Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Exp Mol Med. 2018 Jan 5;50(1):e416. doi: 10.1038/emm.2017.165.
Genomic analyses of primary liver cancer samples reveal a complex mutational landscape with vast intertumor and intratumor heterogeneity. Different primary liver tumors and subclones within each tumor display striking molecular and biological variations. Consequently, tumor molecular heterogeneity contributes to drug resistance and tumor relapse following therapy, which poses a substantial obstruction to improving outcomes of patients with liver cancer. There is an urgent need to the compositional and functional understanding of tumor heterogeneity. In this review, we summarize genomic and non-genomic diversities, which include stemness and microenvironmental causes of the functional heterogeneity of the primary liver cancer ecosystem. We discuss the importance and intricacy of intratumor heterogeneity in the context of cancer cell evolution. We also discuss methodologies applicable to determine intratumor heterogeneity and highlight the best-fit patient-derived in vivo and in vitro models to recapture the functional heterogeneity of primary liver cancer with the aim to improve future therapeutic strategies.
原发性肝癌样本的基因组分析揭示了一个复杂的突变景观，具有广泛的肿瘤间和肿瘤内异质性。不同的原发性肝癌肿瘤和每个肿瘤内的亚克隆显示出显著的分子和生物学变化。因此，肿瘤分子异质性导致了治疗后的耐药性和肿瘤复发，这对提高肝癌患者的治疗效果构成了重大障碍。迫切需要对肿瘤异质性的组成和功能进行理解。在这篇综述中，我们总结了基因组和非基因组的多样性，包括原发性肝癌生态系统功能异质性的干性和微环境原因。我们讨论了肿瘤内异质性在癌细胞进化中的重要性和复杂性。我们还讨论了适用于确定肿瘤内异质性的方法，并强调了最适合的患者来源的体内和体外模型，以重现原发性肝癌的功能异质性，旨在改善未来的治疗策略。
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