Ovarian cancer (OVCA) is the most lethal gynecologic cancer. Chemoresistance remains a major hurdle to successful therapy and patient survival. The secreted isoform of the actin-associated protein, gelsolin (plasma gelsolin; pGSN), is highly expressed in chemoresistant than chemosensitive OVCA cells, although the mechanism underlying the differential expression is not known. Also, its overexpression significantly correlates with shortened survival of OVCA patients. DNA methylation plays a key role in the regulation of genes expression and contributing to cancer development and chemoresistance with the help of DNA methyltransferases (DNMTs) or Ten eleven translocation (TETs) enzymes. TET1 is the most studied isoform of TETs family and primarily responsible for 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) oxidation to initiate demethylation and increase in the expression of methylated genes. Whether pGSN expression in OVCA cells is regulated by DNA methylation and TET1 regulates the differential pGSN expression between chemosensitive and resistant OVCA cells is not known. In this study, we hypothesized pGSN overexpression in chemoresistant OVCA cells is due to the hypomethylation at its promoter region by TET1. Our objective was to investigate whether DNA methylation and specifically TET1 plays a role in the regulation of differential pGSN expression and chemosensitivity in OVCA. Chemosensitive and resistant OVCA cell lines of different histological subtypes were used in this study to measure pGSN and TET1 mRNA abundance and protein contents by qPCR and Western blotting respectively. Cisplatin-induced chemoresponsiveness was morphologically assessed by Hoechst staining (apoptosis). Infinium HumanMethylation450 BeadChip assay was used for global methylation analysis of twelve (12) different OVCA cells and to investigate the role of DNA methylation specifically in pGSN regulation and pGSN-induced chemoresistance. DNMTs and TETs were pharmacologically inhibited in sensitive and resistant OVCA cell using specific inhibitors. Gain-and-loss-of-function assays were carried to identify the relationship between TET1 and pGSN in OVCA chemoresponsiveness. Differential protein and mRNA expressions of pGSN and TET1 were observed between sensitive and resistant OVCA cells and cisplatin reduced their expression in sensitive but not in resistant cells. Global methylation analysis revealed hypomethylation in resistant cells compared to sensitive cells. Pharmacological inhibition of DNMTs increased pGSN protein levels in sensitive OVCA cells and decreases their responsiveness to cisplatin, however we did not observe any difference in methylation level at pGSN promoter region. TETs inhibition resulted in hypermethylation at multiple CpG sites and decreased pGSN protein level in resistant OVCA cells which was also associated with enhanced response to cisplatin, findings that suggested the methylation role of TETs in the regulation of pGSN expression in OVCA cells. Further, we found that TET1 is inversely related to pGSN and positively related to chemoresponsiveness of OVCA cells. This project does not only broaden our knowledge about the mechanistic insights into the epigenetic regulation of pGSN in OVCA chemoresistance, but it also reveals a new potential target to re-sensitize chemotherapy resistant OVCA cells. This may provide a future strategy to improve overall OVCA patient survival.

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Problématique : Le tabagisme est un facteur de risque établi pour le cancer de l'ovaire mucineux. Cependant, son association avec d'autres types de cancers de l'ovaire demeure incertaine. Ce mémoire examine l'association entre le tabagisme et le risque de cancer de l'ovaire, et plus spécifiquement, selon le comportement et les sous-types histologiques. Méthodes : Nous avons utilisé les données de l'étude sur la prévention du cancer de l'ovaire au Québec (PROVAQ), une étude cas-témoins qui comprenait 498 cas et 908 témoins recrutés entre 2011 et 2016. Ces données ont permis de conceptualiser des variables qui représentent les comportements tabagiques au cours de la vie. La régression logistique inconditionnelle a été utilisée pour estimer les rapports de cotes ajustés (OR) et les intervalles de confiance à 95 %. Résultats : Le risque de cancer épithélial de l'ovaire était augmenté à la fois chez les anciennes fumeuses (OR = 1,3, IC à 95 % = 1,01–1,67) et chez les fumeuses actuelles (OR = 1,27, IC à 95 % = 0,92–1,72) par rapport à celles n'ayant jamais fumé. Bien qu'aucune association n'ait été observée avec les tumeurs invasives, nous avons observé un risque accru de cancers de l'ovaire dans les limites de malignité chez les fumeuses actuelles (OR = 2,11, IC à 95 % 1,29–3,44) et les anciennes fumeuses (OR = 1,76, IC à 95 % 1,12–2,76), en particulier parmi celles avec une plus grande intensité et durée d’exposition. En accord avec les études épidémiologiques précédentes, nous avons trouvé un risque accru de cancers de l'ovaire mucineux chez les fumeuses actuelles. En outre, nous avons également trouvé une augmentation significative du risque de cancer ovarien séreux dans les limites de malignité chez les anciennes fumeuses (OR = 2,42, IC à 95 % 1,35–4,36). Conclusion : Tout en confirmant les associations rapportées dans les études précédentes, les résultats de ce mémoire suggèrent la nécessité d’appliquer des techniques histopathologiques plus avancées pour mieux comprendre l’effet du tabagisme sur le risque de cancer de l'ovaire. / Background: Cigarette smoking is an established risk factor for mucinous ovarian cancer. However, the association of smoking with other types of epithelial ovarian cancers remains unclear. This thesis examines the association between cigarette smoking and ovarian cancer risk, and more specifically, according to tumors behavior and histological subtype. Methods: We used data from the Prevention of Ovarian Cancer in Quebec (PROVAQ) study, a population-based case-control study that included 498 cases and 908 controls recruited from 2011 and 2016. Information on smoking behaviors was extracted and used to conceptualize various metrics that represent lifetime smoking behaviors. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: The risk of epithelial ovarian cancer was increased in both former smokers (OR = 1.3, 95% CI = 1.01–1.67) and current smokers (OR = 1.27, 95% CI = 0.92–1.72) compared to never smokers. While no association was observed with invasive ovarian cancers, we observed an increased risk of borderline ovarian tumors among both current (OR=2.11, 95% CI 1.29–3.44) and former smokers (OR=1.76, 95% CI1.12–2.76), particularly among those with greater intensity and duration of exposure. In agreement with previous epidemiological studies, we found an increased risk of mucinous ovarian cancers among current smokers. In addition, a strong association between the risk of borderline serous with past smoking (OR=2.42, 95% CI 1.35–4.36) was also observed. Conclusion: While confirming associations reported in previous studies, the results from this thesis suggest the need to continue applying more advanced histopathology techniques to better understand the effect of smoking on ovarian cancer risk.

Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach against OC cells and cancer stem cells (CSC). CSC represents a subpopulation of the tumor characterized by enhanced chemoresistance as well as the increased capability of self-renewal and metastasis. We designed a codon-optimized third-generation CAR containing the highly active single chain variable fragment (scFv) “SWA11” against CD24. We equipped the human NK-cell line NK-92 with the anti-CD24 CAR and an anti-CD19 control CAR using lentiviral transduction. Engineered NK-92 cells showed high cytotoxic activity against CD24-positive OC cell lines (SKOV3, OVCAR3). This effect was restricted to CD24-expressing cells as shown after lentiviral transduction of CD24-negative cell lines (A2780, HEK-293T) with CD24 transmembrane proteins. Additionally, NK-92 cells equipped with our novel anti-CD24 CAR were highly effective against patient-derived primary ovarian cancer cells. The activation of NK cells was shown by specific IFN secretion upon antigen stimulation. To further reduce possible off-target effects in vivo, we applied a dual-CAR approach using an anti-CD24-CD28-41BB fusion protein linked via a 2A sequence to an anti-mesothelin-CD3-CAR. The dual-CAR was simultaneously active against CD24 and mesothelin expressing cells. Our novel anti-CD24-CAR showed a highly cytotoxic effect against OC cell lines and primary OC cells and will be evaluated in future in vivo trials as a promising immunotherapeutic approach against OC.

Women with gynecological (GYN) cancer experience a wide spectrum of physical, emotional and social effects after diagnosis and treatment of their cancer. The insufficient availability of local support groups, limited transportation for the rural Chinese population and a shortage of oncologists make it difficult to have face-to-face support groups for Chinese GYN cancer patients. However, the wide access of Internet has provided an opportunity for people to have online support groups. The purpose of this study was to observe and describe the types of support given to and by Chinese GYN cancer survivors in a QQ chat group. This was a qualitative study that used the directed content analysis approach. A QQ group was observed for two weeks between March 10th (12:01am) and March 24st (11:59pm) 2018 Beijing time. Observed online posts were copied and pasted into a WORD ™ document for analysis. There were 4 themes observed: sharing experience, information exchange, emotional support and Guardian Against Cancer group member benefits. The results of the study suggested that women supported each other but little evidence-based support was observed. Healthcare providers should be monitoring and engaging in conversations with group members. Well-planed and organized information sessions should also be beneficial for members. Further research on understanding members’ needs on online support groups and the effectiveness of intervention should be conducted.

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