Tesis: "Pancreatic cancer stem cell"

1

Sasaki, Naoya. "Alpha-fetoprotein-producing pancreatic cancer cells possess cancer stem cell characteristics". Kyoto University, 2012. http://hdl.handle.net/2433/157414.

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2

Zheng, Xuehai. "Role of stem cell protein PIWIL4 in the tumorigenesis of human pancreatic cancer". [Huntington, WV : Marshall University Libraries], 2008. http://www.marshall.edu/etd/descript.asp?ref=.

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3

Zhao, Yue. "Characterization and targeted therapy of stem cell-like side population cells in pancreatic cancer and esophageal cancer". Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-168236.

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4

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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5

RITELLI, Rossana. "Generating a pancreatic cancer mouse model: from Cancer Stem Cells to in vivo imaging strategies". Doctoral thesis, Università degli Studi di Verona, 2010. http://hdl.handle.net/11562/344615.

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Presupposti: nonostante gli enormi sforzi della ricerca per lo studio del carcinoma del pancreas, a tutt’oggi questo tumore aggressivo rimane incurabile e necessita di terapie mirate che garantiscano un miglioramento concreto della qualità della vita dei pazienti. Pertanto, è forte il bisogno di creare un sistema efficace e mirato all’identificazione di nuovi composti per la cura del cancro del pancreas. Scopo: lo scopo di questo lavoro è quello di contribuire alla generazione di un sistema che porti selezione di nuovi composti per il trattamento del carcinoma pancreatico. Questo sistema include tecniche, protocolli e un modello cellulare e animale di tumore del pancreas indispensabili per testare in vitro un alto numero di composti e per la successiva validazione in vivo dei composti selezionati. Risultati: nel corso di questo lavoro, abbiamo innanzitutto completato la caratterizzazione delle Panc1-sfere, che sono cellule tumorali presentanti caratteristiche di staminalità, precedentemente isolate nel nostro laboratorio dalla linea cellulare Panc1. Tali cellule coincidono con la subpopolazione cellulare più chemoresistente a numerosi composti già in uso clinico, pertanto sono ritenute essere il modello cellulare più indicato per la selezione di nuovi farmaci sia in vitro che in vivo. Al fine di studiare il comportamento in vivo delle Panc1-sfere, dapprima abbiamo inoculato queste cellule in sede orto topica in topi immunodeficienti e seguito la crescita tumorale ortotopici tramite Risonanza Magnetica (RMI). I nostri risultati hanno dimostrato che le Panc1-sfere rappresentano la subpopolazione più aggressiva perché crescono più velocemente rispetto alla controparte aderente, metastatizzano con maggiore frequenza e sono positive ai markers mesenchimali. Inoltre, abbiamo osservato che la RMI non è in grado di rilevare masse che poi sono state trovate nel corso delle necropsie, pertanto abbiamo effettuato un secondo esperimento, utilizzando due tecniche di Imaging in più: l’ecografia e l’Imaging Ottico. I risultati dimostrano che l’utilizzo contemporaneo di più tecniche di Imaging è estremamente utile perché fornisce informazioni complementari garantendo una maggiore precisione soprattutto per seguire in vivo gli effetti dei composti che saranno selezionati dallo screening in vitro. Conclusione: i nostri risultati dimostrano che il tumore ortotopico generato inoculando le Panc1- sfere è un buon modello che può essere usato nello validazione in vivo di nuovi composti potenzialmente in grado di curare questa malattia. Inoltre, proponiamo un protocollo combinato delle tre metodiche di Imaging che, considerando i limiti e i vantaggi di ciascuna, garantisce di monitorare la crescita tumorale in ogni sua fase, sempre nelle migliori condizioni.
Background: Pancreatic cancer remains a highly aggressive and not curable cancer in spite of the ample research in the last decades. Since conventional treatment approaches have not satisfactory effects because they don’t result in a significant improvement of the disease outcome, an effective research system is still strongly needed, in order to accurately predict the clinical efficacy of novel compounds developed for pancreatic cancer treatment. Aim: the aim of the current study is to contribute to the generation of a complete and straightforward system useful for the identification and pre-clinic screening of novel drug for the treatment pancreatic cancer. This system should provide the techniques, the protocols and a pancreatic cancer model suitable firstly for in vitro high-throughput compounds screening and then for in vivo validation of the selected molecules. Results: findings previously obtained in our laboratory have already demonstrate potential stemlike behavior of Panc-1 cells growing as 3-dimensional spheres (Panc1-spheres), isolated from adherent Panc-1 cell line. In this study we continued with the in vivo characterization of Panc-1 spheres because we used them as pancreatic cancer cell line model in the compounds screening system we are generating. So, we performed subcutaneus and orthotopical injections in nude mice with adherent Panc1 and Panc1-spheres cells. Tumor growths were followed using MRI. In order to deepen the characterization of Panc1-spheres, we also studied EMT on tumors derived from this experiment such as in vitro in both cell lines. Moreover, we observed that an improvement of imaging strategies was actually needed, in order to better control above all the formation of small masses as metastasis and early primary tumors, since MRI was not sufficient when used alone. For this reason, we also decided to focus our attention to the most important non-invasive small animalimaging modalities available today, in particular MRI, Micro-Ultrasound (US) and In Vivo Optical Imaging. Then, we correlated these techniques, arriving to the point to have an “imaging protocol”, able to offset some of the limitation of each modality when used alone, to be used in the compounds screening system we would like to generate. Conclusion: Our findings have demonstrated that the pancreatic cancer spheres are more than just cancer stem-like cells. Our mouse model, established with Sphere-growing cells, may be used for the testing of novel compounds specifically designed to target this stem-like compartment, resistant to standard chemotherapies. A combined imaging approach, with combine MRI, Optical imaging and US, in this contest become extremely important, in order to follow primary tumor sizes and metastasis detection before and after the treatment with novel compounds.

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6

Zhao, Yue [Verfasser] y Peter [Akademischer Betreuer] Nelson. "Characterization and targeted therapy of stem cell-like side population cells in pancreatic cancer and esophageal cancer / Yue Zhao. Betreuer: Peter Nelson". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1049393317/34.

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7

Maruno, Takahisa. "Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging". Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265166.

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京都大学
新制・論文博士
博士(医学)
乙第13427号
論医博第2231号
新制||医||1053(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授松田道行, 教授渡邊直樹, 教授川口義弥
学位規則第4条第2項該当
Doctor of Medical Science
Kyoto University
DFAM

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8

Karim, Karzan Khowaraham. "Investigating the effects of curcumin and resveratrol on pancreatic cancer stem cells". Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/33155.

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Anti-proliferative and cancer stem-cell targeting abilities of curcumin and resveratrol individually have been shown in different cancers. This project aimed to assess the activity of these compounds, alone and in combination in pancreatic cancer cell lines (PCCLs) and stellate cells. Anti-proliferation assays were performed for curcumin and resveratrol alone and in combination, combined with end point markers of activity including apoptosis and cell cycle arrest. Pancreatic cancer stem cell populations were defined using the cell surface markers CD44, CD24, ESA, CD133, ALDH-1 activity or sphere forming ability, and finally Nanog expression was assessed. The intracellular uptake of curcumin and its metabolites was analysed by HPLC. The PCCLs were more sensitive to curcumin than resveratrol, and combinations of these compounds showed anti-proliferative efficacy through apoptosis and cell cycle arrest at low, clinically achievable concentrations (CACs) in 2 out of 4 cell lines. Capan-1 cells exhibited the highest sensitivity to curcumin, which was able to enhance the effectiveness of resveratrol treatments in targeting cancer stem-like populations. Spheroid growth was significantly inhibited by curcumin and resveratrol combinations in Capan-1 cells, correlating with decreased ALDH1 activity and Nanog expression. In human pancreatic cancer tissue, various stem-like populations were identified based on expression of ALDH1 or CD24+/CD44+, which may provide a suitable target in vivo. Capan-1 cells metabolised curcumin to detectable amounts of curcumin glucuronide. However, curcumin metabolites did not show any significant activity at CACs. Curcumin alone may have activity against pancreatic cancer stem cells, and enhances efficacy at low concentrations when in combination with resveratrol. Capan-1 cells are able to internalise curcumin, and this cell line exhibited the greatest sensitivity to treatment. Overall, the results suggest that curcumin and resveratrol warrant further investigation as combination therapies for targeting cancer stem-like cells and stellate cells responsible for the dense stroma observed in pancreatic cancer.

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9

CREMONESE, Giorgia. "Prostate Stem Cell Antigen (PSCA): a putative target for immunotherapy and diagnosis in prostate, pancreatic and bladder carcinoma". Doctoral thesis, Università degli Studi di Verona, 2010. http://hdl.handle.net/11562/342880.

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L’immunoterapia basata sull’utilizzo di anticorpi non coniugati, coniugati a tossine o radiomarcati, che riconoscono antigeni associati a tumore, è promettente per la cura di tumori solidi o ematici. Un possibile target per l’immunoterapia potrebbe essere il prostate stem cell antigen (PSCA), un antigene appartenente alla famiglia delle “GPIanchored protein”. Il PSCA è un antigene di superficie espresso a bassi livelli nel tessuto prostatico sano ed over espresso nel tumore prostatico, pancreatico e della vescica. L’espressione di PSCA è inoltre correlata positivamente a “Gleason score” e allo stadio della patologia nel tumore prostatico. Il presente lavoro di tesi descrive la generazione e caratterizzazione di un anticorpo monoclonale murino anti PSCA (mAb), ottenuta tramite la tecnologia dell’ibridoma, e del suo frammento anticorpale a singola catena (scFv), generato clonando la regione variabile della catena leggera (VL) e della catena pesante (VH) nel vettore di espressione pHEN-2. Tramite citofluorimetria è stato dimostrato che l’anticorpo monoclinale possiede una buona affinità e specificità di legame all’antigene. Il potenziale diagnostico dell’anticorpo è stato dimostrato tramite Western Blot su lisati di tessuti neoplastici di prostrata e pancreas, in cui l’anticorpo è in grado di legare l’antigene denaturato e glicosilato, e tramite ELISA, in cui l’anticorpo si lega all’antigene espresso da cellule precedentemente fissate. Il potenziale terapeutico dell’anticorpo è stato valutato tramite saggio di proliferazione: l’anticorpo da solo non è in grado di indurre morte cellulare tramite un meccanismo diretto, mentre in seguito a coniugazione chimica con la catena A della ricina (RTA) rivela effetto citotossico su cellule PC-3 hPSCA con IC50 (concentrazione in grado di inibire la massima proliferazione cellulare del 50%) pari a 1.3x10-9, valore 100 volte più piccolo di quello ottenuto con la sola tossina RTA. Il frammento scFv è stato prodotto nel ceppo batterico E. Coli. Mediante analisi citofluorimetrica su cellule PSCA positive e saggio immunoenzimatico sull’antigene ricombinante è stato verificato che il frammento anticorpale mantiene le stesse caratteristiche di specificità di legame all’antigene dell’anticorpo monoclinale parentale, ma possiede affinità minore. Quando l’ scFv viene reso bivalente, tramite il cross-linking dei monomeri utilizzando un anticorpo anti-myc, l’affinità raggiunge quasi quella dell’anticorpo parentale. Successivamente l’scFv è stato unito attraverso fusione genetica al dominio enzimatico della tossina batterica Pseudomonas aeruginosa exotoxin A (PE40). L’immunotossina risultante è espressa nel ceppo batterico E. Coli e si accumula nei corpi d’inclusione. L’analisi citofluorimetrica su cellule PSCA positive fatta utilizzando i corpi d’inclusione rinaturati e contenenti l’immunotossina di fusione ha confermato che l’interazione tra l’scFv e l’antigene viene conservata in seguito alla fusione con la tossina PE40. L’effetto citotossico dell’immunotossina purificata scFv-PE40 verrà valutata prima in vitro su linee cellulari PSCA positive e negative e poi in modelli in vivo che permetteranno di valutare anche eventuali effetti collaterali.
Antibody-based therapy using unconjugated, toxin-conjugated or radiolabeled immunoglobulins recognizing tumor-associated antigens has proven beneficial for solid and hematolymphoid neoplasms. A suitable target could be prostate stem cell antigen (PSCA), a member of the “GPI-anchored protein”. PSCA is a cell surface-antigen expressed at low levels in normal prostate tissue and over expressed in prostate, pancreatic and bladder carcinomas. Moreover PSCA expression is positively correlated with Gleason score and with pathologic stage in prostate cancer. The present thesis describes the generation and characterization of the murine anti PSCA monoclonal antibody (mAb), obtained by hybridoma technology, and its fragment single chain (scFv), generated by cloning the variable heavy (VH) and light (VL) chain sequences in the expression vector pHEN-2. The mAb showed the ability to recognize with good affinity and specificity the native PSCA by flow cytometry. The diagnostic potential of the mAb was demonstrated by Western Blot performed with prostate and pancreatic neoplastic tissue lysates, showing the binding to denaturated and glycosylated PSCA, and by ELISA performed with fixed cells. The mAb was also assessed for its possible use in the therapeutic approach: the cell-proliferation assay demonstrated that the antibody alone is not able to induce cell death through a direct mechanism, while when it is conjugated to the ricin A chain toxin (RTA) by chemical linkage it can poison PC-3 hPSCA cells with an IC50 (i.e. concentration inhibiting 50% of the maximal cell proliferation) of 1.3x10-9 M, value 100 fold lower than the IC50 of the RTA toxin alone. The scFv was produced in E. Coli bacteria; flow cytometric analysis on PSCA-positive cells and immunoenzymatic assay on the recombinant antigen proved that the antibody fragment maintains the binding specificity of the parental monoclonal antibody. The affinity of the scFv is lower than the affinity of mAb but it is partially recovered making the scFv divalent by cross-linking the scFv monomers via an antibody-mediated myc- Tag interaction. To create a fusion immunotoxin (IT) the scFv was later genetically fused to the enzymatic domain of Pseudomonas aeruginosa exotoxin A (PE40). The resulting IT was expressed in E. Coli bacteria and it is accumulated in the inclusion bodies. The flow cytometric analysis on PSCA-positive cells performed with the whole refolded inclusion bodies extract containing the fusion IT confirmed that the interaction of scFv with the PSCA is preserved after fusion to PE40. The efficacy of purified scFv-PE40 will be analyse in vitro on positive and negative cell lines and subsequently in vivo models which also will be useful to study the side effects of this new drug.

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10

Capodanno, Ylenia. "Identifying therapeutic implications of cancer stem cells in human and canine insulinoma". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31175.

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Pancreatic neuroendocrine tumours (PNETs) are the most common neuroendocrine tumours diagnosed in humans and dogs. Due to the highly heterogeneous nature of these tumours, definitive data are still lacking over the molecular mechanisms involved in their cancerous behaviour. This study focused on insulinoma (INS), as it is the most commonly diagnosed PNET in human and veterinary oncology. INS is an insulin-producing tumour that causes a hypoglycaemic syndrome related to the excessive insulin production. In humans, it is often a small benign neoplasm readily curable by surgical resection whereas, in dogs, INS is often malignant. Despite current treatment modalities, malignant canine and human INS have a poor prognosis as patients tend to develop metastases in liver and lymph nodes that do not respond to current therapies. From a comparative oncology perspective, the close resemblance of canine and human malignant INS makes canine INS an interesting study model for human INS. Cancer stem cells (CSCs) are critical for the engraftment and chemoresistance of many tumours. Although CSCs have been isolated from a range of solid tumours, a comprehensive characterisation of INS CSCs has not yet been reported. In this study, it was confirmed that INS CSCs can be enriched and are potential targets for novel INS therapies. Highly invasive and tumourigenic human and canine INS CSCs were successfully isolated and exhibited greater resistance to chemotherapy, which may play a significant role in the poor prognosis of this disease. To date, the mechanisms by which tumours spread and the clinical causes of chemoresistance remain only partially understood. Here, RNA-sequencing analysis was performed over a small set of canine INS tumour samples in order to identify mechanisms involved in INS carcinogenesis through different stages of the disease. Preliminary data showed that distinct gene profiles characterised early and late stage of canine INS. Interestingly, differential gene expression and gene pathways analysis, highlighted that sets of genes involved in pancreatic embryogenesis and insulin secretion were overexpressed in canine primary INS lesions compared with normal pancreas. The Notch pathway is fundamental in pancreatic embryogenesis and it has been previously associated with carcinogenesis of neuroendocrine tumours and with the CSC phenotype. Protein analysis showed that the Notch pathway is activated in both human and canine INS CSCs, particularly when treated with chemotherapy, indicating that the Notch pathway may be involved in chemoresistance. Additionally, it was demonstrated that inhibition of the Notch pathway decreased INS CSCs' survival and chemoresistance, both in vitro and in vivo. These findings provide preclinical evidence that anti-Notch therapy may improve outcomes for patients with malignant INS.

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11

Eriksson, Emma. "Preclinical evaluation of immunostimulatory gene therapy for pancreatic cancer". Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330189.

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Pancreatic cancer is characterized by its desmoplastic tumor microenvironment and the infiltration of immunosuppressive cells. It is a devastating disease where most patients are diagnosed at a late stage and the treatment options are few. The development of new treatments is surly needed. One treatment option explored is the use of immunotherapy with the intent to activate the immune system and change the balance from pro-tumor to anti-tumor. This thesis presents the idea of using oncolytic adenoviruses called LOAd-viruses that are armed with immunostimulatory- and microenvironment-modulating transgenes. For effective treatment of pancreatic cancer, the virus needs to be able to be given in addition to standard therapy, the chemotherapy gemcitabine. In paper I, the immunomodulatory effect of gemcitabine was evaluated in blood from pancreatic cancer patients receiving their first 28-day cycle of treatment with infusions day 1, 8 and 15 followed by a resting period. Gemcitabine reduced the level of immunosup-pressive cells and molecules but the effect did not last throughout the resting period. On the other hand, gemcitabine did not affect the level or proliferative function of effector T cells indicating that gemcitabine could be combined with immunotherapy. The LOAd700 virus expresses a novel membrane-bound trimerized form of CD40L (TMZ-CD40L). In paper II, LOAd700 showed to be oncolytic in pancreatic cancer cell lines as well as being immunostimulatory as shown by its capacity to activate dendritic cells (DCs), myeloid cells, endothelium, and to promote expansion of antigen-specific T cells. In paper III, LOAd703 armed with both 4-1BBL and TMZ-CD40L was evaluated. LOAd703 gave a more profound effect than LOAd700 on activation of DCs and the virus was also capable of reducing factors in stellate cells connected to the desmo-plastic and immunosuppressive microenvironment. In paper IV, LOAd713 armed with TMZ-CD40L in combination with a single-chain variable fragment against IL-6R was evaluated. The virus could kill pancreatic cancer cells lines through oncolysis and could also reduce factors involved in desmoplasia in stellate cells. Most interestingly, LOAd713 could reduce the up-regulation of PD-1/PD-L1 in DCs after CD40 activation. Taken together, LOAd703 and LOAd713 seem to have interesting features with their combination of immunostimulation and microenvironment modulation. At present, LOAd703 is evaluated in a clinical trial for pancreatic cancer (NCT02705196).

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12

SCIANO', Fabio. "Development of natural and synthetic compounds as kinase inhibitors targeting cancer cells and cancer stem cells". Doctoral thesis, Università degli Studi di Palermo, 2023. https://hdl.handle.net/10447/580156.

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13

Hammer, Katharina [Verfasser] y Martin [Akademischer Betreuer] Müller. "Engineering of oncolytic adenoviruses for delivery by mesenchymal stem cells to pancreatic cancer / Katharina Hammer ; Betreuer: Martin Müller". Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1180394909/34.

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14

Ai, Jiaoyu [Verfasser], Hana [Akademischer Betreuer] Algül, Hana [Gutachter] Algül y Roland M. [Gutachter] Schmid. "Bcl-3 deficiency regulates cancer stem cell-ness and metastatic properties in pancreatic ductal adenocarcinoma / Jiaoyu Ai ; Gutachter: Hana Algül, Roland M. Schmid ; Betreuer: Hana Algül". München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1174671459/34.

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Yin, Yefeng [Verfasser] y Ingrid [Akademischer Betreuer] Herr. "Simvastatin targets pancreatic cancer stem-like cells and sensitizes PDA cells to chemotherapeutic drugs via Sonic hedgehog signaling / Yefeng Yin ; Betreuer: Ingrid Herr". Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177384094/34.

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16

Beloribi-Djefaflia, Sadia. "Les effets des lipides exosomaux sur les cellules tumorales pancréatiques humaines : entre apoptose et survie". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5005.

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Grâce à la production de nanoparticules lipidiques, les SELN (Synthetic Exosomes-Like Nanoparticles), mimant la composition des exosomes produits par les cellules tumorales pancréatiques humaines SOJ-6, nous avons démontré que les effets apoptotiques des exosomes naturels étaient dus aux lipides. En effet, nous avons montré que les SELN dont le rapport rafts/phospholipides est le plus élevé, interagissent avec les cellules SOJ-6 au niveau des rafts et perturbent la voie Notch. Cela conduit à la diminution de l'expression du facteur de survie Hes-1, qui est accentuée par la perte d'activité du complexe PTEN-GSK-3β. Ces dérégulations induisent l'apoptose dépendante de la mitochondrie des cellules SOJ-6, caractérisée par l'augmentation du ratio Bax/Bcl-2, l'activation de la caspase 9 et la dégradation de l'ADN. En revanche, les cellules MiaPaCa-2 résistent aux SELN, ce qui s'explique par leur caractère indifférencié. Ainsi la surexpression de marqueurs de cellules souches tels que l'ALDH et CXCR4 leur confèrent une grande résistance. Elles sont toutefois sensibles à la cyclopamine un inhibiteur de la voie Hedgehog, dont les effets sont atténués si les cellules MiaPaCa-2 sont préincubées avec les SELN, prouvant que ces cellules mettent en place des voies de survie leur permettant d'échapper à l'apoptose. Nos investigations ont montré que dans les cellules MiaPaCa-2, sous l'effet des SELN, l'activation de la voie canonique NF-кB permet d'induire la transcription du gène codant SDF-1α, seul ligand connu du récepteur CXCR4. Le facteur produit et sécrété active de manière auto et paracrine une voie de survie Akt-dépendante
It has been previously reported that exosomes released by the human pancreatic tumoral cell line SOJ-6 could induce their own apoptosis. Thanks to the production of lipid nanoparticles, SELN (Synthetic Exosomes-Like Nanoparticles) mimicking the lipid composition of natural exosomes, we have shown that lipids were responsible for the observed effects. Indeed, we showed that SELN with the higher ratio rafts/phospholipids could interact with SOJ-6 cells at the level of the rafts to perturb the Notch pathway, preferentially localized in these lipid microdomains. This induces a decreased expression of the main target of this pathway, the survival factor Hes-1. This decrease is intensified by the activation of the complex PTEN-GSK-3β. These deregulations drive cells towards the mitochondria-dependent apoptosis as shown by the increase of the ratio Bax/Bcl-2, the caspase 9 activity and the DNA fragmentation. Whereas MiaPaCa-2 cells are resistant to SELN, which is explained by their stem-like cell phenotype, contrarily to the well-differentiated SOJ-6 cell line. Although the over-expression of some stem cell markers, such as ALDH and CXCR4 is responsible for their resistance, they remain sensitive to the cyclopamine, a Hedgehog inhibitor. We found out that MiaPaCa-2 cells pre-incubation with SELN could protect them from the inhibitory effect of the cyclopamine, meaning that upon SELN incubation, a survival pathway is triggered in MiaPaCa-2 cells. So we showed that, upon SELN incubation, the canonical NF-кB pathway is activated in MiaPaCa-2 cells to promote SDF-1α expression. Once released, SDF-1α interacts with its receptor CXCR4 to activate an Akt-dependent survival pathway

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17

Sarvi, Sana. "Small cell lung cancer and cancer stem cell-like cells". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9542.

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Small cell lung cancer (SCLC) is a highly aggressive malignancy with extreme mortality and morbidity. Although initially chemo- and radio-sensitive, almost inevitable recurrence and resistance occurs. SCLC patients often present with metastases, making surgery not feasible. Current therapies, rationally designed on underlying pathogenesis, produce in vitro results, however, these have failed to translate into satisfactory clinical outcomes. Recently, research into cancer stem cells (CSCs) has gained momentum and form an attractive target for novel therapies. Based on this concept, CSCs are the cause of neoplastic tissue development that are inherently resistant to chemotherapy, explaining why conventional therapies can shrink the tumour but are unable to eliminate the tumour completely, leading to eventual recurrence. Here I demonstrate that SCLC H345 and H69 cell lines contain a subset of cells expressing CD133, a known CSC marker. CD133+ SCLC sub-population maintained their stem cell-like phenotype over a prolonged period of culture, differentiated in appropriate conditions and expressed the embryonic stem cell marker Oct-4 indicating their stem-like phenotype. Additionally, these cells displayed augmented clonogenic efficacy, were chemoresistant and tumorigenic in vivo, distinct from the CD133- cells. Thus, the SCLC CD133 expressing cells fulfil most criteria of CSClike definition. The molecular mechanisms associated with CD133+ SCLC chemoresistance and growth is unknown. Up-regulated Akt activity, a known promoter of resistance with survival advantage, was observed in CD133+ SCLC cells. Likewise, these cells demonstrated elevated expression of Bcl-2, an anti-apoptotic protein compared to their negative counterpart explaining CD133+ cell chemoresistance phenotype. Additionally, CD133+ cells revealed greater expression of neuropeptide receptors, gastrin releasing peptide (GRP) and V1A receptors compared to the CD133- cells. Addition of exogenous GRP and arginine vasopressin (AVP) to CD133+ SCLC cells promoted their clonogenic growth in semi-solid medium, illustrating for the first time neuropeptide dependent growth of these cells. A novel peptide (peptide-1) was designed based on the known structure of the substance P analogues that have shown benefit in animal models and in early clinical trials. This compound inhibited the growth of SCLC cells in in vitro with improved potency and stability compared to previous analogues and reduced tumorigenicity in vivo. Interestingly, peptide-1 was more effective in CD133+ cells due to increased expression of neuropeptide receptors on these cells. In conclusion, my results show that SCLC cells retain a sub-population of cells that demonstrate CSC-like phenotype. Preferential activation of Akt and Bcl-2 survival pathways and enhanced expression of neuropeptide receptors contribute to CD133+ SCLC chemoresistance and growth. Therefore, it can be proposed that CD133+ cells are the possible cause of SCLC development, treatment resistance and disease recurrence. Despite being chemoresistant, CD133+ cells demonstrated sensitivity to peptide-1. The identification of such new analogue that demonstrates efficacy towards resistant CD133+ SCLC cells is a very exciting step forward in the identification of a potential new therapy for resistant disease.

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18

Shah, Nadia Nisa. "Human embryonic stem cells : prospects for pancreatic β-cell differentiation". Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495052.

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The focus of this thesis was to explore different strategies in trying to generate putative pancreatic β-cells using one of the initial Wisconsin H7 hES cell lines. Prior to this, human pancreas development was assessed during the first trimester of pregnancy in an attempt to determine the spatial and temporal expression of development and mature pancreatic β-cell markers during this period. Spontaneous differentiation of hES cells can be induced by the formation of embryoid bodies (EBs) in suspension culture. EBs began to express markers of pancreatic β-cell development and function at a molecular, protein and functional level upon differentiation over a 3-week period. The constitutive over-expression of the terminal β-cell marker PAX4 enhances this process, whereas karyotypic abnormalities induced in hES cells over prolonged culture can hinder differentiation potential towards pancreatic β-cells. Directed differentiation strategies which mimic mouse pancreas development have led to the elucidation of an in vitro protocol to generate putative definitive endoderm from hES cells through the application of Wnt3a and Activin A in the presence of low serum. Indirect co-culture of this H7 hES cell-derived putative definitive endoderm with mouse islets did not lead to the differentiation of fully functional pancreatic β-cells. The hES cell-derived putative definitive endoderm did however influence the aging mouse islets in a positive manner by allowing the maintenance of insulin secretagogue-induced functional responses which are usually lost in culture. This may prove useful in maintaining viability of human islets during culture to be used for transportation therapies.

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19

Alldinger, Ingo, Dag Dittert, Matthias Peiper, Alberto Fusco, Gennaro Chiappetta, Eike Staub, Matthias Löhr et al. "Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136495.

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Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Results: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change > 3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin [β-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Conclusion: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

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20

Alldinger, Ingo, Dag Dittert, Matthias Peiper, Alberto Fusco, Gennaro Chiappetta, Eike Staub, Matthias Löhr et al. "Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer". Karger, 2005. https://tud.qucosa.de/id/qucosa%3A27709.

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Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Results: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change > 3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin [β-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Conclusion: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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21

Quinn, Bridget A. "Novel Therapeutic Strategies for Pancreatic Cancer". VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/4671.

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Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available are the same that have been used for almost 2 decades. There is a dire need for both novel treatments for this disease as well as novel strategies of treatment. This body of work will introduce and provide evidence in support of a novel combination therapy for pancreatic cancer treatment, a novel strategy of modifying currently used chemotherapeutics for pancreatic cancer therapy, and a novel transgenic preclinical mouse model of pancreatic cancer. Sabutoclax, an antagonist of the anti-apoptotic Bcl-2 proteins, and Minocycline, a commonly used antibiotic, show potent synergy when used in combination in both pancreatic cancer cells and in multiple immune-deficient and immune-competent mouse models of pancreatic cancer. Sabutoclax alone is capable of inducing cell cycle arrest and apoptosis in cells and its cytotoxicity is enhanced significantly when combined with Minocycline. This combination results in the loss of Stat3 activation both in vitro and in vivo, which is essential for its toxicity. It also inhibits tumor growth and prolongs survival in the KPC transgenic mouse model of pancreatic cancer. Also presented here are studies that demonstrate efficacy in vivo of modified versions of Gemcitabine and Paclitaxel. These drugs are linked to a peptide that shows specificity for the EphA2 receptor, which is overexpressed on the surface of pancreatic cancer cells and only minimally on normal cells. This peptide results in increased cellular uptake of drug, as it is bypassing its normal mechanism of entry. These normal mechanisms are often dysregulated in cancer, leading to decreased uptake and drug resistance. The use of these modified drugs show significantly increased tumor growth inhibition as compared to the parent drug alone. Finally, we provide data on the characterization of a novel transgenic mouse model of pancreatic cancer. This model, the Pan Met View (PMV) mouse, combines the commonly used KPC transgenic mouse model of pancreatic cancer and a mouse that expresses a Luciferase reporter gene under the control of the cancer-specific promoter, CCN1. Our data shows that double transgenic PMV mice can now be used to follow primary tumor and metastasis development in real time by Bioluminescent imaging (BLI) through disease progression and potentially therapy. This strategy will enhance the use of genetically engineered mouse models (GEMMS) to study cancer initiation and progression with potential to non-invasively monitor therapy. These chapters present novel and exciting data that have the potential to open multiple avenues of translational study and result in significant advances in pancreatic cancer therapy.

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22

Evans, James Donald. "Regulation of cell proliferation and apoptosis in pancreatic cancer". Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366246.

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23

Turner, Alison Joanne Claire. "Retinoic acid : the effects on pancreatic cancer cell lines". Thesis, St George's, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301132.

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24

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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25

Weng, Chen. "SINGLE-CELL TRANSCRIPTOMICS OF HUMAN PANCREATIC ISLETS IN DIABETES AND ΒETA CELL DIFFERENTIATION". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1612882103714773.

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26

Anderson, John Edward. "Pancreatic cancer as a target for adoptive T-cell immunotherapy". Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490060.

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The aim of this thesis was to investigate pancreatic cancer as a target for chimeric immune (CIR) based adoptive T ceil therapy and to irlcntiif\! presence of carcinoembryonic (CEA) and 5T4 antigen targets pancreatic tumour tissue. order to confirm the effectiveness of any it is important to identify a suitable model system. The immunotherapy mechanism on this thesis is based requires CIR specific recognition of the target antigens CEA or 5T4. Therefore two pancreatic and one gastric cancer cell expressing these were identified by immunofluorescent staining and Western Blot analysis. The general is numbers of T cells are required when targeting cancer tissue with adoptive immunotherapy. It is therefore necessary to be able to generate the of cells required a laboratory setting. different methods of T cell activation, using either anti-CD3s OKT3 or antibiotin T cell activation beads, were assessed comparing the rates of cell expansion, viability and cytokine production. To enable T cells to express CIR requires the genetic modification of T lymphocytes, also termed transduction. this thesis a retrovirus based on a murine leukaemia was used. As part the genetic modification process a retroviral clone expressing the 5T4 trans gene was produced. Pancreatic cancer patients' T cells were transduced two alternative transgenes . expressing a CIR specific for either the 5T4 or CEA antigen. levels of transduction efficiency achieved were assessed by staining and flow cytometer analysis. The specific cytotoxic function of the transduced cells was compared against that of untransduced T cells same patients by co-culturing the cells with the three Cancer lines previously shown to express CEA and 5T4 surface antigens. Cancer survival was assessed using a WST-1 cell proliferation assay. results confirmed specific cancer cell cytolysis was mediated by CIR T cells. After showing the adoptive immunotherapy model used was effective at reducing pancreatic and gastric cancer cell numbers vitro, it was important to identify the target antigens' expression true solid pancreatic cancer tissue specimens. Tissue was collected from pancreaticoduodenectomy that had been resected because of the suspicion cancer. Immunohistochemical staining identified the presence of CEA 5T4 antigens the pancreatic tumour tissue. of the findings of the in vitro model used this thesis and the expression of the target antigens indicated by immunohistochemical an~ true pancreatic cancer tissue, adoptive T cell immunotherapy have the potential, further development, to play a role the over survival outcome of pancreatic cancer patients.

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27

Ngamjariyawat, Anongnad. "The beneficial Effects of Neural Crest Stem Cells on Pancreatic β–cells". Doctoral thesis, Uppsala universitet, Institutionen för neurovetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233157.

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Patients with type-1 diabetes lose their β-cells after autoimmune attack. Islet transplantation is a co-option for curing this disease, but survival of transplanted islets is poor. Thus, methods to enhance β-cell viability and function as well as methods to expand β-cell mass are required. The work presented in this thesis aimed to study the roles of neural crest stem cells or their derivatives in supporting β-cell proliferation, function, and survival. In co-culture when mouse boundary cap neural crest stem cells (bNCSCs) and pancreatic islets were in direct contact, differentiating bNCSCs strongly induced β-cell proliferation, and these proliferating β-cells were glucose responsive in terms of insulin secretion. Moreover, co-culture of murine bNCSCs with β-cell lines RIN5AH and β-TC6 showed partial protection of β-cells against cytokine-induced β-cell death. Direct contacts between bNCSCs and β-cells increased β-cell viability, and led to cadherin and β-catenin accumulations at the bNCSC/β-cell junctions. We proposed that cadherin junctions supported signals which promoted β-cell survival. We further revealed that murine neural crest stem cells harvested from hair follicles were unable to induce β-cell proliferation, and did not form cadherin junctions when cultured with pancreatic islets. Finally, we discovered that the presence of bNCSCs in co-culture counteracted cytokine-mediated insulin-producing human EndoC-βH1 cell death. Furthermore, these two cell types formed N-cadherin, but not E-cadherin, junctions when they were in direct contact. In conclusion, the results of these studies illustrate how neural crest stem cells influence β-cell proliferation, function, and survival which may improve islet transplantation outcome.

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28

Li, Fangfang. "Regulation of pancreatic β-cell death and cancer cell migration by TPRM2 channels". Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/13374/.

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Yeo, Wendy Wai Yeng. "Differentiation of skeletal muscle-derived stem cells into beta pancreatic lineage". Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTS091.

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Le diabète de type 1 (DT1) est caractérisé par des niveaux élevés de glucose en raison de la destruction des cellules ß pancréatiques sécrétrices d'insuline. Cependant, les thérapies actuelles de remplacement des cellules bêta du pancréas impliquant la transplantation d'îlots pancréatiques sont techniquement difficiles et limitées par la disponibilité de don d'organes. Bien que les cellules souches embryonnaires et les cellules souches pluripotentes induites soient intensément étudiées, aucune de ces deux sources de cellules souches ne peut être utilisée directement sans le risque de développement de tumeurs. Les cellules souches dérivées du muscle squelettique (MDSC) sont une source de cellules alternative intéressante car elles sont multi-potentes et peuvent donc se différencier vers plusieurs lignages cellulaires tels que des cellules cardiaques à battement autonome “pacemaker-like” et des cellules neuronales. Par conséquent, nous avons émis l'hypothèse qu'elles pourraient se différencier en lignées de type pancréatique. Les objectifs de cette étude étaient donc d'étudier le potentiel des MDSC (1) à se différencier in vitro en cellules beta pancréatiques exprimant l'insuline et (2) à se différentier in vivo dans le pancréas et ainsi réduire l'hyperglycémie chez la souris modèle d'un diabète de type 1. Dans cette étude, les MDSC de muscle de souris ont été isolées via une série de passages des cellules les moins adhérentes en culture. Les cellules souches ainsi isolées peuvent adhérer sur une couche de cellules de types fibroblastes ou sur une matrice extra-cellulaire de type laminine pour ensuite se différentier in vitro ou bien être utilisées comme cellules souches MDSC non-adhérentes et non différentiées pour les études in vivo. In vitro, les MDSC peuvent se différencier spontanément en agrégats de cellules formant des îlots et exprimant des marqueurs de cellules bêta identifiés par immunofluorescence et analyse “PCR transcription inverse”. Ceci a été confirmé par immuno-analyse montrant l'expression des protéines nécessaires à la fonction des cellules ß, comme Nkx6.1, MafA et Glut2. Les MDSC différenciées en aggrégats cellulaires de type îlots pancréatiques montrent une sécrétion d'insuline en réponse au glucose in vitro. Cependant, dans des modèles murins de DT1 induit par la streptozotocine, l'injection intra-péritonéale des MDSC n'a pas permis de rétablir chez les souris diabétiques une normoglycémie du glucose sanguin en dépit d'un engreffement des MDSC dans les tissus pancréatiques. Ces données montrent que les MDSC peuvent constituer une source de cellules souches alternative intéressante pour le traitement du diabète
Type 1 Diabetes (T1D) is characterized by high and poorly controlled glucose levels due to the destruction of insulin-secreting pancreatic ß-cells. However, current ß-cell replacement therapies, involving pancreas and pancreatic islet transplantation are technically demanding and limited by donor availability. While embryonic stem cells and induced pluripotent stem cells are intensely investigated, neither can be used due to safety issues. Skeletal muscle-derived stem cells (MDSC) are an attractive alternative cell source as they have the potential to undergo multilineage differentiation into beating pacemaker-like cells and neuronal cells. Hence, it is hypothesised that they can differentiate into pancreatic lineages. This led to the goals of this study, which were (1) to investigate the potential of MDSC to differentiate into mature insulin expressing cells in vitro and (2) to reduce hyperglycemia in mouse model type 1 diabetes. In this study, MDSC were isolated from mouse via a serial pre-plating based on the adhesive characteristics of cultured cells, in which the cells of interest adhered to plates at a later time for in vitro differentiation, while the non-adherence undifferentiated MDSC were used for in vivo study. The MDSC were found to spontaneously differentiate into islet-like aggregates and expressed ß-cell markers in vitro, as determined by immunofluorescence and reverse transcription PCR analyses. This was further confirmed by immunoblotting analysis showing expression of proteins required for ß-cell function, such as Nkx6.1, MafA and Glut2. The differentiation of MDSC into islet-like clusters demonstrated glucose responsiveness in vitro. In streptozotocin-induced T1D mouse models, intraperitoneal injection of the undifferentiated MDSC did not restore the blood glucose levels of the diabetic mice to normoglycemia despite successful engraftment of MDSC into the pancreatic tissues. Taken together, these data show that MDSC may serve as an alternative source of stem cells for the treatment of diabetes

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30

Hill, William. "Heterotypic cell-cell interactions between KrasG12D cells and normal neighbours in early pancreatic cancer". Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/119038/.

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At the initial stages of tumourigenesis, transformation occurs in a single cell within a healthy epithelial sheet. Competitive interactions between normal and Ras-transformed cells can drive the elimination of mutant cells from tissues to protect from carcinogenesis. Moreover, we have previously demonstrated that normal cells detect and eliminate Ras-transformed cells via differential EphA2 signalling. KrasG12D expressing cells (KrasG12D cells) initiate and drive the earliest stages of pancreatic cancer yet it is unclear if normal pancreatic cells can eliminate oncogenic cells. Here we use low level, stochastic induction of KrasG12D mutations in the pancreas to model the interaction of normal and transformed epithelial cells. We show that Ras-transformed cells adopt a contractile morphology and are eliminated from healthy tissue when present at low numbers. When surrounded by normal cells, KrasG12D cells become segregated, increase in compactness and are often extruded. We find that E-cadherin-based cell-cell contacts are downregulated and internalised in mutant cells when surrounded by normal neighbours in an EphA2-dependent manner. Our evidence also suggests that normal cells suppress progression of Ras-transformed cells to an early disease state. Together, this study suggests that non-transformed pancreatic epithelial cells can eliminate KrasG12D cells from the tissue via EphA2 signalling. These data identify a novel putative tumour-suppressive mechanism in the adult pancreas that mutant cells must first overcome to drive tumourigenesis. Understanding the earliest stages of pancreatic carcinogenesis will provide insight into how risk factors promote disease and may elucidate how pancreatic cancer spreads around the body.

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31

Chinswangwatanakul, Vitoon. "The role of thrombin and thrombin receptor in pancreatic cancer". Thesis, Imperial College London, 1999. http://hdl.handle.net/10044/1/7660.

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32

Wilkie, Alexander David. "Evasion of Cell Death in Burkitt’s Lymphoma and Pancreatic Cancer Cells". Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367897.

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This thesis examined exploitation of cell death to combat cancer from two angles: investigating cell death signalling pathways to find new targets for treatment, and using the novel anti-austerity approach to combat the tolerance of cancer cells to nutrient deprivation. Cancers often display high levels of genetic diversity, even within cancers of a particular organ. These genetic differences often make treatments which work with a particular cancer ineffective on another - even from the same origin, and lead to differences in outcomes to selective pressures such as nutrient deprivation. Current treatments are aimed at killing rapidly proliferating cells and often have severe side effects. Their efficacy is highly dependent on early diagnosis and many cancers are resistant to chemotherapeutic drugs. In addition, cancer cells on the inside of tumours have the ability to survive under adverse conditions such as nutrient deprivation due to intermittent blood supply, Therefore, alternative treatment strategies must be explored. Defects in cell death play a large contributing factor to cancer progression and tumour growth and the evasion of cell death by cancers presents a major problem in its treatment Conventional cancer treatment relies on the activation of cell death in fast growing cancer cells while attempting to leave normal cells undamaged. Therefore, selective triggering of cell death in a cancer cell would be extremely useful. In order to achieve this goal a thorough understanding of the cell death response of a particular cell type to a particular stimulus must be known. Moreover, any novel or unusual cell death signalling pathways would provide more opportunities and targets for attempting to trigger selective cell death in cancers.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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33

Chen, Y. "Functional characterisation of tumour-specific T cell responses in pancreatic cancer". Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1553215/.

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BACKGROUND AND AIMS: Pancreatic cancer (PC) has a poor prognosis and effective diagnostic tools and therapies are currently unavailable. This project has explored the role of T cell responses in PC patients as a potential therapy. METHODS: Serum mesothelin (MSLN) levels were tested in patients with pancreatic diseases. CD4+ and CD8+ T cell responses against full-length overlapping MSLN peptide pools were identified. CEA691, together with pre-chosen MSLN547 and WT1-126 were used to stimulate T cell lines from PC patients. Antigen-specific function and phenotype were characterised in the ex-vivo expanded T cell lines after repeated Ag exposure. Further experiments used inhibitory receptor blockade to augment the function of T cells isolated from cancer patients. RESULTS: Soluble MSLN was elevated in PC patients compared to normal controls, but could not distinguish the malignant from benign pancreatic disease. MSLN-specific CD4+ T cell responses were significantly increased in PC patients compared to controls, indicating an expansion of MSLN-specific CD4+ T cell in PC patients, and new epitopes were identified. It was possible to generate CEA691, WT126 and MSLN547-specific HLA-A*02 restricted T cell lines from PC patients. The ex vivo expanded CEA691-specific T cells demonstrated Ag-specific cytotoxicity and were able to recognize and kill HLA-A2+ CEA+ pancreatic cell lines in vitro. Blockade of PD-1 and TIM-3 further enhanced T cell function in vitro. CONCLUSION: We found that tumour associated antigen (TAA)-specific T cells were identifiable in the peripheral repertoire of patients with pancreatic cancer, and the function of these cells were preserved in some cases. Such antigen-specific function and cytotoxicity was more common in relatively early stages of the disease than the terminal stage, and PD-L1 blockade further improved the responses, suggesting that TAA-specific T cells together with checkpoint inhibition could be potential strategies for the treatment of pancreatic cancer.

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34

Kalubowilage, Madumali. "Liquid biopsies of solid tumors: non-small-cell lung and pancreatic cancer". Diss., Kansas State University, 2017. http://hdl.handle.net/2097/35385.

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Doctor of Philosophy
Department of Chemistry
Stefan H. Bossmann
Cancer is a group of diseases that are characterized by uncontrolled growth and spread of cells. In order to treat cancer successfully, it is important to diagnose cancers in their early stages, because survival often depends on the stage of cancer detection. For that purpose, highly sensitive and selective methods must be developed, taking advantage of suitable biomarkers. The expression levels of proteases differ from one cancer type to the other, because different cancers arise from different cell types. According to the literature, there are significant differences between the protease expression levels of cancer patients and healthy people, because solid tumors rely on proteases for survival, angiogenesis and metastasis. Development of fluorescence-based nanobiosensors for the early detection of pancreatic cancer and non-small-cell lung cancer is discussed in this thesis. The nanobiosensors are capable of detecting protease/arginase activities in serum samples over a broad range. The functionality of the nanobiosensor is based on Förster resonance energy transfer and surface energy transfer mechanisms. The nanobiosensors for protease detection feature dopamine-coated Fe/Fe₃O₄ nanoparticles, consensus (cleavage) peptide sequences, meso-tetra(4-carboxyphenyl)porphine (TCPP), and cyanine 5.5. The consensus peptide sequences were synthesized by solid-supported peptide synthesis. In this thesis, improved consensus sequences were used, which permit faster synthesis and higher signal intensities. TCPP, which is the fluorophore of the nanoplatform, was connected to the N-terminal end of the oligopeptides while it was still on the resin. After the addition of TCPP, the TCPP-oligopeptide was cleaved off the resin and linked to the primary amine groups of Fe/Fe₃O₄-bound via a stable amide bond. In the presence of a particular protease, the consensus sequences attached to the nanoparticle can be cleaved and release TCPP to the aqueous medium. Upon releasing the dye, the emission intensity increases significantly and can be detected by fluorescence spectroscopy or, similarly, by using a fluorescence plate reader. In sensing of arginase, posttranslational modification of the peptide sequence will occur, transforming arginine to ornithine. This changes the conformational dynamics of the oligopeptide tether, leading to the increase of the TCPP signal. This is a highly selective technology, which has a very low limit of detection (LOD) of 1 x 10⁻¹⁶ molL⁻¹ for proteases and arginase. The potential of this nanobiosensor technology to detect early pancreatic and lung cancer was demonstrated by using serum samples, which were collected from patients who have been diagnosed with pancreatic cancer and non-small cell lung cancer at the South Eastern Nebraska Cancer Center (lung cancer) and the University of Kansas Cancer Center (pancreatic cancer). As controls, serum samples collected from healthy volunteers were analyzed. In pancreatic cancer detection, the protease/arginase signature for the detection of pancreatic adenocarcinomas in serum was identified. It comprises arginase, MMPs -1, - 3, and -9, cathepsins -B and -E, urokinase plasminogen activator, and neutrophil elastase. For lung cancer detection, the specificity and sensitivity of the nanobiosensors permit the accurate measurements of the activities of nine signature proteases in serum samples. Cathepsin -L and MMPs-1, -3, and -7 permit detecting non-small-cell lung-cancer at stage 1.

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35

Blacking, Thalia Margaret. "Investigating the cancer stem cell hypothesis in canine tumours". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5563.

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The cancer stem cell hypothesis has recently re-emerged as a compelling paradigm for the development and progression of neoplastic disease. The hypothesis proposes that a specific subset of “cancer stem cells” (CSC), believed to share many features with normal stem cells, is exclusively responsible for maintaining tumour growth and driving progression. If the CSC hypothesis applies, it may require re-evaluation of the clinical approach to neoplasia. Spontaneous cancer in the domestic dog represents a significant welfare problem, with dogs developing many tumours strongly reminiscent of those affecting humans. This study sought to investigate whether cells with characteristics of CSC are identifiable in canine cancer. Assays to identify, isolate and characterise CSC were adapted to the canine system, and cancer cell lines and spontaneous tumours of diverse origin evaluated for the presence of candidate populations. Whilst analysis of surface expression patterns did not identify specific subpopulations within canine cancer cell lines, these were detectable in cells derived directly from primary tumours. Assays for stem cellassociated drug resistance mechanisms could also be used to identify subsets of putative canine CSC. Formation of “tumourspheres” by canine cancer cell lines was found to be highly density-dependent, so a potentially unreliable method of isolating CSC. Expression of the cell surface glycoprotein CD44 was associated with cellular proliferation status, although it may not represent a stable canine CSC marker. The NFκB survival pathway, associated with apoptosis resistance of some putative CSC, was constitutively active in canine cancer cell lines; suppression using specific inhibitors could reduce cell viability, indicating that this may represent a rational therapeutic target. Overall, these studies demonstrated that CSC assays may be adapted to the canine model system, although they require rigorous interrogation to distinguish apparent CSC attributes from basic biological properties. Cell lines have provided a stable background upon which to optimise assays, but appear less likely to demonstrate discrete CSC subpopulations. Putative CSC subsets may be more readily identifiable within heterogeneous primary tumour cells. The application of some of these adapted assays within a clinical setting may enable further characterisation of individual patients’ tumours, and inform therapeutic regimes for improved treatment outcomes.

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36

Emich, Helena. "Clinical implications of cancer stem cell properties in oral squamous cell carcinoma". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8479.

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CD44 has been described as a marker of cancer stem cells in oral squamous cell carcinoma (OSCC). The main objective of this study was to characterise expression of CD44 in both fresh samples of human OSCC and in cell lines generated from them, and to examine its correlation with selected clinicopathological parameters of the tumours of origin. The epithelial fraction in 20 fresh OSCC samples was identified by the standard method using the negative selection technique with antibodies against non-tumour cells. A novel method of identifying the epithelial fraction, termed positive selection, was also developed and used for analysis of 14 additional OSCC samples. This new method, using epithelial-specific antibodies, led to a considerable improvement in the efficiency and the accuracy of the procedure. The frequency of CD44+ cells in the epithelial fraction of the tumour specimens was assessed by FACS and varied widely (3-97%). High frequency of CD44+ cells in tumour samples was found to be associated with high tumour grade, discohesive invasion front and presence of lymph node metastases (p<0.01, as calculated with Spearman’s ranked test and Fisher’s exact test). It was also observed, that the percentage of CD44+ cells changes when cells isolated from tumour samples are propagated in culture. Nearly all cells in cell lines generated from OSCC samples showed CD44 expression when analysed by FACS. However, a markedly higher level of CD44 expression (as assessed by median fluorescence intensity for cell surface CD44) was found for early passage cell lines generated from metastatic OSCC and lymph node metastases as compared to cell lines generated from nonmetastatic OSCC. These findings show that a high frequency of CD44+ cells in fresh OSCC tissue and a high level of CD44 expression in cultured OSCC cells correlate 11 with more aggressive tumour behaviour. These results might provide important information of prognostic and therapeutic value.

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37

Redmond, K. M. "C flip : A key apoptosis regulator in non-small cell lung cancer and pancreatic cancer". Thesis, Queen's University Belfast, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517510.

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38

Prokop, Katherine Jane. "Cell Death Characterization In Tumor Constructs Using Irreversible Electroporation". Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/51655.

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Pancreatic and prostate cancer are both prevalent cancers in the United States with pancreatic being one of the most aggressive of all cancers and prostate cancer being one of the most common, ranking as the number one cancer in men. Treatment of both cancers can be quite challenging as the anatomy of the pancreas and prostate, as well as the development and diagnosis of the disease can greatly limit treatment options. Therefore, it is necessary to develop new cancer treatments to help manage and prevent these cancers. Irreversible electroporation is a new non-thermal focal ablation therapy utilizing short, pulsed electric fields to damage cell membranes leading to cell death. The therapy is minimally invasive, involving the insertion of needle electrodes into the region of interest and lasts less than two minutes. Heat sink effects that thermal therapies experience near large blood vessels do not affect irreversible electroporation. This allows the treatment to be used on tumors near vasculature as well as critical structures without harming these vital regions. While irreversible electroporation is a promising new cancer therapy, further developments are necessary to improve treatment planning models. This work aims to further understand the electric field thresholds necessary to kill different types of cancer cells with a focus on pancreatic and prostate cancer. The work is done using an in vitro tumor (hydrogel) model as this model is better than traditional cell suspension studies, with added benefits over the immediate use of tissue and animal models.
Master of Science

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39

Pantelidou, Constantia. "E1B19K-deleted oncolytic adenoviruses enhancee the cytotoxicity of DNA-damaging drugs in pancreatic cancer through deregulation of cell-cycle mechanisms". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8819.

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Pancreatic cancer is an aggressive disease with poor prognosis and a high fatality rate. Gemcitabine, the standard first-line chemotherapy for advanced disease, has negligible effects, necessitating the development of new therapies. We previously demonstrated that deletion of the anti-apoptotic gene E1B19K (AdΔ19K) in a replication-selective adenoviral mutant, caused synergistically-enhanced cell-killing when combined with low-dose DNA-damaging drugs in pancreatic cancer xenograft models. To delineate the cellular pathways targeted by the combination treatment we employed AdΔ19K and gemcitabine or irinotecan, with the goal of identifying cellular factors that are essential for the synergistic cell-killing. We hypothesised that AdΔ19K and DNA-damaging drugs act synergistically to deregulate cell-cycle mechanisms. Pancreatic cancer cell death induced by AdΔ19K and DNA-damaging drugs is apoptotic and time-dependent. AdΔ19K could not block DNA-damage responses (DDR) elicited by the drugs, despite virus-mediated degradation of the DDR factor Mre11. Mre11 siRNA-mediated knockdown augmented the synergistic cell death. Mitotic-index analysis in synchronised cells and immunofluorescence microscopy suggested that AdΔ19K promotes mitotic entry of gemcitabine-treated DNA-damaged cells. Moreover, AdΔ19K inhibited drug-induced accumulation of Claspin, a DDR protein whose degradation is required for checkpoint recovery. Treatment with AdΔ19K and gemcitabine accelerated Claspin degradation, and siRNA-mediated Claspin knockdown enhanced the synergistic cell death. Time-lapse microscopy in histoneH2B mCherry-expressing cells showed that AdΔ19K enhanced gemcitabine-induced mitotic catastrophe, characterised by prolonged mitosis, chromosome missegregation errors, cytokinesis failure and formation of multinucleated cells. Moreover, live-cell imaging revealed that the majority of cells treated with AdΔ19K and gemcitabine die before mitotic entry. 5 These findings suggest that E1B19K-deleted adenoviruses cannot prevent cell-cycle checkpoint responses elicited by DNA-damaging drugs, but enhance drug-induced cell death by downregulating DDR factors, such as Mre11 and Claspin. Additionally, the virus enhances mitotic catastrophe of DNA-damaged cells escaping cell-cycle checkpoints, eventually leading to increased apoptosis. Through these studies cellular pathways and factors involved in the synergistic cell killing were identified, that could be explored in the future to develop improved targeted therapies for pancreatic cancer.

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40

Bossard, Maud. "The role of epithelial cell-derived tumour necrosis Factor Alpha in pancreatic carcinogenesis". Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8563.

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Activating mutations of the kras proto-oncogene are found in more than 90% of human pancreatic ductal adenocarcinoma (PDAC) and can result in increased activity of the NF-κB pathway, leading to constitutive production of proinflammatory cytokines such as TNF-α. Pancreatic cancer progression occurs through a series of pre-invasive lesions, pancreatic intraepithelial neoplasias (PanIN lesions), which progress into invasive carcinoma. The aim of this thesis is to understand the autocrine role of TNF-α produced by premalignant epithelial cells in pancreatic tumour progression. This cytokine has already been shown to be involved in the progression of cancer. The major hypothesis therefore tested was that TNF-α secreted by pre-malignant epithelial cells promotes the early stages of pancreatic carcinogenesis by sustaining an inflamed microenvironment. In the spontaneous kras+/LSL-G12D; pdx1-cre mouse model of pancreatic cancer, concomitant genetic deletion of the TNF-α/IKK2 pathway substantially delayed pancreatic cancer progression and resulted in downregulation of the classical Notch target genes hes1 and hey1. Cell lines from the different PanIN bearing mice were established and used to dissect the cooperation between TNF-α/IKK2 and Notch signalling during PanIN progression. Optimal expression of Notch target genes was induced upon TNF-α stimulation of the canonical NF-κB signalling pathway, in cooperation with basal Notch signals. Mechanistically, TNF-α stimulation resulted in phosphorylation of histone H3 at the hes1 promoter and this signal was lost upon ikk2 genetic deletion. HES1 suppressed the expression of pparg, which encodes for the anti-inflammatory nuclear receptor PPAR-γ. Thus, crosstalk between TNF-α/IKK2 and Notch sustained an intrinsic inflammatory profile of the transformed cells. The treatment of PanIN bearing mice with rosiglitazone, a PPAR-γ agonist, also delayed PanIN progression. A malignant cell-autonomous, low-grade inflammatory process was shown to operate from the very early stages of kras-driven pancreatic carcinogenesis, which may cooperate with the Notch signalling pathway to promote pancreatic cancer progression.

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41

Kimura, Azuma. "Small molecule AT7867 proliferates PDX1-expressing pancreatic progenitor cells derived from human pluripotent stem cells". Kyoto University, 2019. http://hdl.handle.net/2433/242422.

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42

Sharpe, Benjamin Peter. "Prostate cancer stem cells : potential new biomarkers". Thesis, University of Bath, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698969.

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Prostate cancer is a leading cause of cancer-related death in men, and while many men diagnosed with the disease will have an indolent clinical course, 20-25% of men will experience disease recurrence which is invariably lethal. There is an urgent need for prognostic biomarkers that will predict disease recurrence and risk-stratify patients upon diagnosis, allowing for personalised therapies. This thesis attempts to identify new prognostic biomarkers for prostate cancer and investigates their patterns of protein expression in human primary prostate tumour tissue. Cancer stem cells are cancer cells thought to be uniquely capable of self-renewal and tumorigenicity, and may have a role in tumour recurrence. Using a literature searching approach, potential biomarkers related to stem cells, cancer stem cells or recurrence in prostate cancer were identified, and ALDH7A1, BMI1, SDC1, MUC1-C, Nestin and ZSCAN4 were chosen for investigation. An in silico approach was also used for biomarker identification, with RS1 and SLC31A1 selected as their mRNA was found to be upregulated in recurrent tumours. The expression patterns of all 7 potential biomarkers were examined by immunohistochemistry on prostate tumour tissue and benign tissue from prostate biopsies and prostatectomies. BMI1, ALDH7A1, MUC1-C and Nestin showed no relationship to recurrence or other clinical features. RS1 protein levels increased in patients with recurrence within 5 years, negatively correlated with AR expression, and a meta-analysis showed that the RS1 gene was amplified in up to 32% of castration-resistant prostate tumours. ZSCAN4 was heterogeneously expressed in a subset of 26% of prostate tumours with unclear characteristics and was not expressed in benign tissue, but was not associated with recurrence. Finally, SDC1 expression was lost in tumour epithelium, but a population of unidentified SDC1-expressing cells were found in the stroma of a third of tumours, and an increased burden of these cells was associated with primary Gleason pattern 5 tumours. These cells do not overlap with common epithelial, mesenchymal or stromal lineages, but may be migratory. In summary, the data presented in this thesis identifies 3 potential new biomarkers for prostate cancer, and provides the basis for future characterisation of their wider roles in the disease.

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43

Schiarea, Silvia. "Mass spectrometry-based characterisation of the secretome of pancreatic cancer cell lines". Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520740.

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44

Russell, Ronan [Verfasser]. "Molecular insights into early cell fate specification and pancreatic cancer / Ronan Russell". Ulm : Universität Ulm. Fakultät für Naturwissenschaften, 2016. http://d-nb.info/1084112132/34.

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45

Shelper, Todd Benjamin. "Exploring Morphology and Drug Interactions in Pancreatic Cancer with 3D Cell Culture". Thesis, Griffith University, 2014. http://hdl.handle.net/10072/367976.

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Pancreatic cancer continues to have one of the poorest prognoses amongst all cancers, with a 95% mortality rate. Standard of care chemotherapy has failed to provide significant clinical benefits, which has led to the development of targeted agents against validated signalling pathways. However, to date the approach of targeted agents alone, or in combination with traditional chemotherapeutics, has failed to significantly improve the prognosis for pancreatic cancer patients. The current standard of care chemotherapy for advanced pancreatic cancer provides only a modest increase in survival of several months. Models that improve the predictive potential of drug discovery programs and gain greater insights into the complexity of tumour biology are therefore urgently required. To better understand the mechanisms influencing the anti-cancer activities of current and novel therapies, we have developed a 3D in vitro micro-tumour cell culture model. Current in vitro models utilising cell monolayer cultures are unable to recapitulate the biological and physiological complexities of the in vivo pancreatic tumour microenvironment and may be poor predictors of drug efficacy. Pancreatic adenocarcinomas are characterised as having a highly dense and poorly vascularised stroma that is made up of extracellular matrix (ECM) components and host cells. This complex tumour microenvironment has been implicated in the chemoresistance profiles observed in pancreatic tumours.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Eskitis Institute for Cell and Molecular Therapies
Science, Environment, Engineering and Technology
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46

Patel, Sabina. "The Development of Tetracycline Dependent Pancreatic Cancer Cells and the Evaluation of CapG and Gelsolin Expression on Pancreatic Cancer Cell Motility In Vitro". Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491370.

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Precise control of the level of protein expression in cells can facilitate functional studies providing information on the role of given proteins. In this thesis, I describe the generation of tetracycline-inducible pancreatic cancer cells and the subsequent use of these in the functional characterisation of an actin capping protein, CapG. Such cells were obtained in three pancreatic cancer cell lines, Panc-I, Suit-2 and MiaPaCa-2 cells through consecutive transfections with two plasmid constructs. The first of these harboured a second-generation reverse tetracycline-controlled transactivator protein (rtTA) whilst the second, contained the gene of interest (CapG or luciferase) under the control of a tetracycline response promoter element (pTRE). Suit-2 derived tetracycline inducible clones, along with stable doxycycline-inducible hepatoma cell lines, were used to study the effect of modulating CapG expression on cell motility. Here I report that stable introduction of a pTRE2hygCapG construct into two doxycycline-inducible clones derived from Suit-2 cells, Suit-2 ptet1I and Suit-2 ptet29 clones resulted in a dose and time-dependent increase of CapG expression in response to doxycycline. Moreover, doxycycline-mediated upregulation of CapG expression led to a significant increase in the wound healing capacity of Suit-2 ptet29 cells. The expression of a related actin binding and cell motility protein, gelsolin was also determined. Immunostaining of benign (n=24 patients) and malignant (n=68 patients) pancreatic ductal cells revealed higher gelsolin expression in the malignant state (P

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47

Wong, Kit-man Sunny y 王傑民. "Isolation and characterization of cancer stem cells in non-small cell lung cancer". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47250665.

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Tumor heterogeneity has long been observed and recognized as a challenge to cancer therapy. The cancer stem cell (CSC) model is one of the hypotheses proposed to explain such a phenomenon. A specific cancer stem cell marker has not been determined for non-small cell lung cancers (NSCLC), preventing the definitive evaluation of whether the biology of NSCLC is governed by the CSC model. This study aimed to analyze the expression of candidate CSC markers and using the identified putative marker, to isolate CSC and determine the applicability of the CSC model in NSCLC. The expression or activities of four putative stem cell markers, CD24, CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1) were measured by flow cytometry in eight NSCLC cell lines before and after chemotherapy for 24 hours. Markers with increased expression after treatment were considered potential CSC markers and used for isolating tumor cell subpopulations from the untreated cell lines by fluorescence-activated cell sorting (FACS). Confirmatory analyses using widely acceptable methodology were performed to test for CSC properties in the marker+ and marker- subpopulations. Isolated subpopulations were further characterized by functional and phenotypic studies. Flow cytometry showed amongst the 4 markers, only ALDH1 expression was significantly enhanced by chemotherapeutic treatment, suggesting ALDH1 could be a CSC marker. Untreated ALDH1+ cells formed significantly more and larger cell spheres in non-adherent, serum-free conditions than ALDH1- cells. Likewise, higher in vitro tumorigenic ability was observed in ALDH1+ subset using colony formation assay. Furthermore, a higher resistance to cytotoxic drugs was observed in ALDH1+ compared to ALDH1- cells. In vivo studies also showed ALDH1+ cells showed higher tumorigenicity than ALDH1- cells; as few as 2,500 ALDH1+ cells formed tumor in SCID mice which were serially transplantable to 2nd and 3rd recipients, while no tumor was formed from ALDH- cells with even ten times the number of cells. Also, expression analysis revealed higher expression of the pluripotency genes, OCT4, NANOG, BMI1 and SOX9, in ALDH1+ cells. In view of previous studies reporting CD44 as a CSC marker in lung cancer, double marker selection of putative CSC was performed to compare ALDH1+CD44+ and ALDH1-CD44+ subpopulations. Results of the spheroid body formation assay and cisplatin treatment experiments revealed the ALDH1+CD44+ subpopulation possessed higher self-renewal ability and chemo-resistance. Cell migration and invasion assays showed differences between the ALDH1+CD44+ and ALDH1- CD44+ subpopulations. The significance of these observations require further investigation. In conclusion, the result showed that ALDH1 could be a marker for NSCLC stem cells as evidenced by enhanced self-renewal and differentiation abilities in ALDH1+ subpopulation. Furthermore, this study observed the presence of at least two potential stem cell subpopulations in NSCLC cells with differential selfrenewal, chemotherapy resistance and cell mobility properties. Further investigations are required to validate these observations and to investigate the underlying mechanisms. Better understanding of these issues would help to solve the challenges brought by tumor heterogeneity in lung cancer therapy.
published_or_final_version
Pathology
Master
Master of Philosophy

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48

Jangamreddy, Jaganmohan Reddy. "Cancer and cancer stem cell targeting agents : A focus on salinomycin and apoptin". Doctoral thesis, Linköpings universitet, Avdelningen för cellbiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-113709.

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Current cancer treatments involving surgery, radiotherapy, and chemotherapy target the vast majority of cancer cells, but they are only partially effective in eliminating the disease. Failure to eliminate cancer with conventional treatments can lead to recurrence, which usually kills patient. This often occurs when cancer cells develop resistance to cancer drugs or when cancer-initiating cells (cancer stem cells), unaffected by existing treatment procedures, are present. Here, we studied two drugs, salinomycin and apoptin, that exhibit great potential in the future of cancer treatment not only for restricting malignancy, but also in preventing tumor recurrence. Salinomycin is an antibiotic that was used in poultry farming that is now used clinically to target cancer stem cells, and apoptin is a chicken anemia virus-derived protein that is capable of detecting and killing transformed cells. In this study, we delved into the molecular mechanism of salinomycin action leading to cancer cell death. We showed that salinomycin induces autophagy in both cancer and normal primary cells. We further demonstrated that salinomycin promotes mitochondrial fission, thus increasing mitochondrial mass and mitochondria-specific autophagy, mitophagy. Salinomycin-induced cell death was both necrotic and apoptotic as determined by increased release of HMGB1 and caspase-3, -8 and -9 activation. We also found that stress responses of normal and cancer cells to salinomycin differ and this difference is aggravated by starvation conditions. We proposed that a combinational treatment with glucose starvation, or glucose analogues such as 2DG or 2FDG, might enhance the effects of salinomycin on cancer cells while protecting normal cells. We previously reported that apoptin interacts with BCRABL1, a protein that is expressed in patients with chronic myeloid leukemia (CML). We located a minimal region on the apoptin protein that triggers inhibition of downstream BCR-ABL1 signaling effects. This deca-peptide region was tested on patient samples and was shown to effectively kill cancer cells derived from patients, similar to the drug Imatinib. We further show that the apoptin decapeptide is cytotoxic to Imatinib-resistant patient-derived cancer cells. Thus, we identified a novel therapeutic targeting agent that can not only overcome drug resistance, but it can also induce cancer cell death without affecting normal cells.

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49

Oshima, Nobu. "Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors". Kyoto University, 2014. http://hdl.handle.net/2433/192147.

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Oshima N, Yamada Y, Nagayama S, Kawada K, Hasegawa S, et al. (2014) Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors. PLoS ONE 9(7): e101735. doi:10.1371/journal.pone.0101735
Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第18547号
医博第3940号
新制||医||1006(附属図書館)
31447
京都大学大学院医学研究科医学専攻
(主査)教授千葉勉, 教授野田亮, 教授武藤学
学位規則第4条第1項該当

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50

Bastien, Jacynthe. "Inhibitor of apoptosis proteins and associated factors in pancreatic cancer". Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/29194.

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Since the phenomenon was first identified, apoptosis has been proposed to serve as a barrier to the development of cancer in metazoans. Over the years, the inability to carry out apoptosis has been implicated in the initiation, formation and progression of tumors. Moreover, acquired resistance to apoptosis is now believed to represent a major obstacle to the successful application of oncotherapies. Caspases play a central role in the induction and execution of apoptosis. As such, their activity must be tightly regulated. To date, inhibitor of apoptosis proteins (IAPs) are the only known intrinsic regulators of caspase function. The present study focused on the identification of molecular targets differentially expressed in normal and cancer cells that could serve to facilitate the rational design of anti-cancer therapies. We hypothesized that variations in the levels of key apoptotic regulators such as caspases, IAPs and their antagonists could conceivably contribute to the acknowledged resistance of pancreatic cancer cells to cytotoxic therapies. Our first specific aim was to derive an expression profile of apoptotic modulator/effector genes in pancreatic cancer cell lines. Our analysis uncovered a tendency towards up-regulation of IAP expression (namely cIAP-2) and down-regulation of pro-apoptotic factors such as caspases and the Xiap antagonist Xaf-1 in these cell lines. In particular, Xaf1 protein expression appeared to be completely repressed in neoplastic cell lines. Moreover, over-expression of one or more IAPs was observed in several solid malignancies. Lastly, while Xiap expression and subcellular localization were not altered in evolving intraductal lesions and pancreatic tumors, immunohistological surveys uncovered over-expression and nuclear redistribution of cIAP-1, cIAP-2 and survivin in pancreatic adenocarcinomas. Our second objective was to determine if differential expression of IAPs influenced the sensitivity of three human pancreatic cancer cell lines to drug-induced apoptosis. In vitro studies uncovered a good correlation between transcriptional up-regulation of IAPs, caspase-dependent cleavage of Xiap, activation of downstream effector caspase-3 and rapidity of onset of etoposide-induced apoptosis in these cell lines. In particular, endogenous levels of cIAP-2 mRNA appeared to be good predictors of etoposide-responsiveness. However, attempts at sensitizing pancreatic cancer cells to etoposide by down-modulating Xiap expression via over-expression of Xaf-1 or siRNA-mediated degradation of Xiap were unsuccessful. (Abstract shortened by UMI.)

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