Fibroblast Growth Factor-2 facilitates the growth and chemo-resistance of leukemia cells in the bone marrow by modulating osteoblast functions.
Fibroblast Growth Factor-2 facilitates the growth and chemo-resistance of leukemia cells in the bone marrow by modulating osteoblast functions.
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DOI：
10.1038/srep30779
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发表时间：
2016-08-02
影响因子：
4.6
通讯作者：
Naoe T
中科院分区：
文献类型：
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作者：
Sugimoto K;Miyata Y;Nakayama T;Saito S;Suzuki R;Hayakawa F;Nishiwaki S;Mizuno H;Takeshita K;Kato H;Ueda R;Takami A;Naoe T
基质细胞和成骨细胞在形成和调节骨髓（BM）造血微环境中发挥着重要作用。我们已经报道 FGF2 损害正常造血的基质细胞支持。在这里，我们检查了 FGF2 对白血病微环境的影响。在体外，FGF2 显着减少基质层中基质依赖性和基质非依赖性 G0 白血病细胞的数量。因此，放置在 FGF2 处理的基质层上的 CML 细胞对伊马替尼更敏感。相反，FGF2 通过 FGFR1 IIIc 增加成骨细胞的增殖，但其对成骨细胞支持白血病细胞生长的作用有限。接下来，我们用 Ara-C 治疗人类白血病小鼠模型，并给予/不给予全身性 FGF2。与对照组相比，FGF2 治疗小鼠的骨髓切片骨小梁增厚，白血病细胞数量增加。与仅用Ara-C处理的小鼠相比，FGF2/Ara-C处理的小鼠的白血病细胞密度增加，尤其是在骨内膜区域。有趣的是，FGF2 并不促进 Ara-C 处理的脾脏中白血病细胞的存活。微阵列分析表明，FGF2 不会改变成骨细胞中与造血相关的许多基因的表达，但会调节参与血管生成和成骨细胞分化的调节网络。这些观察结果表明，FGF2 通过调节成骨细胞功能促进骨髓中白血病细胞的生长。
Stromal cells and osteoblasts play major roles in forming and modulating the bone marrow (BM) hematopoietic microenvironment. We have reported that FGF2 compromises stromal cell support of normal hematopoiesis. Here, we examined the effects of FGF2 on the leukemia microenvironment. In vitro, FGF2 significantly decreased the number of stromal-dependent and stromal-independent G0-leukemia cells in the stromal layers. Accordingly, CML cells placed on FGF2-treated stromal layers were more sensitive to imatinib. Conversely, FGF2 increased the proliferation of osteoblasts via FGFR1 IIIc, but its effects on osteoblast support of leukemia cell growth were limited. We next treated a human leukemia mouse model with Ara-C with/without systemic FGF2 administration. BM sections from FGF2-treated mice had thickened bone trabeculae and increased numbers of leukemia cells compared to controls. Leukemia cell density was increased, especially in the endosteal region in FGF2/Ara-C -treated mice compared to mice treated with Ara-C only. Interestingly, FGF2 did not promote leukemia cell survival in Ara-C treated spleen. Microarray analysis showed that FGF2 did not alter expression of many genes linked to hematopoiesis in osteoblasts, but modulated regulatory networks involved in angiogenesis and osteoblastic differentiation. These observations suggest that FGF2 promotes leukemia cell growth in the BM by modulating osteoblast functions.