Biology of plasma cell tumor development

人类浆细胞肿瘤最常见的是多发性骨髓瘤，这是一种无法治愈的癌症。骨髓瘤细胞似乎对多种生长因子有反应，包括 IL-6 和胰岛素样生长因子 I (IGF-I)，这些因子可能有助于生存和增殖。骨髓瘤的标志之一是在整个骨髓中传播，但人们对影响这一过程的机制知之甚少。 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 的骨髓瘤细胞会发生显着的形态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 途径相关，表明细胞运动可能发生变化。使用迁移实验证明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系迁移/侵袭。迁移与 RhoA 和 PKC α、β 和 mu 的激活相关。 Rho 相关激酶抑制剂可阻断 PKC mu 激活和迁移。因此，在Wnt诱导的迁移中，PKC mu的激活受到RhoA的调节。此外，免疫共沉淀研究揭示了 RhoA 与 PKC mu 和 PKC 以及称为 Dishevelleds 的上游元件之间的关联，表明存在调节 Wnt 信号传导的大分子信号复合物。这些结果表明Wnts也可能充当迁移/侵袭促进因子，因此对于疾病进展期间骨髓瘤细胞的运动很重要。

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. One of the hall marks of myeloma is dissemination throughout the bone marrow yet little is known about the mechanisms affecting this process. 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 cell lines. Migration is associated with activation of both RhoA and PKCs alpha, beta and mu. Rho associated kinase inhibitors block both PKC mu activation and migration. Thus, in Wnt induced migration, activation of PKC mu is regulated by RhoA. Furthermore, co-immunoprecipitation studies revealed association between RhoA and PKC mu and PKCs and upstream elements known as Dishevelleds suggesting a macromolecular signaling complex regulating Wnt signaling. 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.