Notch信号通路和多发性骨髓瘤

Notch信号通路是介导细胞和细胞之间直接接触的主要信号通路之一，调控了多细胞机体的细胞凋亡、增殖和分化，是造血微环境调节造血细胞增殖与分化的重要信号通路，与多种血液系统恶性肿瘤的发病有关。多发性骨髓瘤（multiple myeloma，MM）是以浆细胞克隆性增殖为特征的B系肿瘤。由于骨髓瘤细胞的增殖比例低及多药耐药的形成，因此其对常规剂量的化疗药耐药，使得MM的临床治疗仍十分困难。近年来的研究发现，多发性骨髓瘤病人肿瘤细胞和骨髓瘤细胞株都大量表达Notch的配体Jagged-2，而正常的浆细胞或是其它恶性疾病来源的病人肿瘤细胞低量表达Jagged-2。Jagged-2可诱导基质细胞分泌白介素6（IL-6）、血管内皮生长因子（vascular endothelial growth factor，VEGF）、胰岛素样生长因子－1（Insulin—like growth factor 1，IGF－1）。Notch信号通路激活后可通过与NF－κB，C—myc的相互作用，调节细胞的增殖，促进骨髓瘤细胞的生长，从而抑制骨髓瘤细胞的凋亡，它与骨髓瘤的发生和耐药有关。抑制Notch信号通路能诱导骨髓瘤细胞的凋亡，增强化疗药的细胞毒作用。研究表明，单独使用Notch信号通路的特异性化学抑制剂γ－分泌酶抑制剂（γ－secrctase inhibitors，GSI）可通过特异性阻滞Notch信号通路从而诱导骨髓瘤细胞的凋亡，并且与传统化疗药物联合应用可以增强骨髓瘤细胞对化疗药的敏感性。本文就Notch信号通路的组成、Notch信号通路的作用机制及Notch信号通路与多发性骨髓瘤的关系进行综述．

Notch Signaling Pathway and Multiple Myeloma

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 prolifererative plasma cells. It is very difficult to cure MM patients with a low proliferation rate of the MM cell and drug resistence 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-κB 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 γ-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.