Biology of plasma cell tumor development

人类浆细胞肿瘤最常见的形式是多发性骨髓瘤，这是一种无法治愈的癌症。骨髓瘤细胞似乎对许多生长因子有反应，包括IL-6和胰岛素样生长因子I(IGF-I)，它们可能有助于生存和增殖。骨髓瘤的霍尔标志之一是扩散到整个骨髓，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WNTS的不适当表达。我们最近描述了骨髓瘤浆细胞中典型的Wnt/β连环蛋白和Wnt/RhoA通路的激活。暴露于WNT-3a的骨髓瘤细胞发生了显著的形态变化和肌动蛋白细胞骨架的广泛重排。这些形态变化与Wnt/RhoA途径有关，提示细胞运动性可能发生变化。迁移实验表明，WNT-3a可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。迁移与RhoA和PKCα、β和Mu的激活有关。Rho相关的激酶抑制剂可以阻断PKCu的激活和迁移。因此，在Wnt诱导的迁移过程中，PKC Mu的激活受RhoA的调节。此外，免疫共沉淀研究表明，RhoA和PKCµ、PKCs和上游元件Dishevelleds之间存在关联，表明存在调节Wnt信号的大分子信号复合体。这些结果表明，WNTS还可能作为迁移/侵袭促进因子发挥作用，从而在疾病进展过程中对骨髓瘤细胞的运动起重要作用。 这个项目的前身是公元前05553-28年的Z01

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. This project was formerly Z01 BC 05553-28 LG