Dissertations / Theses: '3211 Oncology and carcinogenesis'

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Al-Damouk, Jawdet Dakhel. "Malnutrition and experimental oral carcinogenesis." Thesis, University of Glasgow, 1988. http://theses.gla.ac.uk/2731/.

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The work was undertaken to examine the effects of nutritional deficiencies on cancer induction. Two of the most common and widely distributed nutrients, iron and folic acid, were examined to evaluate the effects of their deficiency on animals. The Syrian golden hamster was the animal model for all experimental work. In the first part of the study an attempt was made to induce iron deficiency in young adult male hamsters by feeding iron deficient diet coupled with repeated venesection of 1.5ml every two weeks. Following twelve weeks on this regime a superficial biopsy was taken, on week 13, from the medial wall of one pouch in each hamster in order to evaluate the effect of iron depletion on the epithelial compartment thicknesses. After allowing the biopsy sites to heal for two weeks, a solution of 0.25% DMBA in acetone was painted, three times per week, for eight weeks, on a defined one square centimetre area in each pouch of each hamster of the experimental and control groups. The hamsters were then maintained on the same dietary regimes for twelve weeks before being killed at the beginning of week 37 for analysis. Iron deficiency anaemia could not be induced in the experimental animals of this study. The effect of the iron deficient diet on epithelial compartment thicknesses at the stage of the biopsy was not clear. However, restriction of iron intake did cause animals to develop significantly fewer grossly seen tumours and histologically identified carcinomas than control animals. In the second part of this thesis an attempt was made to investigate alternative hamster dietary components that have less iron contamination than the diet given in the first part of this thesis. Casein and calcium lactate were the main contributers to iron in the hamster diet. Casein could not be substituted by another source of protein for hamsters. However, other sources for calcium with less iron contamination were available and therefore investigated in this part of the study. Three groups of young adult male and female hamsters were given the fully nourishing powdered diet used in previous studies. However, calcium lactate was substituted for by either calcium acetate, calcium chloride or calcium sulphate in each group. None of the three diets was accepted by the animals and many of them died of starvation. When calcium salts were replaced by calcium lactate the surviving animals accepted the diet and recovered quickly afterwards. This study proved that calcium lactate could not be substituted by any other calcium salt with less iron content and therefore iron contamination in the hamster diet could not be further reduced by this method. In the third part of this thesis the effect of nutritional folate deficiency on cancer induction was studied. A group of young adult female hamsters was given folate deficient diet for four weeks. On week 5, DMBA in acetone at a concentration of 0.25% was painted on a defined one square centimetre area of the medial wall of each pouch in each hamster in folate deficient and control groups. The carcinogen was applied three times per week for eight weeks following which animals were maintained on the same dietary regimes for a further 13 weeks before being killed at the beginning of week 27 for the final analysis of the study. It was found that nutritional folate deficiency had significantly reduced the number of animals developing grossly counted tumours and histologically identified carcinomas. The folate deficient animals also developed significantly less tumours and carcinomas compared to control groups. In the last part of this thesis, the effect of combined iron and folate deficiency was examined for its role in carcinogenesis of the hamster cheek pouch. Two groups of young adult male hamsters were fed powdered diet lacking iron and folic acid and a third group was fed diet lacking iron only. One of the combined deficiency groups and the iron deficiency group were bled 1.0-1.3ml every week. On week 6 of the study DMBA in acetone at a concentration of 0.25% was painted three times per week for eight weeks on the same area of the pouch used in the previous studies. The animals were then maintained on the same experimental regimes for a further eleven weeks before being sacrificed, on week 25, for the final analysis of the study. In this study, iron deficiency anaemia was induced in animals of the bleeding groups. Animals in the group with combined iron and folate deficiency without bleeding showed low normal folate levels and normal haemoglobin levels. The two groups that were bled repeatedly showed iron deficiency anaemia. In all groups, the numbers of tumours counted grossly and the numbers of carcinomas identified histologically were significantly reduced compared to control animals in the previous studies. The folate deficient diet did not appear to influence the induction of iron deficiency. The studies reported in this thesis proved that nutritional folate deficiency not only reduces the incidence, but it also reduces the numbers of tumours and carcinomas in the hamster cheek pouch. Iron deficiency anaemia was also found to significantly reduce the numbers of tumours and carcinomas of the hamster cheek pouch. It was not possible to produce combined iron and folate deficiency under the conditions of these studies. However, animals fed on a diet lacking iron and folic acid had significantly reduced numbers of grossly seen tumours and histologically identified carcinomas in the cheek pouch in response to DMBA applications. In each of the reported studies, the nutritional deficiency of iron and folic acid, whether individually or combined was found to significantly reduce the growth rate of affected animals.

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Singhal, Rishi. "Tissue and plasma metabolomics in oesophago-gastric carcinogenesis." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4246/.

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Introduction Oesophageal cancer has a poor prognosis. Early diagnosis and the use of chemotherapy and surgery for local disease are key to improving survival. This study was designed to see if plasma and tissue metabolic profiles could be used to identify oesophago-gastric malignancy, indicate the presence of unstable pre-malignant (Barrett’s) epithelium or predict response to chemotherapy. Methods Patients were recruited from University Hospitals Birmingham between May 2009 and March 2010. Nuclear Magnetic Resonance (NMR) metabolomics was performed on filtered plasma and extracted tissue samples. Results Some 258 participants were recruited. NMR metabolomics discriminated between normal, Barrett’s and neoplastic epithelium. Tissue levels of hypoxanthine were highest in oesophageal adenocarcinoma compared to adjacent normal mucosa. Levels in Barrett’s mucosa in the presence of cancer fell between normal and neoplastic mucosa. 3-hydroxybutyrate levels were elevated both in cancer tissues and plasma compared to controls. Plasma levels of 3-hydroxybutyrate were higher in patients with node positive and full thickness tumours compared to those who were node negative with early local disease. Conclusion NMR metabolomics identified metabolic profiles that characterized different histologic tissue types. Metabolites involved in oesophageal carcinogenesis might influence diagnostic and management strategies in these patients.

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Calapre, Leslie. "Heat stress: A risk factor for skin carcinogenesis." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2015. https://ro.ecu.edu.au/theses/1757.

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BACKGROUND: The incidence of skin cancer in Australia has increased rapidly in the last few decades. Ultraviolet radiation (UV) is a major risk factor for skin carcinogenesis. UV, particularly the UVB spectrum, causes formation of cyclobutane pyrimidine dimers (CPD) in cellular DNA. Persistent and incorrectly repaired CPDs lead to DNA mutations and consequently, formation of cutaneous lesions. Interestingly, recent epidemiological studies have shown a significant increase in skin cancer incidence in geographical locations with high environmental temperatures. Thus, heat stress may potentiate the effects of UV exposure and act as an additional risk factor for skin cancer. Previous studies in mice have shown that repeated and concurrent exposure to UVB and heat stress, increases the rate and incidence of cutaneous tumour formation relative to UVB alone. However, the effects of UVB plus heat on human epidermal cells have yet to be determined. Furthermore, the exact mechanisms responsible for the observed effects of heat stress need to be characterised in skin keratinocytes to increase knowledge of its risk in skin cancer. Heat stress induces upregulation of heat shock proteins (HSPs), particularly HSP72 and HSP90 which are known to affect the activity of the p53 protein. Furthermore, heat stress has been linked with increased Sirtuin1 (SIRT1) protein activity. SIRT1 is an important histone deacetylase that helps maintain chromosomal integrity but can also induce post-translational modifications of the p53 protein. By mediating deacetylation of the p53 protein, SIRT1 can diminish the ability of p53 to bind to its downstream gene targets. The p53 protein is an integral mediator of the cellular stress response in skin cells, particularly keratinocytes. Thus, impairment of p53 transcription factor functions could compromise the ability of epidermal cells to mount an appropriate response to DNA damage. Moreover, loss of p53 function may induce survival of cells harbouring DNA lesions. We hypothesise, therefore, that exposure to UVB plus heat induces survival of DNA damaged keratinocytes and that these cells escape apoptosis surveillance as a result of heat-mediated alteration to the p53 signalling pathway. Thus, exposure to heat stress could exacerbate the carcinogenic effects of UV and increase the risk of skin tumour formation in humans AIMS: In this study, we aimed to determine whether repeated exposure to UVB followed immediately by heat stress (39°C) has a more damaging effect on human keratinocytes than UVB alone. In particular, we assessed the effects on DNA damage, apoptosis, cell cycle and DNA repair. Furthermore, we aimed to unravel the mechanism through which heat mediates the survival of UVB DNA-damaged keratinocytes, focusing on the effects on the p53 signalling pathway. MATERIALS AND METHODOLOGY: Primary adult human epidermal keratinocytes (NHEK) and ex vivo punch biopsies of normal human skin called NativeSkin® (Genoskin, France), were used as experimental models for this study. A UV cabinet fitted with a TLUVB Narrowband lamp (Philips, GERMANY), with a spectral output of 290 -315 nm, was used to administer UVB irradiation at a dose of 1 KJ/m². Heat stress involved culture in a normal CO2 incubator, with temperature maintained at 39°C for three hours. The temperature used in the experiments was based on previous measurements of skin surface temperature of open cut miners, who are prone to intense heat stress, in the Pilbara region of Western Australia. For UVB plus heat exposures, cells and skin models were sequentially exposed to 1 KJ/m2 of UVB, (at room temperature), followed immediately by 3 hours incubation at 39°C once per day, for four consecutive days. Unexposed skin models and NHEK, maintained at 37ºC, were used as experimental controls. Cell proliferation, apoptosis and whole genome expression profiles were analysed at four hours post day 4 exposure, to understand earlier events, and at 2 days post-exposure, to assess persistent outcomes of these exposures. Treated primary NHEK cells were counted in a Vi-CellTM Viability Analyser and the level of apoptosis for exposed primary cells was determined using Annexin V/Propidium Iodide apoptosis assay at 4 hours and 2 days post exposure. To determine the presence of DNA damage, total and active p53 protein, as well as total and active SIRT protein, in the skin models and primary NHEKs, immunohistochemistry and/or immunocytochemistry was performed. Skin FFPE and primary NHEKs were incubated with antibodies to thymine dimers (CPD, DNA damage) and p53 (total), acetylated p53-382 (active), SIRT1 (total) or SIRT1-p (active) antibodies. To measure apoptosis in skin, an anti-pan-cytokeratin marker was used to label keratinocytes and active-caspase-3 antibodies were used to identify apoptotic cells. To determine the expression of p53-downstream target genes at 4 hours, quantitative RT-PCR was performed using TaqMan probes for BAX, Survivin (BIRC5), ERCC1 and XPC genes, with Human 18S gene as the endogenous reference gene. Relative quantification of the expression levels of each transcript in each sample were calculated using the Delta-Delta CT method relative to untreated controls. A whole genome expression analysis was performed at 2 days postexposure using the Human HT-12 Expression v4 BeadChip (Illumina, USA). The Ingenuity Pathway Analysis (IPA) (Qiagen, USA) software was used to annotate the effects of altered gene expression on cell function and upstream signalling pathways. Two-way ANOVA was used to analyse differences across treatment groups, while parametric unpaired t-tests were used to detect differences between specific treatment groups in all experimental categories, i.e. proliferation, apoptosis and gene expression, with p-values RESULTS: Outcome 1 –Using ex vivo skin models and NHEKs, we show for the first time that UVB plus heat treated keratinocytes exhibit DNA damage, as observed after UVB treatment alone. However, apoptosis was significantly reduced, possibly as a result of inactivation of the p53-mediated stress response, in DNA damaged cells of UVB plus heat treated samples. Furthermore, whole genome expression and IPA upstream analysis showed that heat induces SIRT1 activation, which was confirmed via immunohistochemistry assays. Heat-induced SIRT1 expression was linked to a decrease in acetylated p53 and consequently, downregulation of p53-regulated pro-apoptotic and DNA damage repair genes. These results suggest that p53-mediated cell cycle arrest and apoptosis, known to be induced by UVB, are ablated with the addition of heat, leading to survival of DNA damaged cells after UVB plus heat treatment. Outcome 2 – We further confirmed that SIRT1 activation did not inhibit the transcription of the p53 protein but mediated deacetylation of p53, resulting in significant deregulation of expression of p53 downstream gene targets and decreased keratinocyte apoptosis in UVB plus heat treated samples. Importantly, chemical inhibition of SIRT1 by Ex-527, a known chemical inhibitor of SIRT1, in UVB plus heat exposed keratinocytes, resulted in reactivation of the p53 signalling pathway and increased apoptosis of DNA damaged keratinocytes. This clearly demonstrated the role of heat-mediated SIRT1 activation in the survival of DNA damaged keratinocytes after exposure to UVB plus heat. CONCLUSION: In this study, we showed that the efficiency of cellular stress response to UVB-induced DNA damage is diminished in the presence of heat and, for the first time, provide a molecular mechanism that explains these effects. With the novel use of an ex vivo human skin model, this study showed that heat stress prevents human keratinocytes, damaged by UV irradiation, from undergoing apoptosis and/or necrosis. We found UV plus heat exposure mediates SIRT1 activation which has been found to induce deacetylation of p53 and, consequently, the inactivation of the p53 signalling pathway. SIRT1 inhibition precluded the downregulation of p53 signalling by UV plus heat exposure, restoring apoptosis levels to those observed in UVB-only exposures. Thus, we demonstrated that SIRT1 activation is the main molecular mechanism driving UVB plus heat-induced survival of DNA damaged keratinocytes. Overall, the results of this study suggest that by allowing the survival of DNA damaged keratinocytes, via induction of SIRT1 activation, heat stress can exacerbate the carcinogenic effects of UVB radiation. Exposure to heat stress, in addition to UV, could therefore increase the accumulation of mutations in keratinocytes, possibly leading to the transformation of normal cells into pre-cancerous cells. Further research is warranted to determine the role of UVB plus heat in skin cancer pathogenesis. Such knowledge could be utilised in public health campaigns to decrease risk, particularly for people exposed to combinations of these environmental hazards in workplaces such as in the mining, construction and petroleum industries.

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Nelson, Adam William. "Estrogen receptor beta modulates prostate carcinogenesis." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267736.

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Prostate cancer (PC) is characterised by dependence upon androgen receptor (AR) as its driving oncogene. When organ-confined, radical treatment can be curative, however there is no cure for advanced, castration-resistant prostate cancer (CRPC). There is therefore a need to better understand the biology of PC, and how influencing AR can modify disease progression. Estrogen is essential for prostate carcinogenesis with evidence from epidemiological, in vitro, human tissue and animal studies. Most suggests that estrogen receptor beta (ERβ) is tumour-suppressive, but trials of ERβ-selective agents have not improved clinical outcomes. ERβ has also been implicated as an oncogene, therefore its role remains unclear. Additional evidence suggests interplay between ERβ and AR, the mechanisms of which are uncertain. The study hypothesis ‘ERβ is an important modulator of prostate carcinogenesis’ was developed to establish whether targeting ERβ could affect PC progression. Much of the confusion around ERβ stems from use of inadequately validated antibodies and cell line models. The first phase of this work was to test ERβ antibodies using an ERβ-inducible cell system. Eight ERβ antibodies were assessed by multiple techniques, showing that commonly used antibodies are either non-specific or only specific in one modality. Two reliable antibodies were identified. Next, cell lines previously used to study ERβ were assessed using validated antibodies and independent approaches. No ERβ expression was detected; an important finding that casts doubt on previously published ERβ biology. Subsequently, a PC cell line with inducible ERβ expression (LNCaP-ERβ) was developed and validated to enable controlled experiments on the effects of ERβ on proliferation, gene expression and ERβ/AR genomic cross-talk. Phase three of this work focused on ERβ biology in PC and its relationship to AR. Interrogation of clinical datasets showed that greater ERβ expression associated with favourable prognosis. Gene expression data from men treated with androgen deprivation therapy revealed that AR represses ERβ. This was confirmed in vitro. The LNCaP-ERβ cell line was treated with androgen and/or ERβ-selective estrogen. Activated ERβ in the presence of androgen-stimulated AR inhibited cell proliferation and down-regulated androgen-dependent genes. Genome-wide mapping of ERβ binding sites reveals that ERβ antagonises AR through competition for shared DNA binding sites. In conclusion, ERβ expression is down-regulated by AR during malignant transformation of prostate epithelium. We reveal an antagonistic relationship between ERβ and AR whereby sustaining or replacing ERβ may inhibit tumour growth through down-regulation of AR-target genes. In future, an ERβ-selective compound may be used to slow or abrogate PC progression.

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Gupta, Ashok Kumar. "Molecular mechanisms of ionizing radiation carcinogenesis in mouse skin." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/282881.

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Ionizing radiation is a physical agent that is tumorigenic in all exposed tissues. These radiation-induced secondary neoplasms tend to be more aggressive and carry a poor prognosis. Our knowledge of the molecular mechanisms of ionizing radiation carcinogenesis is not as advanced as compared to chemical carcinogenesis. We have used repeated exposure to low LET radiation in the mouse skin model to study the molecular mechanisms of ionizing radiation as a complete carcinogen and as a tumor progression agent. Shaved backs of CD-1 mice were treated with fractionated doses of beta-irradiation in a complete carcinogenesis experiment. A total of 27 carcinomas and sarcomas were seen. Cell lines were established from four sarcomas and one squamous cell carcinoma. Biochemical studies revealed that three sarcoma cell lines were derived from rhabdomyosarcornas. All four sarcoma cell lines had a p53 null phenotype. We screened cDNA expression libraries from three cell lines for dominant transforming activities. GAPDH was isolated as a candidate transforming gene in the squamous cell carcinoma cell line. Using a papilloma producing mouse keratinocyte cell line, we have shown that repeated doses of ionizing radiation are equally effective as a tumor progression agent when compared to N-methyl N'-nitro-N-nitrosoguanidine (MNNG). In this model, elevated reactive oxygen species levels were seen in both radiation and MNNG progressed cells. Elevated transcription factor transactivation as well as constitutive activation of Erk-1/2 and p38 MAP kinase activities were found to be potential mediators of the reactive oxygen species mediated mitogenic signaling in the progressed phenotype. Analyses of the anti-oxidant defense mechanisms showed that attenuation of catalase activity was a potentially important mechanism for the establishment of the pro-oxidant state. Forced re-expression of catalase in the malignant variants resulted in a reduction in transcription factor transactivation. Taken together, the results from experiments presented in this dissertation suggest that inactivation of gene products that maintain genomic stability, such as p53, may be an important step during neoplastic transformation with fractionated doses of ionizing radiation. Altered expression patterns of genes related to cell metabolism and oxidative stress can be functionally involved during the later stages of ionizing radiation-induced malignant transformation.

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Wilt, Stephen Ray. "Effect of selenium on chemical carcinogenesis in animal models /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487261553056718.

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Gnanapragasam, Vincent Jeyaseelan. "Fibroblast growth factor 8 as a model of androgen receptor mediated carcinogenesis in human prostate cancer." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247915.

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Wan, Lei. "Dietary Tomato and Lycopene Modulate Critical Androgen-driven mRNA and miRNA Expression in Early Prostate Carcinogenesis." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1388489457.

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Babbar, Naveen. "Regulation and function of spermidine/spermine N¹ acetyl transferase (SSAT) in colon carcinogenesis." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/289966.

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Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumorigenic activities against colorectal cancer. NSAIDs work by inhibiting cyclooxygenases (COX) enzyme. Sulindac, a NSAID prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Microarray analysis was used to detect COX independent effects of sulindac on gene expression in human colorectal cells. Spermidine/spermine N 1-acetyl transferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was one of the genes induced by clinically relevant sulindac sulfone concentrations. Promoter analysis and mutational studies were done to map the sulindac sulfone dependent response sequences in SSAT 5' flanking sequences, which led to the identification of two Peroxisome Proliferator Activated Receptors (PPARs) response elements (PPREs) in the SSAT gene. PPRE-2 is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPARgamma in the Caco-2 cells, while PPRE-1 is not required for the induction of SSAT by sulindac sulfone, but can be bound by both PPARdelta and PPARgamma. Clinically relevant concentrations of sulfone reduced intracellular polyamine levels, inhibited cell growth and induced apoptosis in colon cancer cells. Further, only sulindac sulfone induced apoptosis could be partially rescued by exogenous polyamines. Upon evaluating other NSAIDs for their action on SSAT gene expression, it was found that they induce SSAT mRNA in either a COX dependent or independent mechanism in colon cancer cells. Studies with physiologically relevant concentrations of aspirin show that these concentrations can induce SSAT expression thereby leading to a decrease in polyamine levels. Activating mutations in K-ras, which is a late process in colon carcinogenesis, led to the suppression of SSAT expression in the Caco-2 cells due to the inhibition of PPARgamma by ERK. K-ras didn't have any effect on the induction of SSAT by sulindac sulfone but partially abolished the apoptosis caused by sulindac sulfone, indicating a possible role of mutant K-ras in sulindac resistant colon polyps. Sulindac sulfone, or Exisulin(TM) have been recently used in clinical trials for the prevention of colon, lung and prostate cancer. The data shown here, suggest that one of the mechanisms, by which sulindac sulfone could act as a chemopreventive agent is to induce the expression of SSAT thereby leading to a decrease in the intracellular polyamines. This reduction in polyamines plays an important part in the apoptosis induced by sulindac sulfone in the colon cancer cells. Further, induction of SSAT seems to a general mechanism for different NSAIDs like aspirin, indomethacin, ibuprofen, sulindac and celecoxib in colon cancer. Aspirin is able to induce SSAT and decrease intracellular polyamines at physiological concentrations, which can lead to a significant reduction in adenoma recurrence. Also, activated K- ras suppressed SSAT, but was not able to abolish the induction of SSAT by sulindac sulfone indicating the potential of using sulindac sulfone in colon cancer chemoprevention.

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Pickering, Curtis Reid. "Understanding the early events in breast carcinogenesis by inactivating p16INK4a in primary human mammary epithelial cells." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3324574.

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Groisman, Iris Jaitovich. "Interaction of hepatitis B virus with cellular defense : mechanisms in relation to liver carcinogenesis." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36944.

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Hepatocellular carcinoma (HCC) is one of the major causes of cancer morbidity and mortality worldwide. However, its incidence is subject to variations: high incidence in sub-Saharan Africa and Asia, intermediate in Mediterranean countries and the Middle East, and low in Western European countries and North America. While different etiological factors have been implicated in the development of HCC, infection with the hepatotropic viruses hepatitis B virus (HBV) and hepatitis C virus (HCV), and exposure to liver carcinogens are the most frequently addressed as directly implicated in HCC development. Epidemiological studies indicate that infection with HBV and exposure to the cyclic mycotoxin Aflatoxin B1 constitute the major risk factors in some regions where the incidence of HCC is elevated. Strikingly, in areas were there is coexistent exposure to both these agents, the incidence of HCC is even higher. In order to elucidate the molecular mechanisms that may lead to a concomitant effect of both HBV and Aflatoxin B1 in HCC development, I hypothesized that HBV may decrease cellular defense mechanisms such as detoxification of active metabolites and/or DNA repair processes increasing the likelihood of mutations.
Detoxification of reactive compounds by phase II enzymes is an important cellular defense process involved in cell susceptibility to carcinogens. I have demonstrated that the activity of human Glutathione Transferase A1 (hGSTAl) enzyme is down-regulated in HBV infected cells. This data correlates with a decrease in protein and mRNA levels. I linked this inhibition---at least partially---to a transcriptional down-regulation of hGSTAl gene expression by the x protein of the HBV (HBx). Strikingly, Oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione), which has been found to have cancer chemoprotective properties, overcomes the effect of HBx on the hGSTAl promoter in in-vitro experiments. This result adds new evidence for the importance of the use of Oltipraz as an HCC chemoprotective agent.
I have demonstrated that the HBx is directly involved in the decrease of Nucleotide Excision Repair (NER) activity. Although HBx direct interaction with the tumor suppressor protein p53 was postulated to lead to decreased DNA repair mechanisms, I have shown that this process occurs in both p53-proficient and p53-deficient cells. The results of my work provide evidence that HBx-induced NER inhibition is associated with down-regulation of the expression of the TFIIH factors XPB and XPD. The decreased expression of both genes is regulated by HBx at the transcriptional level. These results were observed in both p53-proficient and p53-deficient cell lines. Interestingly, HBx was found to be capable of transcriptional down-regulation while maintaining its transactivation capacity. In addition, liver tissue from transgenic mice for HBx show decreased levels of XPB and XPD corroborating the results obtained in vitro.
Hence, the HBx protein seems to alter two cellular defense mechanisms that can increase susceptibility to liver carcinogenesis.

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Washo-Stultz, Delon Elizabeth. "The role of oxidative stress in bile salt-induced apoptosis: Relevance to colon carcinogenesis." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289150.

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Previous work from our laboratory indicated that the bile salt, sodium deoxy-cholate (NaDOC), induced apoptosis in cultured cells and in normal goblet cells of the colonic mucosa, and that the normal-appearing flat mucosa of patients with colon cancer exhibited apoptosis resistance. Secondary bile acids are known promoters of colon cancer, but the mechanism by which they promote cancer is still largely unknown. We have shown that high physiologic concentrations (0.5 mM) of NaDOC activates the redox-sensitive transcription factor, NF-κB, and also causes the formation of nitrotyrosine residues, a footprint for the formation of reactive nitrogen species, including peroxynitrite, in plasma membrane-associated proteins of cells. These observations indicate that this bile salt induces oxidative stress within the cells. Since peroxynitrite is formed from the reaction between nitric oxide and superoxide anion, we specifically looked at the role of nitric oxide and superoxide anion in NaDOC-induced apoptosis. Pretreatment of cells with the inhibitor/antioxidants, L-NAME (N-nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthase, CuDIPSH, a superoxide dismutase mimetic compound, Trolox, a water-soluble analog of α-tocopherol, Melatonin, a fat and water soluble antioxidant, N-acetyl-cysteine, a GSH enhancer, U-74389G, a lazeroid that inhibits superoxide anion and free radical lipid peroxidation and U83836E, a lazeroid that is 100X more potent than trolox, alone, or in combination, sensitized cells to apoptosis induced by 0.5 mM NaDOC. We also investigated the effects of inhibitors of certain pathways known to generate ROS, mitochondrial complexes I and II of the electron transport chain and arachidonic acid metabolism, on bile salt-induced apoptosis. Both rotenone and TTFA, inhibitors of mitochondrial complex I and complex II respectively, protected HT-29 cells from NaDOC-induced apoptosis. The inhibitor of COX-1, Sulindac Sulfide, sensitized cells to NaDOC-induced apoptosis and so did the combination of the COX-2 and LOX inhibitors, NS-398 and Esculetin. These results suggest that nitric oxide and reactive oxygen species (ROS) may be part of a signaling pathway that is responsible for apoptosis resistance. The results also indicate that antioxidants may possess anti- cancer properties.

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Qureshi, Muhammad Asif. "Dissecting the role of LMP1 (CAO) induced chronic inflammation in EBV associated carcinogenesis." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3404/.

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Latent membrane protein 1 (LMP1) is the primary oncogene of Epstein-Barr virus (EBV), which is associated with various malignancies including nasopharyngeal carcinoma (NPC) – a tumour of epithelial origin. The NPC tissues are so heavily infiltrated with leukocytes that the tumour is sometimes also called lympho-epithelioma. In order to understand the mechanisms involved in LMP1 induced carcinogenesis (and inflammation-associated carcinogenesis in general), our lab has generated transgenic mice expressing an NPC variant of LMP1 (LMP1CAO) in the epidermis. LMP1 induced signalling pathways are activated in the pathological tissue, including NFκB, JNK, MAPK and p38 MAPK. In addition multiple proteins involved in proliferation and inflammation are upregulated including EGFR and its ligands, VEGF, and MMP9 amongst others. The skin of these mice, particularly the ears, develops a progressive inflammatory pathology from birth, initiating with hypervascularization (Stage1 (St1)) and hyperplasia (St2), increasing inflammation, leading to necrosis (St3), ulceration (St4), keratocanthoma (St5) and occasional carcinoma formation. The transgenic model permits an analysis of chronic inflammation as it leads to carcinoma, and the important factors involved in this. This thesis describes the experiments and the pre-clinical trials conducted to dissect the inflamed milieu internal of the pre-neoplastic transgenic tissue, with a focus on the immune cells, immune response, autoantigens, danger signals, oxidative stress and perturbed metabolic pathways. The transgenic tissue showed increased infiltration of mast cells, helper T-cells (CD4+), cytotoxic T-cells (CD8+/GranzymeB+) and Treg cells (CD4+/CD25+/FoxP3+). Inhibition of leukocyte recruitment using in vivo L-selectin inhibition not only resulted in slowed progression of the pathology but also could reverse the phenotype, suggesting a prognostic as well as therapeutic potential of L-selectin inhibition. Several inflammatory markers and cytokines, including STAT3, s100A9, CD30, CD30L, L-selectin, IL-3 and IP-10, were upregulated in the transgenic tissue compared to the controls. The role of a pro-inflammatory environment in the progression of the LMP1CAO induced pathology was investigated further by genetic removal of a chemokine decoy receptor D6 that resulted in accelerated progression of the pre-neoplastic as well as neoplastic pathology. Antibody deposition is a feature of this pathology. In order to identify the antigenic targets, various proteomic techniques were used. Immunoprecipitation experiments showed that the chitinase like proteins (CLPs) specifically Chi3L1, Chi3L3 and Chi3L4, are autoantigens in the LMP1CAO induced inflammation. Western blot and IHC analyses of the LMP1CAO tissue revealed that CLPs are expressed at an early stage of inflammation while active chitinases are expressed at the later stages. Moreover, an attempt was made to investigate the sera and biopsies from NPC patients for the expression and secretion of human CLPs, CHI3L1 and CHI3L2. In another approach, the T-cell/B-cell interaction (and thus Ig class switching) was disrupted through genetic elimination of CD40. The LMP1CAO/CD40KO mice showed delayed progression of the inflammatory phenotype during later stages, suggesting that Ig deposition is factorial in this process. Metabolic fingerprinting of the LMP1CAO tissue revealed deregulation of several metabolic pathways and suggested that “metabolic demand precedes the increased supply during pre-neoplasia”. Several metabolic changes indicative of increased cell proliferation were identified in the transgenic tissue, including upregulation of phospholipid metabolism intermediates, such as choline, phosphocholine, glycerophosphocholines and lysophosphatidic acid. A tumour specific glycolytic programme was operational in the transgenic tissue along with increased levels of glutamine, suggesting tumour-like energy consumption. The transgenic tissue was under oxidative stress indicated by increased levels of H2O2. Finally, in vivo administration of an anti-oxidant, N-acetylcysteine (NAC), arrested the inflammatory phenotype at very early stages, suggesting that oxidative stress is one of the inciting dangers/damages in the LMP1CAO induced inflammation. To summarize, the investigations presented herein have identified several candidates of diagnostic and therapeutic potential that are worth exploring further; not only in relation to the LMP1CAO induced carcinogenesis but also for various cancers in general.

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Slater, Sarah Jane. "Does BFR1, a component of the transcription factor (TFIIIB), have a role in prostate carcinogenesis?" Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7479/.

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Prostate cancer is the commonest cancer diagnosed in UK men and the second commonest cause of cancer mortality. There is an urgent need to improve our ability to differentiate indolent from aggressive disease to achieve optimal evidence-based treatment choices. Tumourigenesis involves deranged cellular proliferation, which in turn necessitates gene translation to drive protein synthesis. The transcription products of RNA polymerase III (Pol III) play a critical role in protein synthesis. TFIIB-related factor 1 (BRF1) is a vital transcription factor and functions as part of the Pol III transcription apparatus to mediate transcription of transfer RNAs (tRNAs). tRNAs). In this thesis, using a range of in vitro/ in vivo pre-clinical models and clinical resources, I have characterised the status of BRF1 in prostate cancer. Abnormal BRF1 expression has been previously suggested in small pilot studies in a number of tumour types. Our recent immunohistochemistry data showed evidence of upregulated BRF1 expression in clinical prostate tumours. I observed high levels of BRF1 expression in a comprehensive panel of human prostate cancer cell lines. To further examine the functional significance of BRF1 in prostate cancer, BRF1 expression was manipulated. Upon transient over-expression of BRF1, cell proliferation was upregulated in several prostate cancer cell lines. In contrast, when Brf1 expression was reduced, cell proliferation decreased, along with associated G2/M accumulation. To test the in vivo function of BRF1 in prostate carcinogenesis, a genetically engineered mouse model (GEMM) was developed with enhanced Brf1 expression in the prostate, namely Pten-Brf1, while Pten was deleted to recapitulate commonly observed activation of PTEN/AKT pathway in clinical prostate cancer. The Pten-Brf1 mice harboured enhanced growth of their prostate tumours, although they were histologically similar to prostate tumours driven by homozygous Pten deletion (or Pten-). Overall, Pten-Brf1 mice survived significantly shorter period than the control Pten- mice. In summary, my research conducted in this thesis highlights a potential role for BRF1 (as part of the Pol III transcriptional apparatus) in prostate carcinogenesis. Further research is therefore warranted to define its role as a cancer biomarker and as a novel target for therapy.

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15

Duncan, F. Jason. "The Effects of Black Raspberry Extract on UVB-Induced Inflammation and Carcinogenesis." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1235661753.

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16

Demicco, Elizabeth G. "Non-classical nuclear factor-kappa B complexes in mammary gland development and tumorigenesis." Thesis, Boston University, 2005. https://hdl.handle.net/2144/37131.

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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
Post-natal mammary gland development is a complex process in which epithelial proliferation and branching of lactiferous ducts is followed by extensive formation of lobuloalveolar units that produce milk. Classical nuclear factor-kappa B (NF-κB) p65/p50 transcription factors are dynamically induced in the mammary gland during pregnancy, and inhibitor of NF-κB-alpha (IκB-α) deficiency leads to hyperplasia of the mammary epithelium. To further elucidate the role of NF-κB factors in mammary development, we examined NF-κB subunit expression in the mammary glands of transgenic mice expressing the IκB-α S32/36A super-repressor (SR) protein under control of the mouse mammary tumor virus (MMTV)-long terminal repeat promoter, in which mammary gland development is transiently delayed, but not completely blocked. Developmental recovery correlated with induction of RelB/p52 NF-κB complexes, which failed to interact with an IκB-α fusion protein and potently induced cyclin D1 and c-myc promoter activities. Activation of IκB-α kinase alpha (IKKα) and NF-κB inducing kinase (NIK) was detected by day 5.5, and were hypothesized to be responsible for the induction of ReIB/p52. In support of this hypothesis, we found that constitutively active IKKα induced p52, RelB, and cyclin D1 in untransformed mammary epithelial cells. Moreover, mammary tumors induced by high-dose 7,12-dimethylbenz(a)anthracene (DMBA) treatment in wild type FVB/N mice, displayed increased RelB/p52 binding activity. These results implicate activation of RelB/p52 complexes by the alternative NF-κB signaling pathway in branching of lateral ducts and alveolar development during mammary gland development, and in mammary carcinogenesis.
2031-01-01

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17

Leong, Yeh Chwan. "Reprogramming to cancer induced pluripotent stem cells elucidates the contribution of genetic and epigenetic alterations to breast carcinogenesis." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/53330/.

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The induced pluripotent stem cells (iPSCs) technology has revolutionized disease modelling by enabling the generation of patient-specific pluripotent stem cells for the study of complex disorders such as cancer. Somatic cell reprogramming through iPSCs induces global epigenetic reconfiguration of the chromatin which converts cancer cells to an embryonic stem cell-like state with potential reversion of tumorigenicity. Therefore, reprogramming can be used to answer the question as to whether epigenetic alterations alone can be sufficient to induce carcinogenesis, independent of genetic defects. In addition, it can used to dissect the relative contribution of genetics and epigenetics and epigenetics to tumorigenicity. In this study, the triple negative breast cancer (TNBC) cell line BT-549 and oestrogen receptor positive (ER+) cell line MCF7 were successfully reprogrammed by using the non-integrative episomal vectors expressing OCT4, SOX2, L-MYC, KLF4, LIN28, EBNA1, shRNA against TP53, and microRNA-302/367 cluster together with treatment of sodium butyrate. Pluripotency of cancer-derived iPSCs was confirmed by RT-PCR, RT-qPCR and immunofluorescence staining for expression of pluripotency markers. Differentiation potential of iPSCs was also assessed by using in vitro differentiation either spontaneous or directed to the mammary lineage. Functional assays indicated potential loss of tumorigenicity in re-differentiated cells derived from cancer iPSCs. The same approach was applied to study an immortalised, non-malignant mammary epithelial cell line MCF10A and two of its derived isogenic lines harbouring the two most frequent mutations in breast cancer, PIK3CAH1047R (+/-) and TP53(-/-), created by using CRISPR-Cas9 gene editing. Reprogramming induced a tumorigenic phenotype in iPSCs (PIK3CAH1047R (+/-) isogenic line only) and re-differentiated progenies (in both wild type MCF10A and PIK3CAH1047R (+/-) cell lines), suggesting the contribution of PIK3CA mutation in enhancing malignant transformation. Results in this study suggested that epigenetics alone and/or its interaction with genetic defects (e.g. PIK3CA mutation) has significant impact on breast cancer carcinogenesis. The dissection of the molecular mechanisms underlying the loss and gain of tumorigenicity using the iPSC models generated in this study could provide general understandings on breast carcinogenesis, which in turn could have important clinical implications.

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18

Wu, Hsiao-Chi David 1967. "Gene mutations in experimental models of carcinogenesis and their effects on responses to chemopreventive agents in the azoxymethane-treated rat model." Diss., The University of Arizona, 1997. http://hdl.handle.net/10150/282340.

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The Ki-ras oncogene and the p53 tumor suppressor gene are mutated in a high percentage of human colon cancers. The mutation status of these two genes were assessed in colon adenocarcinomas obtained from azoxymethane (AOM)- and dimethylhydrazine (DMH)-treated rats, widely used experimental models of human colon carcinogenesis. The status of p53 mutations was examined using polymerase chain reaction (PCR) amplification of these sequences. In so doing, it was discovered that the rat p53 gene is structurally distinct from the human p53 gene, since it is missing one intron between exons 6 and 7. Further analysis using single stranded DNA conformational polymorphism (SSCP) analysis and direct DNA sequencing of the highly conserved regions of rat exons 5-7, highly mutated in human colon cancers, revealed no p53 mutations in any of these regions. Mutations at codon 12 of the Ki-ras gene were also characterized. Mutation frequency was approximately 60% which is close to the frequency of Ki-ras mutations found in human cancers. Since Ki-ras mutations have been shown to occur early in human colon carcinogenesis, while p53 mutations are thought to occur in late stage tumors, these data suggest this model may be a good for early, but not late, events of human colon carcinogenesis. It was also found that the non-steroidal anti-inflammatory drug (NSAID), sulindac sulfone, could reduce Ki-ras mutation frequency in this model. NSAIDs are agents being studied as a possible chemopreventive agent in both human colon cancers and the AOM model. Previous studies have found that the NSAIDs, sulindac and its sulfone metabolite, decrease the frequency of colon tumors in the AOM model. In this study, sulindac and sulindac sulfone specifically induced apoptosis in normal rat embryo cells (RECs) transfected with either an EJ-ras or activated myc and ras but not in non-transfected RECs. These data suggest that sulindac and sulindac sulfone may be reducing tumor frequency and Ki-ras frequency by inducing apoptosis in those cells with specific mutations that give them carcinogenic potential, possibly through non-prostaglandin dependent pathways.

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Spees, Colleen K. "Dysregulation of p53 Gene Expression in Human Prostate Carcinogenesis and Its Relationship to Angiogenesis." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313523656.

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20

Hammer, Anisha Mathur. "Elucidating the Roles of Stromal PDGF-receptors alpha and beta in Mammary Gland Development and Carcinogenesis." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492446436437557.

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21

Teng, Kun-Yu Teng. "Molecular mechanisms underlying microRNA-122 mediated suppression of liver inflammation, fibrosis, and carcinogenesis." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1511206344798557.

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22

Lan, Shang-Lun. "Vitamin D in Normal Breast Tissue Correlates to Early Breast Carcinogenesis." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471623716.

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23

Sullivan, Nicholas James. "Interleukin-6 as a Potential Mediator of Breast Cancer Progression and Non-Melanoma Skin Carcinogenesis." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249493495.

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24

Simón, Extremera Pilar. "Estudio de los mecanismos moleculares que promueven la progresión del carcinoma escamoso de piel." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/403427.

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El carcinoma escamoso (SCC) es el segundo tumor de piel más frecuente en humanos caucásicos. Estudios recientes demuestran que el crecimiento tumoral es mantenido por una población de células tumorales, las células madre del cáncer (CSCs), con capacidad de autorenovación y diferenciación, las cuales serían además responsables del desarrollo de metástasis. Nuestros estudios previos demostraron que los carcinomas escamosos de piel de estadios tempranos, que muestran características de diferenciación epitelial (WD- SCCs), progresan a carcinomas indiferenciados y con características mesenquimales (PD/S-SCCs), los cuales presentan un crecimiento mucho más agresivo y una mayor capacidad metastásica que los WD-SCCs. El objetivo principal esta tesis es estudiar los mecanismos moleculares que promueven la progresión del SCC de piel de ratón y determinar si el origen o la localización de las células madre (SCs) epidérmicas favorece la progresión de los SCCs y el desarrollo de PD-SCCs. Nuestros resultados demuestran que, tanto la población de SCs de la epidermis interfolicular (IFE) y su progenie, como las SCs del bulge del folículo piloso y su progenie, contribuyen a la generación de WD-SCCs y PD-SCCs en los ratones K14-HPV16. Sin embargo, observamos que se produce un mayor desarrollo de PD-SCCs a partir de las SCs del folículo piloso y su progenie que a partir de las SCs de la IFE y su progenie. Estos resultados sugieren que la generación de los tumores más indiferenciados y agresivos estaría favorecida por el origen folicular de las SCs. Por otra parte, demostramos que durante la progresión de los WD-SCCs a PD/S-SCCs se produce una expansión de la población de CSCs y una fuerte inducción del programa de transición epitelio-mesénquima (EMT), que correlaciona con un incremento del crecimiento tumoral y un mayor desarrollo de metástasis. La caracterización molecular de las CSCs de los SCCs en diferentes estadíos de progresión demostró, que las características y las vías de señalización que regulan la proliferación y la supervivencia de esta población de células cambian a lo largo de la progresión. Así, los PD/S-SCCs presentan atenuada la vía de señalización de β-catenina, la cual juega un papel importante en estadios tempranos de progresión. Además, mientras que la activación autocrina de la vía de EGFR promueve la proliferación de las CSCs de WD-SCCs, esta vía está atenuada en las CSCs de los PD/S-SCCs, donde se produce la activación autocrina de las vías de PDGFRα y FGFR1. Nuestros datos demuestran que la activación de la vía de FGFR1 en PD/S-SCCs induce significativamente la proliferación de las CSCs y el crecimiento tumoral, mientras que la activación autocrina de la vía de PDGFRα promueve la capacidad de migración e invasión de las CSCs y, en consecuencia, el desarrollo de metástasis de los PD/S-SCCs. Estudios previos mostraron que determinadas señales o factores del microambiente tumoral, promueven la proliferación y la diseminación de las CSCs y en consecuencia, el crecimiento tumoral y el desarrollo de metástasis. Nosotros demostramos que durante la progresión de los SCCs, se producen importantes cambios en el microambiente tumoral, como una disminución del porcentaje de células inmunes que infiltran el tumor, un aumento de la angiogénesis e importantes cambios en la expresión de citoquinas y de sus respectivos receptores. En este sentido, observamos que los PD/S-SCCs presentan un aumento de la expresión de citoquinas angiogénicas como Ccl2, Cx3cl1 y Sdf-1α, correlacionando con el aumento de la angiogénesis observada en estos tumores. Además, demostramos que la activación autocrina de la vía de PDGFRα induce la producción de SDF-1α y la activación autocrina de esta vía a través de CXCR4 en las CSCs de los SCCs avanzados. La activación de la vía de SDF-1α/CXCR4 induce significativamente la proliferación y la capacidad de invasión de las CSCs de PD/S-SCCs, así como el crecimiento de los tumores avanzados y el desarrollo de metástasis. Por lo tanto, estos resultados indican PDGFRα estimula la invasión y migración de las CSCs y el desarrollo de metástasis a través de la activación de la vía de SDF-1α.
Tumor growth is sustained by cancer stem cells (CSCs), which is also responsible of metastases development and resistance to chemotherapy. Our previous studies demonstrated that mouse skin squamous cell carcinoma (SCCs) exhibiting epithelial differentiation traits (WD-SCCs), progress to undifferentiated carcinomas with mesenchymal features (PD/S-SCCs), which show aggressive growth and enhanced metastasis compared to WD-SCCs. Our major aim was to determine mechanisms involved in skin SCC progression. We found that, although stem cells (SCs) from interfolicular epidermis (IFE) and those from hair follicles contribute to the generation of PD-SCCs in K14-HPV16 mice, the percentage of PD-SCCs generated from hair follicle SCs and its progeny was higher than from IFE SCs, suggesting that the progression from WD-SCCs to PD- SCCs may be favored by the follicular origin of SCs. The characterization of SCCs at different stages of progression demonstrated that PD/S-SCCs show an expansion of CSCs and a strong induction of the EMT program, correlating with the aggressive growth and enhanced metastasis associated to these tumors. Furthermore, features and signaling pathways regulating proliferation/survival and dissemination of these CSCs change during progression. Thus, whereas WNT/-catenin signaling and an autocrine activation of EGFR promote the proliferation and survival of WD-SCC CSCs (E-CSCs), these signaling were attenuated in PD/S-SCC CSCs (L- CSCs). In contrast, an autocrine activation of FGFR1 and PDGFRα pathways were induced in L- CSCs. Activation of FGFR1 signaling induced L-CSCs proliferation and tumor growth, whereas the autocrine activation of the PDGFRα signaling induced L-CSCs migration and invasiveness, and metastasis development. Previous studies demonstrated that signals from tumor microenvironment promote CSCs proliferation and dissemination. Here, we demonstrated that the microenvironment features change during SCCs progression. Thus, tumor immune infiltrate was strongly reduced and the angiogenesis was induced in advanced SCCs, whereas the cytokines expression by tumor cells dramatically changed, suggesting that the activation of cytokine-dependent signaling may contribute to PD/S-SCC growth and metastasis. Finally, we demonstrated that the activation of the PDGFRα pathway in L-CSCs induces SDF-1α synthesis and an autocrine activation of CXCR4 in L-CSCs, which promote tumor growth and metastasis. Therefore, PDGFRα stimulates metastasis development through of the activation of SDF-1α pathway.

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Quattrochi, Brian J. "Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/776.

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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One unifying aspect of PDAC is mutational activation of the KRAS oncogene, which occurs in over 90% of PDAC. Therefore, inhibiting KRAS function is likely an effective therapeutic strategy for this disease, and current research in our lab and others is focused on identifying downstream effectors of KRAS signaling that may be therapeutic targets. miRNAs are powerful regulators of gene expression that can behave as oncogenes or tumor suppressors. Dysregulation of miRNA expression is commonly observed in human tumors, including PDAC. The mir-17~92 cluster of miRNAs is an established oncogene in a variety of tumor contexts, and members of the mir-17~92 cluster are upregulated in PDAC, but their role has not been explored in vivo. This dissertation encompasses two studies exploring the role of miRNAs in pancreatic tumorigenesis. In Chapter II, I demonstrate that deletion of the mir-17~92 cluster impairs PDAC precursor lesion formation and maintenance, and correlates with reduced ERK signaling in these lesions. mir-17~92 deficient tumors and cell lines are also less invasive, which I attribute to the loss of the miR-19 family of miRNAs. In Chapter III, I find that Dicer heterozygosity inhibits PDAC metastasis, and that this phenotype is attributable to an increased sensitivity to anoikis. Ongoing experiments will determine whether shifts in particular miRNA signatures between cell lines can be attributed to this phenotype. Together these findings illustrate the importance of miRNA biogenesis, and the mir-17~92 cluster in particular, in supporting PDAC development and progression.

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26

Quattrochi, Brian J. "Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/776.

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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One unifying aspect of PDAC is mutational activation of the KRAS oncogene, which occurs in over 90% of PDAC. Therefore, inhibiting KRAS function is likely an effective therapeutic strategy for this disease, and current research in our lab and others is focused on identifying downstream effectors of KRAS signaling that may be therapeutic targets. miRNAs are powerful regulators of gene expression that can behave as oncogenes or tumor suppressors. Dysregulation of miRNA expression is commonly observed in human tumors, including PDAC. The mir-17~92 cluster of miRNAs is an established oncogene in a variety of tumor contexts, and members of the mir-17~92 cluster are upregulated in PDAC, but their role has not been explored in vivo. This dissertation encompasses two studies exploring the role of miRNAs in pancreatic tumorigenesis. In Chapter II, I demonstrate that deletion of the mir-17~92 cluster impairs PDAC precursor lesion formation and maintenance, and correlates with reduced ERK signaling in these lesions. mir-17~92 deficient tumors and cell lines are also less invasive, which I attribute to the loss of the miR-19 family of miRNAs. In Chapter III, I find that Dicer heterozygosity inhibits PDAC metastasis, and that this phenotype is attributable to an increased sensitivity to anoikis. Ongoing experiments will determine whether shifts in particular miRNA signatures between cell lines can be attributed to this phenotype. Together these findings illustrate the importance of miRNA biogenesis, and the mir-17~92 cluster in particular, in supporting PDAC development and progression.

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Gao, Jingfang. "Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer." Doctoral thesis, Linköping : Univ, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-10516.

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Nguyen, Canh Vinh Ngoc. "Investigating Cancer Cell Sensitivity to Anticancer Drugs in Relation to Heat Shock Factor 1 Expression." Thesis, 2021. https://vuir.vu.edu.au/42972/.

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Breast cancer (BrCa) is the most common cancer diagnosed in women, with many patients progressing to advanced stages where prognosis is poor and morbidity more likely. Ninety per cent of patients will succumb to their disease primarily due to metastasis. Metastatic cancer cells are invasive, migratory and highly resistant to standard chemotherapies. Therefore, greater knowledge is needed to characterize mechanisms by which cancer cells become resistant to anticancer agents. A mechanism by which cancer cells may develop resistance is through stimulating stress response pathways such as the heat shock response (HSR). This pathway is regulated by heat shock factor 1 (HSF1), which transcriptionally regulates transcription of heat shock proteins (HSP) as well as many non-HSPs. HSPs protect normal cells during exposure to proteotoxic stresses; however, HSF1 has also been found to facilitate pro-metastatic pathways in cancer, distinct from the canonical HSR. HSF1 expression is known to be significantly increased in multiple cancers and significantly correlates with poor clinical outcomes; yet little is known regarding the role of HSF1 in the resistance/sensitivity of cancer cells towards anticancer therapeutics. To address this, the aim of this project was to examine whether HSF1 may have a direct role in mediating anticancer drug sensitivity in cancer cells and whether anticancer drugs stimulate HSF1 activation. To achieve this, a series of doxycycline-inducible HSF1 knockdown (KD) BrCa cell lines, T47D and MDA-MB-231, were generated. From previous bioinformatic studies, HSF1 was identified as potentially mediating the sensitivity of cancer cells to several anticancer drugs. A number of these drugs were screened in both the T47D and MDA-MB-231 series of doxycycline-inducible HSF1 KD cells. From these screens, it was identified that loss of HSF1 resulted in a significant decrease in the sensitivity of MDA-MB-231 cells towards the EGFR inhibitor, Lapatinib, but this was not evident in the less advanced T47D BrCa cells. However, the T47D cells were found to be increased in their sensitivity to doxorubicin with HSF1 knockdown. To determine whether anticancer drugs stimulated the HSR, T47D and MDA-MB-231 heat shock element (HSE) bioluminescent reporter cells were generated. Cells were successfully generated to express firefly luciferase under the control of HSE, indicative of HSF1 activity and the quantitative assessment of anticancer drug induced- stress. However, these reporter cell models revealed the previously undetermined impact of drug vehicles (DMSO, EtOH) upon HSE activation indicative of the potential for false positives within drug screens if not properly controlled. This work has identified that HSF1 plays a role in mediating the sensitivity of aggressive BrCa cells to the EGFR inhibitor, Lapatinib. Conversely, HSF1 mediates resistance to doxorubicin in the less aggressive T47D BrCa cells. Moreover, the use of HSE reporter cells to determine HSR activation by anticancer drugs needs stringent controls in relation to drug vehicles due to the potential for these vehicles to activate the HSR leading to false positives within anticancer drug screens.

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Sah, Baidya Nath Prasad. "Identification of bioactive peptides produced in synbiotic yoghurt having anticancer properties." Thesis, 2016. https://vuir.vu.edu.au/32311/.

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Cancer is the most widely recognized reason for human deaths globally. Conventional anticancer therapies, including chemotherapy and radiation, are very costly and induce severe side effects on the individual. The discovery of anticancer compounds including dairy-derived peptides may thus be a better alternative for cancer prevention and management. Anticancer peptides exist in the amino acid chain of milk proteins and can be generated during proteolytic activities such as gastrointestinal digestion or food processing including fermentation by lactic acid bacteria (LAB) and probiotics. However, proteolytic capacity of these bacteria is strain specific. The study was conducted to establish proteolytic activity of Lactobacillus (L.) acidophilus (ATCC® 4356™), L. casei (ATCC® 393™) and L. paracasei subsp. paracasei (ATCC® BAA52™) in yogurt. Crude peptides were separated by ultra-high centrifugation and tested for antioxidant and antimutagenic activities. The degree of proteolysis highly correlated with these bioactivities, and its value (11.91 %) for samples containing all the cultures was double that of the control. Liberated peptides showed high radical scavenging activities with 1,1- diphenyl-2-picrylhydrazyl and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), IC50 1.51 and 1.63 mg/ml respectively and strong antimutagenicity (26.35 %). These probiotics enhanced the generation of bioactive peptides in yogurt.

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Cree, Tabitha. "Investigating the role of FK506 binding protein 25 in cell proliferation and differentiation." Thesis, 2021. https://vuir.vu.edu.au/42901/.

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Peptidyl prolyl isomerases (PPIase) are a class of enzymes that are required to catalyse the conversion of proline residues from cis to trans conformation. There are several classes of PPIase molecules, including parvulins, cyclophilins, and FK506 binding proteins (FKBPs). Among these PPIase molecules each class contains a conserved PPIase domain that facilitates protein to protein interactions. These PPIase molecules have diverse functions in cellular function and disease progression. FKBPs are a group of immunophilin molecules that are known to interact with immunosuppressant molecules FK506 and rapamycin to stop the immune response and inhibit mTOR, respectively. The structure and function of FKBPs is diverse, these proteins act to facilitate protein to protein interactions, act as co-chaperones, translocate throughout the cell in response to stress events, and bind to DNA. Importantly, FKBPs have been implicated in the pathogenesis of cancer, largely through their roles in co-chaperoning hormone receptors in hormone responsive cancers i.e. breast and prostate cancers. Of particular interest, FKBP25, a 25kDa protein that consists of two functional domains, an N terminal basic helix–loop–helix and C terminal PPIase domain. FKBP25 is known to be involved in protein folding, cytoskeletal dynamics, DNA damage repair, double stranded RNA binding, interacting with the pre-ribosome, and cellular stress responses. Despite the variety of roles that FKBP25 is known to play, there is limited research regarding FKBP25 role in disease and cell differentiation. To address this, initial studies investigated the role of FKBP25 in breast cancer progression and epithelial to mesenchymal transition (EMT). Here it was found that FKBP25 protein expression is reduced in both mesenchymal breast cancer cell types, including BT-549, Hs578t, MDA-MB-231. To further understand the potential role of FKBP25 in breast cancer pathogenesis, a variety of mutations that contribute to malignant transformation were examined. Here it was found that the oncogenic mutations, that are associated with growth pathways in fact increased FKBP25 expression. However, in an epidermal growth factor mediated model EMT in MDA- MB-468 breast cancer cells, it was identified that FKBP25 protein expression was reduced. This implies that the loss of FKBP25 protein expression may be required for de-differentiation and progression of cancer cells. As such, it was hypothesised that FKBP25 protein expression was correlated with the level of cellular differentiation. To examine this hypothesis, next a model of mesenchymal to epithelial transition (MET) was analysed. The C2C12 model of myogenesis to study the role of FKBP25 in an MET-like example of cell differentiation. Previous studies have identified that FKBP25 is the most highly expressed FKBP in skeletal muscle and is expressed in the top 10% of the skeletal muscle proteome. Here it was identified that in proliferative myoblasts there is a higher level of FKBP25 protein expression compared to that of post mitotic myotubes. This was further demonstrated in a model of C2C12 quiescence where it was demonstrated that upon removal from the cell cycle, myoblasts accumulate greater levels of FKBP25 protein expression, which is then reduced upon re-entry to the cell cycle. Interestingly, this trend was not observed in human primary myoblasts, however, was identified in human rhabdomyosarcoma cells which may be due to the presence of p53 and MyoD mutations. Furthermore, in vivo models of muscle plasticity were examined to assess the impact of FKBP25 on skeletal muscle regeneration considering FKBP25 is the most highly expressed FKBP in mature skeletal muscle. Here it was discovered that FKBP25 protein expression is increased in models of regeneration including, chronic mechanical loading, murine muscular dystrophy (mdx), and denervation. It is hypothesised that this was observed due to extensive cytoskeletal remodelling to repair structural damage caused by hypertrophy and atrophy of fibres. Next, we examined the impact of FKBP25 knockdown (25KD) on cell biology and function of MDA-MB-468 and C2C12 cells. 25KD cells were developed using doxycycline inducible SMARTvector (Dharmacon, CO, USA) short hairpin RNA technology. After confirming adequate 25KD, it was observed that in both cell lines 25KD resulted in an increase in proliferation compared to respective non-targeting (NT) cells. Furthermore, in MDA-MB-468 cells, it was observed that there were no changes to invasion outgrowth or migration in vitro. However, it was demonstrated that 25KD resulted in decreased anchorage dependent growth, which could be explained by alterations to cytoskeletal stability. Conversely, in C2C12 myoblasts it was found that 25KD resulted in a significant increase in wound healing migration. Upon investigation of myogenic regulatory factor expression in differentiated 25KD myotubes it was revealed that there were no changes in protein expression. Furthermore, upon measurement of fibre diameter and fusion index it was found that there were no discernible changes to myotube formation. Finally, the influence of 25KD on tubulin regulation and dynamics was assessed. Initially, the presence of microtubule (MT) post-translational modifications was assessed, including detyrosination and acetylation which are associated with MT stability. Both C2C12 and MDA-MB-468 25KD cells showed no changes to stabilising modifications. Similarly, upon examination of MT stabilising protein stathmin, both C2C12 and MDA-MB-468 25KD showed no change to stathmin expression. After this, the impact of 25KD on tubulin polymerisation under control and paclitaxel treated (induction of maximal polymerisation) conditions was explored. However, here no differences in MT polymer content was found in either 25KD in either C2C12 or MDA- MB-468 cells. In conclusion, this thesis has examined the potential role of FKBP25 in cell differentiation and de-differentiation in EMT and MET-like models. It was found that FKBP25 is required for some cell processed including proliferation, anchorage dependent growth, and migration. It was hypothesised that this was a result of cytoskeletal reorganisation and altered MT dynamics, however, this was unable to be demonstrated. Further studies should further examine the impact of 25KD on MT dynamics using methods less prone to error. Nonetheless, FKBP25 was demonstrated to have a role in cell proliferation and differentiation. Maintenance of FKBP25 protein in both cancers and skeletal muscle could help to preserve epithelial-like phenotype and maintain structural integrity, respectively.

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Mikkelsen, Kathleen. "The Effects of Vitamin B6 and B12 on Inflammation and Cancer." Thesis, 2022. https://vuir.vu.edu.au/43344/.

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We are only just beginning to understand the intricate relationship between nutrition, immune health, inflammation, and cancer. Epidemiological studies have demonstrated a clear association between inflammation and cancer development. Both undernutrition and overnutrition (malnutrition) have been shown to have a significant impact on immune health and function. Even in countries where food is plentiful, a diet high in processed food can be high in calories whilst being nutritionally deficient. The emergence of B vitamins as anti-inflammatory and anti-cancer agents is an area which in recent years has gained interest within the scientific community and as the development of genetic and epigenetic investigative techniques becomes more available to a greater number of researchers, there is ongoing investigation occurring concerning how nutrition affects gene expression. Low blood serum vitamin B6 is frequently noted in patients with high inflammatory markers and vitamin B6 supplementation has previously been shown to downregulate inflammation and oxidative stress in both inflammation and as an anti-cancer mechanism. In contrast, the effects of vitamin B12 supplementation have been shown within the literature to be ambiguous with links both to cancer progression and pro-inflammatory actions versus tumour regression and anti-inflammatory properties. The purpose of this thesis was to ascertain, with greater clarity, the mechanisms of action of high dose vitamin B6 and B12 on inflammation and cancer. This was achieved by conducting studies on both cancer and immune cells and using protein and gene studies to ascertain the effects of high-dose vitamin B supplementation. It was found that high dose vitamin B6 was shown to have an anti-proliferative effect on promonocytic lymphoma cells, likely due to a downregulation of the mevalonate pathway (MVP) whereby vitamin B6 acted in a ‘steroid-like' fashion to reduce MVP, restoring mutant p53 function and re-establishing the G1/S checkpoint. Vitamin B6 2 was also shown to have a broad-spectrum, anti-inflammatory effect on key inflammatory pathways in lipopolysaccharide (LPS) stimulated monocytes. In contrast, vitamin B12 supplementation produced an upregulation in key inflammatory gene expressions and showed a dose-dependent effect on inflammation. The important and novel findings from this thesis conclude, that high dose vitamin B6 may prove to be an important nutraceutical agent in both inflammatory and oncological medicine and that B12 over-supplementation may potentially contribute to inflammation and tumourigenesis so caution should be taken when supplementing in dosages above the recommended daily intake.

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Campelj, Dean G. "Unravelling the mechanisms of chemotherapy-induced cachexia and the potential of mitoprotective therapeutic strategies." Thesis, 2021. https://vuir.vu.edu.au/42914/.

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Chemotherapy is an effective first-line cancer-treatment to slow or even cure cancer. Despite it being widely used to treat a variety of cancers, the majority of agents used induce a myriad of serious sequalae. Recently, chemotherapy emerged as a key contributing factor to the induction of devastating wasting condition, cachexia. Cachexia involves the progressive loss of body mass, underscored by severe skeletal muscle wasting and dysfunction (skeletal myopathy). Unravelling the molecular mechanisms involved in the onset and persistence of chemotherapy-induced cachexia represents a complex scientific challenge and is of great clinical interest to identify novel drug targets and efficacious adjuvants. This thesis characterised the impact of individual chemotherapeutic agents on the skeletal muscular system of mice [doxorubicin (DOX) and irinotecan (IRI), 5-fluorouracil (5FU)] and evaluated the therapeutic efficacy of mitoprotective adjuvant candidates, sodium nitrate (with DOX) and BGP-15 (for 5FU and IRI) to protect body mass and skeletal muscle during chemotherapy. Additionally, since chemotherapeutic agents are usually administered to cancer patients in combination regimens which might escalate cachexia, we also characterised the impact of the ‘7+3’ (cytarabine and daunorubicin) chemotherapy induction regimen (CIR) utilised as standard treatment against acute myeloid leukemia. In this regard, we developed and characterised a novel murine model of AML CIR-induced cachexia. We also used this model to trace the course of cachexia during and after treatment and to evaluate whether voluntary exercise could be protective. The major findings of thesis were that the onset and severity of chemotherapy-induced cachexia is agent/regimen specific. While DOX, an anthracycline and topoisomerase-II inhibitor, and IRI, a topoisomerase- I inhibitor, induced a cachectic phenotype characterised by diminished body composition indices, and skeletal myopathy, 5FU, an anti-metabolite, did not cause cachexia. Interestingly, the multi-agent CIR induced severe cachexia. The recovery post-CIR was mixed with skeletal muscle mass returning to normal levels, while body and lean mass not completely recuperating in the 2-week recovery period. At the molecular level, the expression of key structural cytoskeletal proteins, i.e. dystrophin, were impacted by IRI and 5FU whether skeletal myopathy was observed or not. These data suggest that loss of dystrophin might be an early event in the myopathy associated with cachexia. With regard to the adjuvant candidates evaluated, sodium nitrate was not protective against DOX-induced cachexia, despite protecting against early signs of cardiomyopathy. BGP-15 displayed modest protection against IRI-induced cachexia but was not afforded the opportunity when evaluated in combination with 5FU. Alongside the CIR voluntary activity was not protective against cachexia, rather it potentiated CIR-induced cachexia, likely driven through enhanced loss of fat mass. Overall, these findings highlight that further investigation is required regarding the efficacy of mitoprotective adjuvant therapies against chemotherapy-induced cachexia.

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Henckels, Eric Patrick. "Regulation of Matrix Metallopeptidase-1 in Breast Cancer Metastasis." Thesis, 2013. https://doi.org/10.7916/D8TT4Z9W.

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Matrix Metallopeptidase 1 (MMP-1) expression has repeatedly been correlated to tumorigenesis and metastasis. Yet, MMP-1 regulation in a metastatic context remains largely unknown. Here we confirm differential MMP-1 expression in mammary carcinoma cells with varied metastatic potentials and identify a mechanism differentially regulating MMP-1. We show that MMP-1 expression is regulated by an AP-1 element in its promoter in highly metastatic MDA-MB-231 mammary carcinoma cell derivatives. Fra-1, an AP-1 family transcription factor, differentially binds this element in highly metastatic derivatives compared to low-metastatic cells and is required for MMP1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. There was no change in protein degradation rates, while protein synthesis rates of Fra-1 increased. These results suggest that protein translation of Fra-1 is differentially regulated in these cells. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression is sufficient to increase cell motility and anchorage independent growth. These results suggest that Fra-1 regulation is critical for regulation of MMP-1 and metastasis.

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Heinz-Taheny, Kathleen M. "Grape seed extract as an adjunct for modulating colon carcinogenesis /." 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3301146.

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Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.
Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0952. Adviser: Matthew A. Wallig. Includes bibliographical references (leaves 123-136) Available on microfilm from Pro Quest Information and Learning.

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Charoensinphon, Noppawat. "Inhibition of lung carcinogenesis by polymethoxyflavones." 2013. https://scholarworks.umass.edu/dissertations/AAI3603063.

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Lung cancer is the leading cause of cancer-related death worldwide. Exclusively found in citrus peels, the inhibitory effects of polymethoxyflavones (PMFs) on 3 human non-small cell lung cancer cells have been investigated. Results showed that monodemethylated PMFs at 5-position potently inhibited lung cancer cells than those of their permethoxylated counterparts. The inhibition of cancer cells caused by monodemethylated PMFs was associated with both extensive cell cycle arrest and apoptosis as a result of modulation of key oncogenic signaling proteins. Treatment with different bioactive compounds in combination may enhance inhibitory effects on lung cancer due to their synergistic interaction among these agents. Results showed that both nobiletin/atorvastatin (NBT/ATST) and tangeretin/atorvastatin (TAN/ATST) co-treatments at low doses exerted strong synergy as confirmed by isobologram analysis, and also produced much stronger inhibitory effects on lung cancer cells in comparison to those produced by NBT, TAN, or ATST alone at higher doses. Flow cytometry analysis showed both NBT/ATST and TAN/ATST co-treatments significantly induced cell cycle arrest and apoptosis, and these molecular events were involved with prenylation of RhoA which subsequently resulted in alteration of key signaling proteins. Supplementation of mevalonate or geranylgeranyl pyrophosphate significantly counteracted the effects caused by NBT/ATST. Inhibitory effects of metabolites of PMFs against lung cancer cells were significantly stronger than those produced by their parental compounds. Treatments of PMFs significantly inhibited lung tumorsphere formation and aldehyde dehydrogenase bright cells implicating the potential utilization of these compounds to target lung cancer stem cells.

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Rajbhandari, Presha. "Systematic elucidation of transcriptional network necessary for initiation and maintenance of high-risk neuroblastoma." Thesis, 2016. https://doi.org/10.7916/D8J67H0X.

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Neuroblastoma is a heterogeneous pediatric malignancy originating from the developing sympathetic nervous system, with poor long-term survival for high-risk patients (~40%). About half of advanced neuroblastomas harbor high-level amplification of the MYCN gene, and these tumors show few, if any, additional driver lesions. Despite significant increase in the body of knowledge of genetics in neuroblastoma, all the high-risk patients follow similar therapeutic procedures and little advancement has been made on molecular target based therapies. The major challenge is to dissect the complexity and heterogeneity of these tumors to find driver genes and activated pathways that are essential for the survival of these cancer cells. We used an integrated systems biology approach to define the core regulatory machinery responsible for maintenance of an aggressive neuroblastoma phenotypic state. In the first part of the thesis, I will discuss our computational approach to decipher the tumor heterogeneity by subtype classification, followed by identification of master regulator protein modules for three distinct molecular subtypes of high-risk neuroblastomas, which were validated in a large independent cohort of cases. We propose that such modules are responsible for integrating the effect of mutations in upstream pathways and for regulating the genetic programs and pathways necessary for tumor state implementation and maintenance. The second part of the thesis is focused on experimental validation of putative master regulators in the subtype of neuroblastomas associated with MYCN amplification. By using RNAi screening followed by experimental and computational analyses to elucidate the interdependencies between the top master regulators, we identified TEAD4-MYCN positive feedback loop as a major tumor maintenance mechanism in this subtype. While MYCN regulates TEAD4 transcriptionally, TEAD4 regulates MYCN through transcriptional and post-translational mechanisms. Jointly, MYCN and TEAD4 regulate 90% of inferred MR proteins and causally orchestrate 70% of the subtype-specific gene expression signature. TEAD4 gene expression was associated with neuroblastoma patient survival independently of age, tumor stage and MYCN status (P=2.1e-02). In cellular assays, MYCN promoted growth and repressed differentiation, while TEAD4 activated proliferation and DNA damage repair programs, the signature hallmarks of MYCN-amplified neuroblastoma cells. Specifically, TEAD4 was shown to induce MYCN-independent proliferation by transactivating key genes implicated in high-risk neuroblastoma pathogenesis, including cyclin-dependent kinases, cyclins, E2Fs, DNA replication factors, checkpoint kinases and ubiquitin ligases. The critical role of the core master regulator module in controlling tumor cell viability, both in vitro and in vivo, and its clinical relevance as a prognostic factor highlights TEAD4 as a novel and highly effective candidate target for therapeutic intervention. In this thesis, we demonstrate that interrogation of tumor specific regulatory networks with patient-derived gene expression signatures can effectively elucidate molecular subtypes as well as the core transcriptional machinery driving subtype specific hallmarks. This approach enables identification of oncogenic and non-oncogenic dependencies of high-risk neuroblastoma and is applicable to other tumor subtypes.

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Kim, Christine Sheila. "The FYN-TRAF3IP2 gene fusion drives oncogenic NF-κB signaling in peripheral T cell lymphoma." Thesis, 2020. https://doi.org/10.7916/d8-5w9r-w324.

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Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack actionable targets for directed therapies in most cases. Here we report the identification of FYN-TRAF3IP2 as a novel highly recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, FYN-TRAF3IP2 triggers aberrant NF-κB activity by engaging TRAF6 downstream of T cell receptor signaling. Moreover, FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Therapeutically, abrogation of NF-κB signaling in FYN-TRAF3IP2-induced tumors via IκB kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results formally demonstrate an oncogenic role for FYN-TRAF3IP2 and NF-κB signaling in the pathogenesis of PTCL.

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Schoenfeld, David Aaron. "Characterizing the Mechanism of Tumor Suppression by PBRM1 in Clear Cell Renal Cell Carcinoma." Thesis, 2015. https://doi.org/10.7916/D8B56JJX.

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In this study, we investigated the mechanisms by which PBRM1 functions as a tumor suppressor in clear cell renal cell carcinoma. PBRM1, also known as BAF180 or Polybromo, is a member of the PBAF SWI/SNF chromatin remodeling complex. Cancer sequencing studies have revealed that SWI/SNF components are widely mutated in cancer. PBRM1 is recurrently mutated in various human malignancies, but it has a particularly high mutation rate in clear cell renal cell carcinoma: ~40% of clear cell renal cell carcinomas have a PBRM1 mutation, making it the second most highly mutated gene in clear cell renal cell carcinoma behind VHL. Although many recent studies have looked at how other SWI/SNF components function in cancer control, relatively little is known about the tumor suppressive mechanisms of PBRM1 in clear cell renal cell carcinoma. To investigate PBRM1 function, we manipulated its expression in clear cell renal cell carcinoma cell lines. In cell lines with intact PBRM1, we stably knocked down its expression using shRNA. In a cell line with mutant PBRM1, we stably restored expression of the wild-type protein. We found that PBRM1 deficiency significantly enhanced the growth properties of cells, but only when the cells were grown under stressful conditions, such as reduced serum or a 3-D culture environment. To investigate genes and pathways influenced by PBRM1 that may confer this growth advantage, we compared gene expression differences in the clear cell renal cell carcinoma cell lines and murine embryonic fibroblasts with or without PBRM1. We found that PBRM1 regulated numerous cancer-related genes and pathways. One gene, ALDH1A1, was consistently upregulated with PBRM1 deficiency across our cell lines. Further expression analysis using two different clear cell renal cell carcinoma primary tumor datasets revealed that PBRM1 mutation in primary tumors was also associated with higher ALDH1A1 levels. ALDH1A1, or aldehyde dehydrogenase 1, is part of the retinoic acid metabolic pathway and irreversibly converts retinaldehyde to retinoic acid. It functions in hematopoietic stem cell development, white versus brown fat programming, and insulin signaling. Numerous studies have also identified ALDH1A1 as a marker of tumor-initiating cells, also known as cancer stem cells. Not much is known about the regulation of ALDH1A1 expression in cancer, and it has not previously been linked to PBRM1 or SWI/SNF. We confirmed that stable knockdown of PBRM1 in clear cell renal cell carcinoma cell lines resulted in higher ALDH1A1 mRNA and protein expression, and also higher ALDH1-class enzyme activity. Alternatively, re-expression of wild-type PBRM1, but not cancer-associated mutant PBRM1, lowered ALDH1A1 expression and activity in the PBRM1-mutant line. Additionally, inhibiting ALDH1A1 or knocking it down in the context of PBRM1 deficiency reduced anchorage-independent growth, while over-expressing ALDH1A1 in the PBRM1-normal setting increased tumorsphere-forming capacity. These results suggest that ALDH1A1 is not only a marker of tumor-initiating cells, but can also increase the tumorigenic potential of cells. Based on our gene expression analysis, we additionally explored PBRM1 regulation of the EGFR and IFN pathways. PBRM1 decreased total EGFR protein levels and dampened downstream signaling. These changes had functional consequences, as PBRM1 deficiency led to faster growth in response to EGF stimulation. However, it did not create a setting of oncogenic addiction, as PBRM1 deficient cells were also more resistant to EGFR inhibition. Alternatively, PBRM1 deficiency reduced basal and IFNα-induced levels of IFI27, a pro-apoptotic interferon response gene, and made cells more resistant to growth inhibition by IFNα. PBRM1 mutations in cancer would thus be expected to have wide-ranging effects on a cell, and the targeting of any one specific downstream pathway might have limited efficacy. Finally, we investigated the molecular mechanisms of how PBRM1 deficiency could alter transcription, keeping in mind that PBRM1 is one subunit of the larger PBAF complex. In our clear cell renal cell carcinoma cell lines, we found that mRNA and protein levels of another PBAF-specific subunit, ARID2, increased with PBRM1 deficiency. PBRM1 mutation in primary tumors was also associated with significantly higher ARID2 expression. Immunoprecipitation and glycerol gradient fractionation experiments suggested that more ARID2 may associate with the SWI/SNF components BRG1 and SNF5 after PBRM1 knockdown. ARID2 ChIP-seq analysis revealed that this remnant PBAF-like complex was bound to fewer locations in the genome, and its binding locations were broadly redistributed. Both gained and lost ARID2 binding were associated with differential gene expression, of both upregulated and downregulated genes, indicating that the genomic context influences whether PBAF-binding is activating or repressive. Interestingly, we also found that ARID2 was required for some of the pro-tumorigenic changes associated with PBRM1 deficiency, such as upregulation of ALDH1A1 and EGFR levels, but not others, such as decreased IFI27 levels, implying alternative modes of transcriptional regulation. In total, this study implicates PBRM1 in the regulation of numerous cancer-related genes and pathways in clear cell renal cell carcinoma. PBRM1 mutation would alter the genomic binding of a residual PBAF-like complex containing ARID2, leading to transcriptional changes that promote tumor formation and growth. A better understanding of this oncogenic mechanism may reveal novel therapeutic opportunities.

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Yoh, Kathryn Elizabeth. "Ras, p63 and breast cancer." Thesis, 2016. https://doi.org/10.7916/D8ZS2WQK.

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As a master regulator of the epithelial state, p63 is a family member of the well-known tumor suppressor p53. It has previously been connected to a cancer-associated process, epithelial-to-mesenchymal transition (EMT), and here we find that it can be regulated by oncogenes involved in breast tumorigenesis. Specifically, activated forms of PIK3CA and H-RAS are able to strongly repress expression of ∆Np63α, which is the major p63 isoform in epithelial cells. In mammary epithelial lines, this oncogene downregulation occurs at the transcriptional level, and complete repression occurs over the course of several days. As p63 is repressed, the cells undergo EMT and acquire the ability to invade individually through a 3D collagen matrix. Strikingly, even when p63 is suppressed but no oncogene action is present, these cells undergo a mesenchymal shift, suggesting the importance of this gene in maintaining the epithelial state. Furthermore, it is particularly interesting that p63 protein and RNA levels are often low in breast tumors. By connecting H-RAS and PIK3CA signaling to p63, it is hypothesized that such oncogene suppression could account for tumor progression in cases where p63 levels are low. Here, it is proposed that p63 acts in a tumor-suppressive manner, although it can be overcome by oncogenes leading to changes in differentiation state and migratory capability, therefore drastically affecting breast carcinogenesis.

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El-Koha, Omra A. "Predictors of response of AIDS-associated Kaposi sarcoma to standard chemotherapy." Thesis, 2006. http://hdl.handle.net/10413/7583.

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Predictors of response of AIDS-associated Kaposi-Sarcoma to standard chemotherapy Overview: Kaposi Sarcoma is the most common HIV-associated cancer. Its etiology and pathogenesis is not fully understood. Little is known about what predicts prognosis, survival and therapeutic response in HIV-KS. In South Africa given the high seroprevalence rates of HIV-l and human herpes virus 8 (HHV 8), Kaposi's sarcoma is a significant problem. The majority of patients have been treated solely with palliation due to the poor outcome associated with a diagnosis of HIV-KS, more so in the absence of highly active antiretroviral therapy (HAART). Since the national ARV rollout programme and the availability and accessibility of HAART to all patients with a diagnosis of HIV-KS, a new strategy has to be established to enable adequate patient selection for chemotherapy. There have been a few published studies addressing the predictors of response to chemotherapy in the first world. However, this is the first study of these factors in HIV-l infected African patients with Kaposi's sarcoma. Aim: To identify and assess the potential value of several parameters predictive of outcome, survival and therapeutic response in HIV- infected patients with KS. Clinical, hematological, biochemical, immunological and virological variables were evaluated. Methods: We collected data from 25 patients with AIDS-KS who were enrolled in a phase III randomized controlled trial comparing HAART alone with the combination of HAART and chemotherapy. All patients were from the combination therapy arm. The following variables were evaluated as predictors of prognosis and therapeutic response: age, gender, ethnic origin, Haemoglobin (Hb), white blood cells (WBCs), lymphocytes, neutrophils, platelets, S.albumin, ALP, GGT, CD4 count, HIV viral load. These variables were assessed in patients at baseline and month 6 of therapy. Patients were staged into good risk and poor risk according to the AIDS clinical trial group (ACTG) criteria. The outcomes assessed were response to treatment and mortality. Results: A total of 25 patients participated to the study. Of these 16(64%) were males and 9(36%) were females, with male: female ratio of 2.7:1. Median age was 34 years (24-47); all patients were of Black African origin. Of the 21 patients, 15 (71.4%) were of good prognosis and 6(28.6%) were of poor prognosis. At baseline the median values of the different variables were as follows: Hb 10.9 g/dl, WBCs 5.95x109/L, lymphocytes 1.7 x109/L, neutrophils 3 x10 9 /L, platelets 272 x10 9 /L, S.albumin 30 gil, total protein 88 gil, ALP 64 U/L, and GTT 21 U/L, CD4 count was 255 cells/mm 3 , HIV-RNA viral load was 42000( 4.610gs). At month 6, 22 patients remained alive, their median values were: Hb 12.2 g/dl, WBCs 4.65 x109/L, lymphocytes 1.5 x109/L, neutrophils 3 x10 9 /L, platelets 301 x109/L, S.albumin 36.5 gil, total protein 84.5 gil, ALP 78.5 U/L, GTT 44.5 U/L, CD4 count 288 cells/mm3 , HIV-RNA viral load was 50500( 4.6910gs). The baseline median CD4 and HIV-RNA viral load counts for the 3 patients who died before month 6 were 47 cells/mm3 and 31000(4.610gs); respectively. Response to therapy was evaluated in 21(84%) patients as 4(16%) patients were missing, of the 21 patients 3 (14.3%) had complete response and 18(85.7%) had partial response. With respect to sex 2(14.3%) males had complete response and 12(85.7%) had partial response, 1(14.3%) female had complete response and 6 (85.7%) had partial response. Non-parametric statistics were used because of the small sample size and the skewness of the data. Variables were described using medians and ranges, and compared between two independent groups using Mann-Whitney tests. Baseline and month 6 comparisons were done using Wilcoxon signed ranks tests. Receiver Operating Characteristic (ROC) curves were used to analyze cut points to optimize sensitivity and specificity of a quantitative variable for a dichotomous outcome. Discussion In the univariate analysis age and sex didn't influence prognosis and therapeutic response, the influence of ethnic origin couldn't be assessed as all patients were of the same ethnic origin. Baseline WBCs (P= 0.004) and lymphocytes (P=0.026) were significantly associated with complete response. Higher values of GGT (p=O.OOl); ALP (P=0.006) were associated with more deaths. Baseline CD4 count and HIV viral load were not of predictive value, lthough change CD4 (P=002) and VL (p=.OOO) over time was significant and most likely attributed to response to therapy. 90.9 % of patients reached undetectable HIV-l Viral loads at month 6. CONCLUSION: Neither CD4 count nor HIV viral load at baseline predicted prognosis or survival; however there was a borderline significance of CD4 (P=0.058) towards a better survival.
Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2006.

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(9452786), Elia G. Farah. "IDENTIFYING AND TARGETING PATHWAYS INVOLVED IN ENZALUTAMIDE-RESISTANT PROSTATE CANCER." Thesis, 2020.

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Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is an FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In these studies, we uncovered that NOTCH signaling and DNA methylation are a deregulated in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patients with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide-resistance. The expression of Notch signaling components was upregulated in enzalutamide-resistant cells suggesting the activation of the pathway. Inhibition of this pathway in vitro and in vivo promoted an increase in the sensitivity to enzalutamide with an impact on AR expression. On the other hand, DNMT activity and DNMT3B expression were upregulated in resistant lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role for p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2 cells. DNA methylation inhibition, using low-concentration decitabine, and DNMT3B knockdown induced a re-sensitization of resistant prostate cancer cells and tumors to enzalutamide. Decitabine treatment in enzalutamide-resistant induced a decrease in the expression of AR-V7 and changes in genes from the apoptosis, DNA repair and mRNA splicing pathways. Decitabine plus enzalutamide treatment of 22RV1 xenografts induced a decrease in tumor weight, KI-67 and AR-V7 expression and an increase in Cleaved-Caspase3 levels. All the above suggest that Notch signaling and DNA methylation pathways are deregulated after enzalutamide resistance onset, and targeting these pathways restores the sensitivity to enzalutamide.

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(5930147), Dino P. Petrov. "Discovery of Novel Inhibitors for the Human Papillomavirus E6 Protein." Thesis, 2021.

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The human papillomavirus (HPV) has been a “companion” of humanity for as long as humanity has existed. The migration of peoples around the globe has given rise to more than 170 different types of the virus, which cause a variety of conditions. All five genera of HPV infect epithelial cells in the body, but only the Alphapapillomaviruses infect the genital mucosa. Most infections are benign and typically regress to subclinical within two years, but persistent infections can cause precancerous lesions. HPV types 16 and 18 are among the highest risk and account for the majority of cervical cancer, and more than 90% of all other HPV-related cancers. While the two vaccines, Gardasil and Cervarix, have been successfully implemented in the US market and some European and Asian countries, complete world penetrance has been burdened by multiple factors, including financial constraints and social norms. Treatments for established papillomas are invasive (cryosurgery, conization, etc.) and advanced malignant HPV-related tumors have been targeted with chemo- and radiotherapy with varied success. The high morbidity and long-term effects of current treatment options make clear the need for easy-to-administer, low-cost therapies, which can specifically treat both early and advanced HPV-associated cancers.

The hallmark of HPV tumors is the inactivation of p53, an evasion strategy key to the progression of HPV- derived cancers. Through an interaction between the viral protein E6 and the E3 ubiquitin ligase E6AP, p53 is polyubiquitinated and targeted for proteasomal degradation, allowing infected cells to bypass their own defense mechanisms. This work explores interruption of the association between E6 and E6AP as an opportunity to combat the infection and resulting malignancies.

In the first part of this project, disruption of the E6-E6AP interactions is pursued through the development of helical stabilized peptidomimetics of the LxxLL motif, which E6AP uses for E6 recognition and binding. Several reports have indicated that targeting the E6 binding groove is a viable means for disrupting the interaction. However, reported peptides were not cell permeable or optimized for α-helicity and proteolytic resistance (for reference, the LxxLL motif is an α-helix when bound). To address this challenge a peptide stabilization strategy was applied, which uses an all-hydrocarbon chain to connect two non-adjacent residues and enforce α-helicity. Results from in silico simulations and biochemical assay with these new stapled peptides showed that affinity for E6, α-helicity, and cell permeability can all be improved with the installment of the proper staple.

The second question examined by this work is whether fragment-based drug design can be successfully employed to derive new small-molecule inhibitors of the formation of the E6-E6AP complex. From a design perspective, the significant challenge was to define discreet binding hot-spots capable of accommodating fragments with reasonable affinity, which can then be linked together into a complete ligand. Using existing structural knowledge of the E6 protein and computational hot-spot searching tools, three previously-unidentified regions (sub-pockets) on E6 were discovered, which are near but not directly engaged by either the E6AP motif or p53. Using high-throughput in silico and biochemical screening, three sets of sub-pocket specific fragments were defined and elaborated into larger molecules with two different scaffolds. As a result, the work herein presents a stepwise approach to targeting the E6-E6AP protein-protein interaction – the discovery of new binding hot spots, the identification of site-specific fragments, and the design of complete molecules with versatile scaffold.

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Ko, Suh Youn. "Effect of Netrin-1 on the mature enteric nervous system and colorectal cancer." Thesis, 2017. https://vuir.vu.edu.au/36972/.

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The enteric nervous system (ENS) plays a pivotal role in regulating gastrointestinal functions including intestinal wall movement, water/electrolyte absorption and secretion. Clinical studies have alerted that enteric neuropathy is induced by colorectal cancer (CRC), and this deficit may be a primary reason for CRC patients experiencing clinical symptoms such as constipation and diarrhoea. Manifested clinical symptoms are likely to be seen in CRC patients undergoing chemotherapy, as chemotherapeutic agents are known to be associated with neurotoxicity as a side-effect. Despite this, no efficient treatment for enteric neuropathy is currently available. This heightens the importance of developing neuroprotective treatment. This thesis hypothesised that Netrin-1 could be an ideal candidate as a neuroprotective agent, as it is a well-known axonal guidance cue in the developing central nervous system, and its expression in the adult nervous system is shown to be involved in nerve regeneration after injury. It is recently found that Netrin-1 plays a guidance role in the developing ENS for establishing vagal afferent innervations to the gut. However, the role of Netrin-1 in the mature ENS is yet to be elucidated. In addition to the nervous system, Netrin-1 is found to play a regulatory role in tumourigenesis. This therefore makes the use of Netrin-1 complicated, and thus far it is unclear whether Netrin-1 can be used therapeutically. This thesis aims to investigate the effect of Netrin-1 on adult enteric neurons and colorectal cancer cells at a cellular level, and uncover the impact of Netrin-1 treatment on the ENS under cancer condition in an in vivo model. The results of in vitro studies, shown in this thesis, demonstrate that Netrin-1 exerts neurotrophic guidance for post-natal enteric neuronal precursor cells by an increase in migration and neurite outgrowth, whilst no apparent effect of Netrin-1 was noted on differentiated neurons. Furthermore, Netrin-1 treatment inhibited caspase-3 activation, which was induced by CRC secretion, in precursor cells. In addition, the effect of Netrin-1 on murine CRC cells indicated that Netrin-1 plays a role in tumourigenesis. Netrin-1 activated pFAK/pMEK/pERK signalling pathway in colorectal cancer cells via UNC5H2 and Neogenin receptors, resulting in increased proliferation, adhesion and migration. In contrast to these effects of Netrin-1 shown in in vitro models, the in vivo study of this thesis demonstrated that a high concentration of Netrin-1 treatment in CRC mice inhibited tumour growth. Furthermore, Netrin-1 treatment did not affect any obvious changes in the ENS component of the CRC mice. A potential reason why the ENS was unaffected by Netrin-1 treatment could be due to the following new findings shown in this thesis. Namely, that Netrin-1 is intrinsically expressed in the mature myenteric plexus of the colons in mice. Specifically, Netrin-1 and DCC receptors are present and co-localised in almost all ganglia and processes of the mature myenteric plexus of the colon in healthy and CRC conditions. Furthermore, Netrin-1 expression was found to correlate with ChAT and nNOS phenoptypes in healthy and CRC conditions. Differential expression of Netrin-1 and changes in the distribution of Netrin-1 expression in relation to ChAT were found to be evident in CRC condition. Collectively, this thesis provides groundwork for a potential therapeutic use of Netrin-1 as a neurotrophic factor for the adult enteric neurogenesis, and exhibited a potential safe use of Netrin-1 treatment for the ENS in the context of cancer.

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44

Sukmak, Vatinee. "The relationship between health status, social support, psychological symptoms and coping skills in patients receiving chemotherapy in a Thai context." Thesis, 2000. https://vuir.vu.edu.au/15341/.

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This study examined the relationship between health status, social support, psychological symptoms and coping skills in patients receiving chemotherapy and/or radiotherapy in Thailand. The convenience sample consisted of 249 patients receiving chemotherapy in the initial test and 158 receiving chemotherapy in the second test. Also, a total of 209 patients receiving radiotherapy participated in the study.

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Taylor, Cheryl M. "Environmental factors affecting the risk of breast cancer." Thesis, 2007. https://vuir.vu.edu.au/15710/.

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Breast cancer is one of the leading causes of mortality and morbidity amongst females of the Australian population. There is still uncertainty as to the causes of breast cancer, however, there are some factors that are thought to increase one's likelihood of developing the disease. These factors include age, gender, family history of the disease especially if there are first degree relatives affected, history of benign breast disease, age at menarche, age at menopause, number of full term pregnancies and the use of hormone therapies. Some researchers suggest that as the incidence of breast cancer is rising, and coincides with increased industrialisation, they suggest that environmental pollutants may contribute to breast cancer risk. This thesis further explores this theory.

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Stojanovska, Vanesa. "Potential Mechanisms Underlying Oxaliplatin-Induced Enteric Neuropathy." Thesis, 2017. https://vuir.vu.edu.au/40586/.

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Cisplatin, carboplatin and oxaliplatin are platinum-based agents that are amongst the most widely used drugs for the treatment of cancer in the clinical setting. Despite their therapeutic efficacy, these platinum-based drugs are associated with a myriad of dose-limiting side-effects. These include acute and chronic peripheral neuropathies (paraesthesias, dysaesthesias), and gastrointestinal complications (nausea, vomiting, constipation and diarrhoea). These side-effects decrease quality of life and cause life-threatening cardiac and renal sequeale consequent to malnutrition, dehydration and fluid and electrolyte imbalances, which in severe cases, can lead to death. Extensive research into the mechanisms underlying chronic peripheral neuropathies associated with platinum-based agents has focused on drug accumulation within the dorsal root ganglia (DRG). Only recently, a few studies have demonstrated damage to the enteric nervous system (ENS) following platinum-based chemotherapy. The ENS is an intrinsic and complex orchestration of nerves embedded throughout the entirety of the gastrointestinal tract innervating the musculature and mucosa. The mechanisms underlying ENS toxicity remain unknown. Furthermore, the gastrointestinal tract receives extrinsic innervations and it is also unknown if these nerves are vulnerable to platinum-based drugs. Platinum-based drugs mediate their cytotoxic effects through the formation of interstrand and intrastrand DNA adducts, particularly binding to the N7 position of guanine nucleotides. Essentially, these platinum lesions inhibit DNA replication through the distortion of the helical structure. DNA damage typically results in the induction of canonical apoptotic cascades. Until recent years apoptosis was deemed an immunologically ‘silent’ or ‘tolerogenic’ event. However, unlike cisplatin and carboplatin, there is substantial evidence shown in models of cancer that oxaliplatin prompts a fatal immune response against cells committed to apoptosis. This phenomenon is termed ‘immunogenic cell death’. Oxaliplatin-induced cytotoxicity results in the hallmark presentation of damage-associated molecular patterns (DAMPs) which can be recognised by antigen-presenting cells, and thus, stimulating phagocytosis of apoptotic cells and/or debris. The gastrointestinal tract harbours ~70% of the body’s immune system, and so it is unknown whether oxaliplatin treatment can induce changes in immunological responses which may directly or inadvertently induce ENS damage. Given the bi-directional communication between the immune and nervous systems, exploring the consequences of oxaliplatin-induced cytotoxicity and potential immunogenicity may provide insight into the multifaceted mechanisms underlying neuronal damage and death which impact gastrointestinal function.

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Stubbs, Marika Jane. "Qualitative description of the adult patient experience of cancer-related cachexia (CRC) : a pilot study : a thesis presented in partial fulfilment of the requirements for the degree of Master of Philosophy in Nursing, Massey University, Palmerston North, New Zealand." 2008. http://hdl.handle.net/10179/785.

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This thesis explores the experience of living with cancer-related cachexia (CRC) from the patient perspective. Critique of the literature indicates few examples where patients have had the opportunity to speak. Following a challenging recruitment process, six people living with the syndrome were interviewed to elicit their narrative. Their stories were examined and themes identified relating to their personal feelings and how these affected social interactions. Thematic analysis was applied to produce what is a rich qualitative description of the experience from this small sample. Living with CRC requires development of strategies to survive. Emergent themes included the loss of sense of self and a changing relationship to the social world, social isolation and dissatisfaction with truth-telling by health professionals. Recommendations are made to mitigate the suffering of patients by empowering them through better information and acknowledgement of their condition. The balance between nutrition and wellbeing is re-examined, calling for a reorientation of perspective from a focus on intake towards a focus on quality of life. This clearly falls within the nurse-as patient-advocate paradigm and the relevance and meaning of this research to the nursing profession is explored. Potential areas for further research in regards to both patient experience and nursing practice are extrapolated.

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McQuade, Rachel. "Chemotherapy-Induced Gastrointestinal Dysfunction and Enteric Neuropathy." Thesis, 2017. https://vuir.vu.edu.au/34679/.

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Colorectal cancer (CRC) is a leading cause of morbidity and mortality affecting more than 1.4 million people annually worldwide. Due to the aggressive and asymptomatic nature approximately 60% of CRC sufferers are diagnosed at or beyond stage III resulting in prognostic outlook relying heavily on the successful application of chemotherapeutic treatment. Chemotherapeutic agents oxaliplatin, 5-fluorouracil and irinotecan represent the backbone of CRC treatment, significantly enhancing tumour regression and patient survival. However successful application of these cytotoxic chemotherapies is hindered by undesirable neurological and gastrointestinal (GI) side-effects. Chronic GI side-effects often result in dose limitations and, in severe circumstances, cessation of anti-cancer treatment, presenting a constant challenge in efficient and tolerable treatment of CRC. It is believed that chemotherapy-induced GI side-effects are a direct result of intestinal mucositis; however adjacent systems such as the enteric nervous system have been overlooked. This thesis aims to uncover the effects of in vivo administration of anti-cancer chemotherapeutics oxaliplatin, 5-fluorouracil and irinotecan on the enteric nervous system and GI function, and examine the neuroprotective efficacy of a cytoprotective agent BGP-15.

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Kadife, Elif. "The Functional and Biological Implications of EphB4 Receptor Overexpression and Knockout in Colorectal Cancer." Thesis, 2018. https://vuir.vu.edu.au/40587/.

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Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in Australia and globally. Early detection and intervention is vital for the longevity of patients with any cancer, however, this appears to be most challenging with CRC, as it is largely asymptomatic. For this reason, most cases are not diagnosed until the cancer has metastasised, primarily to the liver. At this late stage of diagnosis, 5- year patient’s survival is predicted to be less than 10%. However, even when CRC is diagnosed and treated in the initial stages of neoplastic growth, high recurrence rates in patients still present as a serious issue. The problems associated with treatment and recurrence raise the need to identify molecular targets, so that specific and aggressive therapeutic interventions may be designed and developed. One such potential target is the erythropoietin-producing hepatocellular B4 (EphB4) receptor. The Ephs constitute the largest family of tyrosine kinase receptors. The activation of Eph receptors is achieved through association with their corresponding cell- bound ‘Eph receptor interacting’ (Ephrin) ligands. The signalling by the Eph receptors and their membrane-bound ligands, the Ephrins, is unique among the tyrosine kinases as both the receptor and ligand are found on the cell surface. Bidirectional interaction results in the phenomena of ‘forward’ signalling via the Eph receptor carrying cells and ‘reverse’ signalling in those cells expressing the Ephrin ligands. Several members of the Eph receptor receptor family, including EphB4, have been implicated with progression of many different types of cancer. However, EphB4 receptor’s contribution towards CRC yields the most contradictory findings. Some studies suggest that EphB4 is upregulated in late and metastatic stages of CRC, while others argue that EphB4 expression is often silenced in the progressive state of the disease. Due to the promising results achieved in other types of cancers, it is important to elucidate the role of EphB4 receptors in CRC in order to develop more specific and aggressive cancer therapies. The overall aim of this study is to elucidate the influence of EphB4 receptor expression on the development and progression of CRC. To achieve this, we used modified derivatives of multiple human and a mouse CRC cell line in in vitro and in vivo experiments. In vitro experiments were utilised to study effects of EphB4 overexpression and knockout on proliferative aptitude, migratory and invasive abilities of human and mouse CRC cells. In vivo subcutaneous models of CRC were used to evaluate the ability of high, low and knockdown of EphB4 receptor expression to influence morphological changes, rate of growth, vascularization and tumour-stromal interactions. The time course and rate of metastasis of CRC cells to the liver were studied in in vivo orthotopic and intra-splenic metastasis models. The level of EPHB4 and EPHRINB2 expression was investigated using databases to determine their correlation with survival and disease-free outcomes of CRC patients. The results of this study provide evidence that high EphB4 receptor expression significantly increases the rate of proliferation, migration and invasion of CRC cells in vitro, and enhances tumour growth in vivo due to enhanced vascularisation. Knockout of EphB4 expression reduces these effects. EphrinB2 appears to inhibit proliferation in cells overexpressing EphB4 and its expression correlates with poor patient outcome.

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Nurdiani, Rahmi. "Anti-carcinogenic peptides derived from fish by-products." Thesis, 2017. https://vuir.vu.edu.au/32642/.

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Fish by-products can account up to 75% of total weight of fish catch, harvested or processed. Despite their high economic value, by-products have been used mainly for the production of low-value products resulting in a low profit for the fish industry. Thus, it is imperative to develop efficient and effective technologies for the recovery of valuable ingredients from fish by-products. The main focus of this thesis was to develop a simple hydrolysis process to extract valuable compounds and liberate bioactive peptides from fish by-products of fish species endemic to Australia as well as exploring the essential physiological properties of these bioactive peptides, especially their potent use for colon cancer treatment.

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Dissertations / Theses on the topic '3211 Oncology and carcinogenesis'

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