Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
Leukemia. 2013 Jul;27(7):1558-66. doi: 10.1038/leu.2013.27. Epub 2013 Jan 28.
Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF-1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch-targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels.
多发性骨髓瘤（MM）是一种致命的造血恶性肿瘤，其特征是骨髓（BM）中恶性浆细胞的增殖和骨病。骨髓瘤和 BM 细胞之间的相互作用促进了肿瘤的进展和对治疗的耐药性。趋化因子受体 4（CXCR4）及其配体基质细胞衍生因子-1（SDF-1）在这个过程中起主要作用，并与预后不良相关。Notch 通路在骨髓瘤细胞中活跃，导致增殖增加、抗凋亡和溶骨性活性增强。我们假设 CXCR4/SDF-1 轴介导 Notch 信号在骨髓瘤细胞中的作用。在这里，我们表明 Notch 正向调控骨髓瘤细胞系中 CXCR4/SDF-1 的表达和功能，并且强制 CXCR4 激活部分挽救了肿瘤细胞免受 Notch 抑制的影响。此外，我们提供的证据表明，体内 Notch 阻断显著减少了小鼠异种移植中人类骨髓瘤细胞对 BM 的浸润。这是第一个证据表明，通过降低 CXCR4 和 SDF-1 水平，针对 Notch 的方法可有效防止 MM 细胞迁移、增殖和抗凋亡。
