Combined locoregional-immunotherapy for liver cancer. Journal of hepatology Locoregional therapies are commonly used to treat patients with hepatocellular carcinoma. It has been noted for many years that locoregional therapies may have additional systemic effects other than simple tumour elimination. Immunological "side effects" have been described in response to locoregional therapies in animal studies and in patients. With the advent of immunotherapy for hepatocellular carcinoma, there is increasing interest in determining the best way to combine immunotherapy with locoregional therapies. Herein, we provide a compact summary of answered and unanswered questions in the field, including: What animal model is best suited to test combined immune-locoregional treatments? How does tumour cell death affect immune responses? What type of immune responses have been observed in patients treated with different types of locoregional therapies? What can be surmised from the results of the first study testing the combination of locoregional therapy with immune checkpoint blockade? Finally, we discuss the outlook for this rapidly growing area of research, focussing on the issues which must be overcome to bridge the gap between interventional radiology and cancer immunology. 10.1016/j.jhep.2019.01.027

Functional and genetic deconstruction of the cellular origin in liver cancer. Marquardt Jens U,Andersen Jesper B,Thorgeirsson Snorri S Nature reviews. Cancer During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis. 10.1038/nrc4017

Molecular and histological correlations in liver cancer. Calderaro Julien,Ziol Marianne,Paradis Valérie,Zucman-Rossi Jessica Journal of hepatology Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, both at the molecular and histological level. High-throughput sequencing and gene expression profiling have identified distinct transcriptomic subclasses and numerous recurrent genetic alterations; several HCC subtypes characterised by histological features have also been identified. HCC phenotype appears to be closely related to particular gene mutations, tumour subgroups and/or oncogenic pathways. Non-proliferative tumours display a well-differentiated phenotype. Among this molecular subgroup, CTNNB1-mutated HCCs constitute a homogeneous subtype, exhibiting cholestasis and microtrabecular and pseudoglandular architectural patterns. Another non-proliferative subtype has a gene expression pattern similar to that of mature hepatocytes (G4) and displays a steatohepatitic phenotype. In contrast, proliferative HCCs are most often poorly differentiated, and notably include tumours with progenitor features. A novel morphological variant of proliferative HCC - designated "macrotrabecular-massive" - was recently shown to be associated with angiogenesis activation and poor prognosis. Altogether, these findings may help to translate our knowledge of HCC biology into clinical practice, resulting in improved precision medicine for patients with this highly aggressive malignancy. This manuscript reviews the most recent data in this exciting field, discussing future directions and challenges. 10.1016/j.jhep.2019.06.001

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. Affo Silvia,Yu Le-Xing,Schwabe Robert F Annual review of pathology Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix-associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy. 10.1146/annurev-pathol-052016-100322

Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis. Sia Daniela,Villanueva Augusto,Friedman Scott L,Llovet Josep M Gastroenterology 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. 10.1053/j.gastro.2016.11.048