Department of Radiology, The Laboratory for Minimally Invasive Tumor Therapies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, United States of America.
Department of Radiology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
PLoS One. 2022 Jul 20;17(7):e0266522. doi: 10.1371/journal.pone.0266522. eCollection 2022.
Radiofrequency ablation (RFA) of intrahepatic tumors induces distant tumor growth through activation of interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-MET) pathway. Yet, the predominant cellular source still needs to be identified as specific roles of the many types of periablational infiltrating immune cells requires further clarification. Here we report the key role of activated myofibroblasts in RFA-induced tumorigenesis and successful pharmacologic blockade. Murine models simulating RF tumorigenic effects on a macrometastatic tumor and intrahepatic micrometastatic deposits after liver ablation and a macrometastatic tumor after kidney ablation were used. Immune assays of ablated normal parenchyma demonstrated significantly increased numbers of activated myofibroblasts in the periablational rim, as well as increased HGF levels, recruitment other cellular infiltrates; macrophages, dendritic cells and natural killer cells, HGF dependent growth factors; fibroblast growth factor-19 (FGF-19) and receptor of Vascular Endothelial Growth Factor-1 (VEGFR-1), and proliferative indices; Ki-67 and CD34 for microvascular density. Furthermore, macrometastatic models demonstrated accelerated distant tumor growth at 7d post-RFA while micrometastatic models demonstrated increased intrahepatic deposit size and number at 14 and 21 days post-RFA. Multi-day atorvastatin, a selective fibroblast inhibitor, inhibited RFA-induced HGF and downstream growth factors, cellular markers and proliferative indices. Specifically, atorvastatin treatment reduced cellular and proliferative indices to baseline levels in the micrometastatic models, however only partially in macrometastatic models. Furthermore, adjuvant atorvastatin completely inhibited accelerated growth of macrometastasis and negated increased micrometastatic intrahepatic burden. Thus, activated myofibroblasts drive RF-induced tumorigenesis at a cellular level via induction of the HGF/c-MET/STAT3 axis, and can be successfully pharmacologically suppressed.
射频消融（RFA）治疗肝内肿瘤可通过激活白细胞介素 6/信号转导和转录激活因子 3（STAT3）/肝细胞生长因子（HGF）/酪氨酸蛋白激酶 Met（c-MET）通路诱导远处肿瘤生长。然而，仍需要确定主要的细胞来源，因为许多类型的围消融浸润免疫细胞的特定作用仍需要进一步阐明。在这里，我们报告了活化的肌成纤维细胞在 RFA 诱导的肿瘤发生中的关键作用，并成功地进行了药物阻断。我们使用了模拟 RF 对大转移瘤和肝消融后肝内微转移灶以及肾消融后大转移瘤的肿瘤发生效应的小鼠模型。对消融的正常实质进行免疫检测，结果显示，在消融边缘有大量活化的肌成纤维细胞，以及 HGF 水平增加，募集其他细胞浸润；巨噬细胞、树突状细胞和自然杀伤细胞、HGF 依赖性生长因子；成纤维细胞生长因子 19（FGF-19）和血管内皮生长因子受体 1（VEGFR-1），以及增殖指数；Ki-67 和 CD34 用于微血管密度。此外，大转移模型在 RFA 后 7 天表现出远处肿瘤生长加速，而微转移模型在 RFA 后 14 和 21 天表现出肝内转移灶大小和数量增加。多日阿托伐他汀是一种选择性的成纤维细胞抑制剂，可抑制 RFA 诱导的 HGF 和下游生长因子、细胞标志物和增殖指数。具体来说，阿托伐他汀治疗将微转移模型中的细胞和增殖指数降低到基线水平，但在大转移模型中仅部分降低。此外，辅助阿托伐他汀完全抑制了大转移的加速生长，并消除了肝内微转移负担的增加。因此，活化的肌成纤维细胞通过诱导 HGF/c-MET/STAT3 轴在细胞水平上驱动 RF 诱导的肿瘤发生，并且可以成功地进行药物抑制。
