Feng Jihua, Rouse Clay Douglas, Taylor Lila, Garcia Santiago, Nguyen Ethan, Coogan Isabella, Byrd Olivia, Berchuck Andrew, Murphy Susan K, Huang Zhiqing
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Duke University School of Medicine, 701 West Main Street, Suite 510, Duke, P.O. Box 90534, Durham, NC 27701, USA.
Department of Emergency, The Second Affiliated Hospital, Guangxi Medical University, Nanning 530021, China.
Int J Mol Sci. 2025 Jan 1;26(1):320. doi: 10.3390/ijms26010320.
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 ( = 0.047) and tumor volume ( = 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 ( < 0.05), including , , , , , , , and . 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 ( < 0.05). The correlation between , , 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 ( < 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. : The aging microenvironment contributes to OC development and progression because of changes in the immune response regulatory genes and , secreted by adipocytes, preadipocytes, or neutrophils, and by altering omega-5 metabolism.
卵巢癌（OC）的死亡率在女性妇科恶性肿瘤中仍然是最高的。高龄是OC发生和进展的最大风险因素，但关于衰老肿瘤微环境（TME）的作用却知之甚少。我们对大鼠异种移植瘤在OC形成前后的年轻和老龄性腺脂肪组织进行了RNA测序和脂质组学分析。老龄大鼠的肿瘤形成率（P = 0.047）和肿瘤体积（P = 0.002）显著高于年轻大鼠。RNA测序数据显示，年轻和老龄大鼠脂肪组织组之间的基因表达谱存在显著差异（P < 0.05），包括[具体基因未列出]。在肿瘤发生时，年轻和老龄大鼠性腺脂肪组织中的脂质成分也发生了变化，老龄大鼠中的游离脂肪酸（FFA）和甘油三酯（TG）水平更高。此外，衰老的TME显示免疫细胞组成发生变化，特别是与炎症相关的细胞，包括中性粒细胞、髓样树突状细胞、CD4 + T细胞（非调节性）和肥大细胞活化（P < 0.05）。还确定了[具体基因未列出]、中性粒细胞和ω-5、FFA 18:3水平之间的相关性。此外，在老龄大鼠中下调的ω-5在体外抑制OC细胞增殖（P < 0.001）。我们的研究表明，衰老的TME通过基因/通路表达、脂质代谢和免疫细胞分布的年龄相关变化促进OC增殖。针对衰老的脂肪微环境，特别是脂质代谢，是OC的一种有前景的治疗策略，值得进一步研究。结论：衰老的微环境由于脂肪细胞、前脂肪细胞或中性粒细胞分泌的免疫反应调节基因[具体基因未列出]的变化以及ω-5代谢的改变，有助于OC的发生和进展。
