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。参与这些肿瘤发展的生化损伤一直很难确定特征，与这种疾病最常见的生物学联系是白介素6的明显关键作用。我们之前已经证明了胰岛素样生长因子受体I(IGF-IR)信号通路在小鼠浆细胞肿瘤发生中的作用。我们现在已经将这些研究扩展到人类骨髓瘤，并表征了通过这种受体传递信号的生化成分和生物学效应。研究发现，IGF-IR在几乎所有的骨髓瘤细胞系中都高度表达。IGF-I刺激骨髓瘤细胞系可激活两个细胞信号级联反应。第一种途径导致丝裂原活化蛋白激酶的激活，随后导致细胞增殖，第二种途径是Akt激酶的激活，导致抑制正常诱导细胞死亡的过程。这两条通路的联合作用表明，IGF-I信号可能在骨髓瘤细胞的存活中发挥重要作用。这种可能性在体内进行了测试，结果表明，与未治疗的对照组相比，接受IGF-I治疗的SCID小鼠的骨髓瘤细胞株生长明显更快。与这一途径的重要性相关的其他研究发现，肿瘤抑制基因PTEN中有2/8的线路存在缺陷，该基因参与调节IGF信号的凋亡臂。在一个品系中突变该基因可显著抑制细胞死亡，并重新引入正常的PTEN基因，不仅恢复了正常的功能，而且阻止了体内肿瘤的生长。为了确定导致多发性骨髓瘤发生或发展的病变，我们已经启动了表达克隆研究，以确定候选基因。从骨髓瘤细胞系构建了表达cDNA文库，并初步将其导入NIH3T3细胞。转化的菌落已经被分离出来，拯救的基因目前正在分析中。其中第一个被鉴定的基因是细胞RAS基因，它在117位包含一个不常见的突变。来自这些文库的其他基因正在研究中。这些文库还被引入依赖于IL-6的B9细胞和依赖于IL-3的32D细胞中，以试图识别将消除对这些细胞因子的需求的表达基因。目前正在建立从早期诊断的骨髓瘤患者那里获取材料的方案，以便构建类似的表达文库并寻找原发疾病中的生化损害。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. 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. We have previously demonstrated a role for the Insulin-like growth factor receptor I (IGF-IR) signaling pathway in murine plasma cell tumor development. We have now extended these studies to human myeloma and characterized the biochemical elements and biological effects of signaling through this receptor. IGF-IR was found to be highly expressed in virtually all myeloma lines. Stimulation of myeloma lines with IGF-I lead to activation of two cellular signaling cascades. The first of these resulted in activation of mitogen activated protein kinases followed by cellular proliferation, and the second the activation of Akt kinase leading to inhibition of processes normally inducing cell death. The combined effects of stimulation of these two pathways suggest that IGF-I signaling may play a significant role in survival of myeloma cells. This possibility was tested in vivo where it was demonstrated that myeloma lines grew significantly faster in SCID mice treated with IGF-I as compared to untreated controls. Additional studies relating to the importance of this pathway revealed defects in 2/8 lines in the tumor suppressor gene PTEN which participates in regulation of the apoptotic arm of IGF signaling. Mutation of this gene in one line lead to marked inhibition of cell death and re-introduction of a normal PTEN gene not only restored normal function, but prevented tumor growth in vivo . In an attempt to identify lesions contributing to either initiation or progression of multiple myeloma, we have initiated expression cloning studies to identify candidate genes. Expression cDNA libraries have been constructed from myeloma lines and transfected initially into NIH 3T3 cells. Transformed colonies have been isolated and rescued genes are currently being analyzed. The first of these to be characterized is a cellular Ras gene which contains an uncommon mutation at position 117. Additional genes from these libraries are under study. The libraries are also being introduced into IL-6 dependent B9 cells and IL-3 dependent 32D cells in an attempt to identify expressed genes which will abrogate the requirement for these cytokines. Protocols are currently being established to obtain materials from early diagnosis myeloma patients in order to construct similar expression libraries and search for biochemical lesions in primary disease. This project was formerly Z01 BC 05553-28 LG