Department of Pancreatic Surgery, Pancreatic Cancer Institute, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Cancer Res. 2021 Feb 15;81(4):873-884. doi: 10.1158/0008-5472.CAN-20-2818. Epub 2020 Dec 21.
The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC.
肝源性细胞因子在癌症相关恶病质综合征中的作用和意义仍不清楚。在这里，我们报告称，在肝细胞癌 (HCC) 模型中，瘦素和 Igf1 信号通路的组合平衡显著缓解恶病质。首先，我们生成了稳定显示局灶性病变、厌食症和脂肪组织和肌肉组织消耗的 HCC 双转基因斑马鱼模型。从这些斑马鱼中敲除 lepR 或 mc4R 部分恢复了食欲，对组织消耗没有产生适度或无影响。然而，在 lepR 突变背景中遗传补充 Igf1 可有效缓解恶病质样表型，而不影响肿瘤生长。同样，在斑马鱼 HCC 模型、具有外源性 IGF1 的哺乳动物细胞系和两种小鼠异种移植模型上，施用 Stat3/Socs3 抑制剂 napabucasin 可恢复胰岛素敏感性并挽救非肿瘤组织的消耗。总之，这些结果描述了瘦素和 Igf1 正常化在治疗某些 HCC 相关恶病质中的协同作用，这是一种实用策略。意义：用正常表达的 Igf1 破坏瘦素信号可显著挽救 Ras 和 Myc 驱动的 HCC 斑马鱼模型中的厌食症、肌肉消耗和脂肪消耗。
