文章：

自分泌胰岛素样生长因子1和干细胞因子支持人类骨髓瘤细胞的自我更新，而不是白细胞介素6

Autocrine insulin-like growth factor 1 and stem cell factor but not interleukin 6 support self-renewal of human myeloma cells

原文发布日期：2013-06-07

DOI: 10.1038/bcj.2013.18

类型: Original Article

开放获取: 是

英文摘要：

An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-κB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential.

摘要翻译： 

在本研究中，我们鉴定了支持八种骨髓瘤细胞系自我更新的生长因子。所有能够形成自我集落的细胞系均显示组成型P-AKT和P-ERK1,2表达，但未表达P-STAT3且不表达CD45，提示存在胰岛素样生长因子1（IGF1）循环。我们发现阻断性抗胰岛素样生长因子1受体（IGF1R）单克隆抗体能抑制集落形成，该抑制作用与IGF1R表达水平相关并伴随P-AKT水平降低。伊马替尼或阻断性抗干细胞因子（SCF）单克隆抗体同样抑制了两种表达C-KIT和SCF的细胞系的集落形成，并降低P-AKT水平。此外，PI3K/AKT通路抑制剂渥曼青霉素也能抑制集落形成。而阻断白细胞介素（IL）6受体则未抑制集落形成，这与细胞缺乏组成型P-STAT3的表达高度一致。研究显示原代细胞频繁共表达IGF1R/IGF1，但不共表达C-KIT/SCF或IL6R/IL6，提示体内自发性生长可能通过IGF1R实现。尽管IGF1R和C-KIT在克隆形成生长中作用相似且共享信号通路，但二者预后价值相反，提示它们可能作为替代标志物。事实上，我们证实C-KIT和IGF1R的预后价值均不独立于MMSET表达。本研究揭示了IGF1在骨髓瘤细胞中的自分泌作用，并强化了在IGFR1+ CD45+/−患者（如MMSET+患者）中靶向IGF1R的临床意义。

原文链接：

Autocrine insulin-like growth factor 1 and stem cell factor but not interleukin 6 support self-renewal of human myeloma cells