Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kajiwara, Kamakura, Kanagawa, Japan.
Clin Exp Metastasis. 2011 Oct;28(7):649-59. doi: 10.1007/s10585-011-9398-4. Epub 2011 Jun 18.
Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.
先前的临床前和临床研究表明表皮生长因子受体 (EGFR) 在破骨细胞分化和癌症骨转移发病机制中可能发挥作用。在这项研究中，我们研究了表皮生长因子受体酪氨酸激酶抑制剂（TKI）厄洛替尼对人非小细胞肺癌（NSCLC）细胞系 NCI-H292 骨侵袭的影响。首先，我们建立了一种新的 NCI-H292 细胞溶骨性骨侵袭模型，该模型通过将癌细胞接种到 scid 小鼠的胫骨中制成。在该模型中，NCI-H292 细胞明显激活了胫骨中的破骨细胞，导致溶骨性骨破坏。厄洛替尼通过抑制骨转移部位成骨细胞/基质细胞中核因子-κB 配体（RANKL）的表达来抑制破骨细胞的激活，从而抑制 NCI-H292 细胞引起的溶骨性骨破坏。厄洛替尼在体外抑制 NCI-H292 细胞的增殖。厄洛替尼抑制溶骨性因子的产生，如甲状旁腺激素相关蛋白（PTHrP）、IL-8、IL-11 和血管内皮生长因子（VEGF）在 NCI-H292 细胞中的产生。此外，厄洛替尼还抑制了 RANKL 在体外诱导的成骨细胞/基质细胞的增殖和破骨细胞的分化。总之，厄洛替尼通过抑制肿瘤在骨转移部位的生长、肿瘤细胞中溶骨性因子的产生、成骨细胞/基质细胞的增殖以及破骨细胞从骨髓细胞的分化，抑制肿瘤诱导的溶骨性骨侵袭。
