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Kimura, Yoshito. "ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice." Kyoto University, 2018. http://hdl.handle.net/2433/235986.
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Koustoulidou, Sofia. "Imaging p53 in pancreatic ductal adenocarcinoma." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:5e8aab43-59ca-45d9-9944-48f106e2826e.
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Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic cancer cases and is characterised by poor survival rates and resistance to current therapeutic regimes as the majority of patients present with an already advanced disease at the time of diagnosis. Mutations of the TP53 tumour suppressor gene are a frequent event in tumourigenesis and appear in around 75% of pancreatic cancer cases just before the full development of PDAC and metastasis into the surrounding tissues. Molecular imaging tools, such as SPECT, using monoclonal antibodies specific towards tumour associated antigens, could aid the in vivo characterisation of biological processes and provide a non-invasive method for early diagnosis of cancer. Toward this end, a commercially available mouse monoclonal antibody against total p53 protein (anti-p53 (1C12)) was selected. Anti-p53 (1C12) was first evaluated in vitro regarding its specificity and affinity in cell lines with variable p53 status, derived from a genetically engineered mouse model of PDAC (KPC mice). The subcellular localisation of the p53 protein in the cell lines used was also studied. Following the selection of the antibody, the anti-p53 (1C12) was conjugated to the cell penetrating peptide TAT to facilitate cellular and nuclear translocation and then to p-SCN-Bn-DTPA to allow labeling with 111In. Further in vitro evaluation was performed on the conjugated antibody, conferring subcellular translocation in fixed cells, unaffected binding affinity, favourable radiochemical yield and purity, and stability of the radioconjugate in serum. Retention of the radioconjugates was also observed and was signicantly different when compared to radiolabeled non-specific IgG1-TAT in cells harbouring mutant p53. The ability of 111In-BnDTPA-p53 (1C12)-TAT to selectively target endogenously expressed p53 was assessed in vivo using mouse allograft tumour models of the cell lines evaluated in vitro, and in genetically engineered KPC mice. This provided a preliminary 'proof-of-principle' concept for diagnostic detection of PDAC. The knowledge acquired from the current study may be used to develop a first imaging tracer against p53 which could significantly improve the biological evaluation of cancer.
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Cardenas, Alex. "Sphingosine-1-Phosphate in Pancreatic Ductal Adenocarcinoma." Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/306974.
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Pancreatic ductal adenocarcinoma is an extremely lethal cancer that is difficult to treat. A better understanding of the biology of pancreatic ductal cancer will help to develop targeted therapies that may improve clinical outcomes. Recently, the lipid signaling molecule sphingosine-1-phosphate (S1P) has emerged as a driver of malignant behavior in many types of cancer. Its role in pancreatic cancer remains unknown. Pancreatic cancer cells express high levels of the S1P receptor known as S1PR1, which is the receptor most important for mediating growth and migration through S1P signaling. In addition, the subcellular expression of the sphingosine kinases is altered in pancreatic cancer cells, which may contribute to their malignant behavior. Exogenous S1P increases pancreatic cancer cell migration, while inhibition of S1P signaling decreases the metabolic activity of pancreatic cancer cells as well as their ability to invade and migrate. Taken together, these results demonstrate the importance of S1P signaling in maintaining malignant behavior in pancreatic cancer cells. In addition, inhibition of S1P signaling represents a potential therapeutic target in pancreatic ductal cancer.
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Jacobetz, Michael. "Optimizing drug delivery in pancreatic ductal adenocarcinoma." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609438.
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Machado, de Morais Ferreira R. "Investigating the origins of pancreatic ductal adenocarcinoma." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1473228/.
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Pancreatic ductal adenocarcinoma (PDAC) comprises 85% of all pancreatic cancers and is characterised by an extremely poor prognosis. It is becoming increasingly obvious that attention has to be focused on early tumour development, when the disease is still manageable. Thus, in this study, I aimed to assess the contribution of adult acinar and duct cells to PDAC development and to identify PDAC tumour-initiating cells (TICs). Our laboratory had previously identified Fbw7 as a potent tumour suppressor in PDAC (unpublished data). Fbw7F/F; KRasLSL-G12D/wt; Pdx1-Cre mice exhibited accelerated PDAC onset compared with KRasLSL-G12D/wt; Pdx1-Cre mice. I confirmed this observation and demonstrated that Fbw7 loss in the pancreatic epithelium had a greater proliferative effect in ductal cells, in the presence and absence of KRasG12D, leading to increased numbers of duct cells positive for phosphorylated histone 3. The selective loss of Fbw7 in adult ductal cells with concomitant KRasG12D expression (Fbw7F/F; KRasLSLG12D/ wt; Ck19-CreER mice) led to PDAC development, which was not preceded by mucinous lesions. These results were confirmed with the loss of p53 with simultaneous KRasG12D expression in adults duct cells (p53F/F; KRasLSL-G12D/wt; Ck19-CreER mice). The absence of mucinous PDAC precursors was not dependent on the genotype, as loss of Fbw7 in KRasG12D-expressing acinar cells allowed the development of mucinous murine pancreatic intraepithelial neoplasia (PanIN). Additionally, I induced bystander PanINs using orthotopic transplantation of PDAC cells. These results provide evidence that ductal cells can originate PDAC and that different pancreatic cells types might adopt different routes to PDAC development. Additionally, the observation of bystander PanINs questioned the sole pre-neoplastic nature of these lesions highlighting the need for a deeper understanding of PDAC biology. In the present work, I have also described a new marker of TICs within PDAC derived from pancreatic progenitors and adult ductal cells. Marker-high PDAC cells exhibited higher in vitro organoid-forming capacity, compared with marker-low cells, isolated from the primary tumour and after long-term cultures. Contrasting with marker-low tumour cells, marker-high cells were capable of forming secondary tumours at low numbers, demonstrating efficient tumour-initiating capacity and recapitulating the histology of the primary tumour source. These results could provide useful information for the development of PDAC targeted therapies.
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Lee, Alex Y. L. "Cell of origin in pancreatic ductal adenocarcinoma." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61174.
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Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a ductal morphology. Prior research has identified both pancreatic acinar and ductal cells as possible cells of origin for histologically similar PDAC. However, because different mutations were induced in acinar and ductal cells, apt comparisons could not be made to address whether the tumor cell of origin influences PDAC initiation, development, and other tumor differences. To address this open question, I induced oncogenic Ras expression (KrasG¹²D) with concomitant homozgyous Trp53 deletion at 4 weeks of age in a ductal cell specific (Sox9CreER; KrasLSL-G12D; Trp53flox/flox (“Duct:KPcKO”)) and an acinar cell specific (Ptf1aCreER; KrasLSL-G12D; Trp53flox/flox (“Acinar:KPcKO”)) mouse model. I found that Duct:KPcKO mice met their humane endpoints earlier (82 days post injection, p.i.) than the Acinar:KPcKO mice (128 days p.i.), for reasons associated with differences in the timing of PDAC onset. While tumors from both cells of origin were similarly proliferative and shared many physical characteristics, Duct:KPcKO mice developed tumors much earlier than Acinar:KPcKO mice and this was further associated with a difference in precursor lesion initiation. Specifically, ductal cells only formed high-grade lesions while acinar cells formed precursor lesions of all grades. These findings suggest that cell type intrinsic differences may allow ductal cells to rapidly form PDAC under genetically favorable conditions. In comparison, acinar cells likely require additional steps to alter cell identity and become duct-like – thus delaying PDAC initiation and extending survival. Taken together, I have demonstrated, by using cell type specific mouse models, that cell of origin can alter disease initiation, progression and impact PDAC phenotype.Medicine, Faculty of
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Gall, Tamara. "Predicting disease recurrence in pancreatic ductal adenocarcinoma." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/41847.
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Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is one of the most lethal tumour types worldwide. The majority of patients present late with locally advanced or metastatic disease. Therefore, despite advances in operative techniques, perioperative management and oncological treatments, the overall 5-year survival remains < 5%. The reason for poor survival is due to disease recurrence even after curative surgical resection for small tumours. Determining factors that lead to disease recurrence may help in identifying those with a poor prognosis so that treatment options can be tailored to each patient. We investigated whether operative technique, clinicopathological factors or specific genetic mutations could influence disease recurrence. Further, we sought to identify a biomarker in the peripheral circulation that could be used as a prognostic marker. We confirmed that a positive medial resection margin and a high frequency of KRAS mutation in the tumour tissue result in early disease recurrence. Further, that the altered expression of five microRNAs may be useful as a blood-based prognostic predictor.
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Kawesha, Anthony. "Prognostic molecular markers in resected ductal pancreatic carcinoma." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7596/.
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Previous studies of molecular prognostic markers following resection for exocrine pancreatic cancer have produced conflicting results. The aim of this study was to undertake a comprehensive analysis of potentially useful markers in a large multicentre patient population and compare these markers with standard pathological prognostic variables. Formalin fixed, paraffin-embedded specimens of pancreatic ductal adenocarcinoma were analysed from 157 patients (100 men and 57 women with a median [range] age of 60 [33-77] years) who had undergone pancreatectomy. Immunhistochemistry was used to detect expression of p16\(^{INK4}\), p53, p21\(^{WAF1}\), cyclin D1, c-erbB-2 and c-erbB-3. In a selected number of p53 positive and negative staining cases, mutational analysis was undertaken using DNA obtained from microdissected specimens. Mutations in codons 12 and 13 of the K-ras oncogene were detected by SSCP and sequencing following DNA extraction and amplification by PCR. The median [range] survival post-resection was 12.5 [3-83] months. Abnormalities of p16\(^{INK4}\), p53, p21\(^{WAF1}\), cyclin D1, c-erbB-2 and c-erbB-3 expression were found in 87%, 41%, 75%, 72%, 33% and 57% of cases, respectively. There was no significant correlation between expression of any of these markers and patient survival. K-ras mutations were found in 73 (75%) out of 97% cases with amplifiable DNA. The presence of K-ras mutation alone did not correlate with survival, but there were significant differences in survival according to the type of K-ras mutation (p=0.0007). Reduced survival was found in patients with GaT, cGT and GcT K-ras mutations compared to GtT, aGT and GaC mutations. In conclusion survival was associated with the type of K-ras mutation but not the expression of p16\(^{INK4}\), p53, p21\(^{WAF1}\), cyclinD1, c-erbB-2 and c-erbB3.
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Isohookana, J. (Joel). "Emerging novel prognostic markers in pancreatic ductal adenocarcinoma." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220352.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, the 5-year survival rate being less than 5%. At the time of diagnosis, 90% of PDACs extend beyond the pancreas and distant metastases are often present. Due to aggressive growth, local expansion and early appearance of metastasis, primary PDAC tumours are local enough for curative surgical resection in only 10–20% of the cases. Adjuvant chemotherapy is indicated in these curative-treated cases, with slight improvement in survival. PDAC is considered to represent a heterogeneous group of biologically and prognostically different malignancies. Characterization of these subgroups is essential and there is an urgent need for more accurate biomarkers and targeted treatments in PDAC. In the current work, we immunohistochemically investigated the expression levels and prognostic values of oxidative stress markers (8-OHdG, Keap1, Prx I, II, III, V and VI), epigenetic histone modifiers (KDM4A, KDM4B, KDM4D and SIRT1–4), and cell-cycle regulators (p16, Rb, CDK4) and DNA-repair enzymes (FEN1 and MGMT) in the cohort of surgically treated PDAC patients. We found that Keap1 expression was associated with better pancreatic cancer-specific survival. Expression of antioxidative peroxiredoxins I, III, V and VI was also connected with a more favourable tumour characteristics and Prx I and VI showed prognostic value. When considering the biology of PDAC, we noticed that pivotal epigenetic regulation also occurred in exocrine pancreatic tissue adjacent to resection margins. Overexpression of the cell-cycle regulator CDK4 and the DNA-repair enzyme FEN1 in the whole population, and elevated expression level of MGMT in the most high-risk patients were connected with worse prognosis. The results of the study can be utilized in the future when individualized therapies are being designed for PDAC patients. Due to occurrence of the epigenetic regulation also in exocrine pancreatic tissue adjacent to resection margins, it could be evaluated in future for routine diagnostics and treatment optimization. The potential role of MGMT in the development of PDAC chemoresistance should be studied in the futureTiivistelmä Haiman duktaalinen adenokarsinooma (PDAC) on yksi aggressiivisimmista syöpäsairauksista. Viiden vuoden elossaoloennuste on vain lähellä 5 prosenttia. Diagnoosihetkellä 90% haiman adenokarsinoomista yltää haiman ulkopuolelle ja usein kasvain on jo lähettänyt etäpesäkkeitä. Kasvutaipumuksen sekä metastasoinnin takia kuratiivinen kirurginen hoito on mahdollista vain 10–20% tapauksista. Liitännäissolunsalpaajahoito on aiheellista näissä kuratiivistavoitteisesti hoidetuissa tapauksissa. Kuitenkin vaikutus kokonaiselossaoloaikaan on melko vähäinen. Uusimman tutkimustiedon valossa PDAC:aa pidetäänkin heterogeenisenä ryhmänä biologisesti ja ennusteellisesti erilaisia tautiryhmiä. Näiden tautiryhmien tunteminen ja tunnistaminen riittävän tarkkojen merkkiaineiden avulla olisi ensiarvoisen tärkeää, jotta hoitoja voitaisiin kohdentaa niistä hyötyville potilaille. Väitöskirjatutkimuksessa selvitimme immunohistokemiallisin menetelmin oksidatiivisen stressin merkkiaineiden (8-OHdG, Keap1, Prx I, II, III, V ja VI), epigeneettisten histonimodifikaattorien (KDM4A, KDM4B, KDM4D ja SIRT1–4) sekä solusyklin säätelijöiden (p16, Rb, CDK4) ja DNA-korjausentsyymien (FEN1 ja MGMT) ilmentymistä ja ennusteellista arvoa kirurgisesti hoidetuilla PDAC-potilailla. Tutkimuksessamme totesimme, että kasvainkudoksen Keap1-ilmentymä yhdistyi parempiennusteiseen taudinkuvaan. Antioksidatiivisten peroksiredoksiinien I, III, V ja VI ilmentyminen yhdistyi niin ikään suotuisampaan kasvaimen fenotyyppiin ja Prx I ja VI osoittivat ennusteellista arvoa. Havaitsimme lisäksi, että PDAC:n biologiaan keskeistesti vaikuttavaa epigeneettistä säätelyä tapahtuu myös malignin haimakudoksen viereisessä eksokriinisessä haimakudoksessa. Solusyklin säätelijä CDK4:n ja DNA-korjausentsyymi FEN1:n voimakas ilmentyminen koko tutkimuspopulaatiossa sekä kohonnut MGMT:n ilmentyminen korkeimman riskin potilailla yhdistyivät huonompaan taudin ennusteeseen. Väitöskirjatyön tutkimustuloksia voidaan tulevaisuudessa hyödyntää, kun tutkitaan yksilöllisiä hoitomuotoja PDAC-potilailla. Koska epigeneettistä säätelyä tapahtuu myös syövän viereisessä eksokriinisessa haimakudoksessa, voidaan tulevaisuudessa tämän kudoksen arviointia mahdollisesti käyttää rutiinisti diagnostiikassa sekä hoidon optimoinnissa. MGMT:n mahdollinen rooli PDAC:n kemoresistenssin kehittymisessä tulisi tulevaisuudessa selvittää
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Mohammad, Jiyan Mageed. "Therapeutic Potential of Piperlongumine for Pancreatic Ductal Adenocarcinoma." Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/31347.
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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies because it is often diagnosed at a late disease stage and has a poor response rate to currently available treatments. Therefore, it is critical to develop new therapeutic approaches that will enhance the efficacy and reduce the toxicity of currently used therapies. Here we aimed to evaluate the therapeutic potential and mechanisms of action for piperlongumine (PL), an alkaloid from long pepper, in PDAC models. We postulated that PL causes PDAC cell death through oxidative stress and complements the therapeutic efficacy of chemotherapeutic agents in PDAC cells. First, we determined that PL is one of the most abundant alkaloids with antitumor properties in the long pepper plant. We also showed PL in combination with gemcitabine, a chemotherapy agent used to treat advanced pancreatic cancer, reduced tumor weight and volume compared to vehicle-control and individual treatments. Further, biochemical analysis, including RNA sequencing and immunohistochemistry, suggested that the antitumor activity of PL was associated with decreased cell proliferation, induction of cell cycle arrest, and oxidative stress-induced cell death. Moreover, we identified that c-Jun N-terminal kinase (JNK) inhibition blocks PL-induced cell death, translocation of Nrf2, and transcriptional activation of HMOX1 in PDAC. Finally, high-throughput drug and CRISPR screenings identified potential targets that could be used in combination with PL to treat PDAC cells. Collectively, our data suggests that cell cycle regulators in combination with PL might be an effective approach to combat pancreatic cancer.NIH
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Dawkins, Joshua Benjamin Newton. "Aberrant downstream mechanisms following depletion of KMT2C and KMT2D in Pancreatic Ductal Adenocarcinoma." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/24591.
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Genomic sequencing of pancreatic ductal adenocarcinoma (PDAC) tumours has highlighted the existence of wide genetic diversity alongside frequent mutations in KRAS, TP53 and SMAD4. Within this heterogeneity many components of the epigenetic machinery are mutated, including the histone H3 lysine 4 methyltransferases KMT2C and KMT2D, which are frequently subject to mutation and can identify patients with a more favorable prognosis. In this thesis low expression of KMT2C and KMT2D were shown to also define better outcome groups, with median survivals of 15.9 vs 9.2 months (p = 0.029), and 19.9 vs 11.8 months (p = 0.001) respectively. Experiments across eight human pancreatic cell lines following their depletion suggest that this improved outcome may be due to attenuated cell proliferation, with decreased progression of cells from G0/G1 observed upon KMT2D loss. Whole transcriptome analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes respectively, with 19 common to both. Gene set enrichment analysis revealed a significant downregulation of genes relating to cell-cycle pathways, confirmed by interrogation of the International Cancer Genome Consortium and The Cancer Genome Atlas PDAC data series. Furthermore, these experiments highlighted a potential role for NCAPD3, a subunit of the condensin II complex, as a PDAC outcome predictor across four patient gene expression series. Alongside this, Kmt2d depletion in cells derived from murine models of pancreatic cancer led to an increase in their response to the antimetabolites 5-fluorouracil and gemcitabine. Taken together, the studies herein suggest that lower levels of this methyltransferase may mediate the sensitivity of PDAC patients to particular treatments. Altogether, these data suggest a potential therapeutic benefit in targeting these methyltransferases within PDAC, especially in those patients that demonstrate higher KTM2C/D expression.
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Patil, Shilpa [Verfasser]. "EZH2-GATA6 axis in Pancreatic ductal adenocarcinoma / Shilpa Patil." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1218780746/34.
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Naidoo, Kalnisha. "Molecular mechanisms of lymphatic invasion in pancreatic ductal adenocarcinoma." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8606.
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Pancreatic Ductal Adenocarcinoma (PDAC) is one of the five leading causes of cancer-related deaths in the West, and this, largely, is due to metastatic disease. In order to better understand PDAC metastatic spread and identify novel therapeutic targets, we analysed the proteome of primary tumours and matched lymph node (LN) metastases. As frozen specimens of metastatic lesions are scarce, we examined formalin-fixed paraffin-embedded (FFPE) tissues. Whilst such tissue is in routine diagnostic use, the cross-linkages induced by fixation have, in the past, precluded proteomic investigation for research purposes. Recent technological advances have, however, overcome this technical limitation. Using laser capture microdissection (P.A.L.M system), we isolated malignant epithelia from seven FFPE primary PDAC tumours and matched LN metastases. Following dissection, samples were analysed in duplicate using Multidimensional Protein Identification Technology (MudPIT); this resulted in the identification of 1504 proteins, 854 of which were common to all samples analysed. Comparison of the obtained proteins with data from previous proteomics studies on pancreatic tissue, pancreatic juice, serum and urine resulted in a less than 30 % overlap, indicating that our study has expanded the current database of proteins expressed in this malignancy substantially. Statistical analysis further showed that 115/854 proteins (13.5%) were significantly differentially expressed (g-value ≥ 3.8). Two proteins, S100P and 14-3-3 sigma, with highly significant g-values were confirmed to be significantly differentially expressed (S100P: p = 0.05 and 14-3-3 sigma: p < 0.001) 4 in a larger series of 55 cases of matched primary PDAC and LN metastases using immunohistochemistry. We chose to investigate further the roles of S100P in lymphatic invasion in vitro and in vivo. By co-culturing a Panc1 S100P-overexpressing clone (S5L), or a vector control clone (V3L), with human dermal lymphatic endothelial cells (HDLEC), we were able to show that different receptors mediate S5L adhesion to resting and activated HDLEC as opposed to V3L; and that the presence of S5L cells in these co-cultures significantly increased permeability at one (p = 0.02), four (p = 0.002) and eight (p = 0.007) hours post-seeding, and significantly increased translymphatic endothelial migration at 72 hours (p = 0.006). Using the V3L and S5L cell lines, which were transduced to express luciferase, we also created an orthotopic mouse model of PDAC, as well as experimental metastatic mouse models, in CD1 nude mice. These models were used to evaluate the effects of S100P on primary tumour growth, metastasis and site-specific growth. S100P was only found to significantly increase primary tumour growth in this model (n = 10 animals/group), both by bioluminescence (p = 0.002) and tumour weight (p = 0.01). No metastases (spontaneous and/or experimental) were seen however. Thus, this model can be used to evaluate the anti-tumour efficacy of novel therapies to S100P in the future.
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Arumugam, Prabhu. "Role of polymeric immunoglobulin receptor in pancreatic ductal adenocarcinoma." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/31708.
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Introduction: Polymeric immunoglobulin receptor (pIgR) traffics Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither are expressed in the normal pancreas. Recent work has demonstrated pIgR to be upregulated in hepatocellular carcinoma, even though it is not expressed in normal liver cells. High pIgR levels are associated with poor survival and distant metastases for a number of cancers such as nasopharyngeal cancers, lung and oesophageal cancers. Recent work from our laboratory suggested pIgR may be upregulated in pancreatic ductal adenocarcinoma (PDAC). My aim was to assess pIgR's role in PDAC by interrogating human PDAC tissue samples as well using cell biology experimental tools. Methods: pIgR expression was manipulated (siRNA and shRNA) in cell lines to evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D organotypics models. Tissue Microarrays of patients with PDAC were analysed after pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a combined bio-marker panel. Results: Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα) could not modulate pIgR expression in PDAC cell lines despite this effect being seen in other studies using colorectal and nasopharyngeal cancer cell lines. Downregulation in pIgR expression in Capan1 cell line resulted in reduction of cellular proliferation (n= 3, P < 0.05, Friedman test), adhesion (n= 3, P < 0.05, Kruskal-Wallis) and migration (n= 3, P < 0.05, Kruskal-Wallis). In 3D organotypic models, pIgR downregulation resulted in reduced cancer cell invasion (n= 9, P < 0.05, Kruskal- Wallis) and diminished contraction of gels (n= 9, P < 0.05, Kruskal-Wallis). In human PDAC, decreased E-cadherin expression correlates with increased pIgR expression through pancreatic intra-epithelial neoplasia (PanIN) progression. There was no IgA expression in PDAC. pIgR expression had no clinical correlation with routine prognostic measures such as differentiation, lymph node metastasis (n= 88, P=0.5012, Kruskal-Wallis). Even in combination with stromal indices (α-smooth muscle action (SMA) and Picrosirius red), low pIgR scores had no statistically significant impact on prognosis but had a trend towards better survival (n= 88, P=0.2791, Mann-Whitney U test). Conclusion: pIgR may be involved in progression from pre-neoplastic lesions such as PanIN to PDAC. pIgR may have a biological impact on cellular motility and invasion due to yet to be deciphered signalling cascades with marked effect on cellular phenotype. Careful analysis is required to study the impact of pIgR on prognostic impact bearing in mind the histological sub-types of pancreatic cancer.
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Puleo, Francesco. "Pancreatic ductal adenocarcinoma: From biomarkers discovery to personalized treatment." Doctoral thesis, Universite Libre de Bruxelles, 2018. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/271618.
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En 2016, environ 53 070 patients ont reçu un diagnostic d'adénocarcinome canalaire pancréatique (PDA) aux États-Unis et la plupart d'entre eux mourront de leur maladie dans les 5 ans. Le registre belge du cancer rapporte une incidence estimée à 1200 nouveaux cas par an. La survie globale à 5 ans pour toutes stades confondus a marginalement augmenté au cours des 50 dernières années, passant de 2 à 6%, malgré l'imagerie, les soins périopératoires et l'amélioration des techniques chirurgicales.La chirurgie reste la seule chance de guérison, cependant, seulement 10-15% des patients nouvellement diagnostiqués sont jugés éligibles pour une chirurgie. Même s'il existe peu d'autres modalités de traitement efficaces qui puissent considérablement prolonger la survie globale, la plupart des patients finiront par mourir de métastases au foie, au poumon et / ou au péritoine, les sites de propagation les plus courants. Les patients, les cliniciens et les chercheurs restent frustrés par le manqué d’outils thérapeutiques et des nouvelles stratégies sont nécessaires pour comprendre et mieux prendre en charge cette maladie.Le terme «cancer» engendre un sentiment de peur et colère, en particulier quand on est confronté au diagnostic dévastateur de cancer du pancréas. En plus, une réaction commune est de personnifier le cancer comme une entité maléfique qui doit être combattue pour sauver la vie du patient. Les armes pour cette bataille comprennent le scalpel d'un chirurgien, la chimiothérapie, la radiothérapie, les thérapies ciblées, les immunothérapies, les approches holistiques et la foi religieuse. Mais nous avons trop souvent oublié ou sous-estimé la contribution de la recherche translationnelle pour la médecine de précision, pour mieux adapter les thérapies et éviter les toxicités inutiles.Dans un sens biologique, qu'est-ce qu'un cancer du pancréas ou un cancer? Le cancer est une maladie génétique, soumise à un phénomène évolutif avec ses propres règles, contraintes et caractéristiques prévisibles qui mènent finalement à un phénotype unique.La stratégie "one size fits all" dans la PDA a souvent échoué dans les essais de nouveaux médicaments dans une population non sélectionnée.Cette thèse est une contribution modeste et authentique à une approche plus personnalisée du PDA, de l'acquisition tissulaire, à l'analyse de biomarqueurs tissulaires, à une analyse moléculaire plus profonde afin de mieux comprendre cette maladie mortelle et de proposer l'intégration de biomarqueurs dans le developpement d’etudes cliniques guides par les analyses moléculaires.Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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Nishikawa, Yoshihiro. "Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis." Kyoto University, 2019. http://hdl.handle.net/2433/243291.
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Bonito, Benedetta. "Studies of ion channel mechanisms in pancreatic ductal adenocarcinoma (PDAC)." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/45534.
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Pancreatic Ductal Adenocarcinoma (PDAC) is the most common type of pancreatic neoplasia, accounting for more than 90% of all pancreatic cancer cases. Despite improvements in early diagnosis and treatment, the 5-year survival rate has remained unvaried for many decades. The aim of this PhD project was to elucidate the roles of two specific ion channels in the pathophysiology of PDAC: voltage-gated sodium channel (VGSC) and the Ca2+- activated K+ channel KCa3.1. Human pancreatic cell lines of different metastatic potential were used: HPDE (human pancreatic ductal epithelial) cells, Panc-1, MiaPaCa-2, BxPC-3 and Capan-1 cells. VGSCs, typically expressed in neuronal, ‘excitable’ cells, were also found earlier to be functional in several different carcinomas, where they are linked to promotion of the metastatic potential. KCa3.1, which serves a diversity of physiological roles such as cell-volume regulation in erythrocytes and migration in macrophages and microglia, may also promote tumour invasiveness as shown for some tumours including gliomas end endometrial cancer. Initially, the expression of different VGSC subtypes (Nav1.1 - Nav1.7) was screened in PDAC cell lines and abundant levels of mRNA and protein were found. However, whole-cell patch clamp recordings detected a small inward current (~ 30 pA/pF) only in the 10% of MiaPaCa-2 cells, one of the most aggressive cell lines available. Based on the PCR, western blot and patch clamp results obtained, we hypothesized that epidermal growth factor receptor (EGFR) might suppress VGSC expression to protect the Na+/H+ exchanger (NHE1), which has been proposed to serve a ’backbone’ function in driving PDAC metastasis by promoting extracellular acidosis. Indeed, when the EGFR pathway was blocked pharmacologically (by AG1478 10 μM) an increased inward Na+ current was detected by whole-cell patch clamp. Further experiments showed that a combination treatment of AG1478 and TTX (tetrodotoxin) and cariporide (an NHE1 inhibitor) and TTX could reduce cell migration further than treatments alone. This suggested that inhibition of the EGF-EGFR signalling cascade increases VGSC activity and this promoted metastatic cell behaviours. We also found that KCa3.1 channel was overexpressed at mRNA, protein and functional levels in PDAC compared to control cells . We demonstrated both pharmacologically and by gene - silencing approach that this channel regulated the migration and proliferation of MiaPaCa-2 cell line, revealing its potential as another target for therapy, as it has been also suggested in other carcinomas (i.e. endometrial cancer). These results are discussed in their respective chapters. The Thesis ends with a General Discussion chapter, where recent findings on the pathophysiology of PDAC are further highlighted in relation to the findings of the thesis.
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Sutaria, Dhruvitkumar S. "INVESTIGATION OF DIFFERENTIALLY EXPRESSED NONCODING RNAS IN PANCREATIC DUCTAL ADENOCARCINOMA." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480550158159039.
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Roshan, Moniri Mani. "Pancreatic ductal-derived mesenchymal stem cells : their distribution, characterization and cytotoxic effect on pancreatic cancer cells." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43529.
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Mesenchymal stem cells (MSCs) have attracted significant attention in cancer research as a result of their accessibility, tumor-oriented homing capacity, and the feasibility of auto-transplantation. This study detected the sensitivity of pancreatic cancer cell lines (PCCs) to pancreatic-derived, engineered MSCs under different culture conditions. Pancreatic ductal tissue was extracted from adult human pancreas. MSCs were derived and expanded ex-vivo and verified to fulfil criteria for human MSCs according to the guidelines of the International Society for Cellular Therapy. MSCs were analyzed for distribution and migratory capacity to the site of pancreas and PCCs in in vivo and in vitro models, and found to have homing capacity to the pancreas and towards PCCs (MSCs were attracted to all PCCs compared to normal human A1F8 cells and they displayed significant attraction to the media obtained from cancer cells compared to normal media (p<0.05)). PCCs (BXPC3, ASPC1, Panc-1, TRM6 and HP62) were analyzed by FACS for TNF-α Related Apoptosis Inducing Ligand (TRAIL) receptors. MSCs engineered with non-secreting TRAIL (MSCnsTRAIL) and secreting TRAIL (MSCstTRAIL) and PTEN (MSCPTEN) were used for both direct and indirect co-cultures. TRAIL/PTEN expression was assessed by both ELISA and western blot analysis; higher molecular weight was observed in the MSCnsTRAIL (56kDA) compared with MSCstTRAIL (26kDa). The TRAIL content of supernanatats from MSCstTRAIL was significantly higher than MSCnsTRAIL (p<0.05). PTEN-RFP fusion protein showed a higher molecular weight of 74 kDa in comparison with endogenous PTEN (47 kDa). A real time detection of MSCs cytotoxicity on PCCs displayed proportional cancer cell death to the ratio of conditioned media used from MSCnsTRAIL, MSCstTRAIL, and MSCPTEN. Naive MSCs exhibit intrinsic cytotoxic effect on pancreatic cancer cells and this effect was potentiated by TRAIL/PTEN-engineering. This study provides a practical platform for the development of MSC-based therapy for pancreatic cancer.
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Ge, Ouyang [Verfasser]. "Prognostic value of PALB2 expression in pancreatic ductal adenocarcinoma / Ouyang Ge." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1206183829/34.
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Al-Adsani, Amani Mustafa. "Transdifferentiation of pancreatic AR42J-B13 cells to hepatocyte and ductal phenotypes." Thesis, University of Bath, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503389.
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Cook, Natalie. "The Notch pathway is a therapeutic target in pancreatic ductal adenocarcinoma." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609962.
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Ikuta, Kozo. "Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice." Kyoto University, 2019. http://hdl.handle.net/2433/242408.
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Chan, Derek Steven Hung Che. "Tumoral immune privilege in a murine model of pancreatic ductal adenocarcinoma." Thesis, University of Cambridge, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709503.
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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.
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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.
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Morita, Toshihiro. "CXCR4 in tumor epithelial cells mediates desmoplastic reaction in pancreatic ductal adenocarcinoma." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/264657.
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京都大学新制・課程博士
博士(医学)
甲第23376号
医博第4745号
新制||医||1051(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授 中山 健夫, 教授 佐藤 俊哉, 教授 平井 豊博
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM
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Chan, Michelle Tsz Ting. "Regulation of primary, immortalized, and metatstatic human pancreatic ductal cells by insulin." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43770.
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Epidemiological studies have reported positive correlation between type 2 diabetes and risk of pancreatic cancer. Hyperinsulinemia occurring during early diabetes has been postulated to be a possible pathophysiological mechanism in promoting pancreatic cancer, but the mechanisms by which elevated insulin levels contribute to pancreatic carcinogenesis are still unknown. Here, the effects of insulin and its associated mechanism on cellular viability were examined in three cell models that are meant to represent three stages in pancreatic cancer progression. Furthermore, using small molecule inhibitors, the role of RAF/ERK pathway and PI3K/AKT pathway on cellular viability were also compared across three cell models. Different stages of pancreatic cancer progression were modeled in vitro with primary human pancreatic ductal cells, an immortalized pre-malignant human pancreatic ductal cell line (HPDE), and an advanced metastatic human pancreatic adenocarcinoma cell line (PANC1). All cell types were serum starved and treated with insulin, IGF1, or small molecule inhibitors targeting RAF1, MEK, AKT, or PI3K, then subjected to cell viability assays, cell death assays, and Western blot analysis for ERK and AKT activation. We observed that cell viability was promoted by exogenous insulin in PANC1 cells, and not in primary cells. In PANC1 cells, the insulin-mediated enhancement of cell viability was associated with sustained AKT activation. Furthermore, insulin-mediated reduction in cell death was not observed. When comparing the roles of RAF/ERK and PI3K/AKT pathways on cell viability, we observed an increase in cell death in primary cells when AKT was inhibited. In contrast, cell death was induced in HPDE and PANC1 cells when the RAF1 or MEK were inhibited. If extrapolated, the data suggest that hyperinsulinemia may not play a role in initiating pancreatic cancer, but high levels of insulin may accelerate the cancer progression.
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Distler, Marius, Felix Rückert, Maximilian Hunger, Stephan Kersting, Christian Pilarsky, Hans-Detlev Saeger, and Robert Grützmann. "Evaluation of survival in patients after pancreatic head resection for ductal adenocarcinoma." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-127053.
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Background: Surgery remains the only curative option for the treatment of pancreatic adenocarcinoma (PDAC). The goal of this study was to investigate the clinical outcome and prognostic factors in patients after resection for ductal adenocarcinoma of the pancreatic head.
Methods: The data from 195 patients who underwent pancreatic head resection for PDAC between 1993 and 2011 in our center were retrospectively analyzed. The prognostic factors for survival after operation were evaluated using multivariate analysis.
Results: The head resection surgeries included 69.7% pylorus-preserving pancreatoduodenectomies (PPPD) and 30.3% standard Kausch-Whipple pancreatoduodenectomies (Whipple). The overall mortality after pancreatoduodenectomy (PD) was 4.1%, and the overall morbidity was 42%. The actuarial 3- and 5-year survival rates were 31.5% (95% CI, 25.04%-39.6%) and 11.86% (95% CI, 7.38%-19.0%), respectively. Univariate analyses demonstrated that elevated CEA (p = 0.002) and elevated CA 19–9 (p = 0.026) levels, tumor grade (p = 0.001) and hard texture of the pancreatic gland (p = 0.017) were significant predictors of a poor survival. However, only CEA >3 ng/ml (p < 0.005) and tumor grade 3 (p = 0.027) were validated as significant predictors of survival in multivariate analysis.
Conclusions: Our results suggest that tumor marker levels and tumor grade are significant predictors of poor survival for patients with pancreatic head cancer. Furthermore, hard texture of the pancreatic gland appears to be associated with poor survival.
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Ene-Obong, Abasi E. "Immune cell infiltration and interaction with stellate cells in pancreatic ductal adenocarcinoma." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8305.
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Pancreatic ductal adenocarcinoma (PDAC) is a disease with very poor prognosis amongst all pancreatico-biliary cancers. PDAC is characterised by a pronounced desmoplastic stroma which upon depletion has been associated with immune cell mediated tumour clearance. In situ analyses of various immune cell markers in the stromal compartments may provide a lucid picture of immune cell migration to the tumour epithelia. Automated, unbiased, high throughput imaging and analysis of specifically designed tissue microarrays, from surgically resected tissue samples of PDAC, advanced PDAC, and other pancreatico-biliary diseases; stained for distinct immune cell markers was carried out in the juxtatumoural stroma and the panstromal compartments. Prognostic significance was determined with X-Tile software. In vitro and in vivo assays were undertaken to outline the possible mechanisms. Immune cell infiltration to PDAC was higher than infiltration to other pancreatico-biliary diseases with the exception of CD8+ T cells. While CD4+, CD68+ and myeloperoxidase+ cells could infiltrate the juxtatumoural stroma of PDAC; CD3+, CD8+, Foxp3+ and CD20+ cells could not in the early stage PDAC patients tissue analysed and also in an independent validation cohort of advanced stage PDAC patients. Survival analyses demonstrated pro-survival effects of having high CD8+ densities. CD8+ T cells could only infiltrate the juxtatumoural compartment of KPC mice after stromal collapse resulting from targeting stellate cells with All-trans Retinoic Acid. 17 In vitro migration assays demonstrated increased CD8+ T cell migration towards activated pancreatic stellate cells compared to quiescent pancreatic stellate cells and appeared to be dependent on CXCL12. T cells are hindered from migrating to the juxtatumoural compartment by activated pancreatic stellate cells as a result of an increase in CXCL12 secretion. Rendering activated pancreatic stellate cells quiescent results in a reduction of CXCL12 secretion which may allow CD8+ T cells to migrate to the tumours and perform cytotoxic functions.
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James, Andrew. "Metabolic regulation of the plasma membrane calcium pump in pancreatic ductal adenocarcinoma." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/metabolic-regulation-of-the-plasma-membrane-calcium-pump-in-pancreatic-ductal-adenocarcinoma(0533b59c-e6ee-41fb-ad32-cb4784eadfa1).html.
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with poor prognosis and limited treatment options. Since many patients present with metastatic disease and are thus ineligible for surgical resection, PDAC is almost ubiquitously fatal; new treatment options are therefore needed to combat this disease. A key hallmark of many cancers, including PDAC, is metabolic reprogramming and a shift towards a high glycolytic rate, known as the Warburg effect. This allows cancer cells to generate ATP in the face of hypoxia and to meet the increased metabolic requirements associated with rapid proliferation. We hypothesised that this shift towards glycolytic metabolism has important implications for the regulation of cytosolic Ca2+ ([Ca2+]i) in PDAC, since the plasma membrane Ca2+ ATPase (PMCA), which is critical for maintaining low [Ca2+]i and thus cell survival, is dependent on ATP to extrude cytosolic Ca2+. The relative contributions of mitochondrial vs glycolytic ATP in fuelling the PMCA in human PDAC cell lines (PANC-1 and MIA PaCa-2) were therefore assessed. Moreover, the effects of numerous mechanistically distinct metabolic inhibitors on key readouts of cell death, [Ca2+]i and ATP were investigated. Treatment with glycolytic inhibitors induced significant ATP depletion, PMCA inhibition, [Ca2+]i overload and cell death in both PANC-1 and MIA PaCa-2 cells, while mitochondrial inhibitors had no effect. Subsequently, these experiments were repeated on PDAC cells cultured in media formulated to "switch" their highly glycolytic phenotype back to one more reliant on mitochondrial metabolism. Culture in nominal glucose-free media supplemented with either galactose (10 mM) or alpha-ketoisocaproate (KIC, 2 mM) resulted in a switch in metabolism in MIA PaCa-2 cells, where proliferation rate and glycolysis were significantly decreased, and in the case of cells cultured in KIC, oxidative phosphorylation rate was preserved (assessed using Seahorse XF technology). Following culture of MIA PaCa-2 cells in either galactose or KIC, glycolytic inhibition failed to recapitulate the profound ATP depletion, PMCA inhibition and [Ca2+]i overload observed in glucose-cultured MIA PaCa-2 cells. These data demonstrate that in PDAC cells exhibiting a high rate of glycolysis, glycolytically-derived ATP is important for fuelling [Ca2+]i homeostasis and thus is critical for survival. Finally, using a cell surface biotinylation assay, the keyglycolytic enzymes LDHA, PFKP, GAPDH, PFKFB3 and PKM2 were all found to associate with the plasma membrane in MIA PaCa-2 cells, possibly in a tyrosine phosphorylation-dependent manner. To investigate whether the dynamic membrane-association of glycolytic enzymes provides a privileged supply of ATP to the PMCA in PDAC, the effects of tyrosine kinase inhibitors was assessed on PMCA activity. However, while these inhibited PMCA activity, this occurred without accompanying global ATP depletion. These data indicate that glycolytic ATP is critical for the regulation of [Ca2+]i by the PMCA in PDAC, and that the glycolytic regulation of the PMCA may be an important therapeutic locus. However, further research is required to determine whether membrane-bound glycolytic enzymes regulate its activity.
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Jenq, Harry. "Identifying genes that are required for the maintenance of pancreatic ductal adenocarcinoma." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/78151.
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Thesis (Ph. D. in Biomedical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2012.Cataloged from PDF version of thesis. Vita
Includes bibliographical references.
We searched for genes that are potentially important for the maintenance of Pancreatic Ductal Adenocarcinoma (PDAC). PDAC is the 4th leading cause for cancer-related deaths and exhibits a 5-year survival rate of less than 5%. Since PDAC is a Kras-driven cancer in that greater than 90% of PDACs contain a Kras mutation, we tested genes that are downstream of Kras. We used RNAi technology to inhibit approximately 30 genes in the canonical Kras effector pathways, Mapk, Pi3k, and Ral. These genes were tested in the context of mouse cell lines derived from a genetically engineered mouse model of PDAC with conditional mutations in Kras G12D and p53. An individual gene-by-gene approach and a pooled high-throughput screening strategy were taken to identify important genes. We identified mTOR, and to a lesser extent, Raptor and Rictor, as genes that are important for the maintenance of PDAC both in vitro and in vivo. In addition, we show that inhibition of mTOR and Raptor are synthetic lethal in that PDAC lines are sensitive to their inhibition, while non-tumorigenic cell lines are not as sensitive. Moreover, inhibition of mTOR results in downregulation of mTORCl and mTORC2 targets, while inhibition of Raptor induces downregulation of only mTORC 1 targets. As combination therapies are likely to be more effective, we looked for a drug that could combine effectively with mTOR and Raptor. From screening several small molecule drugs that target the Mapk and Pi3k pathways, we found PDAC lines to be particularly sensitive to AZD6244, while normal cell lines are significantly less sensitive. The combination or either an mTOR or Raptor hairpin and AZD6244 was found to be additive in that the effect on viability is significantly greater than that of each intervention alone. Another approach to combinations is to combine two drugs. AZD6244 and BEZ235, an inhibitor of Pi3k and mTOR, were tested in combination on both PDAC and normal cell lines. The combination was synergistic in PDAC lines but not in normal lines, suggesting that the combination may be effective with low toxicity. In summary, through a screen, we have identified mTOR, Raptor, and Rictor, as being critical components for the maintenance of PDAC.
by Harry Jenq.
Ph.D.in Biomedical Engineering
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Burdyga, Alex. "Control of cAMP signalling in the cellular migration of pancreatic ductal adenocarcinoma." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/12081/.
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Pancreatic ductal adenocarcinoma (PDAC) is characterised by a very high mortality rate and is the 4th most common cause of cancer death (Siegel et al., 2012). The disease initially develops asymptomatically, and at the time of diagnosis patients usually have multiple metastases (Rhim et al., 2012). It would therefore be highly desirable to develop treatments which specifically impede the ability of PDAC cells to metastasise by interfering with the cellular processes responsible for efficient cellular migration. Intracellular signalling cascades, which utilise various signalling proteins, ultimately lead to the appropriate cell coordination and enable efficient cellular motility. One such signalling pathway that participates in the regulation of migration is controlled by the second messenger cyclic adenosine monophosphate (cAMP) (Howe, 2004). Several effectors of cAMP have been found which include protein kinase A (PKA) (Tasken & Aandahl, 2004), exchange factors activated by cAMP (EPAC) (Bos, 2006), and cyclic nucleotide-regulated cation channels (Biel, 2009). PKA has been intimately linked with several cellular processes which contribute towards cell motility. In most cases, the various specific effects of PKA signalling require selective targeting of the kinase into microdomains through interaction with A-kinase-anchoring proteins (AKAPs) (Pidoux & Tasken, 2010). Other cAMP effectors such as EPAC have defined roles in controlling various aspects of migration, such as cellular adhesion to the extracellular matrix (Bos, 2005). The effect of modulating cAMP signalling on the rate of migration has been investigated in several cancer types. Interestingly the results obtained were rather varied; both inhibition and stimulation of migration was observed (Chen et al., 2008; Baljinnyam et al., 2009; Grandoch et al., 2009; Shaikh et al., 2012). However, the effect of cAMP, and its effectors, on the rate of migration has not been investigated in PDAC; this was the main aim of this study. Classical cAMP elevating agents such as forskolin and 3-Isobutyl-1-methylxanthine (IBMX), as well as the cAMP analogue 8-Bromoadenosine 3’5’-cyclic monophosphate (8Br-cAMP), were found to inhibit migration of the PANC-1 cells. The role of cAMP signalling was further supported by the results of experiments utilising cAMP FRET sensors, which were imaged in live single cells. Further characterisation of cAMP effects in 4 other diverse PDAC cell lines yielded similar results, indicating that the mechanism of inhibition was common to all PDAC cell types tested. PANC-1 cell invasion was also inhibited by cAMP elevation. I went on to investigate events such as cell ruffling and focal adhesion assembly, which are processes closely associated with cellular motility. Dual transfection with a cAMP sensor and GFP tagged paxillin revealed a relationship between cAMP elevation and the loss of paxillin from focal adhesions, which was quickly reversible upon cAMP returning back to basal levels. Using a similar approach, peripheral cell ruffling was found to be inhibited by intracellular cAMP elevation. These results indicated that the inhibition of migration upon cAMP elevation was likely to occur as a result of immediate signalling events (and not due to cAMP-dependent changes in gene expression). The final part of the project concentrated on the individual contribution of the downstream effectors of cAMP, with particular emphasis on selective PKA and EPAC modulation. Utilising both PKA and EPAC sensors, I determined the appropriate concentrations of N6-benzoyl-cAMP (6Bnz) and 8-pCPT-2’OMe-cAMP (8pCPT) required to achieve selective PKA and EPAC activation respectively. Interestingly, I found that the two effectors had opposing actions; EPAC activation was found to induce migration, while PKA was found to suppress migration. Further investigation utilised a potent and selective PKA inhibitor peptide (PKI), which upon expression was found to prevent inhibition of ruffling, paxillin loss from focal adhesions, and inhibition of migration in response to cAMP elevation. Furthermore, it was found that suppression of basal PKA activity had a tendency to induce migration. I also utilised a cell permeable peptide (st-Ht31) which inhibits PKA interaction with AKAPs, thus effectively reducing its function by uncoupling the kinase from its specific signalling microdomains. The resulting effect was found to be a large potentiation of PANC-1 migration, which further highlighted the importance of PKA activity in the control of migration.
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Kondratska-Klymenko, Kateryna. "Role of calcium-permeable channels in pancreatic ductal adenocarcinoma resistance to chemotherapy." Thesis, Lille 1, 2015. http://www.theses.fr/2015LIL10099/document.
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L'adénocarcinome pancréatique (PDAC) est la forme la plus fréquente de néoplasme de cet organe puisqu’il représente environ 90% de toutes les tumeurs pancréatiques et constitue l'une des principales causes de décès par cancer chez l’Homme. Le taux de survie à 5 ans n’est que de 6%. L'une des raisons à cela est que, au début du développement du cancer du pancréas, il n'y a pas de symptômes, et donc la majorité des cas sont diagnostiqués à des stades tardifs métastatiques ou invasifs pour lesquels une intervention chirurgicale n’est plus possible. Il a été montré que les cellules du cancer du pancréas présentent plusieurs mutations génétiques qui conduisent à la prolifération incontrôlée des cellules, ainsi qu’à l'évasion de l'apoptose. Les changements de concentration du Ca2+ cytosolique jouent un rôle central dans de nombreux processus cellulaires fondamentaux, et la perturbation des mécanismes de régulation de l'homéostasie du Ca2+ conduit à une grande variété de pathologies graves, dont le cancer. C’est notamment le cas pour les canaux calciques de type SOC, qui régulent une variété de processus cellulaires dépendants du calcium. Cependant, bien que le rôle du Ca2+ et des canaux calciques soit bien établi dans de nombreuses voies de signalisation de différents types cellulaires, les informations sur le rôle des canaux calciques dans le PDAC sont limitées. Donc, l'identification de la nature moléculaire ainsi que des fonctions des canaux calciques revêt une grande importance dans ces cellules car elle pourrait à termes fournir de nouvelles approches relatives au traitement du cancer du pancréas par le ciblage des processus dépendants du calciumPancreatic ductal adenocarcinoma (PDAC) representing the most prevalent pancreatic neoplasm accounting for about 90% of all pancreatic tumors, is one of the leading causes of cancer death in men and women. The current five-year relative survival rate is about 6% . One of the reasons of this is that early stage pancreatic cancer usually has no symptoms and thus the majority of cases are diagnosed at the late metastatic or invasive stages which are not suitable for surgery. Pancreatic cancer cells have been shown to exhibit a number of genetic mutations leading to uncontrolled cell proliferation, as well as evasion of programmed cell death (apoptosis). Changes in the cytosolic free Ca2+ concentration, play a central role in many fundamental cellular processes and disturbance of the Ca2+ homeostasis regulatory mechanisms leads to a vast variety of severe pathologies, including cancer. Among these, store-operated calcium channels (SOCs) have been shown to regulate a variety of calcium dependent cellular processes altered in different cancers. However, although the role of Ca2+ and calcium-permeable channels is well established in many signaling pathways in a variety of cell types, the information of the role of calcium-permeable channels in PDAC cells is limited. Therefore, identification of the molecular nature as well as functions of calcium-permeable channels in these cells is of great importance as it can reveal novel approaches for treating pancreatic cancer through targeting calcium-dependent processes
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Yuan, Yuan. "Small-Molecule Modulators of Pancreatic Ductal Cells: Histone Methyltransferases and \(\beta\)-Cell Transdifferentiation." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10637.
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Small molecules are important not only for treating human diseases but also for studying disease-related biological processes. This dissertation focuses on the effects of small molecules on pancreatic ductal adenocarcinoma cells. Here, I describe the discovery of two small-molecule tool compounds and their applications for interrogating the biological processes related to two distinct diseases in the human pancreas. First, BRD4770 was identified as a histone methyltransferase inhibitor through a target-based biochemical approach, and was used as a probe to study the function of methyltransferases in cancer cells. Second, BRD7552 was discovered as an inducer of Pdx1 using a cell-based phenotypic screening approach, and was used to induce the expression of Pdx1, a master regulatory transcription factor required for \(\beta\)-cell transdifferentiation. This compound is particularly interesting for the study of type-1 diabetes (T1D). The histone methyltransferase G9a catalyzes methylation of lysine 9 on histone H3, a modification linked to aberrant silencing of tumor-suppressor genes. The second chapter describes the collaborative effort leading to the identification of BRD4770 as a probe to study the function of G9a in human pancreatic cancer cells. BRD4770 induces cellular senescence and inhibits both anchorage-dependent and -independent proliferation in PANC-1 cell line, presumably mediated through ATM-pathway activation. Chapter three describes the study of a natural product gossypol, which significantly enhances the BRD4770 cytotoxicity in p53-mutant cells through autophagic cell death. The up-regulation of BNIP3 might be responsible for the synergistic cell death, suggesting that G9a inhibition may help overcome drug resistance in certain cancer cells. Ectopic overexpression of Pdx1, Ngn3, and MafA can reprogram pancreatic exocrine cells to insulin-producing cells in mice, which sheds light on a new avenue for treating T1D. The fourth chapter focuses on a gene expression-based assay using quantitative real-time PCR technique to screen >60,000 compounds for induction of one or more of these three transcription factors. A novel compound BRD7552 which up-regulated Pdx1 mRNA and protein levels in PANC-1 cells was identified. BRD7552 induces changes of the epigenetic markers within the Pdx1 promoter region consistent with transcriptional activation. Furthermore, BRD7552 partially complements Pdx1 in cell culture, enhancing the expression of insulin induced by the introduction of the three genes in PANC-1 cells. In summary, the central theme of my dissertation is to identify novel bioactive small molecules using different screening approaches, as well as to explore their effects in pancreatic ductal cells.Chemistry and Chemical Biology
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Johnson, Natalie Georgette. "The stellate cancer-associated fibroblast in pancreatic ductal adenocarcinoma : its role in chemoresistance." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/23991.
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Introduction: The tumour microenvironment has been found to contribute to cancer survival and progression, and more specifically, the stromal microenvironment has been implicated in the drug resistant nature of cancers such as pancreatic cancer. This microenvironment consists of fibroblasts, pericytes, endothelial cells and the extracellular matrix, with the stellate cancer-associated fibroblast (CAF) being the most predominant cell type present. The aim of this study was to investigate the role of the cancer associated fibroblast in tumourigenesis in Pancreatic Ductal Adenocarcinoma (PDA) with specific reference to the mechanisms involved in chemoresistance via the stellate cancer associated fibroblast. Methods: I investigated the molecular pathogenesis of PDA assessing DNA copy number alterations (CNA) in selection of clinically relevant PDA cell lines (PANC-1, MiaPaCa-2, ASPC-1, SU86.86, HPAC, HS776T, PL5 and PL45), seven primary resected, non immortalised samples (PF3, PF7, PF8, PF9, PF16, PF18 and PF20) and an immortalised stellate cell line using array comparative genomic hybridization (aCGH). All cultures and cell lines were then screened in order to determine their sensitivity to currently used therapeutic compounds. Analysis was done using R software and Graph Pad Prism 5. Results: The non-immortalised stellate CAFs and formalin fixed paraffin embedded stromal fibroblast samples showed no homozygous genomic CNAs. The stellate cancer associated fibroblasts both primary and immortalised appear more responsive to the chemotherapeutic drugs in the compound library compared to the PDA cell lines. Conclusions: This study suggests the absence of homozygous deletions that may lead to a change in phenotype in the stellate CAF. However, the presence of heterozygous deletions and epigenetic changes has not yet been excluded. Further experiments such as micro RNA and epigenetic studies, such as SNP arrays, may identify the presence of aberrations that have aetiological significance in carcinogenesis even if they do not result in CNVs. This higher sensitivity of the stellate CAF to the drugs in the chemotherapy library may favour them as potential targets for management of this hard to street subtype of disease.
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Marchesi, Federica. "Chemokines and their receptors in the metastatic behaviour of human pancreatic ductal adenocarcinoma." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429531.
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N'Guessan, Kombo F. "Phosphatidylserine Externalization in Pancreatic Ductal Adenocarcinoma: Elucidating Mechanisms of Regulation for Combination Therapy." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595847418811418.
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Bell, Leanne Katherine. "Evaluation of tumour perfusion and fibrosis in mouse models of pancreatic ductal adenocarcinoma, using MRI." Thesis, University of Cambridge, 2013. https://www.repository.cam.ac.uk/handle/1810/265615.
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Pancreatic Ductal Adenocarcinoma (PDA) is one of the most lethal solid malignancies primarily because it is staunchly resistant to conventional cytotoxic chemotherapies. Xenograft models are typically not sophisticated enough to reproduce the complex pathophysiology of the clinical disease. This is the main reason why treatments that have shown promise in preclinical mouse models have not translated into improvements in median survival in the clinic. Genetically engineered KPC mice develop PDA in situ which recapitulates the genetic, molecular and pathophysiological features of human PDA. Spontaneous KPC tumours are also chemoresistant and this mouse model therefore provides an ideal platform from which to study the biology of PDA. Recent evidence suggests that poor perfusion and extensive fibrosis may prevent the delivery of cytotoxic agents to neoplastic PDA cells and are therefore at least in part responsible for the chemoresistance demonstrated by human PDA tumours and spontaneous KPC tumours. In this thesis we use non-invasive Magnetic Resonance Imaging techniques (Dynamic ContrastEnhanced (DCE-) MRI, Magnetisation Transfer Imaging (MTI)) and SHG microscopy to evaluate the perfusion properties and fibrosis of three different mouse models of PDA: spontaneous KPC tumours, allografts initiated by transplantation of pancreatic tumour cells derived from a KPC tumour, and allografts initiated by co-transplantation of these cells with pancreatic stellate cells (fibrotic allografts). Using DCE-MRI and MTI we showed that the perfusion of spontaneous KPC tumours and fibrotic allografts decreases with increasing tumour volume while the tumour macromolecular content increases with increasing tumour volume. This is in contrast to the viable portion of non-fibrotic allografts which have a low macromolecular content and exhibit sustained moderate perfusion irrespective of tumour volume. Ex viva SHG microscopy clearly showed differences in the type, distribution and magnitude of fibrosis in these models. Using MTI, we showed a differential between spontaneous and transplanted tumours, but not between fibrotic and non-fibrotic allografts. We subsequently investigated the ability of MTI to detect treatment-induced depletion of the stroma in spontaneous KPC tumours, to assess its possible application as a non-invasive biomarker for treatment response in the clinic. However, we were unable to detect such depletion by MTI, although ex viva SHG microscopy confirmed that it did occur. In summary, our results contribute to the body of know_ledge on the biology of PDA and strengthen the evidence that early detection of PDA would be required to improve the chances of effective drug delivery to PDA tumours.
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Kojima, Kyoko. "Mouse modeling of pancreatic ductal adenocarcinoma (PDAC) search for early diagnostic markers and therapeutic targets /." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009p/kojima.pdf.
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Balmaña, Esteban Meritxell. "Pancreatic cancer markers based on aberrant glycosylation of serum proteins." Doctoral thesis, Universitat de Girona, 2016. http://hdl.handle.net/10803/392636.
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Cancer is one of the leading causes of death worldwide. Pancreatic ductal adenocarcinoma (PDAC) is characterized by high intrinsic aggressiveness and late diagnosis, causing poor prognosis and resulting in the lowest five-year survival rate among all cancers. Nowadays, there is no biomarker for PDAC diagnosis approved. The survival rate of cancer patients increases when they are diagnosed in the early stages of the pathology; and for this reason, the research of new biomarkers is of great interest.
Tumour cells present aberrant glycosylation on their cell surface and also in the secreted glycoconjugates. Hence, a strategy for new tumour biomarker discovery is based on the identification of specific glycoforms.
This work has explored the glycosylation of two serum glycoproteins, the alpha-1-acid glycoprotein (AGP) and the ceruloplasmin (CP). The glycosylation of the epithelial mucins MUC1 and MUC5AC in healthy and PDAC tissues has also been analysed.El càncer és una de les principals causes de mort. L’adenocarcinoma ductal pancreàtic (PDAC) es caracteritza per una alta agressivitat i un diagnòstic tardà, causant un pronòstic desolador i resultant en el càncer amb la taxa relativa de supervivència als cinc anys menor. Actualment no es disposa d’un biomarcador per al diagnòstic del PDAC.La supervivència dels pacients augmenta quan són diagnosticats en els estadis inicials; per aquest motiu, la recerca de nous marcadors és de gran importància. Les cèl·lules tumorals presenten una glicosilació aberrant en la seva superfície cel·lular i també en els glicoconjugats que secreten. Per tant, una estratègia per al descobriment de nous biomarcadors es basa en la identificació de glicoformes específiques. Aquesta tesi ha explorat la glicosilació de dues glicoproteïnes del sèrum, la alfa-1-glicoproteïna àcida i la ceruloplasmina. També s’ha analitzat la glicosilació de les mucines epitelials MUC1 i MUA5AC en teixits sans i de PDAC.
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Alrawashdeh, Wasfi. "Molecular characterization of perineural invasion in pancreatic ductal adenocarcinoma : proteomic analysis and in vitro modelling." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8699.
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Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the 5th most common cause of cancer death in the UK. One of the peculiarities of this malignancy is its ability to invade nerves, a process called perineural invasion (PNI). PNI is found in almost 100% of PDAC, and is associated with poor prognosis, tumour recurrence and generation of pain. However, the molecular bases of PNI remain largely unknown. We investigated the molecular alterations underlying the neuro-epithelial interactions in PNI using one and two dimensional liquid chromatography – mass spectrometry (1D and 2D LC-MS) of laser microdissected PNI and non-PNI cancer from formalin fixed, paraffin embedded PDAC tissues. We also performed 1D LC-MS analysis of invaded and non-invaded nerves from the same cases. In addition, we developed an in vitro model of PNI using a co-culture system comprising PC12 cells, a rat pheochromocytoma cell line, as the neuronal element and PDAC cell lines. The overall proteomic profiles of PNI and non-PNI cancer appeared largely similar; of very few deregulated proteins, we have validated the up-regulation of antiapoptotic protein Olfactomedin 4 in PNI cancer using immunohistochemistry. In contrast, nerve samples demonstrated widespread molecular alterations characteristic of neuronal plasticity upon invasion by cancer cells. Immunohistochemistry confirmed the up-regulation of VGF in nerves from PDAC and chronic pancreatitis (CP) specimens compared to normal pancreas, as well as in invaded compared to non-invaded nerves in PDAC tissues. Furthermore, VGF expression strongly correlated with pain in CP; similar analysis in PDAC cases is still pending. Using the in vitro co-culture model, several PDAC cell lines were able to induce PC12 cells neuronal plasticity including survival, neurite extension as well as VGF expression, recapitulating thus the changes observed in human tissues. PDAC-induced PC12 plasticity was not mediated via NGF, a neurotrophin acting upstream of VGF and thought to be involved in the neuro-epithelial interactions. The induction of VGF expression was shown not to be necessary for PC12 cell survival, however, it contributed to the neurite extension induced by PDAC cell lines. In summary, based on proteomics analysis and in vitro modelling, we show the complex and intricate involvement and crosstalk of both tumoral and neural elements that are activated during perineural invasion in pancreatic cancer.
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Pérez, Garay Marta. "Role of alpha 2,3-sialyltransferases ST3Gal III and ST3Gal IV in pancreatic ductal adenocarcinoma." Doctoral thesis, Universitat de Girona, 2011. http://hdl.handle.net/10803/7644.
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Este trabajo demuestra que los genes que codifican para los enzimas beta-galactosido alfa-2,3-sialiltransferasa 3 (ST3Gal III), y en menor medida beta-galactosido alfa-2,3-sialiltransferasa 4 (ST3Gal IV), están directamente implicados en etapas clave de la progresión tumoral como la adhesión, la migración y la formación de metástasis en las líneas de adenocarcinoma pancreático humano Capan-1 y MDAPanc-28. También, que las Especies Reactivas del Oxígeno (ROS) generadas durante los procesos de proliferación y diferenciación celular o debido a estímulos oxidantes externos, desempeñan un importante papel en el control de la síntesis de ST3Gal III y SLex, y por lo tanto en la regulación del fenotipo metastático. Además, junto al papel pro-adhesivo de la E-Selectina, este trabajo ha descrito efectos prometastáticos adicionales para esta molécula como inductora de la migración y de la secreción de VEGF a través de un mecanismo E-Selectina-SLex dependiente.This work shows that genes that codifying for the enzymes beta-galactoside alpha-2,3-sialyltransferase 3 (ST3Gal III), and in a lower extent beta-galactoside alpha-2,3-sialyltransferase 4 (ST3Gal IV) , are directly implicated in key steps of tumour progression such as adhesion, migration and metastasis formation in the pancreatic adenocarcinoma cell lines Capan-1 and MDAPanc-28. Moreover, Reactive Oxygen Species (ROS) generated in these cell lines during cell proliferation-differentiation processes or by external oxidant stimuli, play a role in the control of ST3Gal III and SLex levels and in the acquisition of a more aggressive phenotype. And, together with the pro-adhesive role of E-Selectin for circulating cells, this work uncovers sE-Selectin dependent migration and VEGF secretion through a SLex depending mechanism, supporting additional pro-metastatic effects for sE-Selectin-SLex interaction.
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Amaravadi, Mohanachary [Verfasser], and Roland [Akademischer Betreuer] Eils. "Identification of pathogenic virus sequences in pancreatic ductal adenocarcinoma / Mohanachary Amaravadi ; Betreuer: Roland Eils." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180608186/34.
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Furuhata, Ayako. "Immunohistochemical Antibody Panel for the Differential Diagnosis of Pancreatic Ductal Carcinoma from Gastrointestinal Contamination and Benign Pancreatic Duct Epithelium in Endoscopic Ultrasound-Guided Fine Needle Aspiration." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225520.
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Jomrich, Gerd, Elisabeth S. Gruber, Daniel Winkler, Marlene Hollenstein, Michael Gnant, Klaus Sahora, and Martin Schindl. "Systemic Immune-Inflammation Index (SII) Predicts Poor Survival in Pancreatic Cancer Patients Undergoing Resection." Springer US, 2019. http://dx.doi.org/10.1007/s11605-019-04187-z.
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Background: The systemic immune-inflammation index based on peripheral neutrophil, lymphocyte, and platelet counts has
shown a prognostic impact in several malignancies. The aim of this study was to determine the prognostic role of systemic immune-inflammation index in patients with pancreatic ductal adenocarcinoma undergoing resection.
Methods: Consecutive patients who underwent surgical resection at the department of surgery at the Medical University of Vienna between 1995 and 2014 were included into this study. The systemic immune-inflammation index was calculated by the formula platelet*neutrophil/lymphocyte. Optimal cutoffs were determined using Youden's index. Uni-and multivariate analyses were calculated by the Cox proportional hazard regression model for overall survival.
Results Three hundred twenty-one patients were included in this study. Clinical data was achieved from a prospective patient database. In univariate survival analysis, elevated systemic immune-inflammation index was found to be significantly associated with shortened patients' overall survival (p = 0.007). In multivariate survival analysis, systemic immune-inflammation index
remained an independent prognostic factor for overall survival (p = 0.004). No statistical significance could be found for platelet
to lymphocyte ratio and neutrophil to lymphocyte ratio in multivariate analysis. Furthermore, area under the curve analysis showed a higher prognostic significance for systemic immune-inflammation index, compared to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio.
Conclusion A high systemic immune-inflammation index is an independent, preoperative available prognostic factor in patients with resectable pancreatic ductal adenocarcinoma and is superior to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio for predicting overall survival in pancreatic ductal adenocarcinoma patients.
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Lenk, Lennart Terje Niklas [Verfasser]. "Metastasis of Pancreatic Cancer: Influence of the hepatic microenvironment on the growth behavior of pancreatic ductal epithelial cells / Lennart Terje Niklas Lenk." Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/114291982X/34.
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Mann, Christopher David. "The Notch pathway as a biomarker in pancreatic ductal adenocarcinoma and its potential therapeutic modulation." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10995.
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Pancreatic ductal adenocarcinoma (PDAC) is the 5th commonest cause of cancer related deaths in the UK and has a poor prognosis with 1-year survival of only 10%. Improved understanding of pancreatic carcinogenesis would allow identification of biomarkers to predict disease progression, prognosis, and allow targeting of novel therapeutics. The Notch pathway involves a group of transmembrane receptors, important in tissue development, which re-activate in a number of malignancies. Preliminary evidence suggests this occurs in PDAC. The aim of this study was to examine Notch pathway components as potential diagnostic and prognostic markers in PDAC, as well as a therapeutic target. Nuclear Notch-1, -3, -4 and their targets HES-1 and HEY-1 were up-regulated in a series of 42 resected PDAC compared to normal pancreas. Further up-regulation was seen when in advanced tumours. Nuclear Notch-3 and its target HEY-1 were associated with shortened survival following resection, with HEY-1 maintaining prognostic significance on multivariate analysis. Notch-1 siRNA knockdown resulted in reduction in viability, G1 arrest and induction of apoptosis, with Notch-3 knockdown resulting in reduction in viability, G2/M arrest and induction of apoptosis. Treatment with the gamma secretase inhibitor (GSI)-I resulted in greater inhibition than seen with combined Notch-1/3 knockdown. These effects however, were not confirmed in a murine xenograft model of PDAC using an alternative GSI, MRK-003. These findings may relate to poor pharmacological activity or reduced bioavailability of this particular agent in the mouse model. Using immunoprecipitation and mass spectrometry, a method was developed to detect a fragment of the Notch receptor in plasma of patients with PDAC. Although Notch-1 could not be detected, Notch-3 was detected in both controls and patients with PDAC, although at higher levels in the later. This may suggest a role as diagnostic biomarker.
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Schäfer, Daniel [Verfasser]. "Cellular immunotherapy of pancreatic ductal adenocarcinoma: Discovery and evaluation of novel target candidates / Daniel Schäfer." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2021. http://d-nb.info/123013803X/34.
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Neuzillet, Cindy. "Inter- and intra-tumoral heterogeneity and dynamics of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma." Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/NEUZILLET_Cindy_2_va_20181015.zip.
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Les fibroblastes associés au cancer (cancer-associated fibroblasts, CAF) sont des chefs d’orchestre du microenvironnement tumoral (stroma) de l'adénocarcinome canalaire pancréatique (AP). L'hétérogénéité du stroma pourrait expliquer les rôles physiopathologiques non univoques (pro- vs. anti-tumoraux) du stroma de l’AP. Nous avons émis l'hypothèse qu'il existe plusieurs sous-types de CAFs dans l’AP qui contribuent à l'hétérogénéité du stroma notamment par leurs interactions avec les cellules tumorales et immunitaires.Ce projet s’est décomposé en trois parties :- Dans la première partie, en appliquant des analyses bioinformatiques étendues et un large éventail de tests in vitro à des cultures primaires de CAF dérivées d’AP, nous avons démontré la diversité biologique des CAFs pancréatiques humains; nous avons identifié quatre sous-types de CAFs avec des caractéristiques moléculaires et fonctionnelles spécifiques (signatures liées à la matrice et au système immunitaire, expression de vimentine et d’actine musculaire lisse, activité proliférative), et nous avons montré que l'hétérogénéité des CAFs avait un impact sur les interactions avec les cellules tumorales dans des modèles organotypiques.- Dans la deuxième partie, nous avons montré que les sous-types de CAFs et leurs combinaisons étaient associés à des caractéristiques phénotypiques distinctes des tumeurs (sous-type moléculaire et grade, abondance et activité du stroma, infiltrats immunitaires, angiogenèse) et à la survie des patients, in silico dans les données publiques de l'ICGC et par immunohistochimie dans une cohorte de patients bien caractérisés.- Dans la troisième partie, nous avons montré que plusieurs sous-types de CAFs peuvent émerger in vitro (expériences avec des milieux conditionnés) et in vivo (xénogreffes orthotopiques) à partir des cellules stellaires pancréatiques suite à leurs interactions dynamiques avec les cellules tumorales, par un processus d'«empreinte», modulé ensuite par d'autres facteurs et/ou partenaires cellulaires dans le microenvironnement tumoral; par ailleurs, nous avons confirmé dans un contexte murin nos résultats sur l'association entre l'expression des marqueurs de sous-types de CAFs et le phénotype immunitaire observé dans les tumeurs humaines. Cette classification unique des CAFs pancréatiques humains (pCAFassigner) démontre l'hétérogénéité phénotypique inter- et intra-tumorale des CAFs dans l’AP. Nos résultats ouvrent la voie à de futures études fonctionnelles et au développement de thérapies ciblant spécifiquement certaines sous-populations de CAFs dans l’APCancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- vs. anti-tumoral) in PDAC. We hypothesised that multiple CAF subtypes exist in PDAC that contribute to stromal heterogeneity through interactions with cancer and immune cells. This project comprised three parts:- In Part 1, by applying extended bioinformatics analysis and a wide range of in vitro assays to human PDAC-derived primary CAF cultures, we demonstrated the biological diversity of human pancreatic CAFs; we identified four CAF subtypes (A-D) with specific molecular and functional features (matrix- and immune-related signatures, vimentin and ?-smooth muscle actin expression, proliferation rate), and we showed that CAF heterogeneity had an impact on the interactions with cancer cells in mini-organotypic models.- In Part 2, we showed that the combination of CAF sub-populations was associated with distinct phenotypic characteristics of the tumours (tumour molecular subtype and grade, stromal abundance and activity, immune infiltrates, angiogenesis) and patient survival, in silico in the ICGC dataset and by immunohistochemistry in an extensively characterised patient cohort.- In Part 3, we showed that several CAF subtypes may emerge in vitro (conditioned media experiments) and in vivo (orthotopic xenografts) from the dynamic interactions of pancreatic stellate cells with cancer cells, through an “imprinting” process, and may be further modulated by other factors and/or cellular partners in the tumour microenvironment; in addition, we confirmed in a murine setting our findings about the association between CAF subtype marker expression and immune phenotype observed in human tumours.This unique classification for pancreatic CAFs (pCAFassigner) demonstrates the inter- and intra-tumoral phenotypic heterogeneity of CAFs in human PDAC. Our results provide a framework for future functional studies and pave the way for the development of therapies targeting specific CAF sub-populations in PDAC
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Jamieson, Nigel Balfour. "An investigation of the prognostic value of pathological and genomic factors in pancreatic ductal adenocarcinoma." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3677/.
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Improving the survival of patients with pancreatic ductal adenocarcinoma (PDAC) remains an oncological and surgical challenge. PDAC pathogenesis is underlined by numerous molecular aberrations occurring at a genetic and epigenetic level, however their spectrum of occurrence and clinical impact has not yet been fully elucidated. The majority of patients present with locally advanced or metastatic disease and even the 15-20% of patients who undergo resection for cure have a median survival limited to 18-24 months. Surgical treatment carries a high morbidity and identification of patients expected to have a poor prognosis could assist in the decision making process. The present thesis examines the prognostic importance of pathological and molecular factors in PDAC, specifically: 1. An examination of the frequency, the prognostic impact of resection margin involvement, and furthermore the prognostic influence of tumour involvement at individual margins. 2. Determination of the prognostic impact of peripancreatic fat invasion following resection of PDAC. 3. The investigation of the relationship of candidate protein biomarker expression with overall survival in a large PDAC tissue microarray cohort using immunohistochemistry. 4. Determining gene expression profiles associated with pancreatic cancer compared to normal tissue using gene expression microarray analysis with subsequent development and validation of a prognostic gene signature. 5. microRNAs were identified that associated with pancreatic cancer clinicopathological factors including survival. 6. Copy number aberrations were identified using array comparative genomic hybridisation that correlated with clinicopathological factors following resection for PDAC. 7. Finally the identification of potentially important regulator genes contributing to pancreatic tumourigenesis, was made by integrating the gene expression, microRNA expression and copy number data from previous sections using a bioinformatic approach. In this work a combination of enhanced pathological staging criteria along with the correlation of molecular marker expression and genomic profiling signatures with clinical outcome data has yielded interesting results in patients undergoing resection for pancreatic cancer that allowed detailed disease characterisation and subsequent clinically relevant outcome stratification.