Inter- and Intratumor Heterogeneity in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is structurally complex system undergoing different molecular and phenotypic changes during tumor development. These changes can be represented by chromosomal and microsatellite instability, gene mutations, and variations in gene, protein expression patterns and morphology, and can operate together with alterations of the tumor cell epigenome and tumor microenvironment in the process of cancer clonal evolution, thus resulting in considerable intertumor (interpatient) and intratumor heterogeneity. In this chapter, we presented the basic information about the nature and the mechanisms of tumor heterogeneity in general and HCC heterogeneity in particular, focusing attention on the role of somatic mosaicism in the development of tumor diversity. To date, intertumor heterogeneity in HCC represented by differences between tumors of different patients has been characterized to comprise both well-known histological types and several molecular subtypes with specific genetic changes and therapeutic interventions. Intratumor heterogeneity of HCC was shown to include differences between tumors of the same origin or tumor cells within the same tumor and to be associated with cancer growth and progression. Moreover, HCCs were found to demonstrate the variability in the distribution of stromal and inflammatory cells in the tumor microenvironment, which also contributes to the biological behavior of tumors. Despite abundant data concerning intratumor heterogeneity in HCC, routine qualitative and quantitative criteria are not suggested to be applied in the capturing of the complete genomic landscape of cancer, and the assessment of the risk of cancer progression and therapy response. Summarizing all the data, we reviewed potential targets and methods for the assessment of intratumor heterogeneity in clinical practice.