Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis
Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis
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DOI：
10.1677/erc.1.00956
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发表时间：
2005-06-01
影响因子：
3.9
通讯作者：
Pinto, A
中科院分区：
文献类型：
--
作者：
Normanno, N;De Luca, A;Pinto, A
一项使用表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼治疗乳腺癌的临床试验发现，骨转移患者的骨痛得到了显著缓解。破骨细胞的激活和分化受骨髓基质细胞（BMSC）的调控，骨髓基质细胞是一种异质细胞室，包括未分化的间充质干细胞（MSC）及其特化后代。在这方面，我们发现人原代骨髓间充质干细胞表达免疫反应性EGFR。EGFR mRNA和蛋白的表达也在两种人类连续的msc样细胞系HDS-1和HDS-2细胞中得到证实。用EGF治疗HDS细胞可显著增加活化的EGFR水平，这在吉非替尼中未观察到。吉非替尼治疗后，HDS细胞中EGFR和Akt的基础活化水平显著降低。通过特异性ELISA和Western blotting技术评估，吉非替尼治疗HDS细胞可显著降低两种细胞系中分泌的巨噬细胞集落刺激因子（M-CSF）和nf - κ B配体细胞相关受体激活剂（RANKL）的水平。最后，与未处理的HDS细胞相比，吉非替尼处理的HDS细胞在条件培养基中维持前破骨细胞分化的能力降低了约45%。这些数据首次证明了EGFR调节骨髓间充质干细胞诱导破骨细胞分化的能力，并有力地支持了吉非替尼在乳腺癌骨病患者中的临床试验。
Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappa B ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease.