (sommario):
Bacillus Calmette-Guerin (BCG) is the most effective intravesical therapy for superficial bladder cancer. It is hypothesised that BCG therapy has a local and systemic effect on antigen-presenting dendritic cells (DC) and that characteristics and variations in DC may reflect those of DC in cancer tissue. Blood, urine and tissue samples were taken from patients with bladder cancer before and during treatment with intravesical BCG. In blood the percentages and numbers of DC expressing maturation, co-stimulatory and intracellular cytokine markers were measured using flow cytometry. Immune responses in bladder cancer were monitored by the identification and characterisation of DC from the urine and tissue of patients with bladder cancer using flow cytometry, immunohistochemistry and electron microscopy. Significantly increased numbers of blood plasmacytoid DC in patients with T1 G3 bladder cancer decreased during BCG therapy so that after 6 treatments there were no differences in the number of blood DC in patients with stages of superficial bladder cancer. DC numbers expressing CD40 increased in the blood of patients treated with BCG. Numbers of DC expressing T helper 1 (Th1) cytokine increased in patients who did not develop an early recurrence of bladder cancer. Immature DC were identified in tissue and urine from patients with superficial bladder cancer and confirmed in samples of urine by immunohistochemistry and electron microscopy. BCG therapy decreased the percentage of DC in the urine of patients who subsequently had recurrent bladder cancer. The therapeutic effect of BCG may be mediated by normalising circulating numbers of plasmacytoid DC and by increasing numbers of DC expressing the costimulatory molecule CD40. In response to BCG therapy increased numbers of circulating Th1 cytokine (IL-12) expressing DC and increased percentages of urine DC may be crucial in preventing recurrent bladder cancer.
30
Nicholl, Amanda Jayne. "Volume regulation in human cancer cells." Thesis, University of Huddersfield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368311.
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31
Baenke, F. "Metabolic dependencies of breast cancer cells." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1387846/.
Testo completoAbstract (sommario):
Cellular metabolism is one of the core processes for cell growth and proliferation. This process is altered in cancer cells as most solid tumours exhibit increased glucose uptake and lactate secretion, a feature known as the Warburg effect. These metabolic changes are the consequence of oncogene activation, loss of tumour suppressor function and/or mutations in metabolic enzymes. However, cancer cell metabolism is not limited to the Warburg effect and the exact role the metabolic machinery plays in facilitating proliferation and cell survival in different cancer types is still poorly understood and requires further study. Breast cancer is a complex and heterogeneous disease at the molecular level. In addition, the PI3K/AKT signalling pathway is frequently activated in breast cancers due to loss of the PTEN tumour suppressor, oncogenic activation of PIK3CA or overexpression of certain growth factor receptors. This study aimed to investigate whether the metabolic requirements of breast cancer cell lines are determined by their molecular alterations. By using RNA interference (siRNA), the expression of 231 metabolic enzymes, transporters and metabolic regulators of the cellular glucose and lipid metabolism were ablated in a panel of 14 breast cancer cell lines and 3 non-malignant breast cell lines with distinct molecular characteristics. Solid breast tumours are known to have regions of high/low delivery of nutrients and oxygen that facilitate changes in the metabolic dependencies of cancer cells that reside within these areas. Moreover, these solid tumours that contain regions of poor oxygen delivery are associated with cancers refractive to treatment and that have poorer overall survival. Thus, to examine the metabolic dependencies of cells that reside in these regions, an environment of low oxygen was recapitulated and the effect of silencing of metabolic genes on cell survival was assessed. Crucially, this approach has led to the identification of previously known and novel metabolic genes that are essential for survival of breast cancer cells for each of the defined breast cancer subgroups. In addition, the characterisation of the metabolic requirements and processes revealed that each subgroup displays a distinct metabolic phenotype that might provide potential novel molecular targets that could be exploited therapeutically.
32
Martinez, Rebecca L. "Chemosensory Evaluation of Prostate Cancer Cells." Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/46316.
Testo completoAbstract (sommario):
Prostate cancer is the most commonly diagnosed disease and second most commonly caused death among men in America. Although much controversy surrounds the current methods of detection, PSA test and biopsy, no new methods have been approved as an effective method of detection. Biomarkers and non-invasive means of detection are being investigated everyday in hopes of discovering new information that could be of use in the prostate cancer field.
One such non-invasive technology is the use of an electronic nose. The electronic nose technology has been utilized in the agricultural, food, biomedical, and environmental. The objective of this current study is to determine the effectiveness of the electronic nose to discriminate between prostate cancer cells (DU-145 and PC-3) and non-tumor forming cells from the urinary tract (SVHUC). Specific factors that will be investigated are incubation period and cell population.
For all three cell lines, two cell populations of 75,000 and 150,000 cells were cultured and tested after 2, 8, 12, and 24 hours using a conducting polymer based hand-held electronic nose. Multivariate analysis was performed on the data and determined that the greatest discrimination between incubation periods was between 2 hours of incubation and the remaining periods of 8, 12, and 24 hour periods. This presents the idea that by 8 hours, ample volatiles were produced to be detected by the electronic nose. Additionally, when compared to one another, all three cell lines showed distinct differences. The cell lines most closely related were PC-3 and DU-145, the prostate cancer cell lines. However some variation was seen between these cell lines, which may be attributed to the presence of PSA in PC-3 cells or other factors affecting prostate cancer patients. Finally, PCA plots clearly illustrated that after 2 hours of incubation, sufficient volatiles were produced to allow the electronic nose to clearly discriminate the three cell lines from one another, demonstrating the importance of incubation period on successful discrimination.
Based on the findings that the electronic nose was effective at discriminating the three cell lines, testing was completed to determine if cell population or cell maturity had the greatest effect on discrimination. The cell lines were cultured and tested immediately using an initial cell population of the highest cell population observed after a 72 hour incubation period. The results concluded that when the cell lines were tested immediately after culturing, the Cyranose was able to detect the individual cell lines in culture while also determining a range of detection for each cell line. The range of detection for DU-145 was found to be 26,200 to 262,000 cells based on interclass m-distances of 6.829-9.170 for cell populations lower than 26,200. A range of detection of 51,400 to 514,000 cells was concluded for PC-3 cells based on interclass m-distances of 5.690-7.400 for cell populations lower than 51,400. Finally, the results showed a range of detection of 19,000 to 190,000 cells for SVHUC based on interclass m-distances of 5.520-9.076 for cell populations lower than 19,000. However, when attempting to discriminate the three cell lines against one another immediately after culture, the electronic nose was unable to make clear distinctions between the three cell lines. When testing cancerous and non-cancerous cells, incubation period of the cells should be the only factor considered. It is evident that the cells need time to metabolize and produce volatiles so that the electronic nose can clearly distinguish these cells from one another in culture.<br>Master of Science
33
Phillips, Tiffany Marie. "Breast cancer stem cells and radiation." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1383484841&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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34
Hakulinen, Juha. "Complement-mediated killing of cancer cells." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/hakulinen/.
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35
Moore, Nathan F. "Slow-Cycling Cancer Cells: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/620.
Testo completoAbstract (sommario):
Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be due to small subsets of stem-like cancer cells that are able to survive chemotherapy and drive tumor re-growth. A more complete understanding of stem-like cancer cell regulation is required to develop therapies to better target and eliminate these cells.
Slow-cycling stem cells are integral components of adult epithelial tissues and may give rise to cancer stem cell populations that share similar characteristics. These slow-cycling adult stem cells are inherently resistant to traditional forms of chemotherapy and transference of this characteristic may help to explain therapy resistance in cancer stem cell populations. Using a novel application for the proliferation marker CFSE, we have identified populations of slow-cycling cancer cells with tumor initiating capabilities. As predicted, slow-cycling cancer cells exhibit a multi-fold increase in chemotherapy resistance and retain the ability to re-enter the cell cycle. Furthermore, we observed consistent over-expression of the CDK5 activator, p35, in slow-cycling cancer cells. Manipulation of p35 expression in cancer cells affects cell cycle distribution and survival when these cells are treated with traditional forms of chemotherapy. Additionally, we demonstrate that alterations in p35 expression affect BCL2 levels, suggesting a mechanism for the survival phenotype.
Combined, our data suggest a model whereby slow-cycling stem-like cancer cells utilize the p35/CDK5 complex to slow cell cycling speed and promote resistance to chemotherapy. Future p35 targeting, in combination with traditional forms of chemotherapy, may help eliminate these cells and reduce tumor recurrence rates, increasing long-term patient survival.
36
Board, Mary. "A study of energy metabolism in neoplastic cells." Thesis, University of Oxford, 1990. http://ora.ox.ac.uk/objects/uuid:d3e13e31-3fe8-4cd8-ad71-50d4e7df4d27.
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37
Tian, Fei. "Effect of the Hedgehog Pathway inhibitor GDC-0449 in lung cancer cells and lung cancer stem cells." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-156374.
Testo completoAbstract (sommario):
The cancer stem cell hypothesis implicates that tumor cell population is heterogeneous with relatively well-differentiated cells and poorly-differentiated cells. Only the small population of tumourigenic poorly-differentiated CSCs can escape the normal limits of self-renewal and has the ability to proliferate and maintain the malignant growth of the tumor.
One characteristic of stem cell is that the ability to exclude DNA dyes, such as Hoechst 33342 via the over-expression of ATP-binding cassette transporters (ABC transporters) on the cell membrane. It makes the detecting of the stem cell possible. After the Hoechst 33342 staining, stem cells extrude this dye and show a typical profile of low fluorescence in Hoechst red versus Hoechst blue bivariate dot plots. These low Hoechst 33342 stained cells are named as side population (SP) cells. This characteristic has enabled purification and characterization of CSCs when carried out alone or in combination with stem cell surface markers.
The CSC hypothesis could have a fundamental influence on cancer therapy. CSCs have shown significant substantial resistance to conventional chemotherapy in contrast to the differentiated cancer cells. It is essential to design a complete therapy strategy first to reduce or minimize proliferating cell mass and then to differentiate or eliminate CSCs, so that the relapses of metastatic cancers could be prevented.
This work aimed at investigating if Hedgehog pathway inhibitor GDC-0449 is effective in the lung cancer cell lines HCC (adeno-carcinoma) and H1339 (small cell lung carcinoma) and also the cisplatin resistant lung cancer cells, and if possible effects of GDC-0449 are mediated via SPs. Furthermore, the effect of GDC-0449 on the calcium homeostasis was also investigated.
GDC-0449 showed dose-dependent inhibitory effects on cell growth in both HCC and H1339 cells. The combination of GDC-0449 and cisplatin gave an additional inhibitory effect. GDC- 0449 could also inhibit the cell growth in cisplatin resistant HCC and H1339 cells.
SP cells as cancer stem-cell-like cells could be found in HCC and H1339 cells. Only the SP cells showed the repopulation ability but not the non-SP cells. GDC-0449 could inhibit the SP cell fraction in both HCC and H1339 cells. So the inhibitory effect of GDC-0449 on cell growth may be mediated via SP.
GDC-0449 affected the expression of the Hh pathway components in both HCC and H1339 cells. In HCC cells, GDC-0449 inhibited the activity of the Hh pathway and the down- regulation of Shh, Patched and Gli-1 could be shown. In H1339 cells, GDC-0449 could also inhibit the pathway activity and decrease the expression of Gli-1 in an autocrine pattern due to the over-expression of Shh. The inhibition of Hh pathway increased the expression of Bmi-1 to compensate the loss of Hh pathway function. The Hh pathway activity could be detected only in SP cells from HCC and H1339 cells.
The application of GDC-0449 on HCC and H1339 naïve and cisplatin resistant cells increased [Ca2+]c by decreasing [Ca2+]ER. GDC-0449 induced Ca2+ release from ER into cytoplasm in HCC and H1339 naïve and cisplatin resistant cells. The Ca2+ overload could lead to apoptosis, which was related to the cell growth inhibitory effect of GDC-0449 in lung cancer cells. The expression of SERCA and IP3R was not detectably influenced by GDC-0449. The effect of GDC-0449 on lung cancer cell Ca2+ -regulating machinery was not via the alternation of the expression of ER Ca2+ regulating channels.
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Ajabnoor, Ghada. "Mechanism of cell death in drug resistant human breast cancer cells." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/842867/.
Testo completoAbstract (sommario):
Anticancer drug resistance occurs as a result of altered response to cytotoxic insult, via inhibition or inactivation of apoptosis (programmed cell death type I, PCDI), which plays a major role in tumour development and progression. An alternative form of cell death - non-apoptotic, or autophagic cell death (PCD II) has recently emerged as a factor contributing to the cytotoxic response of cancer cells. We studied in vitro cell death in a drug resistant model MCF-7 human breast cancer cells with acquired resistance (c. 10- 20 fold) to paclitaxel, termed MCF-7TaxR. It has been reported that the absence of caspase-3 in parental MCF-7 cells (due to chromosome deletion) may explain why they recruit apoptotic and autophagic cell death following cytotoxic insult. We investigated the induction of apoptosis response to staurosporine and Z-VAD (pan-caspase inhibitor) using the Annexin V-FITC/PI assay and studied the effect of anti-Fas on MCF-7TaxR. Results demonstrated the lack of apoptosis induction in paclitaxel resistant breast cancer cells. The oligo GEAiTayRTM human apoptosis microarray and qPCR analysis confirmed the absence of caspase-7 and caspase-9 genes and many other apoptosis genes in MCF-7TaxR cells and their presence in MCF-7 cells. Western blot analysis also confirmed these results. Therefore, we investigated the presence of autophagic cell death in our MCF-7TaxR model. Flow cytometry using Acridine Orange assay, Beclin 1 and LC-3 protein detection, confocal microscopy and detection of Akt/mTOR expression. Data showed evidence of autophagic cell death in MCF-7TaxR cells in the absence of an apoptotic response. Collectively, these findings indicate the lack of involvement of caspase mediated cell death in a paclitaxel drug-resistant cancer cell line MCF-7TaxR, and presence of autophagic cell death as an alternative cell death mechanism.
39
Stordal, Britta Kristina. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells." Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital and The University of Sydney, 2007. http://hdl.handle.net/2123/2467.
Testo completoAbstract (sommario):
Doctor of Philosophy (PhD)<br>The H69CIS200 cisplatin-resistant and H69OX400 oxaliplatin-resistant cell lines developed as part of this study, are novel models of low-level platinum resistance. These resistant cell lines do not have common mechanisms of platinum resistance such as increased expression of glutathione or decreased platinum accumulation. Rather, these cell lines have alterations in their cell cycle allowing them to proliferate rapidly post drug treatment in a process known as ‘regrowth resistance’. This alteration in cell cycle control has come at the expense of DNA repair capacity. The resistant cell lines show a decrease in nucleotide excision repair and homologous recombination repair, the reverse of what is normally associated with platinum resistance. The alterations in these DNA repair pathways help signal the G1/S checkpoint to allow the cell cycle to progress despite the presence of DNA damage. The decrease in DNA repair capacity has also contributed to the development of chromosomal alterations in the resistant cell lines. Similarities in chromosomal change between the two platinum resistant cell lines have been attributed to inherent vulnerabilities in the parental H69 cells rather than part of the mechanism of resistance. The H69CIS200 and H69OX400 resistant cells are cross-resistant to both cisplatin and oxaliplatin. This demonstrates that oxaliplatin does not have increased activity in low-level cisplatin-resistant cancer. Oxaliplatin resistance also developed more rapidly than cisplatin resistance suggesting that oxaliplatin may be less effective than cisplatin in the treatment of SCLC. The resistant cell lines have also become hypersensitive to taxol but show no alterations in the expression, polymerisation or morphology of tubulin. Rather, the PI3K/Akt/mTOR pathway is involved in both platinum resistance and taxol sensitivity as both are reversed with rapamycin treatment. mTOR is also phosphorylated in the resistant cell lines indicating that platinum resistance is associated with an increase in activity of this pathway. The mechanism of regrowth resistance in the platinum-resistant H69CIS200 and H69OX400 cells is a combination of activation of PI3K/Akt/mTOR signalling and alterations in control of the G1/S cell cycle checkpoint. However, more work remains to determine which factors in these pathways are governing this novel mechanism of platinum resistance.
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Caldon, Catherine Elizabeth Garvan Institute of Medical Research Faculty of Medicine UNSW. "Cell cycle control by ID1 and WT1 in breast cancer cells." Awarded by:University of New South Wales. Garvan Institute of Medical Research, 2007. http://handle.unsw.edu.au/1959.4/33125.
Testo completoAbstract (sommario):
Loss of proliferative control is a cornerstone of cancer development, induced by deregulation of mitogenic signalling, insensitivity to anti-proliferative signals and direct changes in cell cycle proteins. In breast cancer these alterations are frequently targeted through cyclins D1 and E, leading to defects in G1/S transition. I have investigated the role of two potential pro-proliferative oncogenes in breast cancer, id1 andwt1. Each protein promotes proliferation in distinct contexts, with unique consquences for breast cancer cells. Using a 3D culture model of non-transformed mammary epithelial cells, I identified that id1 undergoes downregulation via rapid proteosomal degradation and cytoplasmic relocalisation during mammary epithelial morphogenesis. Overexpression of Id1 led to an increase in acinar size via an increase in S phase, and wa dependent on the presence of an intact HLH domain in Id1. Co-expression with the proto-oncogene Bcl2 led to a more disorganised acinar structure, indicating that Id1 overexpression primed the cells for further oncogenic insult. Further, Id1 overexpression was unable to increase acinar size in cyclin D1-/- acini, indicating that Id1 is dependent on cyclin D1 for its proliferative effects. Overall these data identified Id1 as capable of altering the proliferation of normal mammary epithelial cells, a crucial step in early breast carcinogenesis. Wt1 was originally identified as a tumour suppressor, but our data lends support to Wt1 acting as an oncogene in breast cancer. Wt1 is expressed highly in a range of breast cancer cell lines, and is strongly regulated by progestins. Using siRNA, we identified that Wt1 is likely to be a molecular intermediary of progestin as the downregulation of Wt1 mimics a subset of progestin effects on cell proliferation and lipid synthesis. Conversely, the overexpression of the major Wt1 isoform, Wt1 (+/+), led to attenuation of progestin-induced differentiation and growth arrest via maintenance of cyclin D1 levels. The effects of Wt1 overexpression were specific to progestins, and did not affect the actions of anti-estrogens or androgens. Consequently the overexpression of Wt1 (+/+) may disrupt the endocrine response in mammary epithelial cells, and contribute to excess proliferation and failure to differentiate during breast oncogenesis.
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Fong, Jenna. "Breast cancer cells affect bone cell differentiation and the bone microenvironment." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104758.
Testo completoAbstract (sommario):
Breast carcinoma is the most commonly diagnosed cancer among women worldwide, with approximately 1 in 7 expected to be affected during her lifetime. The spread of breast cancer to secondary sites is generally incurable. Bone is the preferred site of metastasis, where the development of a secondary tumour causes severe osteolysis, hypercalcemia and a considerable pain burden. However, how breast cancer cells establish supportive interactions with bone cells is not well understood. We have examined the effects of factors released from MDA-MB-231 and 4T1 breast cancer cells on the differentiation of C57BL6 mouse bone marrow cells. Treatment with cancer-derived factors resulted in a sustained 40–60% decrease in osteoblast differentiation markers, and induced an osteoclastogenic change in the ratio of receptor activator of NF-κB ligand (RANKL) to osteoprotegerin (OPG). Importantly, exposure of bone cells to breast cancer-derived factors stimulated the subsequent attachment of cancer cells to immature osteoblasts. Inhibition of γ-secretase using pharmacological inhibitors DAPT and Compound E completely reversed cancer-induced osteoclastogenesis as well as cancer-induced enhancement of cancer cell attachment, identifying γ-secretase activity as a key mediator of these effects. We next evaluated the effects of breast cancer cells on the energy metabolism of bone cells. Treatment of bone marrow cells with conditioned medium from 4T1 breast cancer cells resulted in an increase in glucose consumption by bone cells, higher mitochondrial transmembrane potential, and a 2.3-fold rise in cellular ATP content. In addition, breast cancer derived factors stimulated the expression of mRNA and protein levels of metabolic sensor, AMP-regulated protein kinase (AMPK). To assess if such change in cell bioenergetics may have consequences for cell differentiation and activity, we used defined models of osteoclastogenesis, and increased precursor metabolic activity by providing excess energy substrates. We have found that an increase in mitochondrial transmembrane potential and cellular ATP levels during osteoclastogenesis resulted in the formation of larger osteoclasts that demonstrate higher resorptive activity. Thus, we have uncovered that osteoblasts act as a critical intermediate of premetastatic signalling by breast cancer cells, and pinpointed γ-secretase as a robust target for developing therapeutics potentially capable of reducing both the homing and progression of cancer metastases to bone. In addition, we have discovered heightened energetics in bone cells exposed to breast cancer cell-released factors, which may contribute to the formation of larger, more active osteoclasts. Modification of the AMPK pathway may prove an important therapeutic target for breast cancer metastasis to bone.<br>Le cancer du sein est le cancer plus diagnostiqué chez les femmes. On estime qu'environ une femme sur sept en sera affectée. La diffusion du cancer du sein aux emplacements secondaires est généralement incurable. L'os est l'emplacement préféré de la métastase, où le développement d'une tumeur secondaire cause de l'osteolyse, de l'hypercalcemie, et une douleur considérable. Cependant, comment les cellules de cancer du sein établissent des interactions supportifs avec des cellules d'os n'est pas bien compris. Nous avons examiné les effets des facteurs libérés des cellules du cancer du sein MDA-MB-231 et 4T1 sur la différentiation des cellules de moelle de la souris C57BL6. Le traitement avec des facteurs cancer-dérivés a produit une diminution de 40-60% des marqueurs de différentiation d'osteoblast, comparé au traitement par l'acide ascorbique, et a induit un changement osteoclastogenique dans le rapport du RANKL/osteoprotegerin. L'exposition des cellules d'os à des facteurs dérivés du cancer du sein a ensuite stimulé l'attachement des cellules cancéreuses aux osteoblasts non mûrs. L'inhibition du γ-secretase utilisant les inhibiteurs pharmacologiques DAPT et le Compound E a complètement inversé l'osteoclastogenise cancer-induit aussi bien que le perfectionnement cancer-induit de l'attachement de cellules cancéreuses, identifiant l'activité de le γ-secretase comme étant le médiateur principal de ces effets. Nous avons ensuite évalué les effets des cellules cancereuse sur le métabolisme énergétique des cellules d'os. Le traitement des cellules de moelle avec le medium conditionné des cellules du cancer du sein 4T1 a eu comme conséquence une augmentation des mitochondries à haut-potentiel de membrane, une augmentation de 2.3 fois le contenu cellulaire de triphosphate d'adénosine, et une consommation plus rapide du glucose. Ce changement de l'énergétique a été accompagné d'une stimulation d'AMPK dans la protéine et l'ADN messagère. Pour évaluer les effets du statut de haute énergie dans les osteoclasts, nous avons élevé l'énergique des osteoclasts avec du pyruvate de sodium. Cette addition a causée une croissance des osteoclasts, avec des plus grands nucleus, et la résorption de plus de substrat. Ainsi, nous avons découvert l'osteoblast comme étant un intermédiaire clé à la signalisation prémetastatique par des cellules du cancer du sein. Nous avons aussi indiqué le γ-secretase comme cible robuste pour le developpement de thérapeutique potentiellement capable de réduire l'autoguidage et la progression des métastases de cancer à l'os. Additonellement, nous avons découvert l'énergétique intensifiée chez les cellules d'os exposées aux facteurs cellule-libérés par le cancer du sein, qui mène à une osteoclastogenesise plus active et plus importante. La modification de la voie d'AMPK peut s'avérer être une cible thérapeutique importante pour que la métastase de cancer du sein aux os.
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Blakemore, Louise Margaret. "Curcumin-induced G2/M cell cycle arrest in colorectal cancer cells." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9809.
Testo completoAbstract (sommario):
Curcumin, a diet-derived chemopreventive and chemotherapeutic agent has been shown to induce G2/M cell cycle arrest, and previous studies suggested that microtubule depolymerisation may be linked to M-phase arrest. However, mechanisms involved have not been elucidated and often non-physiological concentrations of curcumin were used. The goal of this study was to characterise in more detail curcumin-induced cell cycle arrest using a panel of human colorectal cancer cell (CRC) lines, HT-29, SW480, HCT116 p53+/+, HCT116 p53-/- and HCT116 p21-/-. Using physiologically relevant concentrations of curcumin (5-10μM), achievable in the gut tissue following oral ingestion, cell cycle analysis showed that treatment for 12 hours results in significant G2/M arrest in all five cell lines. Curcumin treatment significantly increased the number of cells in M phase in 4 out of the 5 lines tested for this duration, and those with microsatellite instability (HCT116) were found to have a higher mitotic index than those with chromosomal instability. Pre-treatment with caffeine abrogated mitotic arrest in these cell lines, indicating the involvement of the ATM/ATR kinases. Activating phosphorylation of the Chk1 kinase was increased and total protein levels of CDC25C reduced, further implicating the DNA damage pathway in the induction of arrest. Higher levels of HSP70 were also found, indicating proteotoxic stress such as proteasomal inhibition. Image analysis revealed impaired mitotic progression, and significantly higher levels of mitotic spindle abnormalities following curcumin treatment. Aurora B mislocalisation and significantly lower levels of centrosomal separation were found in the HCT116 p53+/+ line. Furthermore, the high levels of pH2A.X staining seen in curcumin-treated mitotic but not interphase cells suggest that aberrant mitosis may result in DNA damage. This proteotoxic and genotoxic stress incurred following curcumin treatment may contribute to the upregulation of NKG2D ligands on the cell surface, leading to CRC lysis and enhancement of the anti-cancer immune response.
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Stordal, Britta. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells." Connect to full text, 2006. http://hdl.handle.net/2123/2467.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of Sydney, 2007.<br>Title from title screen (viewed 10 June 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2007; thesis submitted 2006. Includes bibliographical references. Also available in print form.
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Wilkie, Alexander David. "Evasion of Cell Death in Burkitt’s Lymphoma and Pancreatic Cancer Cells." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367897.
Testo completoAbstract (sommario):
This thesis examined exploitation of cell death to combat cancer from two angles:
investigating cell death signalling pathways to find new targets for treatment, and using the novel anti-austerity approach to combat the tolerance of cancer cells to nutrient deprivation.
Cancers often display high levels of genetic diversity, even within cancers of a particular organ. These genetic differences often make treatments which work with a particular cancer ineffective on another - even from the same origin, and lead to differences in outcomes to selective pressures such as nutrient deprivation. Current treatments are aimed at killing rapidly proliferating cells and often have severe side effects. Their efficacy is highly dependent on early diagnosis and many cancers are resistant to chemotherapeutic drugs. In addition, cancer cells on the inside of tumours have the ability to survive under adverse conditions such as nutrient deprivation due to intermittent blood supply, Therefore, alternative treatment strategies must be explored.
Defects in cell death play a large contributing factor to cancer progression and tumour growth and the evasion of cell death by cancers presents a major problem in its treatment Conventional cancer treatment relies on the activation of cell death in fast growing cancer cells while attempting to leave normal cells undamaged. Therefore, selective triggering of cell death in a cancer cell would be extremely useful. In order to achieve this goal a thorough understanding of the cell death response of a particular cell type to a particular stimulus must be known. Moreover, any novel or unusual cell death signalling pathways would provide more opportunities and targets for attempting to trigger selective cell death in cancers.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Natural Sciences<br>Science, Environment, Engineering and Technology<br>Full Text
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Mai, Thi Trang. "Cell death mechanisms of Marmycin A and Salinomycin in cancer cells." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS014.
Testo completoAbstract (sommario):
Le produit naturel salinomycine (SAL) est largement utilisé comme médicament anticoccidien et maintenant de plus en plus reconnu comme un agent destiné à réduire la proportion de population CD44⁺ / CD24⁻ cellules souches du cancer du sein. Ce facteur est important et intervient lors des rechutes des tumeurs du sein. Pour la première fois, nous avons décrit que l'action n’était pas ionophorique mais que le proton dit "éponge" de la salinomycine ciblait particulièrement la population des cellules souches du cancer. De plus, un analogue alcyne-amine synthétisé de la salinomycine a une action similaire à cette dernière sur la population CD44⁺ / CD24⁻ mais à une concentration inférieure : 30 nM pour 500 nM pour la salinomycine. En utilisant la méthode de clic-imagerie, nous avons observé le composé incolore dans les lysosomes et les auto-lysosomes. En augmentant le pH des vésicules acides, la salinomycine et ses analogues inhibent les activités des cathepsines B, L et D empêchant ainsi l'autophagie. Cette autophagie joue un rôle important dans la survie des cellules souches du cancer conduisant à une augmentation du facteur ROS et à une mort cellulaire par apoptose. Notre étude donne un aperçu du mécanisme par lequel la salinomycine élimine les cellules souches cancéreuses et propose des stratégies pour le traitement de cancers résistants<br>A natural product Salinomycin (SAL) is widely used as an anticoccidial drug now being increasingly recognized as an agent for reducing the proportion of CD44⁺/CD24⁻ breast cancer stem cell which is perceived as important factor for breast tumor relapse. We first time report that not ionophoric action but the proton “sponge” of SAL is responsible for distinguishingly targeting cancer stem cell population. In addition, one SAL-analog alkyne-amine performed the similar action with SAL on CD44⁺/CD24⁻ population but at much lower concentration than SAL, at 30 nM compare to 500 nM of SAL. Using click-imaging method we visually observed the colorless compound saturated in lysosomes and autolysosomes. By raising pH of acidic vesicles, SAL and its analogs inhibit cathepsin B, L, D activity preventing the autophagy which plays an important role in cancer stem cell maintain and survival thus lead to cell death via increasing ROS and apoptosis. Our study provides the insight mechanism how SAL actually eradicates cancer stem cells and suggests sharpened strategies for treating resistant cancers
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Adla, Shalini. "Characterization of the neural cell recognition molecule L1 in breast cancer cells and its role in breast cancer cell motility." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 125 p, 2008. http://proquest.umi.com/pqdweb?did=1459905751&sid=5&Fmt=2&clientId=8331&RQT=309&VName=PQD.
Testo completo
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Chen, Ting-Yeh, and 陳亭曄. "Isolation of colon cancer cells and cancer stem cells from primary colon cancer tissue for establishing patient-specific cancer cell lines." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/7a63c6.
Testo completoAbstract (sommario):
碩士<br>國立中央大學<br>化學工程與材料工程學系<br>106<br>Tumors contain a small subpopulation of cells, i.e., cancer-initiating cells or cancer stem cells (CSCs), which exhibit stem cell properties, possess a self-renewing capacity and are responsible for tumor generation and metastasis. Cancer stem cells persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Furthermore, it is expected to establish primary colon cancer cell lines in vitro, since patient specific colon cancer cell lines is in great advantages of developing patient specific therapy in clinical application.
We are developing a method of establishing cancer cell lines from primary patient colon cancer tissue. Colon cancer tissue is digested by collagenase to generate colon cancer tissue solution. Subsequently, primary colon cancer cell lines were established by (a) culture method on specific culture materials, and (b) the membrane migration method through Nylon mesh filter.1 We investigate which factor is more important to establish the cancer cell lines from minimum amount of colon cancer tissue and determine the optimal conditions to establish patient specific colon cancer cell lines from primary colon cancer tissues. The patient specific colon cancer cell line will be useful for the patient-specific therapy in the future.
In this study, we designed cell sorting dishes from two combined concepts, which are physical cues and biological cues. Different extracellular matrix (ECM) and cell binding domain oligopeptides (biological cues) having different elasticity (physical cues) are immobilized on the cell sorting dishes as biological cues and physical cues for capturing CSCs. Optimal ECM/ECM-derived oligopeptide and elasticity of the dishes for (a) establishment of the patient-specific cancer cell lines and (b) isolation or depletion of CSCs have been shown in this study. Moreover, CSCs identification is quantified by colony forming assay and/or tumor generation in serial xenotransplantation model.
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Lee, Eric, and 李文淵. "The Evolvement of the Cell-Substrate Interaction over Time for Normal Cells and Cancer Cells and for Cancer Cells Treated with Anti-Cancer Medicine." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/38955474704779877017.
Testo completoAbstract (sommario):
碩士<br>國立暨南國際大學<br>生物醫學科技研究所<br>98<br>In this paper, we discussed the cell-substrate interaction by adding several kinds of stimulus to cancer cells and normal cells. In the work, we seeded the living cells onto the silicon wafer surface that was modified with 3- aminopropyltriethoxysilane (γ-APTES)for different periods of time, then removed the cells from the chip and, measured the surface morphology profiles of the γ-APTES layer by atomic force microscopy (AFM) to realize the possible cell-substrate interactions between the cell and the substrate beneath, and to observe the evolvement of cell imprints over time.
The silicon wafer which 2nm-thick SiO2 on the surface was divided into several pieces, the area of each is about 1cm2. The APTES was then coated onto the surface by spin coating process at 3000 rpm, 30s followed by 5 min baking at 120 ℃. All the samples were then put in to a glass container and subjected to a high-temperature and high pressure sterilization process to as sure that no bacteria inflection of the samples. In this work, the human lung adenocarcinoma cells, H1299 and A549, and Madin-Darby Canine Kidney epidermal cell (MDCK),were cultivated first, in an incubator at 37 ℃ and 5 % CO2 environment, and subculturing was carried out for every two days’ cultivation.
After 1, 4, 12, 24 and 72 hr cultivation of the cells on γ-APTES surface, we removed the cells and measured the surface morphology images and profiles of the imprints left on the surface. From the experimental data, we found that the depth of the cell imprints were dependent on the cultivation time. The longer the cultivation time is the deeper the imprint depth will be. However, the imprint depth for the cell after 24 hr cultivation is the same as that after 72 hr cultivation. The difference of the cell imprints between the normal cells (MDCK) and cancer cells (H1299, A549) is that the cancer cells exhibit a deeper trench on one side of the imprints, and the force at the central region of the cell begins to prevail after several hours of cultivation. On the contrary the force of the normal cells seems to be applied to the substrate evenly which causes the cell imprint flat over the whole cell-substrate adhesion region.
In this work, two anti-cancer medicines, staurosporine and Iressa, were added into the cell cultivation solution to see how they affected the cell-substrate interaction. We tried to investigate and explain the role play of these anti-cancer medicines in cell-substrate interaction from the cell molecular biology point of view. The surface morphology profiles of the cells added with different concentration of staurosporine, 10-1, 1, 10, and 102 nM, were measured, which show clearly that the cell imprints are severely influenced by the concentration changes. We noticed that the higher the staurosporine concentration was the shallow the depth of the imprint would be. Cell recovery experiment was also conducted by substitute the staurosporine-contained medium after 24 hr cell cultivation with fresh medium, we found that the final cell imprint of the cell after another 24 hr cultivation was the same as that not being treated with staurosporine. For another anti-cancer medicine Iressa, which has been used particularly to inhibit the epidermal growth factor receptor (EGFR), we found that the cell imprints were not affected by the concentration of Iressa.
In this thesis, a novel method using the post-cell-removal surface morphology profiles measured by AFM was proposed for the investigation of ll-substrate interaction. By adding the cancer cells with anti-medicines, we verified the proposed method is a promising one for cell traction force as well as cell behavior observation.
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Tseng, Ju-Yu, and 曾如玉. "Role of cancer stem cells in colorectal cancers." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/12021328237607934533.
Testo completoAbstract (sommario):
碩士<br>國立陽明大學<br>微生物及免疫學研究所<br>96<br>Colorectal cancer is third common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. Recent observations indicate that, in several types of human cancer, only a phenotypic subset of cancer cells within each tumor is capable of initiating tumor growth. This functional subset of cancer cells is operationally defined as the ‘‘cancer stem cell’’ (CSC) subset. There are two strategies to identify CSCs. Side population (SP) cells have been isolated from several solid tumors, and CRC-CSCs also have a putative marker,CD133 or CD44.We used two strategies to search CSCs candidates in tumor mass and in circulation further prove it exist in circulation by xenotransplantation into NOD/SCID mice. In this study, we found the presences of colorectal cancer cancer stem cell candidates from both tissues and the circulation exhibited interesting correlations to patients’ clinical progression; particularly, the outcome of the stage2A patients (being staged during operation) who had unexpectedly high CSCs will be closely followed-up. While xenotransplantating into NOD/SCID mice, we found tumor growth within lung. It suggests there are CSCs in circulation and xenografted tumor is a pattern almost exclusively in colonic adenocarcinoma.
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Chon, Ka-Hou, and 秦嘉豪. "Dermatopontin Modulates Cell Cycle Progression of Cancer cells." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/77187877083123301322.
Testo completoAbstract (sommario):
碩士<br>國立陽明大學<br>醫學生物技術研究所<br>94<br>The human dermatopontin (DPT), a component of the extracellular matrix, interacts with TGFβ and decorin. The decorin has been shown to suppress the transformation phenotype of colon carcinoma cells. Interestingly, DPT protein sequence is 92% homolog to EQ-1, an early quiescence-1 murine gene, which is induced shortly after
serum deprivation in BALB/c 3T3 cells and its RNA is markedly expressed in heart and lung (1). To test whether DPT is also related to cell quiescence, we have examined its expression in serum-deprived condition in RKO and SKOV3-ip1 cancer cells. We showed that DPT expression was induced in serum-free and suppressed when restimulated with serum by RT-PCR assay. When pCMV-based DPT expression plasmid was transiently transfected into the cells, cell cycle related genes such as D type cyclins were decreased. In contrast, inhibitors of cyclin-dependent kinases, p21 and p27, increased along with the expression of DPT. Most importantly, ectopic expression of DPT appeared to suppress cell proliferation in a MTT assay. In addition, proportion of the cells in G0/G1 phase increased in DPT-transfected cells. To examine whether DPT’s anti-proliferation activity is related to Rb/E2F mediated cell cycle pathway, we tested E2F activity using an E2F-Luc reporter assay. We showed that DPT expression alone did not alter E2F activity. However, DPT expression reduced E1A-mediated E2F activity in a dose dependent manner, suggesting that DPT may be involved in modulating E2F/Rb/E1A complex activity