Gastroenterology

Gastroenterology

Volume 152, Issue 4, March 2017, Pages 745-761
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis

https://doi.org/10.1053/j.gastro.2016.11.048Get rights and content

Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation–progenitor, proliferation–transforming growth factor β, and Wnt–catenin β1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making.

Section snippets

Cell(s) of Origin

Parenchymal (hepatocytes and cholangiocytes) and nonparenchymal cells (fibroblasts, stellate cells, Kupffer cells, and endothelial cells) form the basic hepatic structure (Figure 2); the existence of stem cells in adult liver has been heavily debated. Hepatocytes constitute 60% to 80% of the total liver mass. Architecturally, these cells are organized in lobules, which can be further divided in functional regions or zones.16 Liver zonation is particularly relevant for hepatocytes, because it

Immune Response

Regardless of the cell type that becomes transformed to initiate tumorigenesis, the developing tumor also requires a specific microenvironment. This is particularly relevant to liver tumors, 90% of which develop under conditions of chronic inflammation.2 Factors that contribute to tumor formation include changes in the extracellular matrix of the liver, signaling between parenchymal and nonparenchymal cells, and immune dysfunction.75 An altered immune response is an important factor in

Classification of HCC Based on Molecular Features

Characterization of molecular subtypes and/or oncogene addiction loops has generated treatment algorithms for several types of cancer, including breast cancer, and they have improved patient outcomes. High-throughput technologies, including single nucleotide polymorphism arrays, combined with transcriptomic and exome sequencing analyses, have identified molecular subtypes of liver cancer, with distinct oncogene signaling pathways and recurrent mutations.96 Even though molecular classifications

Molecular Subclasses of iCCA

There is no effective treatment for iCCA. Reasons include our poor understanding of its pathogenesis and the lack of studies conducted specifically in patients with iCCA, apart from patients with all biliary tract cancers13, 14; this is important because iCCAs are characterized by a distinct set of mutations.14 iCCAs were only recently recognized as a distinct entity with both its own unique staging system (see the 7th edition of the American Joint Committee on Cancer Staging Manual118) and ad

Molecular Features of Uncommon Tumors

FLC is a rare primary liver cancer with few treatment options that typically affects children and young adults without background liver disease.60 FLC is now considered a unique molecular entity within primary liver malignancies.138 FLC is caused by an approximate 400-kilobase deletion in chromosome 19 that incorporates the first exon of DNAJB1 into all but the first exon of PRKACA.139 This fusion is detected in 70%138 to 100% of FLCs.139 In addition, exome sequencing and RNA sequencing studies

Challenges in Tumor Heterogeneity

Liver tumors have a high degree of molecular heterogeneity, not only among patients with the same types of tumors but also within regions within the same tumor or tissue.147 Expert recommendations and consensus definitions have been established to better address the extent and role of cancer heterogeneity in oncology research.148

From a clinical perspective, molecular heterogeneity should be considered within the concepts of trunk and branch as well as driver and passenger mutations. Trunk

Prognostic Markers in HCC

Molecular biomarkers have many applications in cancer. They can improve clinical decision making by helping to predict a patient’s outcome, select patients most likely to respond to a specific treatment, and avoid treatments not likely to be effective. Unlike other cancers such as breast149 and colorectal150 cancers, HCC has no molecular markers that have been incorporated into clinical management.

As a general rule, clinical practice guidelines include recommendations based on a specified set

Molecular Markers of iCCA

Even fewer biomarkers of iCCA have been developed than for HCC; there are only level C data for the efficacy of a biomarker for this tumor type. iCCA is one of the few solid tumors for which no systemic molecular therapy has been approved by the Food and Drug Administration.13 Surgery is the only potentially curative option, although chemotherapy with gemcitabine plus cisplatin is the standard for patients with advanced-stage iCCA.162 According to the International Liver Cancer Association

Future Directions

In the past decade, there have been tremendous advances in our understanding of the cellular and molecular complexity of liver cancers. Sophisticated functional studies and NGS-based research studies have provided information about the cells that form liver tumors and the proteins and pathways involved in hepatocarcinogenesis. These studies support a model of multiple cells of tumor origin. Most of the studies, using in vivo lineage tracing models, revealed an unexpected plasticity of mature

Acknowledgments

The authors thank Jill Gregory for her contribution in the design work of the figures.

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    Conflicts of interest The authors disclose the following: A.V. and J.M.L. are coinventors of a patent: “Compositions, Kits, and methods for identification, assessment, prevention and therapy of hepatic disorders.” D.S. and S.L.F. disclose no conflicts.

    Funding Supported by the Andrea Marie Fuquay Memorial Research Fellowship (Cholangiocarcinoma Foundation) (to D.S.), the American Association for the Study of Liver Diseases Foundation Alan Hofmann Clinical and Translational Award (to A.V.), National Institutes of Health grants DKR0156621 and AA 020709 (to S.L.F.), and grants from the US National Cancer Institute (P30CA165979 to J.M.L.), the European Commission Horizon 2020 (HEP-CAR 667273-2 to J.M.L.), the Samuel Waxman Cancer Research Foundation (to J.M.L.), the Grant I+D Program (SAF2013-41027) (to J.M.L.), the Asociación Española Contra el Cáncer (to J.M.L.), and the US Department of Defense (grant number CA150272P3 to A.V., S.L. F. and J.M.L).

    Author names in bold designate shared co-first authorship.

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