Biology of plasma cell tumor development

浆细胞肿瘤发生的生物学

• 批准号: 6761559
• 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/6761559
• 关键词: biological signal transduction; cell growth regulation; cell proliferation; cytokine receptors; enzyme activity; enzyme inhibitors; insulinlike growth factor; interleukin 2; interleukin 6; laboratory mouse; mitogen activated protein kinase; molecular oncology; multiple myeloma; neoplastic process; oncogenes; phosphatidylinositol 3 kinase; plasma cell neoplasm; transcription factor

Plasma cell tumors in humans most commonly occur as multiple myeloma, an incurable form of cancer. Biochemical lesions involved in the development of these tumors have been difficult to characterize and the most common biological association with this disease is an apparent critical role of Interleukin-6. Although IL-6 is one growth factor of importance in myeloma development, we have previously demonstrated a role for the Insulin-like growth factor receptor I (IGF-IR) signaling pathway in myeloma both in vitro and in vivo. Recent studies have focused on biochemical characterization of this signaling pathway. Stimulation with IGF-I ligand leads to activation of two cellular signaling cascades, the mitogen activated protein kinase (MAPK) and PI-3K pathways. Analysis of downstream elements in the PI-3K pathway revealed activation of Akt kinase leading to inhibition of processes causing normal cell death. Akt additionally activates GSK-3 beta and p70S6 kinase. A series of metabolic inhibitors have been used to determine the roles of these various element in tumor cell proliferation and in crosstalk with other pathways. Inhibition of the MAPK pathway results in an approximate 20% decrease in proliferation whereas inhibition of the PI-3K pathway causes an 80% reduction in proliferation. Interestingly, inhibition of PI-3K also effects the MAPK pathway indicating crosstalk between these two cascades but only in one direction as inhibition of MAPK activity does not effect PI-3K. Inhibition of p70S6 kinase decreases proliferation ~ 40% and activation of this kinase is blocked by both MAPK and PI-3K inhibitors. These results indicate extensive cross talk between these two pathways and the mechanisms regulating such interactions are currently under investigation. 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 initiated studies to assess the potential role of Wnts in myeloma. Myeloma cells have been found to express mRNA encoding multiple Wnt receptors (Frizzled proteins) as well as the co-receptors, LDL receptor related proteins (LRP) 5 and 6. In contrast, B cell lymphomas representing an earlier stage in B cell differentiation demonstrate limited expression of Fz mRNA and do not express either of the LRP co-receptors. Exposure of myeloma cells to Wnt proteins results in activation of a classical Wnt/beta catenin pathway and transcriptional activation. Additionally, striking morphological changes are observed in myeloma cells concurrent with extensive rearrangement of the actin cytoskeleton. These morphological changes were found to be associated with activation of a second intracellular pathway involving the nucleotide exchange factor Rho and Rho-associated kinase. Current studies are in progress to further biochemically characterize Wnt signaling in myeloma and to determine the biological consequences linked to activation of Wnt associated signaling cascades. This project was formerly Z01 BC 05553-28 LG

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。参与这些肿瘤发展的生化病变难以表征，与这种疾病最常见的生物学相关性是白细胞介素-6的明显关键作用。 虽然IL-6是骨髓瘤发展中的一种重要生长因子，但我们先前已经证明了胰岛素样生长因子受体I（IGF-IR）信号通路在骨髓瘤中的作用，无论是在体外还是在体内。最近的研究集中在这个信号通路的生化表征。用IGF-I配体刺激导致两个细胞信号级联的激活，即促分裂原活化蛋白激酶（MAPK）和PI-3 K途径。PI-3 K通路中下游元件的分析揭示Akt激酶的活化导致导致导致正常细胞死亡的过程的抑制。Akt还激活GSK-3 β和p70 S6激酶。一系列代谢抑制剂已被用于确定这些不同的元素在肿瘤细胞增殖中的作用以及与其他途径的串扰。MAPK途径的抑制导致增殖减少约20%，而PI-3 K途径的抑制导致增殖减少80%。有趣的是，PI-3 K的抑制也影响MAPK途径，表明这两个级联之间的串扰，但仅在一个方向上，因为MAPK活性的抑制不影响PI-3 K。抑制p70 S6激酶使增殖降低约40%，并且该激酶的活化被MAPK和PI-3 K抑制剂阻断。这些结果表明，这两种途径之间存在广泛的串扰，目前正在研究调节这种相互作用的机制。 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。我们最近启动了研究，以评估Wnt在骨髓瘤中的潜在作用。已发现骨髓瘤细胞表达编码多种Wnt受体（卷曲蛋白）以及共受体LDL受体相关蛋白（LRP）5和6的mRNA。相反，代表B细胞分化早期阶段的B细胞淋巴瘤显示Fz mRNA的有限表达，并且不表达任何一种LRP共受体。骨髓瘤细胞暴露于Wnt蛋白导致经典Wnt/β连环蛋白途径的激活和转录激活。此外，在骨髓瘤细胞中观察到显著的形态学变化，同时伴有肌动蛋白细胞骨架的广泛重排。发现这些形态学变化与涉及核苷酸交换因子Rho和Rho相关激酶的第二细胞内途径的激活相关。目前的研究正在进行中，以进一步生物化学表征骨髓瘤中的Wnt信号传导，并确定与Wnt相关信号级联激活相关的生物学后果。 本项目前身为Z 01 BC 05553-28 LG