Origins of tumor-associated macrophages and neutrophils
Origins of tumor-associated macrophages and neutrophils
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DOI：
10.1073/pnas.1113744109
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发表时间：
2012-02-14
影响因子：
11.1
通讯作者：
Pittet, Mikael J.
中科院分区：
文献类型：
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作者：
Cortez-Retamozo, Virna;Etzrodt, Martin;Pittet, Mikael J.
肿瘤相关巨噬细胞（TAM）和肿瘤相关中性粒细胞（TAN）可以控制癌症的生长，并存在于几乎所有的实体肿瘤中。已知这些细胞分别起源于骨髓中产生的未成熟单核细胞和粒细胞。然而，脾脏也是最近发现的单核细胞的储存库，其可以在急性损伤后的炎症反应中发挥重要作用。在这里，我们评估了脾水库的作用，在基因小鼠肺腺癌模型驱动的致癌Kras激活和失活的p53。我们发现，大量的TAM和TAN前体从脾脏物理迁移到肿瘤基质，并且肿瘤促进脾脏来源的TAM的募集需要趋化因子受体CCR 2的信号传导。此外，在肿瘤发生之前或之后切除脾脏，显著降低TAM和TAN反应，并延迟肿瘤生长。脾脏能够在肿瘤进展过程中维持其储库能力的机制部分涉及典型罕见的髓外造血干细胞和祖细胞（特别是粒细胞和巨噬细胞祖细胞）在脾脏红髓中的局部蓄积，这些祖细胞局部产生CD 11b（+）Ly-6C（hi）单核细胞和CD 11b（+）Ly-6 G（hi）粒细胞。脾粒细胞和巨噬细胞祖细胞及其后代也在临床标本中鉴定。本研究揭示了TAM和TAN的起源，并将脾脏定位为重要的髓外部位，可以持续向生长中的肿瘤提供这些细胞。
Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b(+) Ly-6C(hi) monocytic and CD11b(+) Ly-6G(hi) granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells.