Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Pathology University Hospital RWTH Aachen, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Cancer Lett. 2015 Dec 28;369(2):396-404. doi: 10.1016/j.canlet.2015.09.005. Epub 2015 Sep 21.
Human hepatocellular carcinoma (HCC) is a heterogeneous disease, driven by different risk factors and presenting diverse clinicopathological features and outcomes. Epidemiological and experimental data indicate that the damage-associated molecular pattern molecules S100A8 and S100A9, forming a heterodimer called calprotectin, might be critically involved in HCC development. However, deletion of S100a9 in an inflammation- and cirrhosis-driven mouse model did not show any impairment in liver tumorigenesis, most likely due to functional compensation by other inflammatory cytokines. Here, we investigated the effect of calprotectin ablation in mice treated with diethylnitrosamine, a carcinogen-driven HCC model mimicking cancer development caused by acute liver damage in the absence of prominent chronic inflammation and tissue damage. We found that tumor cell proliferation was diminished in the absence of S100A8/A9, leading to significant reduction of tumor size. Our results demonstrate that calprotectin is required for the progression of non-inflammation driven liver tumor and might represent a therapeutic target for the treatment of HCC formed in non-cirrhotic liver.
人类肝细胞癌 (HCC) 是一种异质性疾病，由不同的风险因素驱动，表现出不同的临床病理特征和结局。流行病学和实验数据表明，损伤相关分子模式分子 S100A8 和 S100A9 形成一种称为钙卫蛋白的异二聚体，可能在 HCC 的发展中起关键作用。然而，在炎症和肝硬化驱动的小鼠模型中敲除 S100a9 并没有显示出对肝肿瘤发生的任何损害，这很可能是由于其他炎症细胞因子的功能补偿。在这里，我们研究了在二乙基亚硝胺处理的小鼠中钙卫蛋白缺失的影响，二乙基亚硝胺是一种致癌物诱导的 HCC 模型，模拟了在没有明显慢性炎症和组织损伤的情况下由急性肝损伤引起的癌症发展。我们发现，在缺乏 S100A8/A9 的情况下，肿瘤细胞的增殖减少，导致肿瘤体积显著缩小。我们的结果表明，钙卫蛋白是无炎症驱动的肝肿瘤进展所必需的，可能成为非肝硬化性肝形成的 HCC 的治疗靶点。
