Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis

Abstract

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.

Keywords: Liver Cancer; Molecular Drivers; Prognosis; Targeted Therapies.

Figure 1.

Mortality trends of patients with different malignancies in the United States from 1990 to 2009 (reprinted with permission from Llovet et al). Changes in cancer mortality among tumor types in the United States. Mortality from liver and bile duct cancers is increasing more rapidly than that from any other cancer in men and women. Data obtained from the 2013 American Association for Cancer Research Cancer Progress Report.

Figure 2.

Structure of the liver lobule and location of candidate cell of origin of liver cancer. Intrahepatic organization of the liver lobule and the localization of hepatic cells that form liver tumors. Different types of cancer (ie, HCC, iCCA, mixed HCC-iCCA) can originate in the liver, depending on the transformation event and the cell type undergoing neoplastic transformation. Hepatic stem or progenitor cells are believed to reside within the most terminal branches of the biliary tree (referred to as canals of Hering). Upon injury, hepatocytes can undergo reversible ductal metaplasia and dedifferentiate into hepatocyte-derived progenitor-like cells. Printed with permission from ©Mount Sinai Health System.

Figure 3.

Multiple cells of origin of primary liver cancers. HCC and iCCA can develop via transformation of mature hepatocytes and cholangiocytes, respectively. There is evidence that hepatic progenitor cells (HPCs), their intermediate states, or dedifferentiated hepatocytes can form liver tumors with progenitor-like features, including mixed HCC-CCA, such as CLC. Mature hepatocytes can also be reprogrammed into cells that closely resemble biliary epithelial cells and contribute to development of iCCA. Printed with permission from ©Mount Sinai Health System.

Figure 4.

Molecular biomarkers of HCC. Genetic features and gene expression of the tumor or its surrounding microenvironment correlate with clinical and pathological features, etiology, and patient outcomes. The proliferation subclass is characterized by proliferation signaling pathways, which involve proteins such as MTOR, NOTCH, and TGF-β and several gene expression signatures associated with poor outcomes of patients (such as the G3 and 5-gene signatures). The nonproliferation subclass is characterized by mutations in CTNNB1, the S3 gene expression signature, and the classic Wnt signaling pathway. Specific mutations associated with etiology (smoking and aflatoxin B exposure) have also been described. An expression pattern of 186 genes in the liver tissue surrounding the HCC can identify patients with HCC at higher risk for tumor recurrence after resection. Printed with permission from ©Mount Sinai Health System.

Figure 5.

Main characteristics of subclasses of iCCA. Analyses of gene expression patterns have shown that iCCAs can be assigned to the proliferation or inflammation subclasses. The proliferation class is characterized by chromosome instability, activation of pathways related to cell cycle progression, mutations in oncogenes, and shorter survival times of patients. Tumors of the inflammation subclass have gene expression patterns associated with activation of an immune response and less aggressive clinical behavior. FGFR2 fusion events are evenly distributed between these subclasses.