The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma
The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma
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DOI：
10.1038/sj.leu.2402875
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发表时间：
2003-04-01
期刊：
影响因子：
11.4
通讯作者：
Pals, ST
中科院分区：
文献类型：
--
作者：
Derksen, PWB;de Gorter, DJJ;Pals, ST
多发性骨髓瘤（MM）的进化依赖于来自骨髓（BM）微环境的复杂信号，支持恶性浆细胞的增殖和存活。一个有趣的候选信号是肝细胞生长因子/分散因子（HGF），因为它的受体Met在MM细胞上表达，而HGF是由BM基质细胞和一些MM细胞系产生的，可以进行旁分泌或自分泌相互作用。为了探索这一假设，我们研究了HGF刺激对MM细胞系和原代MM的生物学效应。我们观察到Met在大多数MM细胞系和大约一半的原发浆细胞肿瘤中表达。HGF刺激MM细胞导致RAS/丝裂原激活的蛋白激酶和磷脂酰肌醇3-激酶/蛋白激酶B （PI3K/PKB）通路的激活，这些信号通路与细胞增殖和存活的调节有关。事实上，功能研究表明，HGF对MM细胞系和原代MM细胞都具有很强的增殖和抗凋亡作用。此外，通过应用特定的信号转导抑制剂，我们证明了MEK是figf诱导的增殖所必需的，而PI3K的激活对于hgf诱导的增殖和拯救MM细胞免于凋亡都是必需的。综上所述，我们的数据表明HGF是一种有效的骨髓瘤生长和生存因子，并表明HGF/Met途径是骨髓瘤的潜在治疗靶点。
The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/ scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and antiapoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for FIGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.