Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China.
Chin Med J (Engl). 2023 Apr 20;136(8):974-985. doi: 10.1097/CM9.0000000000002628. Epub 2003 Apr 4.
Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.
The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al .
In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.
Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.
脂肪组织的渐进性脂质损失是癌症相关恶病质的主要特征。除了肿瘤进展引起的全身免疫/炎症反应外，肿瘤分泌的恶病质配体在肿瘤诱导的脂质损失中也起着至关重要的作用。然而，肿瘤-脂肪组织在脂质动态平衡中的相互作用机制尚不完全清楚。
在果蝇中诱导 yki-肠道肿瘤。进行脂质代谢测定，以研究不同类型胰岛素样生长因子结合蛋白-3（IGFBP-3）处理的细胞的脂肪分解水平。免疫印迹用于显示肿瘤细胞和脂肪细胞的表型。定量聚合酶链反应（qPCR）分析用于检查 Acc1、Acly 和 Fasn 等基因的表达水平。
在这项研究中，揭示了肿瘤衍生的 IGFBP-3 是直接导致成熟脂肪细胞脂质损失的重要配体。高表达于恶病质肿瘤细胞中的 IGFBP-3 拮抗胰岛素/IGF 样信号（IIS），并破坏 3T3-L1 脂肪细胞中脂肪分解和脂肪生成之间的平衡。来自恶病质肿瘤细胞的条件培养基，如 Capan-1 和 C26 细胞，含有大量的 IGFBP-3，强烈诱导脂肪细胞中的脂肪分解。值得注意的是，在恶病质肿瘤细胞的条件培养基中用中和抗体中和 IGFBP-3 可显著减轻脂肪分解作用，并恢复脂肪细胞中的脂质储存。此外，恶病质肿瘤细胞对 IGFBP-3 抑制 IIS 的作用具有抗性，从而使其逃避 IGFBP-3 相关的生长抑制。最后，恶病质肿瘤衍生的 ImpL2，即 IGFBP-3 的同源物，也破坏了果蝇中建立的癌症恶病质模型中宿主细胞的脂质动态平衡。最重要的是，IGFBP-3 在胰腺癌和结直肠癌患者的癌症组织中高表达，尤其是在恶病质癌症患者的血清中高于非恶病质癌症患者。
我们的研究表明，肿瘤衍生的 IGFBP-3 在恶病质相关的脂质损失中起着关键作用，并且可能是癌症患者恶病质诊断的生物标志物。
