Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma.
Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma.
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DOI：
10.18632/oncotarget.4523
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Cai Z
中科院分区：
文献类型：
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作者：
Li Y;Zheng Y;Li T;Wang Q;Qian J;Lu Y;Zhang M;Bi E;Yang M;Reu F;Yi Q;Cai Z
我们以前发现，巨噬细胞（MΦ）浸润骨髓瘤患者的骨髓（BM），并可能在耐药性中发挥作用。本研究分析了骨髓瘤BM表达的趋化因子，这些趋化因子负责将单核细胞募集到肿瘤床。我们发现趋化因子CCL 3、CCL 14和CCL 2在骨髓瘤和BM细胞中高度表达，并且骨髓瘤BM中CCL 14和CCL 3的水平与BM浸润MΦ的百分比正相关。在体外，这些趋化因子负责将人单核细胞化学吸引到肿瘤部位，并在体内负责MΦ浸润到5 TGM 1小鼠模型中的骨髓瘤BM中。令人惊讶的是，我们还发现这些趋化因子在骨髓瘤细胞诱导的体外和在人骨髓瘤异种移植物SCID小鼠模型中刺激MΦ增殖。趋化因子还激活正常MΦ极化和分化为骨髓瘤相关MΦ。Western blot分析显示，这些趋化因子通过激活PI 3 K/Akt和ERK MAPK通路以及c-myc表达促进MΦ的生长和存活信号传导。因此，本研究为MΦ浸润骨髓的机制提供了新的见解，也为提高骨髓瘤化疗疗效提供了潜在的靶点。
We previously showed that macrophages (MΦs) infiltrate the bone marrow (BM) of patients with myeloma and may play a role in drug resistance. This study analyzed chemokines expressed by myeloma BM that are responsible for recruiting monocytes to the tumor bed. We found that chemokines CCL3, CCL14, and CCL2 were highly expressed by myeloma and BM cells, and the levels of CCL14 and CCL3 in myeloma BM positively correlated with the percentage of BM-infiltrating MΦs. In vitro, these chemokines were responsible for chemoattracting human monocytes to tumor sites and in vivo for MΦ infiltration into myeloma-bearing BM in the 5TGM1 mouse model. Surprisingly, we also found that these chemokines stimulated MΦ in vitro proliferation induced by myeloma cells and in vivo in a human myeloma xenograft SCID mouse model. The chemokines also activated normal MΦ polarization and differentiation into myeloma-associated MΦs. Western blot analysis revealed that these chemokines promoted growth and survival signaling in MΦs via activating the PI3K/Akt and ERK MAPK pathways and c-myc expression. Thus, this study provides novel insight into the mechanism of MΦ infiltration of BM and also potential targets for improving the efficacy of chemotherapy in myeloma.