Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells
Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells
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DOI：
10.1182/blood-2003-06-2066
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发表时间：
2004-01-01
期刊：
影响因子：
20.3
通讯作者：
Rudikoff, S
中科院分区：
文献类型：
--
作者：
Qiang, YW;Yao, L;Rudikoff, S
多发性骨髓瘤（MM）是一种无法治愈的癌症形式，其特征在于恶性浆细胞在骨髓中积聚。在这种疾病的过程中，肿瘤细胞穿过内皮屏障并回到骨髓。在后期阶段，骨髓瘤细胞通过血管外渗，并可能在各种器官中播种。胰岛素样生长因子I（IGF-I）是促进MM细胞生长的几种生长因子之一。在目前的研究中，我们已经评估了IGF-I作为影响这些细胞的流动性和侵袭性的趋化因子的能力。结果表明，IGF-1促进通过血管内皮细胞和骨髓基质细胞系的迁移。内源性信号通路的分析表明，蛋白激酶D/蛋白激酶Cmu（PKD/PKCmu）和RhoA都被激活的磷脂酰肌醇3-激酶（PI-3K）依赖的方式。PI-3K，PKC，或Rho相关激酶抑制剂药理学抑制剂废除迁移，而丝裂原活化蛋白激酶（MAPK），Akt，和p70S6激酶抑制剂没有影响。这些结果表明，IGF-I通过激活PI-3K/PKCmu和PI-3K/RhoA途径促进骨髓瘤细胞迁移，而不依赖于Akt。IGF-I作为增殖和迁移因子的鉴定为在MM治疗中针对IGF-I的靶向治疗策略的开发提供了合理的基础。
Multiple myeloma (MM) is an incurable form of cancer characterized by accumulation of malignant plasma cells in the bone marrow. During the course of this disease, tumor cells cross endothelial barriers and home to the bone marrow. In latter stages, myeloma cells extravasate through blood vessels and may seed a variety of organs. Insulin-like growth factor I (IGF-I) is one of several growth factors shown to promote the growth of MM cells. In the current study, we have assessed the ability of IGF-I to serve additionally as a chemotactic factor affecting the mobility and invasive properties of these cells. Results indicate that IGF-l promotes transmigration through vascular endothelial cells and bone marrow stromal cell lines. Analysis of endogenous signaling pathways revealed that protein kinase D/protein kinase Cmu (PKD/ PKCmu) and RhoA were both activated in a phosphatidylinositol 3-kinase (PI-3K)dependent manner. Inhibition of PI-3K, PKCs, or Rho-associated kinase by pharmacologic inhibitors abrogated migration, whereas mitogen-activated protein kinase (MAPK), Akt, and p70S6 kinase inhibitors had no effect. These results suggest that IGF-I promotes myeloma cell migration by activation of PI-3K/PKCmu and PI-3K/RhoA pathways independent of Akt. The identification of IGF-I as both a proliferative and migratory factor provides a rational basis for the development of targeted therapeutic strategies directed at IGF-I in the treatment of MM.