Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs
TL;DR: The characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects are focused on.
About: This article is published in Journal of Hepatology.The article was published on 2013-11-01 and is currently open access. It has received 232 citations till now. The article focuses on the topics: WIF1 & Wnt signaling pathway.
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TL;DR: Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts and development of a p53 target gene expression signature correlating with poor survival was enabled.
1,623 citations
Cites background from "Wnt signaling and hepatocarcinogene..."
...WNT pathway small molecule inhibitors are currently in preclinical and clinical development (Pez et al., 2013)....
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TL;DR: The role of Wnt–β-catenin signalling in liver development and disease, including in liver cancer, NAFLD and liver fibrosis is discussed and important preclinical and clinical studies and future directions in basic and clinical research are highlighted.
Abstract: The canonical Wnt–β-catenin pathway is a complex, evolutionarily conserved signalling mechanism that regulates fundamental physiological and pathological processes. Wnt–β-catenin signalling tightly controls embryogenesis, including hepatobiliary development, maturation and zonation. In the mature healthy liver, the Wnt–β-catenin pathway is mostly inactive but can become re-activated during cell renewal and/or regenerative processes, as well as in certain pathological conditions, diseases, pre-malignant conditions and cancer. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults, Wnt–β-catenin signalling is frequently hyperactivated and promotes tumour growth and dissemination. A substantial proportion of liver tumours (mainly HCC and, to a lesser extent, CCA) have mutations in genes encoding key components of the Wnt–β-catenin signalling pathway. Likewise, hepatoblastoma, the most common paediatric liver cancer, is characterized by Wnt–β-catenin activation, mostly as a result of β-catenin mutations. In this Review, we discuss the most relevant molecular mechanisms of action and regulation of Wnt–β-catenin signalling in liver development and pathophysiology. Moreover, we highlight important preclinical and clinical studies and future directions in basic and clinical research. The Wnt–β-catenin pathway is a highly conserved pathway that regulates embryogenesis and key regenerative processes in adult organs. Here, the authors discuss the role of Wnt–β-catenin signalling in liver development and disease, including in liver cancer, NAFLD and liver fibrosis.
288 citations
TL;DR: This review discusses the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type-specific roles of Wnt / β-catanin signaling as it relates to liver physiology and pathobiology.
Abstract: The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, β-catenin also plays a role at adherens junctions. Wnt/β-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/β-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type-specific roles of Wnt/β-catenin signaling as it relates to liver physiology and pathobiology.
254 citations
TL;DR: The current knowledge regarding the structure, function, and biology of GPC3 is summarized with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.
Abstract: Liver cancer is the second leading cause of cancer-related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican-3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.
207 citations
TL;DR: New aspects on the control of inflammation and cell migration by simple sphingolipids are highlighted, with special emphasis to the role played by ceramide 1-phosphate in controlling these actions.
153 citations
References
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TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
5,042 citations
TL;DR: Some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis are highlighted, and potential therapeutic implications are discussed.
4,926 citations
"Wnt signaling and hepatocarcinogene..." refers background in this paper
...The first phosphorylation event is generated by CK1 at Ser45 which allows the GSK3b-mediated sequential phosphorylation of Thr41, Ser37, and Ser33 [28,29]....
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...CK1a, another component of the destruction complex, may be stabilized by pyrvinium that inhibits both Wnt signaling and cell proliferation, even in the presence of APC or CTNNB1 mutations, as observed in colon cancer cell lines [125]....
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...Axin1 and APC act together as scaffolding proteins through binding of b-catenin, and enhance its N-terminal phosphorylation by GSK3b and CK1....
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...Targeting the b-catenin destruction complex (APC, Axin, CK1, and GSK3b) as a therapeutic target has not been assessed in HCC so far....
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...In absence of the canonical Wnt signaling, cytosolic b-catenin is targeted for degradation by a complex composed of a scaffold of proteins named axin1, APC, and two serine/threonine kinases: the glycogen synthase kinase 3b (GSK3b) and the casein kinase 1 (CK1) [27] (Fig....
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TL;DR: GLOBOCAN 2000 updates the previous data-based global estimates of incidence, mortality and prevalence to the year 2000 and uses a “databased” approach, rather different from themodeling method used in other estimates.
Abstract: Describing the distribution of disease between different populations and over time has been ahighly successfu l way of devising hypothese s about causation and for quantifying the potential for preventive activities.1 Statistical data are also essentia l componentsof diseasesurveillanceprograms. Theseplay acritical role in the developmen t and implementation of health policy, through identification of health problems, decisions on priorities for preventive and curative programs and evaluation of outcomes of programs of prevention, early detection/screenin g and treatment in relation to resource inputs. Over the last 12 years, aseries of estimates of the global burden of cancer have been published in the International Journal of Cancer. 2–6 The methods have evolved and been refined, but basically they rely upon the best availabl e data on cancer incidence and/or mortality at country level to build up theglobal picture. The results are more or less accurat e for different countries, depending on the extent and accuracy of locally availabl e data. This “databased” approach is rather different from themodeling method used in other estimates. 7–10 Essentially, these use sets of regression models, which predict cause-specifi c mortality rates of different populations from the correspondin g all-cause mortality.11 The constant s of the regression equations derive from dataset s with different overal mortality rates (often including historic data from wester n countries) . Cancer deaths are then subdivided into the different cancer types, according to the best availabl e information on relative frequencies. GLOBOCAN 2000 updates thepreviousl y published data-based global estimates of incidence, mortality and prevalence to the year 2000.12
3,748 citations
TL;DR: This review summarizes and compares major signaling pathways that regulate the epithelial-mesenchymal transitions during both development and tumor metastasis and examines their role in carcinoma invasion and metastasis.
2,849 citations
"Wnt signaling and hepatocarcinogene..." refers background in this paper
...Disruption of E-cadherin-mediated adherent junctions is a major event in EMT [35] and because of the interplay between...
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...The possible consequences of inhibiting b-catenin at adherent junctions have to be discuss in respect of their role in epithelio-mesenchymal transition (EMT)....
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...Disruption of E-cadherin-mediated adherent junctions is a major event in EMT [35] and because of the interplay between vol. 59 j 1107–1117 1109 Review cadherin-mediated cell adhesion and canonical/b-catenin signaling [36], targeting b-catenin could also promote the disruption of these junctions leading to enhance EMT....
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TL;DR: Current understanding of Wnt function and signaling mechanisms is reviewed in a comparative approach, highlighting novelty and underscoring questions that remain, and putting emphasis on the latest findings.
Abstract: Wnt proteins are now recognized as one of the major families of developmentally important signaling molecules, with mutations in Wnt genes displaying remarkable phenotypes in the mouse, Caenorhabditis elegans, and Drosophila. Among functions provided by Wnt proteins are such intriguing processes as embryonic induction, the generation of cell polarity, and the specification of cell fate. Until recently, our knowledge of the molecular mechanism of Wnt signaling was very limited, but over the past year, several major gaps have been filled. These include the identification of cell-surface receptors and a novel mechanism of relaying the signal to the cell nucleus. In addition, several components of Wnt signaling are implicated in the genesis of human cancer. These insights have come from different corners of the animal kingdom and have converged on a common pathway. At this junction in this rapidly evolving field, we review our current understanding of Wnt function and signaling mechanisms, doing so in a comparative approach. We have put emphasis on the latest findings, highlighting novelty and underscoring questions that remain. For additional literature, we refer to several previous reviews (McMahon 1992; Nusse and Varmus 1992; Klingensmith and Nusse 1994; Miller and Moon 1996; Moon et al. 1997). We have limited the number of references, particularly in the tables. Fully referenced forms of these tables can be found on the Wnt homepage (http://wwwleland.stanford.edu/∼rnusse/wntwindow.html).
2,622 citations
"Wnt signaling and hepatocarcinogene..." refers background in this paper
...In adult organisms, deregulation of Wnt signaling may lead to tumor development [18,19]....
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