Mp70-17 Deciphering the Effects of Omega-3 Fatty Acid Supplements on Prostate Cancer

Abstract

Inflammation is one contributing factors to prostate cancer (PCa). We have shown that an omega-3 (?3)-rich diet decrease PCa tumor growth by favourably modulating the inflammatory response. In this study, we tested the specific effects of purified ?3 fatty acids (FA) sub-types on tumor growth, inflammatory response, gut microbiota and tumor gene expression compared to ?6 and ?9 in a murine PCa model.METHODS: C57BL/6 mice were daily supplemented with purified FA (?3-eicosapentaenoic acid (EPA), ?3-docosahexaenoic acid (DHA), ?6-arachidonic acid (AA) or ?9-rich high-oleic sunflower oil (HOSO)), and injected s.c. with TRAMP-C2 mouse PCa cells. Feces were collected weekly while blood and tumors were collected at end point. FA incorporation was analyzed in blood and tumors. Bacterial content from fresh fecal DNA was profiled using 16S rRNA metagenomic sequencing. Cytokine and gene expression profiles were analyzed in tumors using BioPlex technology and high-throughput RNA sequencing, respectively.RESULTS: We measured a specific FA incorporation of each group into red blood and tumor cells. Interestingly, only tumors of EPAfed mice had a reduced tumor growth than HOSO-fed control mice. Many pro-inflammatory cytokines were expressed at a significantly lower level in tumors of ?3-EPA and eDHA fed mice compared to ?6-AA-fed mice. We found gene expression changes only in the EPA-fed mice group: differentially expressed genes were related to angiogenesis and inflammatory pathways. We confirmed reduced expression of VEGFR and VEGF as well as smaller CD31-stained blood vessels in EPA-fed tumors. Finally, gut microbiota metagenomic analysis revealed that most bacterial shifts were found in DHA-fed animals. Interestingly, while we observed little changes for the gut microbiota of AA-fed animals, we were able to predict metagenome functional content and found an increase in functions associated to butirosin and neomycin biosynthesis, renal cell carcinoma and glycerophospholipid metabolism compared to control animals.CONCLUSIONS: Both ?3 subtypes modulated intra-tumoral inflammation. Interestingly, DHA was the FA driving the biggest changes in fecal microbiota. However, we found only EPA to significantly reduce PCa tumor growth, potentially achieved by gene expression modulation leading to a reduced angiogenesis and inflammation. Together, these results suggest that both ?3 subtypes modulate inflammation but possibly via separate mechanisms. Our work supports the use of EPA for targeting PCa progression.