Papers by Stefania Cannito
International Journal of Molecular Sciences
Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading... more Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC’s metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.
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Cancers
Primary liver cancers represent the third-most-common cause of cancer-related mortality worldwide... more Primary liver cancers represent the third-most-common cause of cancer-related mortality worldwide, with an incidence of 80–90% for hepatocellular carcinoma (HCC) and 10–15% for cholangiocarcinoma (CCA), and an increasing morbidity and mortality rate. Although HCC and CCA originate from independent cell populations (hepatocytes and biliary epithelial cells, respectively), they develop in chronically inflamed livers. Evidence obtained in the last decade has revealed a role for cytokines of the IL-6 family in the development of primary liver cancers. These cytokines operate through the receptor subunit gp130 and the downstream Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. Oncostatin M (OSM), a member of the IL-6 family, plays a significant role in inflammation, autoimmunity, and cancer, including liver tumors. Although, in recent years, therapeutic approaches for the treatment of HCC and CCA have been implemented, limited treatment options...
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Antioxidants
During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique c... more During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic responses, which are mostly elicited or sustained both by oxidative stress and reactive oxygen species (ROS) and several mediators (including growth factors, cytokines, chemokines, and others) that often operate through the up-regulation of the intracellular generation of ROS. In the present review, we will offer an overview of the role of MFs in the fibrogenic progression of CLD from different etiologies by focusing our attention on the direct or indirect role of ROS and, more generally, oxidative stress in regulating MF-related phenotypic responses. Moreover, this review has the purpose of illustrating the real complexity of the ROS modulation during CLD progression. The re...
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American Journal of Pathology, 2008
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United European gastroenterology journal, 2014
INTRODUCTION: Hepatocytes or HepG2 cells overloaded with saturated lipotoxic free fatty acids, a ... more INTRODUCTION: Hepatocytes or HepG2 cells overloaded with saturated lipotoxic free fatty acids, a condition that mimick lipid accumulation occurring in the liver in some forms of steato-hepatitis, have been recently reported to release pro-angiogenic microparticles (MPs) in a caspase 3-dependent manner, an event which occurs also in vivo and may have a role in the pathogenesis of NAFLD/ NASH (1). AIMS & METHODS: In this study we investigated whether MPs released from fat-laden cells may affect in a paracrine way NLRP3 inflammasome, which is known to be progressively activated in vivo in NAFLD/NASH conditions. MPs were collected and purified as released by fat-laden HepG2 (i.e., HepG2 exposed for 24 hr to 0.25 mM palmitic acid or PA), as recently described (1). HepG2 resting cells were then incubated (15 min-24hrs) with MPs, LPS (100 ng/mL-1 \ub5g/mL) or PA (150 \u2013 500 \ub5M), the latter known to induce NLRP3 inflammasome in hepatocytes. In other experiments activated human THP1 macrophages (48 hrs activation by PMA 25 nM plus 24 hrs in fresh medium) were exposed up to 24 hrs to MPs released by fat-laden HepG2 cells. Expression of NLRP-3, pro-caspase and cleaved caspase 1, pro-IL-1 and cleaved IL-1\u3b2 was evaluated by Western blot analysis in cell lysates, whereas ELISA assays were used to measure IL-1\u3b2 and IL-18 levels released by resting HepG2. RESULTS: MPs were very early (i.e., 1-6 hrs) efficiently internalized by both HepG2 cells and THP1 macrophages, as revealed by means of confocal microscopy. MPs induced a time-dependent increase in the expression of NLRP3 inflammasome components in resting HepG2 cells starting from 6hr and then reaching a plateau at 16-24 hrs, with a kinetics that overlapped the one exerted by PA and was delayed as compared to LPS (1-3 hrs). Interestingly, both MPs and PA, but not LPS, significantly induced caspase-1 activation and consequent release in particular of IL-1\u3b2 in a time-dependent manner. Moreover, MPs also up-regulated NLRP3 inflammasome expression in THP1 human macrophages within 3-6 hrs, resulting in a significantly increased release of IL-1\u3b2. CONCLUSION: Fat-laden cells, by releasing MPs in a paracrine way, can efficiently trigger inflammasome activation in surrounding hepatic cells as well as macrophages, thus identifying an additional new molecular mechanism of inflammation in NASH pathogenesis. REFERENCES: 1.Povero D et al., Science Signaling(2013),6(296),ra88
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United European gastroenterology journal, 2005
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Journal of Hepatology, 2016
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Digestive and Liver Disease, 2017
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Digestive and Liver Disease, 2016
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Digestive and Liver Disease, 2015
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Molecules, 2022
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is characterized by ... more Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is characterized by poor clinical outcomes, with the majority of patients not being eligible for curative therapy and treatments only being applicable for early-stage tumors. CD44 is a receptor for hyaluronic acid (HA) and is involved in HCC progression. The aim of this work is to propose HA- and PEGylated-liposomes as promising approaches for the treatment of HCC. It has been found, in this work, that CD44 transcripts are up-regulated in HCC patients, as well as in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Cell culture experiments indicate that HA-liposomes are more rapidly and significantly internalized by Huh7 cells that over-express CD44, compared with HepG2 cells that express low levels of the receptor, in which the uptake seems due to endocytic events. By contrast, human and murine macrophage cell lines (THP-1, RAW264.7) show improved and rapid uptake of PEG-modified liposomes without...
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The Journal of Pathology, 2022
Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to... more Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in NAFLD/NASH. The role of OSM was investigated in: a) selected cohorts of NAFLD/NASH HCC patients; b) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM; c) murine HCC xenografts; d) a murine NASH-related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis, and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial-to-mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth, but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH-related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM up-regulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro-carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. This article is protected by copyright. All rights reserved.
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American Journal of Pathology, 2008
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Papers by Stefania Cannito