Biology of plasma cell tumor development

浆细胞肿瘤发生的生物学

• 批准号: 7038567
• 负责人: STUART RUDIKOFF
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7038567
• 关键词: biological signal transduction; bone marrow; cell growth regulation; cell line; cell migration; cell proliferation; chemoattractants; gene expression; guanine nucleotide binding protein; immunoprecipitation; insulinlike growth factor; interleukin 6; kinase inhibitor; molecular oncology; multiple myeloma; neoplastic transformation; oncoproteins; plasma cell neoplasm; protein kinase C; protein structure function; tissue /cell culture

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.

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。骨髓瘤的标志之一是在整个骨髓中扩散，但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系的迁移/侵袭。迁移与RhoA和PKC α、β和μ的活化相关。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。此外，免疫共沉淀研究揭示了RhoA和PKC μ和PKC与称为Dishevelleds的上游元件之间的关联，表明调节Wnt信号传导的大分子信号传导复合物。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。