Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 2012 Jan 1;18(1):91-104. doi: 10.1158/1078-0432.CCR-11-0111. Epub 2011 Oct 18.
The ephrin receptors (Eph) are found in a wide range of cancers and correlate with metastasis. In this study, we characterized the role of Eph-B2 receptor in the interaction of Waldenstrom's macroglobulinemia (WM) cells with the bone marrow microenvironment.
We screened the activity of different receptor tyrosine kinases in WM patients and found that Eph-B2 was overexpressed compared with control. Also, we tested the expression of ephrin-B2 ligand on endothelial cells and bone marrow stromal cells (BMSC) isolated from WM patients. We then tested the role of Eph-B2/Ephrin-B2 interaction in the adhesion of WM cells to endothelial cells and BMSCs; the cell signaling induced by the coculture in both the WM cells and the endothelial cells; WM cell proliferation, apoptosis, and cell cycle in vitro and tumor progression in vivo; and in angiogenesis.
Eph-B2 receptor was found to be activated in WM patients compared with control, with a 5-fold increase in CD19(+) WM cells, and activated cell adhesion signaling, including focal adhesion kinase, Src, P130, paxillin, and cofilin, but decreased WM cell chemotaxis. Ephrin-B2 ligand was highly expressed on endothelial cells and BMSCs isolated from WM patients and on human umbilical vein endothelial cells and induced signaling in the endothelial cells promoting adhesion and angiogenesis. Blocking of ephrin-B2 or Eph-B2 inhibited adhesion, cytoskeletal signaling, proliferation, and cell cycle in WM cells, which was induced by coculture with endothelial cells and decreased WM tumor progression in vivo.
Ephrin-B2/Eph-B2 axis regulates adhesion, proliferation, cell cycle, and tumor progression in vivo through the interaction of WM with the cells in the bone marrow microenvironment.
Ephrin 受体（Eph）广泛存在于各种癌症中，与转移相关。本研究旨在探讨 Eph-B2 受体在华氏巨球蛋白血症（WM）细胞与骨髓微环境相互作用中的作用。
我们筛选了 WM 患者中不同受体酪氨酸激酶的活性，发现 Eph-B2 的表达高于对照组。此外，我们还检测了内皮细胞和骨髓基质细胞（BMSC）中 Ephrin-B2 配体的表达情况，这些细胞均来自 WM 患者。随后，我们检测了 Eph-B2/Ephrin-B2 相互作用在 WM 细胞与内皮细胞和 BMSC 黏附中的作用；共培养诱导的 WM 细胞和内皮细胞中的细胞信号；体外 WM 细胞增殖、凋亡和细胞周期以及体内肿瘤进展；以及血管生成。
与对照组相比，WM 患者的 Eph-B2 受体被激活，CD19(+)WM 细胞的表达增加了 5 倍，激活了细胞黏附信号，包括黏着斑激酶、Src、P130、桩蛋白和丝切蛋白，但趋化性降低。Ephrin-B2 配体在 WM 患者分离的内皮细胞和 BMSC 以及人脐静脉内皮细胞上高表达，并在诱导内皮细胞黏附和血管生成的信号。阻断 Ephrin-B2 或 Eph-B2 抑制了共培养诱导的 WM 细胞黏附、细胞骨架信号、增殖和细胞周期，减少了体内 WM 肿瘤的进展。
Ephrin-B2/Eph-B2 轴通过 WM 与骨髓微环境中细胞的相互作用，调节黏附、增殖、细胞周期和体内肿瘤进展。
