Iowa City VA Medical Center and the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
PLoS One. 2013 Jun 11;8(6):e65599. doi: 10.1371/journal.pone.0065599. Print 2013.
Tumor metastasis plays a major role in the morbidity and mortality of cancer patients. Among solid tumors that undergo metastasis, there is often a predilection to metastasize to a particular organ with, for example, prostate cancer preferentially metastasizing to bones and colon cancer preferentially metastasizing to the liver. Although many factors are thought to be important in establishing permissiveness for metastasis, the reasons for organ-specific predilection of each tumor are not understood. Using a B16 murine melanoma model, we tested the hypothesis that organ-specific NK cell subsets play a critical role in organ-specific metastasis of this tumor. Melanoma cells, given intravenously, readily colonized the lungs but not the liver. NK cell depletion (either iatrogenically or by using genetically targeted mice) resulted in substantial hepatic metastasis. Analysis of NK cell subsets, defined by the differential expression of a combination of CD27 and CD11b, indicated a significant difference in the distribution of NK cell subsets in the lung and liver with the mature subset being dominant in the lung and the immature subset being dominant in the liver. Several experimental approaches, including adoptive transfer, clearly indicated that the immature hepatic NK cell subset, CD27+ CD11b-, was protective against liver metastasis; this subset mediated its protection by a perforin-dependent cytotoxic mechanism. In contrast, the more mature NK cell subsets were more efficient at reducing pulmonary tumor load. These data indicate that organ-specific immune responses may play a pivotal role in determining the permissiveness of a given organ for the establishment of a metastatic niche.
肿瘤转移在癌症患者的发病率和死亡率中起着重要作用。在发生转移的实体瘤中，往往有一种向特定器官转移的倾向，例如前列腺癌优先转移到骨骼，而结肠癌优先转移到肝脏。尽管许多因素被认为对转移的许可很重要，但每个肿瘤的器官特异性倾向的原因尚不清楚。我们使用 B16 小鼠黑色素瘤模型检验了以下假说：器官特异性 NK 细胞亚群在该肿瘤的器官特异性转移中起关键作用。静脉内给予的黑色素瘤细胞很容易在肺部定植，但不会在肝脏定植。NK 细胞耗竭（通过药物或使用基因靶向小鼠）导致肝转移显著增加。通过对 NK 细胞亚群的分析，根据 CD27 和 CD11b 的不同表达定义，发现在肺和肝中 NK 细胞亚群的分布存在显著差异，成熟亚群在肺中占优势，而不成熟亚群在肝中占优势。几种实验方法，包括过继转移，清楚地表明，不成熟的肝 NK 细胞亚群 CD27+CD11b-对肝转移具有保护作用；该亚群通过依赖穿孔素的细胞毒性机制发挥其保护作用。相比之下，更成熟的 NK 细胞亚群在减少肺部肿瘤负荷方面更有效。这些数据表明，器官特异性免疫反应可能在决定特定器官对建立转移灶的许可性方面起着关键作用。
