Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre-metastatic Niche.
Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre-metastatic Niche.
复制标题
造血干/祖细胞的激活促进了替代前生态裂市场内的免疫抑制。
DOI：
10.1158/0008-5472.can-15-0204
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Kaplan RN
中科院分区：
文献类型：
--
作者：
Giles AJ;Reid CM;Evans JD;Murgai M;Vicioso Y;Highfill SL;Kasai M;Vahdat L;Mackall CL;Lyden D;Wexler L;Kaplan RN
转移性肿瘤已被证明在远处组织中建立了允许播散的肿瘤细胞的微环境。造血细胞为这一微环境做出了贡献，然而，建立转移前生态位的确切启动事件仍不清楚。在这里，我们跟踪了荷瘤小鼠的造血干细胞和祖细胞(HSPC)的发育命运。我们发现，远处的原发肿瘤驱使HSPC在骨髓内扩张，并动员到血液中。用肿瘤条件培养液处理体外培养的纯化HSPC，可诱导其增殖并分化为免疫抑制的髓系细胞。我们进一步在体内跟踪纯化的HSPC，发现它们在荷瘤小鼠的早期转移部位分化为髓系抑制细胞(MDSCs)。HSPC动员后转移灶CD11b+Ly6g+细胞数显著增加，抑制肿瘤动员后CD11b+Ly6g+细胞数明显减少。此外，HSPC的药理学动员增加了转移，而Gr1+细胞的枯竭则削弱了HSPC动员促进转移的作用。最后，我们检测到新诊断的癌症患者循环中HSPC水平升高，这与转移进展的风险增加有关。综上所述，我们的结果强调骨髓激活是转移过程的最早步骤之一，并确认循环HSPC是转移生态位形成的潜在临床指标。
Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells contribute to this microenvironment, yet the precise initiating events responsible for establishing the pre-metastatic niche remain unclear. Here, we tracked the developmental fate of hematopoietic stem and progenitor cells (HSPCs) in tumor-bearing mice. We show that a distant primary tumor drives the expansion of HSPCs within the bone marrow and their mobilization to the bloodstream. Treatment of purified HSPCs cultured ex vivo with tumor-conditioned media induced their proliferation as well as their differentiation into immunosuppressive myeloid cells. We furthered tracked purified HSPCs in vivo and found they differentiated into myeloid-derived suppressor cells (MDSCs) in early metastatic sites of tumor-bearing mice. The number of CD11b+Ly6g+ cells in metastatic sites was significantly increased by HSPC mobilization and decreased if tumor-mediated mobilization was inhibited. Moreover, pharmacological mobilization of HSPCs increased metastasis, whereas depletion of Gr1+ cells abrogated the metastasis-promoting effects of HSPC mobilization. Finally, we detected elevated levels of HSPCs in the circulation of newly diagnosed cancer patients, which correlated with increased risk for metastatic progression. Taken together, our results highlight bone marrow activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as potential clinical indicators of metastatic niche formation.