Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
Int J Biol Sci. 2024 Aug 1;20(11):4114-4127. doi: 10.7150/ijbs.95463. eCollection 2024.
Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.
骨肉瘤是最常见的原发性恶性骨肿瘤，主要发生在儿童和青少年。神经生长因子（NGF）又称神经营养因子，与癌性骨痛有关；然而，NGF 在骨肉瘤中的作用尚未阐明。在基因组数据共享数据门户中的骨肉瘤样本中，我们检测到更高水平的 NGF 和 M2 巨噬细胞标志物，但没有 M1 巨噬细胞标志物。在细胞实验中，NGF 刺激的骨肉瘤条件培养基被证明可以通过 FAK 和 c-Src 级联下调 miR-513c-5p 水平，促进 M0 向 M2 表型的巨噬细胞极化。NGF 还通过下调 miR-513c-5p 水平，增强 VCAM-1 依赖性单核细胞在骨肉瘤微环境中的黏附，从而增强肿瘤生长。在异种移植模型中，NGF 的过表达被证明可以增强肿瘤生长，而口服 Trk 抑制剂 larotrectinib 则可以显著拮抗 NGF 促进的 M2 巨噬细胞表达和肿瘤进展。这些结果表明，larotrectinib 可能可用作一种治疗剂，旨在减轻 NGF 介导的骨肉瘤进展。
