The significance of intertumor and intratumor heterogeneity in liver cancer

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.