索拉非尼通过干扰胰岛素样生长因子-1 的分泌抑制巨噬细胞诱导的肝癌细胞生长。
Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion.
机构信息
Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany; I. Medical Department, Universitätsmedizin, Mainz, Germany; Clinical Registry Unit, I. Medical Department, Universitätsmedizin, Mainz, Germany.
Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany.
出版信息
J Hepatol. 2015 Apr;62(4):863-70. doi: 10.1016/j.jhep.2014.11.011. Epub 2014 Nov 22.
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) associated macrophages accelerate tumor progression by growth factor release. Therefore, tumor-associated macrophages (TAM) and their initiated signaling cascades are potential therapeutic targets. Aiming at understanding anticancer effects of systemic HCC therapy, we investigated the impact of sorafenib on macrophage function, focusing on macrophage-related growth factor secretion.
METHODS
Macrophage markers, cytokine and growth factor release were investigated in CSF-1 (M1) or GMCSF (M2) maturated monocyte-derived macrophages. Macrophages were treated with sorafenib (1.2-5.0 μg/ml) and culture supernatants were transferred to hepatoma cell cultures to assess growth propagation. Insulin-like growth factor (IGF) signaling was blocked with NVP-AEW541 to confirm the role of IGF-1 in macrophage-driven hepatoma cell propagation. Macrophage activation was followed by ELISA of serum soluble mCD163 in sorafenib-treated patients with HCC.
RESULTS
Alternative macrophages (M2), which showed higher IGF-1 (p=0.022) and CD163 mRNA (p=0.032) expression compared to classical macrophages (M1), increased hepatoma growth. This effect was mediated by M2-conditioned culture media. In turn, sorafenib lowered mCD163 and IGF-1 release by M2 macrophages, which decelerated M2 macrophage driven HuH7 and HepG2 proliferation by 47% and 64%, respectively. IGF-receptor blockage with NVP-AEW541 reduced growth induction by M2-conditioned culture media in a dose dependent manner. A transient mCD163 reduction during sorafenib treatment indicated a coherent M2 macrophage inhibition in patients with HCC.
CONCLUSIONS
Sorafenib alters macrophage polarization, reduces IGF-1-driven cancer growth in vitro and partially inhibits macrophage activation in vivo. Thus macrophage modulation might contribute to the anti-cancer activity of sorafenib. However, more efficient macrophage-directed therapies are required.
背景与目的
肝细胞癌（HCC）相关巨噬细胞通过生长因子释放加速肿瘤进展。因此，肿瘤相关巨噬细胞（TAM）及其引发的信号级联反应是潜在的治疗靶点。为了了解全身性 HCC 治疗的抗癌作用，我们研究了索拉非尼对巨噬细胞功能的影响，重点关注巨噬细胞相关生长因子的分泌。
方法
在 CSF-1（M1）或 GMCSF（M2）成熟的单核细胞衍生巨噬细胞中研究巨噬细胞标志物、细胞因子和生长因子的释放。用索拉非尼（1.2-5.0μg/ml）处理巨噬细胞，将培养上清液转移到肝癌细胞培养物中，以评估生长增殖。用 NVP-AEW541 阻断胰岛素样生长因子（IGF）信号以确认 IGF-1 在巨噬细胞驱动的肝癌细胞增殖中的作用。通过 ELISA 检测索拉非尼治疗 HCC 患者的血清可溶性 mCD163 来跟踪巨噬细胞的激活。
结果
与经典巨噬细胞（M1）相比，具有更高 IGF-1（p=0.022）和 CD163 mRNA（p=0.032）表达的替代巨噬细胞（M2）增加了肝癌的生长。这种作用是由 M2 条件培养基介导的。反过来，索拉非尼降低了 M2 巨噬细胞释放的 mCD163 和 IGF-1，分别使 M2 巨噬细胞驱动的 HuH7 和 HepG2 增殖降低了 47%和 64%。用 NVP-AEW541 阻断 IGF 受体以剂量依赖的方式降低了 M2 条件培养基诱导的生长。索拉非尼治疗期间 mCD163 的短暂减少表明 HCC 患者的 M2 巨噬细胞抑制一致。
结论
索拉非尼改变了巨噬细胞的极化，减少了 IGF-1 驱动的体外癌细胞生长，并部分抑制了体内巨噬细胞的激活。因此，巨噬细胞调节可能有助于索拉非尼的抗癌活性。然而，需要更有效的巨噬细胞定向治疗。
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