Division of General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Hepatol Commun. 2024 Jan 29;8(2). doi: 10.1097/HC9.0000000000000369. eCollection 2024 Feb 1.
Lung metastases are the most threatening signs for patients with aggressive hepatoblastoma (HBL). Despite intensive studies, the cellular origin and molecular mechanisms of lung metastases in patients with aggressive HBL are not known. The aims of these studies were to identify metastasis-initiating cells in primary liver tumors and to determine if these cells are secreted in the blood, reach the lung, and form lung metastases.
We have examined mechanisms of activation of key oncogenes in primary liver tumors and lung metastases and the role of these mechanisms in the appearance of metastasis-initiating cells in patients with aggressive HBL by RNA-Seq, immunostaining, chromatin immunoprecipitation, Real-Time Quantitative Reverse Transcription PCR and western blot approaches. Using a protocol that mimics the exit of metastasis-initiating cells from tumors, we generated 16 cell lines from liver tumors and 2 lines from lung metastases of patients with HBL.
We found that primary HBL liver tumors have a dramatic elevation of neuron-like cells and cancer-associated fibroblasts and that these cells are released into the bloodstream of patients with HBL and found in lung metastases. In the primary liver tumors, the ph-S675-β-catenin pathway activates the expression of markers of cancer-associated fibroblasts; while the ZBTB3-SRCAP pathway activates the expression of markers of neurons via cancer-enhancing genomic regions/aggressive liver cancer domains leading to a dramatic increase of cancer-associated fibroblasts and neuron-like cells. Studies of generated metastasis-initiating cells showed that these cells proliferate rapidly, engage in intense cell-cell interactions, and form tumor clusters. The inhibition of β-catenin in HBL/lung metastases-released cells suppresses the formation of tumor clusters.
The inhibition of the β-catenin-cancer-enhancing genomic regions/aggressive liver cancer domains axis could be considered as a therapeutic approach to treat/prevent lung metastases in patients with HBL.
肺转移是侵袭性肝母细胞瘤（HBL）患者最具威胁的征象。尽管进行了深入研究，但侵袭性 HBL 患者肺转移的细胞起源和分子机制仍不清楚。这些研究的目的是在原发性肝肿瘤中鉴定起始转移细胞，并确定这些细胞是否在血液中分泌，到达肺部并形成肺转移。
我们通过 RNA-Seq、免疫染色、染色质免疫沉淀、实时定量 RT-PCR 和 Western blot 方法检查了原发性肝肿瘤和肺转移中关键癌基因激活的机制，以及这些机制在侵袭性 HBL 患者中起始转移细胞出现的作用。使用模拟起始转移细胞从肿瘤中逸出的方案，我们从 HBL 患者的肝肿瘤中生成了 16 个细胞系，从肺转移中生成了 2 个细胞系。
我们发现原发性 HBL 肝肿瘤中神经元样细胞和癌相关成纤维细胞显著升高，这些细胞被释放到 HBL 患者的血液中，并在肺转移中发现。在原发性肝肿瘤中，ph-S675-β-catenin 通路激活了癌相关成纤维细胞标志物的表达；而 ZBTB3-SRCAP 通路通过促进癌症的基因组区域/侵袭性肝癌结构域激活神经元标志物的表达，导致癌相关成纤维细胞和神经元样细胞的急剧增加。对生成的起始转移细胞的研究表明，这些细胞增殖迅速，进行强烈的细胞间相互作用，并形成肿瘤簇。在 HBL/肺转移释放细胞中抑制β-catenin 可抑制肿瘤簇的形成。
抑制β-catenin-促进癌症的基因组区域/侵袭性肝癌结构域轴可被视为治疗/预防 HBL 患者肺转移的一种治疗方法。
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