Park Sunmi, Kim Minjun, Zhu Jack, Lee Woo Kyung, Altan-Bonnet Grégoire, Meltzer Paul, Cheng Sheue-Yann
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, Maryland, USA.
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, Maryland, USA.
Am J Cancer Res. 2020 Jun 1;10(6):1857-1870. eCollection 2020.
The incidence of thyroid cancer, the most frequent endocrine neoplasia, is rapidly increasing. Significant progress has recently been made in the identification of genetic lesions in thyroid cancer; however, whether inflammation contributes to thyroid cancer progression remains unknown. Using a mouse model of aggressive follicular thyroid cancer (FTC; mice), we aimed to elucidate a cause-effect relationship at the molecular level. The mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of a single allele of the gene. These two oncogenic signaling pathways synergistically activate PI3K-AKT signaling to drive cancer progression as in human FTC. At the age of 5-7 weeks, thyroids of mice exhibited extensive hyperplasia accompanied by 77.5-fold infiltration of inflammatory monocytes as compared with normal thyroids. Global gene expression profiling identified altered expression of 2387 genes, among which 1353 were upregulated and 1034 were down-regulated. Further analysis identified markedly elevated expression of inflammation mediators and cytokines such as, , and genes and decreased expression of , and genes. These changes elicited the inflammatory responses in the hyperplastic thyroid of mice, reflecting early events in thyroid carcinogenesis. We next tested whether attenuating the inflammatory responses could mitigate thyroid cancer progression. We treated the mice with an inhibitor of colony-stimulating factor 1 receptor (CSF1R), pexidartinib (PLX-3397; PLX). CSF1R mediates the activity of the cytokine, colony stimulating factor 1 (CSF1), in the production, differentiation, and functions of monocytes and macrophages. Treatment with PLX decreased 94% and 62% of inflammatory monocytes in the thyroid and bone marrow, respectively, versus controls. Further, PLX suppressed the expression of critical cytokine and inflammation-regulating genes such as , and (25%-80%), resulting in inhibition of 89% tumor cell proliferation, evidenced by Ki-67 immunostaining. These preclinical findings suggest that inflammation occurs in the early stage of thyroid carcinogenesis and plays a critical in cancer progression. Importantly, attenuation of inflammation by inhibitors such as PLX would be beneficial in preventing thyroid cancer.
甲状腺癌是最常见的内分泌肿瘤，其发病率正在迅速上升。最近在甲状腺癌基因损伤的识别方面取得了重大进展；然而，炎症是否促进甲状腺癌进展仍不清楚。我们使用侵袭性滤泡性甲状腺癌（FTC；小鼠）的小鼠模型，旨在阐明分子水平上的因果关系。该小鼠表达显性负性甲状腺激素受体β（记为PV）以及基因单等位基因的缺失。这两条致癌信号通路协同激活PI3K-AKT信号传导，以驱动癌症进展，就像在人类FTC中一样。在5至7周龄时，与正常甲状腺相比，该小鼠的甲状腺表现出广泛的增生，并伴有炎症单核细胞77.5倍的浸润。全基因组表达谱分析确定了2387个基因的表达改变，其中1353个上调，1034个下调。进一步分析发现炎症介质和细胞因子如、和基因的表达明显升高，而、和基因的表达降低。这些变化引发了该小鼠增生性甲状腺中的炎症反应，反映了甲状腺癌发生的早期事件。接下来，我们测试了减轻炎症反应是否可以减轻甲状腺癌进展。我们用集落刺激因子1受体（CSF1R）抑制剂培西达替尼（PLX-3397；PLX）治疗小鼠。CSF1R介导细胞因子集落刺激因子1（CSF1）在单核细胞和巨噬细胞的产生、分化和功能中的活性。与对照组相比，PLX治疗分别使甲状腺和骨髓中的炎症单核细胞减少了94%和62%。此外，PLX抑制了关键细胞因子和炎症调节基因如、和（25%-80%）的表达，通过Ki-67免疫染色证明，导致肿瘤细胞增殖抑制89%。这些临床前研究结果表明，炎症发生在甲状腺癌发生的早期阶段，并在癌症进展中起关键作用。重要的是，用PLX等抑制剂减轻炎症对预防甲状腺癌有益。
