IGF-1R 介导鼻咽癌细胞与破骨细胞之间的串扰，并促进肿瘤骨转移。

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. CONCLUSION: 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.

背景：鼻咽癌（NPC）在亚洲特定地区造成了重大的健康负担，一些 NPC 患者在初始诊断时就已经发生了骨转移。骨转移可导致病理性骨折和疼痛，降低患者的生活质量，并与更差的生存相关。本研究旨在揭示胰岛素样生长因子 1 受体（IGF-1R）在 NPC 骨转移中的复杂作用，为潜在的治疗靶点提供见解。

方法：我们评估了 NPC 细胞中 IGF-1R 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 对促进 NPC 细胞在骨髓内增殖的 IGF-1R/AKT/S6 通路的影响。此外，还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。还在动物实验中研究了 IGF-1 中和抗体、IGF-1R 特异性抑制剂（NVP-AEW541）和 mTORC 抑制剂（雷帕霉素）对鼻咽癌骨转移的影响。

结果：NPC 细胞中 IGF-1R 的表达升高与骨转移的增加趋势相关。破骨细胞分泌的 IGF-1 激活了 IGF-1R/AKT/S6 通路，促进了 NPC 细胞在骨髓内的增殖。肿瘤分泌的 GM-CSF 进一步刺激破骨细胞分化，加剧了骨吸收。IGF-1 中和抗体、NVP-AEW541 和雷帕霉素分别有效地减缓了骨转移的速度并减少了骨破坏。

结论：IGF-1R、IGF-1 和 GM-CSF 之间的复杂相互作用突出了精确控制 NPC 骨转移的潜在治疗靶点，为开发靶向干预措施提供了有价值的见解。