Li Liangge, Geng Jiafeng, Yu Wen, Zhou Feifei, Zheng Zhihuan, Fu Kaiyue, Kong Junjie, Feng Xiujing
Department of Endocrinology, Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Front Pharmacol. 2023 Aug 15;14:1205030. doi: 10.3389/fphar.2023.1205030. eCollection 2023.
Obesity has been associated with the development of 13 different types of cancers, including breast cancer. Evidence has indicated that cancer-associated adipocytes promote the proliferation, invasion, and metastasis of cancer. However, the mechanisms that link CAAs to the progression of obesity-related cancer are still unknown. Here, we found the mature adipocytes in the visceral fat of HFD-fed mice have a CAAs phenotype but the stromal vascular fraction of the visceral fat has not. Importantly, we found the derivate of the potent PPARγ antagonist GW9662, BZ26 inhibited the reprogramming of mature adipocytes in the visceral fat of HFD-fed mice into CAA-like cells and inhibited the proliferation and invasion of obesity-related breast cancer. Further study found that it mediated the browning of visceral, subcutaneous and perirenal fat and attenuated inflammation of adipose tissue and metabolic disorders. For the mechanism, we found that BZ26 bound and inhibited PPARγ by acting as a new modulator. Therefore, BZ26 serves as a novel modulator of PPARγ activity, that is, capable of inhibiting obesity-related breast cancer progression by inhibiting of CAA-like cell formation, suggesting that inhibiting the reprogramming of mature adipocytes into CAAs or CAA-like cells may be a potential therapeutic strategy for obesity-related cancer treatment.
肥胖与包括乳腺癌在内的13种不同类型癌症的发生有关。有证据表明，癌症相关脂肪细胞会促进癌症的增殖、侵袭和转移。然而，将癌症相关脂肪细胞与肥胖相关癌症进展联系起来的机制仍不清楚。在此，我们发现高脂饮食喂养小鼠的内脏脂肪中的成熟脂肪细胞具有癌症相关脂肪细胞的表型，但内脏脂肪的基质血管部分则没有。重要的是，我们发现强效PPARγ拮抗剂GW9662的衍生物BZ26抑制了高脂饮食喂养小鼠内脏脂肪中成熟脂肪细胞重编程为类癌症相关脂肪细胞，并抑制了肥胖相关乳腺癌的增殖和侵袭。进一步研究发现，它介导了内脏、皮下和肾周脂肪的褐变，并减轻了脂肪组织炎症和代谢紊乱。就机制而言，我们发现BZ26通过作为一种新的调节剂结合并抑制PPARγ。因此，BZ26作为PPARγ活性的新型调节剂，即能够通过抑制类癌症相关脂肪细胞形成来抑制肥胖相关乳腺癌进展，这表明抑制成熟脂肪细胞重编程为癌症相关脂肪细胞或类癌症相关脂肪细胞可能是肥胖相关癌症治疗的一种潜在策略。
