METHODS: We assessed IGF-1R expression in NPC cells and explored its correlation with bone metastasis. Experiments investigated the impact of osteoclast-secreted IGF-1 on the IGF-1R/AKT/S6 pathway in promoting NPC cell proliferation within the bone marrow. Additionally, the reciprocal influence of tumor-secreted Granulocyte-macrophage colony-stimulating factor (GM-CSF) on osteoclast differentiation and bone resorption was examined. The effects of IGF-1 neutralizing antibody, IGF-1R specific inhibitor (NVP-AEW541) and mTORC inhibitor (rapamycin) on nasopharyngeal carcinoma bone metastasis were also explored in animal experiments.
RESULTS: Elevated IGF-1R expression in NPC cells correlated with an increased tendency for bone metastasis. IGF-1, secreted by osteoclasts, activated the IGF-1R/AKT/S6 pathway, promoting NPC cell proliferation in the bone marrow. Tumor-secreted GM-CSF further stimulated osteoclast differentiation, exacerbating bone resorption. The IGF-1 neutralizing antibody, NVP-AEW541 and rapamycin were respectively effective in slowing down the rate of bone metastasis and reducing bone destruction.
CONCLUSIONS: The intricate interplay among IGF-1R, IGF-1, and GM-CSF highlights potential therapeutic targets for precise control of NPC bone metastasis, providing valuable insights for developing targeted interventions.
方法:我们评估了IGF-1R在鼻咽癌细胞中的表达,并探讨了其与骨转移的相关性。实验研究了破骨细胞分泌的IGF-1对IGF-1R/AKT/S6途径促进骨髓内NPC细胞增殖的影响。此外,研究了肿瘤分泌的粒细胞-巨噬细胞集落刺激因子(GM-CSF)对破骨细胞分化和骨吸收的相互影响.IGF-1中和抗体的作用,还在动物实验中探索了IGF-1R特异性抑制剂(NVP-AEW541)和mTORC抑制剂(雷帕霉素)对鼻咽癌骨转移的作用。
结果:NPC细胞中IGF-1R表达升高与骨转移趋势增加相关。IGF-1,由破骨细胞分泌,激活IGF-1R/AKT/S6通路,促进骨髓中的NPC细胞增殖。肿瘤分泌的GM-CSF进一步刺激破骨细胞分化,加剧骨吸收。IGF-1中和抗体,NVP-AEW541和雷帕霉素分别在减缓骨转移速率和减少骨破坏方面有效。
结论:IGF-1R之间错综复杂的相互作用,IGF-1和GM-CSF突出了精确控制NPC骨转移的潜在治疗靶点,为制定有针对性的干预措施提供有价值的见解。