Biology of plasma cell tumor development

人类浆细胞肿瘤最常见的是多发性骨髓瘤，一种无法治愈的癌症。骨髓瘤细胞似乎对包括IL-6和胰岛素样生长因子I（IGF-I）在内的许多生长因子有反应，这可能有助于存活和增殖。 我们以前已经证明了IGF-I信号通路在骨髓瘤中的作用，在体外和体内。该途径的激活导致增殖增强和凋亡下调。负责这两种效应的许多下游元件已被表征，并且两者在很大程度上通过PI-3 K/Akt活性进行调节。最近的研究已将IGF-I的分析扩展到迁移现象。正常的浆细胞和可能的早期骨髓瘤细胞必须首先穿过血管进入骨髓，在那里它们驻留并迁移到继发性骨髓部位。在疾病的晚期，这些细胞再次穿过血管，并可能在多个其他器官中播种。目前的实验使用的transmigration分析表明，IGF-I促进迁移和骨髓瘤细胞通过血管内皮或骨髓基质细胞系的入侵。生化分析显示，IGF-I处理导致RhoA和PKC μ的激活，PI-3 K的抑制阻止了激活，将两个靶点置于PI-3 K的下游。有趣的是，Akt的抑制并不影响两者的活化，表明观察到的活化与PI-3 K途径调节增殖和凋亡的分支无关。浆细胞的迁移可以通过抑制PKC或RhoA来消除，这表明在此过程中需要两者。这些发现表明，IGF-I作为一种趋化因子在骨髓瘤发展中的作用，除了以前描述的增殖和抗凋亡作用。 Wnt蛋白已被证明是调节发育的关键元件，并且在人类癌症中已观察到Wnt的不适当表达。我们最近描述了骨髓瘤浆细胞中“经典”Wnt/β连环蛋白和Wnt/RhoA通路的激活。暴露于Wnt-3a的骨髓瘤细胞发生显著的形态学变化和肌动蛋白细胞骨架的广泛重排。这些形态学变化与Wnt/RhoA通路相关，并提示细胞运动性可能发生改变。使用移行测定，证明Wnt-3a可以作为趋化因子，促进骨髓瘤细胞通过血管内皮细胞或骨髓基质细胞的迁移/侵袭，如上文针对IGF-I所述。迁移与RhoA和PKC μ的激活有关。与IGF-I介导的迁移相反，PI-3 K抑制剂不阻断这种作用，而Rho相关激酶抑制剂阻断PKC μ活化和迁移。因此，在Wnt诱导的迁移中，PKC μ的激活受RhoA调节。这些结果表明，Wnt也可能作为迁移/侵袭促进因子发挥作用，因此在疾病进展期间骨髓瘤细胞的运动中很重要。

Plasma cell tumors in humans most commonly occur as multiple myeloma, an incurable form of cancer. Myeloma cells appear to be responsive to a number of growth factors including IL-6 and Insulin-like growth factor I (IGF-I) which likely contribute to both survival and proliferation. We have previously demonstrated a role for the IGF-I signaling pathway in myeloma both in vitro and in vivo. Activation of this pathway leads to enhanced proliferation and down regulation of apoptosis. Many of the downstream elements responsible for these two effects have been characterized and both are largely regulated through PI-3K/Akt activity. Recent studies have extended the analysis of IGF-I to the phenomenon of migration. Normal plasma cells and possibly early myeloma cells must first traverse blood vessels to enter the bone marrow where they reside and migrate to secondary bone marrow sites. During the terminal stages of disease, these cells again traverse blood vessels and may seed multiple other organs. Present experiments using a transmigration assay demonstrate that IGF-I promotes the migration and invasion of myeloma cells through either vascular endothelium or bone marrow stromal cell lines. Biochemical analysis revealed that IGF-I treatment lead to activation of both RhoA and PKC mu and inhibition of PI-3K prevented activation, placing both targets down stream of PI-3K. Interestingly, inhibition of Akt did not affect activation of either indicating that the observed activation was not associated with the branch of the PI-3K pathway regulating proliferation and apoptosis. Migration of plasma cells could be abrogated by inhibition of either PKCs or RhoA indicating a requirement for both in this process. These findings suggest a role for IGF-I as a chemotactic factor in myeloma development in addition to previously described proliferative and anti-apoptotic effects. Wnt proteins have been shown to be critical elements regulating development and inappropriate expression of Wnts has been observed in human cancers. We have recently described activation of the 'canonical' Wnt/beta catenin and the Wnt/RhoA pathways in myeloma plasma cells. Myeloma cells exposed to Wnt-3a undergo striking morphological changes and extensive rearrangement of the actin cytoskeleton. These morphological changes are associated with the Wnt/RhoA pathway and suggest possible alterations in cell motility. Using a transmigration assay, it was demonstrated that Wnt-3a can act as a chemotactic factor promoting the migration/invasion of myeloma cells through vascular endothelial cells or bone marrow stromal cells as described above for IGF-I. Migration is associated with activation of both RhoA and PKC mu. In contrast to IGF-I mediated migration, PI-3K inhibitors do not block this effect, whereas Rho associated kinase inhibitors block both PKC mu activation and migration. Thus, in Wnt induced migration, activation of PKC mu is regulated by RhoA. These results indicate that Wnts may also function as migration/invasion promoting factors and thus be important in the movement of myeloma cells during disease progression.