Effets des acides gras oméga-3 sur le cancer de la prostate
|Advisor:||Fradet, Vincent; Bergeron, Alain|
|Abstract:||Prostate cancer (PCa) is the most frequently diagnosed cancer in Canadian men with 21,300 new cases and is the third-largest cause of cancer mortality with 4100 deaths in 2017. Epidemiological studies have shown that populations with a diet rich in omega (ω)-3 fatty acids(FA) (e.g. coastal Asian populations) have a low incidence of PCa while populations in Western countries with a diet rich in ω6 FA have higher (almost 60 times) incidence of PCa. Dietary fats influence many biological processes including inflammation which is associated with PCa development and progression. Notably, long-chain ω6 FA (LCω6) have pro-inflammatory properties and could contribute to PCa progression. On the opposite, LCω3 such as eicosapentaenoic acid (EPA) and docosahexanenoic acid (DHA) have anti-inflammatory properties and could inhibit PCa progression. I hypothesized that dietary ω3 FA are beneficial against PCa growth and progression mainly via their anti-inflammatory properties. Using the TRAMP-C2 mouse model of PCa, I found that an ω3 FA-enriched diet reduced PCa growth compared to an ω6 FA-enriched diet in both androgen-deprived and non-deprived mice by inducing local antitumor Th1-, Th2-and eosinophil-related immune response. In the quest to further study the effects of individual ω3 FA subtype, I found that dietary supplementation with monoacylglyceride (MAG)-EPA reduced tumor growth by inhibiting vascular endothelial growth factor (VEGF)and vascular endothelial growth factor receptor-2gene (VEGFR2)expression as well as reducing the size of blood vessels in TRAMP-C2 tumors. I also observed that higher level of EPA reduced the size of blood vessels in prostate in a clinical trial testing MAG-EPA supplementation on PCa patients undergoing radical prostatectomy. Finally, I analyzed the effects of an ω3 FA-rich diet intervention versus treatment with a 5α- reductase inhibitor (5ARI) on low-risk PCa patients under active surveillance. I found that 6 months of ω3 FA-rich diet intervention resulted in a reduction of plasma level of pro-inflammatory and pro-angiogenesis cytokines as well as Th2 and Th17 immune response-related cytokines. In order to assess the effects of these interventions on the prostate tissue, I used cytokines assay and mass spectrometry (MS ) assay to analyze proteins in clarified urine obtained after digital rectal examination (DRE urine). I did not succeed at identifying significant variation in protein levels following the interventions in this sample type but I found that crude (non-clarified) DRE urine contained twice the amount of proteins compared to clarified urine, suggesting that this type of sample should be used for further analysis. Overall, my results confirmed the importance of ω3 FA for prevention of PCa progression and provide the rationale to further investigate their effects on immune response, tumor vasculature and tumor progression in PCa patients.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||14 March 2019|
|Collection:||Thèses et mémoires|
All documents in CorpusUL are protected by Copyright Act of Canada.