Gynaecology Oncology Group, University of Newcastle, Newcastle, New South Wales, Australia.
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
Mol Cancer Res. 2018 Feb;16(2):309-321. doi: 10.1158/1541-7786.MCR-17-0466. Epub 2017 Nov 13.
Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer. Adipocyte-derived VEGF-mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. .
肥胖与子宫内膜癌的发病率和死亡率增加有关。尽管体重指数（BMI）或肥胖与子宫内膜癌的发生呈正相关，但脂肪组织对子宫内膜增生和癌症发病机制的贡献尚不清楚。本研究通过证明脂肪细胞条件培养基（ACM）与前脂肪细胞条件培养基（PACM）相比，可增加子宫内膜癌细胞的增殖、迁移和存活，从而阐明了脂肪细胞在子宫内膜癌发病机制中的作用。对 ACM 和 PACM 的比较细胞因子阵列分析显示，ACM 中属于 VEGF 信号通路的一组细胞因子上调。肥胖患者内脏脂肪组织（VAT）中 VEGF 蛋白表达上调，这与异种移植模型中肿瘤生长增加相关。肿瘤大小的增加与 VEGF 信号下游靶点 PI3K/AKT/mTOR 通路的激活有关，该通路的抑制降低了 VAT 对子宫内膜癌细胞的促生长作用。与人类模型系统类似，在过度摄食肥胖小鼠模型中子宫内膜细胞的病理变化与体重增加和 mTOR 信号过度活跃有关。对人类组织标本的分析表明，与非肥胖患者相比，肥胖子宫内膜癌患者的肿瘤血管生成和 VEGF-mTOR 活性增加。综上所述，这些结果提供了证据表明 VEGF-mTOR 信号驱动子宫内膜细胞生长，导致增生和癌症。脂肪细胞衍生的 VEGF-mTOR 信号可能是肥胖女性子宫内膜癌的一个有吸引力的治疗靶点。
