Gan Zhi-Hua, Chen Yu
Department of Hematology, Ruijing Hospital, Shanghai Jiaotong University Medical College, Shanghai 200025, China.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Oct;17(5):1380-3.
Notch signaling pathway is a main pathway through cell-cell interactions, which regulates the programmed cell death, cellular proliferation and differentiation in multiple cell systems, and also is an important signaling pathway to modulate the balance between proliferation and differentiation in hematopoietic environment, and is related with the incidence of multiple hematologic malignancies. Multiple myeloma (MM) is malignant in B cell lineage and characterized by clonal proliferative plasma cells. It is very difficult to cure MM patients with a low proliferation rate of the MM cell and drug resistance to the standard dosage of chemotherapy. In recent years, research has shown that in the malignant plasma cells of the patients with multiple myeloma (MM) and the cell lines, but not in normal plasma cells or tumor cells from patients with other malignancies, the Notch ligand Jagged2 was found to be overexpressed. Jagged2 can induce stromal cells to secrete IL-6, VEGF and IGF-1. Notch activation can interact with NF-kappaB and C-myc to promote the proliferation and to inhibit the apoptosis of MM cells, showing in the relationship between the incidence of myeloma and drug resistance. Inhibition of the Notch signaling pathway may induce the apoptosis of MM cells and enhance the effect of chemotherapy. Study indicated that the specific inhibition of Notch signaling by treatment with a gamma-secretase inhibitor (GSI) alone, a specific pharmacologic inhibitor of Notch signaling, induces the apoptosis of myeloma cells and improves sensitivity of myeloma cell to chemotherapy when combined. In this article the composition of Notch signalling pathway, the mechanism of Notch signalling pathway and the relation of Notch signalling pathway to multiple myeloma were reviewed.
Notch信号通路是一种主要的细胞间相互作用通路,它在多个细胞系统中调节程序性细胞死亡、细胞增殖和分化,也是调节造血环境中增殖与分化平衡的重要信号通路,与多种血液系统恶性肿瘤的发生相关。多发性骨髓瘤(MM)是B细胞系恶性肿瘤,其特征为克隆性增殖的浆细胞。MM细胞增殖率低且对标准剂量化疗耐药,使得治愈MM患者非常困难。近年来的研究表明,在多发性骨髓瘤(MM)患者的恶性浆细胞及细胞系中,而非正常浆细胞或其他恶性肿瘤患者的肿瘤细胞中,发现Notch配体Jagged2过表达。Jagged2可诱导基质细胞分泌IL-6、VEGF和IGF-1。Notch激活可与NF-κB和C-myc相互作用,促进MM细胞增殖并抑制其凋亡,这体现了骨髓瘤发病率与耐药性之间的关系。抑制Notch信号通路可能诱导MM细胞凋亡并增强化疗效果。研究表明,单独使用γ-分泌酶抑制剂(GSI)(一种Notch信号通路的特异性药理学抑制剂)特异性抑制Notch信号,可诱导骨髓瘤细胞凋亡,并在联合使用时提高骨髓瘤细胞对化疗的敏感性。本文对Notch信号通路的组成、Notch信号通路的机制以及Notch信号通路与多发性骨髓瘤的关系进行了综述。