Regulation of Age-Related Lipid Metabolism in Ovarian Cancer

The mortality rate of ovarian cancer (OC) remains the highest among female gynecological malignancies. Advanced age is the highest risk factor for OC development and progression, yet little is known about the role of the aged tumor microenvironment (TME). We conducted RNA sequencing and lipidomic analysis of young and aged gonadal adipose tissue from rat xenografts before and after OC formation. The rates of tumor formation (p = 0.047) and tumor volume (p = 0.002) were significantly higher in the aged rats than in their young counterparts. RNA sequencing data showed significant differences in gene expression profiles between the groups of young and aged rat adipose tissues (p < 0.05), including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3. At the time of tumor generation, there were also changes in the lipid components within the gonadal adipose tissues of young and aged rats, with higher levels of free fatty acids (FFAs) and triglycerides (TGs) in aged rats. Furthermore, the aged TME showed changes in immune cell composition, especially inflammation-related cells, including neutrophils, myeloid dendritic cells, CD4+ T cells (non-regulatory), and mast cell activation (p < 0.05). The correlation between S100a8, S100a9, neutrophil, and omega-5, FFA 18:3 levels was also determined. Additionally, omega-5, which is downregulated in aged rats, inhibited OC cell proliferation in vitro (p < 0.001). Our study suggests that the aged TME promotes OC proliferation resulting from age-related changes in gene/pathway expression, lipid metabolism, and immune cell distribution. Targeting the aging adipose microenvironment, particularly lipid metabolism, is a promising therapeutic strategy for OC and warrants further investigation. Significance: The aging microenvironment contributes to OC development and progression because of changes in the immune response regulatory genes S100a8 and S100a9, secreted by adipocytes, preadipocytes, or neutrophils, and by altering omega-5 metabolism.