CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway

被引:25
作者
Wu, Dan [1 ]
Guo, Xinyi [2 ]
Su, Jing [1 ]
Chen, Ruoying [1 ]
Berenzon, Dmitriy [3 ]
Guthold, Martin [2 ]
Bonin, Keith [2 ]
Zhao, Weiling [1 ]
Zhou, Xiaobo [1 ]
机构
[1] Wake Forest Sch Med, Dept Radiol, Winston Salem, NC 27157 USA
[2] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA
[3] Wake Forest Sch Med, Winston Salem, NC 27157 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2015年 / 1853卷 / 02期
基金
美国国家科学基金会;
关键词
Multiple myeloma; Bone marrow stromal cell; Stiffness; CD138-negative; SDF-1/CXCR4; AKT; FOCAL ADHESION KINASE; MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; DRUG-RESISTANCE; STEM-CELLS; CELLULAR TENSION; PLASMA-CELLS; TUMOR-CELLS; B-CELLS;
D O I
10.1016/j.bbamcr.2014.11.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains incurable and relapses due to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that target molecular mechanisms responsible for drug resistance are attractive. Interactions of tumor cells with their surrounding microenvironment impact tumor initiation, progression and metastasis, as well as patient prognosis. This cross-talk is bidirectional. Tumor cells can also attract or activate tumor-associated stromal cells by releasing cytokines to facilitate their growth, invasion and metastasis. The effect of myeloma cells on bone marrow stromal cells (BMSCs) has not been well studied. In our study, we found that higher stiffness of BMSCs was not a unique characteristic of BMSCs from MM patients (M-BMSCs). BMSCs from MGUS (monoclonal gammopathy of undetermined significance) patients were also stiffer than the BMSCs from healthy volunteers (N-BMSCs). The stiffness of M-BMSCs was enhanced when cocultured with myeloma cells. In contrast, no changes were seen in myeloma cell-primed MGUS- and N-BMSCs. Interestingly, our data indicated that CD138(-) myeloma cells, but not CD138(+) cells, regulated M-BMSC stiffness. SDF-1 was highly expressed in the CD138(-) myeloma subpopulation compared with that in CD138(-) cells. Inhibition of SDF-1 using AMD3100 or knocking-down CXCR4 in M-BMSCs blocked CD138(-) myeloma cells-induced increase in M-BMSC stiffness, suggesting a crucial role of SDF-1/CXCR4. AKT inhibition attenuated SDF-1-induced increases in M-BMSC stiffness. These findings demonstrate, for the first time, CD138(-) myeloma cell-directed cross-talk with BMSCs and reveal that CD138(-) myeloma cells regulate M-BMSC stiffness through SDF-1/CXCR4/AKT signaling. (C) 2014 Elsevier B.V. All rights reserved.
引用
收藏
页码:338 / 347
页数:10
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