Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism.
Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism.
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DOI：
10.1371/journal.pone.0027690
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Abrams SI
中科院分区：
文献类型：
--
作者：
Waight JD;Hu Q;Miller A;Liu S;Abrams SI
髓源性抑制细胞（MDSC）在不同的病理条件下诱导，包括肿瘤，并抑制先天性和适应性免疫。虽然MDSC介导免疫抑制的机制已得到很好的表征，但它们如何发展的细节仍不太清楚。由于MDSC包含多种骨髓细胞类型，即单核细胞和粒细胞，反映了不同的分化阶段，并且这些亚群的比例在不同的肿瘤模型中变化，这进一步复杂化。因此，认为肿瘤形成过程中产生的炎症介质的类型和数量决定了最终MDSC反应的组成。尽管人们对单核细胞MDSC的生物学研究很感兴趣，但我们对粒细胞MDSC的起源的理解仍然存在根本性的差距。在粒细胞MDSC反应增强的情况下，我们假设G-CSF的不适当产生是粒细胞MDSC蓄积的关键起始物。我们在体内观察到大量的G-CSF，其与多种肿瘤模型中的稳健粒细胞MDSC应答相关。使用G-CSF功能丧失和获得的方法，我们首次证明：1）废除G-CSF产生显著减少粒细胞MDSC积累和肿瘤生长; 2）在G-CSF阴性肿瘤中异位过表达G-CSF显著增加粒细胞MDSC积累和肿瘤生长; 3）用重组G-CSF蛋白处理未处理的健康小鼠，诱导出与荷瘤条件下诱导的粒细胞样MDSC非常相似的粒细胞样MDSC。总的来说，我们证明了肿瘤来源的G-CSF通过粒细胞MDSC依赖性机制增强肿瘤生长。这些发现为我们提供了新的见解MDSC亚群的发展和潜在的新的生物标志物或癌症治疗的目标。
Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
4.4
作者：
Okazaki, T;Ebihara, S;Yamaya, M
通讯作者：
Yamaya, M
癌症扩增的骨髓源性抑制细胞通过膜结合 TGF-β1 诱导 NK 细胞无反应。
影响因子：
4.4
作者：
Li, Hequan;Han, Yanmei;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
2.1
作者：
Chakraborty, Arup;Guha, Sushovan
通讯作者：
Guha, Sushovan