A rate-limiting step for circulating tumor cells to colonize distant organ sites is their ability to locate a microenvironmental niche that supports their survival and growth. This can be achieved by features intrinsic to the tumor cells and/or by the conditioning of a “premetastatic” niche. To determine if pulmonary inflammation promotes the latter, we initiated models for inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced sterile inflammation before introducing tumor cells with low metastatic potential into the circulation. All types of inflammation increased the end-stage metastatic burden of the lungs 14 days after tumor cell inoculation without overtly affecting tumor extravasation. Instead, the number and size of early micrometastatic lesions found within the interstitial tissues 96 hours after tumor cell inoculation were increased in the inflamed lungs, coincident with increased tumor cell survival and the presence of nearby inflammation-induced monocyte-derived macrophages (MoDM; CD11b+CD11c+). Remarkably, the adoptive transfer of these MoDM was sufficient to increase lung metastasis in the absence of inflammation. These inflammation-induced MoDM secrete a number of growth factors and cytokines, one of which is hepatocyte growth factor (HGF), that augmented tumor cell survival under conditions of stress in vitro . Importantly, blocking HGF signaling with the cMET inhibitor capmatinib abolished inflammation-induced early micrometastatic lesion formation in vivo . These findings indicate that inflammation-induced MoDM and HGF in particular increase the efficiency of early metastatic colonization in the lung by locally preconditioning the microenvironment. Implications: Inflammation preconditions the distant site microenvironment to increase the metastatic potential of tumor cells that arrive there. This article is featured in Highlights of This Issue, [p. 1971][1] [1]: /lookup/volpage/19/1971?iss=12

中文翻译：

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分泌肝细胞生长因子的单核细胞衍生巨噬细胞促进炎症诱导的肺转移定植

循环肿瘤细胞定植远处器官部位的限速步骤是它们定位支持其生存和生长的微环境生态位的能力。这可以通过肿瘤细胞固有的特征和/或通过“转移前”生态位的调节来实现。为了确定肺部炎症是否促进后者，我们在将具有低转移潜能的肿瘤细胞引入循环之前启动了炎症性哮喘、过敏性肺炎或博来霉素诱导的无菌炎症模型。在肿瘤细胞接种后 14 天，所有类型的炎症都会增加肺的终末期转移负担，而不会明显影响肿瘤外渗。反而，肿瘤细胞接种后 96 小时在间质组织中发现的早期微转移病变的数量和大小在发炎的肺中增加，这与肿瘤细胞存活率增加和附近存在炎症诱导的单核细胞衍生巨噬细胞 (MoDM；CD11b+CD11c+) 相吻合）。值得注意的是，这些 MoDM 的过继转移足以在没有炎症的情况下增加肺转移。这些炎症诱导的 MoDM 分泌许多生长因子和细胞因子，其中一种是肝细胞生长因子 (HGF)，它们在体外应激条件下增强了肿瘤细胞的存活率。重要的是，用 cMET 抑制剂卡马替尼阻断 HGF 信号传导消除了炎症诱导的体内早期微转移病变形成。这些发现表明，炎症诱导的 MoDM 和 HGF 特别是通过局部预处理微环境来提高肺部早期转移定植的效率。启示：炎症为远端微环境提供了先决条件，以增加到达那里的肿瘤细胞的转移潜力。这篇文章被收录在本期的亮点中，[p. 1971][1][1]：/lookup/volpage/19/1971?iss=12