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Abstract：
BACKGROUND: Nasopharyngeal carcinoma (NPC) poses a significant health burden in specific regions of Asia, and some of NPC patients have bone metastases at the time of initial diagnosis. Bone metastasis can cause pathologic fractures and pain, reducing patients\' quality of life, and is associated with worse survival. This study aims to unravel the complex role of insulin-like growth factor 1 receptor (IGF-1R) in NPC bone metastasis, offering insights into potential therapeutic targets.
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.
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.
摘要：
背景：鼻咽癌（NPC）在亚洲特定地区造成了巨大的健康负担，一些NPC患者在最初诊断时就有骨转移。骨转移可引起病理性骨折和疼痛，降低患者的生活质量，并且与更糟糕的生存有关。本研究旨在揭示胰岛素样生长因子1受体(IGF-1R)在鼻咽癌骨转移中的复杂作用,提供对潜在治疗目标的见解。
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。
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。
