Abstract：
Chemotherapy and targeted drugs-induced senescent ovarian cancer cells that accumulate in peritoneal adipose tissue contribute significantly to chronic inflammation, disrupt homeostasis, and may fuel various aspects of cancer progression. However, the pro-senescence effects of chemotherapy and targeted drugs on adipose derived stem cells (ADSCs) within peritoneal adipose tissue remain poorly understood. In this study, we show that the first-line chemotherapy and targeted drugs can induce the cellular senescence of ADSCs in vitro and increase the aging of peritoneal adipose tissue in vivo. These treatments significantly promoted the dysregulation of glucose and lipid metabolism, including insulin resistance and liver lipid accumulation. Our study shows that dasatinib and quercetin, as senolytics, effectively restore glucose homeostasis in mice with ovarian cancer and significantly reduce adipose tissue aging. Importantly, combining these drugs with Carboplatin or Olaparib results in a marked decrease in both peritoneal and adipose tissue metastasis of ovarian cancer cells. Mechanistically, we revealed that there is crosstalk between ovarian cancer cells and senescent ADSCs. The crosstalk increases inflammatory cytokines and chemokines production in ADSCs and notably upregulates chemokine receptors on cancer cells. Collectively, these data indicate that senescent ADSCs induced by chemotherapy and targeted therapy drugs impair adipose tissue function. However, the senolytic drugs dasatinib and quercetin, can significantly ameliorate organ aging and damage induced by these treatments. Notably, dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer, ultimately benefiting the mice undergoing chemotherapy and targeted therapy.
摘要：
化疗和靶向药物诱导的在腹膜脂肪组织中积累的衰老卵巢癌细胞显著促进慢性炎症，破坏体内平衡，并可能推动癌症进展的各个方面。然而,化疗和靶向药物对腹膜脂肪组织内脂肪干细胞(ADSC)的促衰老作用尚不清楚.在这项研究中,研究表明，一线化疗和靶向药物可以在体外诱导ADSCs细胞衰老，在体内增加腹膜脂肪组织的衰老。这些治疗显著促进了糖脂代谢的失调,包括胰岛素抵抗和肝脏脂质积累。我们的研究表明，达沙替尼和槲皮素，作为senoletics，有效恢复卵巢癌小鼠的葡萄糖稳态，并显着减少脂肪组织老化。重要的是,将这些药物与卡铂或奥拉帕尼联合使用可显著减少卵巢癌细胞的腹膜和脂肪组织转移。机械上,我们发现卵巢癌细胞与衰老的ADSCs之间存在串扰。串扰增加了ADSC中炎性细胞因子和趋化因子的产生,并且显著上调癌细胞上的趋化因子受体。总的来说，这些数据表明，化疗和靶向治疗药物诱导的衰老ADSCs会损害脂肪组织功能。然而,抗衰老药物达沙替尼和槲皮素，可以显着改善这些治疗引起的器官老化和损伤。值得注意的是,达沙替尼、槲皮素联合卡铂或奥拉帕尼可减少卵巢癌腹膜和脂肪组织转移,最终使接受化疗和靶向治疗的小鼠受益。
