Biology of plasma cell tumor development

浆细胞肿瘤发生的生物学

• 批准号: 6944688
• 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/6944688
• 关键词: biological signal transduction; bone marrow; cell growth regulation; cell line; cell migration; cell proliferation; chemotaxis; cytokine receptors; enzyme activity; enzyme inhibitors; guanine nucleotide binding protein; insulinlike growth factor; kinase inhibitor; mitogen activated protein kinase; molecular oncology; multiple myeloma; neoplasm /cancer invasiveness; neoplastic growth; oncogenes; phosphatidylinositol 3 kinase; plasma cell neoplasm; protein kinase; protein kinase C; protooncogene; transcription factor

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.

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。 我们之前已经在体外和体内证明了IGF-I信号通路在骨髓瘤中的作用。该通路的激活可促进细胞增殖，下调细胞凋亡。许多负责这两种作用的下游元件已经被表征，并且都在很大程度上通过PI-3K/Akt活性来调节。最近的研究已将IGF-I的分析扩展到移徙现象。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它们所在的骨髓，并迁移到次要的骨髓部位。在疾病的晚期，这些细胞再次穿过血管，并可能种植多个其他器官。目前使用移行试验的实验表明，IGF-I通过血管内皮细胞或骨髓基质细胞系促进骨髓瘤细胞的迁移和侵袭。生化分析表明，IGF-I处理导致RhoA和PKCu的激活，抑制PI-3K阻止了激活，使两个靶点都位于PI-3K的下游。有趣的是，抑制Akt并不影响两者的激活，这表明所观察到的激活与PI-3K通路调节增殖和凋亡的分支无关。浆细胞的迁移可以通过抑制PKCs或RhoA来消除，这表明在这一过程中两者都是必需的。这些发现表明，除了先前描述的增殖和抗凋亡作用外，IGF-I还作为一种趋化因子在骨髓瘤的发展中发挥作用。 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。通过移行试验证明，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的迁移/侵袭，如上所述对于IGF-I。迁移与RhoA和PKC Mu的激活有关。与IGF-I介导的迁移相反，PI-3K抑制剂不能阻断这一作用，而Rho相关激酶抑制剂既能阻止PKC u的激活，又能阻止PKC u的迁移。因此，在Wnt诱导的迁移过程中，PKC Mu的激活受RhoA的调节。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。