Pathology of Hepatocellular Carcinoma

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E. Pathology by systems

Etiological factors such as chronic HBV and HCV infection may cause dysregulated methylation during liver carcinogenesis 50 , Deng et al. P16 is a cell cycle regulator and a tumor suppressor; hence, its suppression promotes tumor progression. More recently, whole genome approaches to characterizing changes in methylation have resulted in more comprehensive assessments of gene methylation in cancer and allowed integration of whole genome methylation with whole genome gene expression data, identifying genes whose expression is truly modulated by methylation 61 — Histone modification. Histones regulate gene expression by determining the open or closed state of chromatin; thus, the level of gene expression depends on the post-translational modifications of histones in the transcriptional unit.

Post-translational histone modifications such as acetylation and methylation of lysine and arginine residues, phosphorylation of serine and threonine residues, and ubiquitination of lysines are directed at the histone tails that protrude from the nucleosomes. High levels of trimethylated histone H3 lysine 4 H3K4me27 have been shown to correlate with reduced overall survival and poor prognosis in HCC In another study, high levels of H3K27me3 correlated with aggressive tumor features such as vascular invasion, large tumor size, multiplicity of tumors, and poor differentiation, and predicted worse prognosis in HCC The regulation of histone modifications appears to be specific to different etiologies.

Hepatocellular Carcinoma

Chromatin remodeling. Chromatin remodeling describes the process of dynamic changes in chromatin structure that regulate gene expression, apoptosis, and DNA repair. Disruption in chromatin remodeling can contribute to cancer initiation and progression. Awareness of the influence of chromatin remodeling processes in HCC development and growth is increasing.

The polycomb group of chromatin remodeling proteins also plays a role in heritable gene silencing. The mechanisms by which they repress gene expression are incompletely understood, but PRC1 is believed to work through ubiquitin ligases which covalently modify histone tails, whereas the main function of PRC2 is to methylate histone H3K27 69 , Knockdown of EZH2 in liver cancer cell lines also reduces levels of the repressive H3K27me3 histone, resulting in re-expression of a distinct subpopulation of tumor suppressor miRNAs that control cell motility and adhesion They have emerged as key factors regulating multiple biological processes, including development, differentiation, and cell proliferation.

MiRNAs mediate carcinogenesis and progression of HCC by directly or indirectly controlling the expression of key proteins involved in cancer-associated pathways.

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Chronic hepatitis and hepatocarcinogenesis are associated with profound changes in miRNA expression MiR, a positive regulator of liver inflammation, is upregulated in both serum and monocytes of patients with chronic HCV. Suppression of miR is associated with intrahepatic metastases and tumor recurrence after surgical resection 78 — In a phenomenon reflecting the complexity of cancer genetic mechanisms, deletions in miRa have been shown to promote the epithelial-mesenchymal transition EMT and spontaneous HCC formation in mouse models Long non-coding RNAs.

LncRNAs regulate gene expression and protein synthesis by diverse mechanisms. Aberrant expression of lncRNA can affect genes involved in hepatocarcinogenesis, microvascular invasion, and metastasis. It has been shown that lnc-MVIH inhibits secretion of phosphoglycerate kinase 1 PGK1 , a glycolytic enzyme known to inhibit angiogenesis 90 , MDIG expression was noted in the nuclei of neoplastic cells and had higher expression in larger and poorly differentiated HCCs Another mechanism by which lncRNAs induce hepatocarcinogenesis was recently described by Lau et al.

Alterations in numerous signaling pathways occur in cancer, and several specific pathways have been observed to be dysregulated in HCC. Changes in liver tissues induced either by chronic viral infection or by exposure to hepatotoxic agents cause upregulation of components of a number of cellular signaling pathways.

There are also substantial contributions to liver carcinogenesis from pathways regulating the tumor microenvironment and pathways that disrupt anti-tumor immunity 88 , Below, we describe the most commonly altered pathways and the mechanisms that lead to specific pathway activation.

Besides improving our understanding of the pathogenesis of HCC, this information is valuable for the identification of novel drug targets. There are multiple additional mechanisms of Wnt pathway activation. There are several other mechanisms for activation of Wnt signaling in HCCs apart from mutations involving the pathway. Overexpression of Wnt ligands or frizzled receptors and epigenetic changes in secreted frizzled-related protein-1 are other mechanisms by which the Wnt pathway is activated in HCC.

This pathway can also be dysregulated by constitutive activation of PI3K because of loss of function of the tumor suppressor gene PTEN by either mutation or epigenetic silencing. A number of receptor tyrosine kinases use heparan sulfate as a co-receptor, and heparan sulfate on the cell surface or in the extracellular matrix can also serve as a storage or concentration site for heparan sulfate-binding ligands.

A pair of heparan sulfate sulfatases, SULF1 and SULF2, have been shown to modulate HCC carcinogenesis and tumorigenesis through effects on the affinity of heparan sulfate for heparan sulfate-binding receptor tyrosine ligands. Besides the efforts to identify specific inhibitors of receptor tyrosine kinases, there are efforts under way to develop sulfatase inhibitors as potential anti-cancer agents — HCC is a highly vascular tumor and angioneogenesis is a dominant feature of this tumor, with the hepatic artery as the major source of its blood supply.

These principles have been used for developing effective therapeutic strategies against HCC, such as transarterial chemoembolization TACE , which works by blocking the arterial supply to the tumor, and sorafenib, which inhibits the angiogenic effects of growth factors such as VEGF. In spite of the rich vascular supply, hypoxia is present in focal areas of the tumor because of disorganized capillarization and the presence of leaky, immature vessels Hypoxia in HCC, in turn, leads to induction of growth factors such as hypoxia-inducible factors 1 and 2 HIF 1 and 2 and IGFs that promote further tumor angiogenesis by transcriptional activation of hypoxia-responsive genes and lead to tumor progression and metastases , HIFs have also been shown to impart chemo- and radio-resistance to HCC tumors, leading to failure of transarterial therapies , and hence their overexpression is associated with poor prognosis.

With this in mind, Coulouarn et al.

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STATs are activated by a variety of cytokines, hormones, and growth factors. The activation occurs through tyrosine phosphorylation by JAKs. Activated STATs stimulate the transcription of suppressors of cytokine signaling SOCS genes that, in turn, bind to phosphorylated JAKs and their receptors to inhibit this pathway, thus preventing over-activation of cytokine-stimulated cells.

JAK stimulation of STATs activates cell proliferation, migration, differentiation, and apoptosis, and deregulation of the inhibitors leads to human diseases, including cancer. The ubiquitin proteasome system is involved in cellular protein degradation. After being tagged with ubiquitin, cellular proteins are degraded by the proteasome. The ubiquitin-activating enzyme E1 mediates ATP-dependent transfer of ubiquitin to a ubiquitin-conjugating enzyme E2 , which in turn transfers the ubiquitin either directly to the substrate protein or to a downstream ubiquitin ligase E3, which then ubiquitinates the specific substrate or substrates The liver faces a constant stream of exogenous antigens from the gut reaching it via the portal vein and hence has a unique tolerogenic immune environment.

HCC tumor cells developing in this background are able to evade immune surveillance by several mechanisms. Several studies have shown that HCC tumor tissues appear to be infiltrated with Tregs and also that patients with HCC have an increased number of circulating Tregs, thus implying that they likely play a pathogenic role in HCC Another mechanism of immune suppression in the tumor microenvironment is an increase in immunosuppressive cytokines—such as interleukin-4 IL-4 , IL-5, IL-8, and IL—with simultaneous suppression of immune activating cytokines: IL-1, TNF, and interferon gamma This unique cytokine signature has been shown to promote tumor metastases, and circulating levels of IL were reported to be associated with poor prognosis — Increased expression of PD-L1 in tumor cells induces apoptosis of effector T cells and contributes to immune evasion The origin of self-renewing cells in HCCs is not clearly understood, and, recently, growing evidence supports the novel notion that tumor initiation is likely driven by a subset of cells with stem cell features.

These cancer stem cells CSCs are considered to be responsible not just for tumor initiation but also for tumor persistence, relapse, and metastasis, thus leading to a more aggressive tumor phenotype CSCs also render a tumor chemoresistant and radioresistant, which may explain why HCCs are generally resistant to conventional chemotherapies and also why newer-generation therapies like sorafenib, which do not target CSCs, are associated with frequent tumor relapse after therapy. Hence, identification and characterization of signaling pathways and biomarkers associated with CSCs are priorities for developing new paradigms of molecular cancer therapeutics in the treatment of HCC HCC is a heterogeneous malignancy resulting from diverse causes of chronic liver injury, with viral hepatitis being the most common etiology.

Regardless of the etiology, there appears to be a final common pathway in the pathogenesis of HCC in which repeated hepatocyte damage sets up a vicious cycle of cell death and regeneration which eventually results in genomic instability and initiation of HCC Figure 2. Recent advances in next-generation sequencing are playing a pivotal role in providing a more comprehensive understanding of the genomic landscape of HCC and in identifying driver mutations Table 1. Also, recognition of specific molecular pathways commonly involved in HCC initiation and progression is facilitating recognition of novel drug targets for HCC.

Currently, sorafenib is the only systemic therapy approved for the management of advanced HCC. A deeper understanding of the molecular pathogenesis of HCC will be instrumental for new drug discovery, which is desperately needed for the thousands of patients with this lethal malignancy. Chronic exposure of the liver to injury from viral hepatitis, alcohol abuse or NASH causes repeated hepatocyte damage and sets up a vicious cycle of cell death and regeneration which eventually results in cirrhosis.

The resultant genomic instability leads to initiation of HCC. Step wise accumulation of multiple genetic events including gene rearrangements, somatic mutations, copy number alterations, epigenetic changes and growth factor pathway alterations eventually lead to tumor progression and metastases. There are several challenges to applying the knowledge gained from understanding the molecular pathogenesis of HCC in the care of patients diagnosed with this malignancy.

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The significant epidemiologic and molecular heterogeneity of HCC has to be overcome before individualized recommendations can be derived from broad generalizations. With further discovery of molecular subclasses, we can hopefully identify more homogenous subgroups that can be specifically targeted for drug development.

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  4. Also, there is an urgent need to identify and validate biomarkers that can be used for early, non-invasive diagnosis and for prognostication. The most critical need of the hour is recognition of druggable molecular targets that can promote drug discovery efforts. Further endeavors to create better experimental models, such as patient-derived xenografts, will encourage personalized drug discovery.

    The authors declare that they have no competing interests. Competing Interests: No competing interests were disclosed. Alongside their report, reviewers assign a status to the article:. All Comments 0.

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    Get XML. How to cite this article. NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances [version 1; peer review: 4 approved].

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