The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferationp21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers.
儿童肝癌，包括肝母细胞瘤和肝细胞癌，是常转移至肺部的危险癌症。尽管顺铂治疗显著改善了预后，但顺铂可能无法完全清除转移起始细胞。我们团队近期研究发现，肝母细胞瘤的转移微环境中存在癌症相关成纤维细胞（CAFs）和类神经元细胞，它们会启动癌症从肝脏向肺部的扩散。本研究发现这些细胞高表达HDAC1，因此我们探究了组蛋白去乙酰化酶抑制剂能否增强顺铂的抗增殖作用，并减少儿童肝癌转移微环境中肿瘤簇的形成。方法：从肝母细胞瘤原发肝肿瘤（hbl）及肺转移灶（LM）中建立新型细胞系，同时从非特指型肝细胞肿瘤（HCN-NOS）样本及肝细胞癌细胞系中建立对照细胞系。分别采用顺铂、SAHA及联合用药处理hbl、LM和hcc细胞，检测药物对细胞数量、肿瘤簇形成及HDAC1-Sp5-p21信号轴的影响。结果：肝母细胞瘤和肝细胞癌组织标本均呈现HDAC1-Sp5通路激活增强现象，该特征在肿瘤来源细胞系中得到重现。伏立诺他（SAHA）通过抑制HDAC可增强顺铂清除hbl与hcc细胞系中CAFs的疗效。虽然类神经元细胞在联合治疗后仍存活，但其增殖受到抑制。值得注意的是，在来自多发性转移侵袭性病例的LM细胞系中，SAHA与顺铂联用克服了顺铂耐药性。这种增强抑制作用的机制包括抑制HDAC1-Sp5通路及上调增殖抑制因子p21。吉西他滨治疗也呈现类似结果，提示清除增殖性CAFs细胞是抑制有丝分裂微环境的关键环节。结论：本研究证实HDAC抑制剂与顺铂联用具有协同清除儿童肝癌转移起始细胞的治疗优势。
肿瘤(癌症)患者之家