Risk factors of primary liver cancer initiation associated with tumour initiating cell emergence: novel targets for promising preventive therapies

Primary liver cancers ranked as the sixth most commonly diagnosed cancers and the third-leading cause of cancer-related death in 2020. Despite encouraging findings on diagnosis and treatments, liver cancer remains a life-threatening disease with a still increasing incidence.Therefore, it is of interest to better characterise and understand the mechanistic process occurring at early steps of carcinogenesis. Inflammatory responses in liver diseases participate in the activation of liver progenitor cells (LPCs) facultative compartment but also to their transformation into cancer stem cells (CSCs) and give rise to primary liver cancer including hepatocellular carcinoma and cholangiocarcinoma. Higher intratumoural heterogeneity has been associated with poorer prognosis and linked to tumour escape from the immune surveillance and to resistance to chemotherapy. A better understanding of the malignant transformation of LPC as tumour initiating cells (ie, CSC) should also provide a potential new therapeutic target for anticancer therapy. In this review, we summarise the recent reports identifying underlying mechanisms by which chronic liver inflammatory responses could trigger the early steps in liver carcinogenesis, notably through the transformation of LPCs into tumour initiating cells

Rôle de la protéine Gas6 dans le foie en régénération à partir d'hépatocytes ou à partir de cellules précurseurs (les cellules ovales)

Lors de la régénération hépatique, les cellules étoilées du foie (CEF) s'activent en myofibroblastes (CEF/MFB) et jouent un rôle clé dans le remodelage matriciel et la réparation tissulaire. Une hépatite induite chez le rat, par l'injection de tétrachlorure de carbone (CC14), entraîne une induction de l'expression de la protéine Gas6 dans les CEF/MFB ainsi que dans les macrophages inflammatoires qui infiltrent les zones centrolobulaires nécrosées. Nous avons montré un effet anti-apoptodique de Gas6 sur des CEF et des CEF/MFB en culture. Après une injection de CC14 à des souris déficientes pour Gas6, nous avons observé un retard dans la réparation tissulaire, étroitement lié à un défaut d'accumulation de CEF/MFB et à un recrutement très limité de monocytes inflammatoires impliqués dans l'activation des CEF en CEF/MFB. In vitro, des propriétés chimiotactiques de Gas6 sur les monocytes circulants ont été mises en évidence. Lorsque la prolifération des hépatocytes résiduels est altérée, le foie régénère à partir de cellules précurseurs intra-hépatiques : les cellules ovales. Dans ce type de régénération, induite chez le rat après une hépatectomie partielle associée à un traitement à l'acétylaminofluorène, les cellules ovales qui s'accumulent transitoirement dans les zones périportales, expriment fortement la protéine Gas6. In vitro, nous avons aussi montré un effet anti-apoptotique de Gas6 sur les cellules WB-F344 utilisées comme modèle de cellules ovales. Gas6 joue donc un rôle dans la régénération hépatique en favorisant le recrutement de cellules inflammatoires, ainsi que l'accumulation transitoire de CEF/MFB et de cellules ovales, en les protégeant contre l'apoptose.In liver regeneration, hepatic stellate cells (HSC) activate into myofibroblasts (HSC/MFB) and play a key role in matrix remodelling and tissue repair. Carbon tetrachloride (CC14)-induced hepatitis leads to Gas6 protein induction in HSC/MFB as well as in infiltrated inflammatory monocytes in centrilobular necrotic areas. An anti-apoptotic effect of Gas6 was shown in cultured HSC and HSC/MFB. In Gas6-deficient mice after CC14-injection, we observed a delay in tissue repair associated with a defect in HSC/MFB accumulation, and a small number of recruited inflammatory monocytes involved in HSC activation into HSC/MFB. In vitro, chemotactic properties of Gas6 were shown on peripheral blood monocytes. When the proliferation of residual hepatocytes is altered, liver regeneration occurs from intra-hepatic precursor cells : the oval cells. In such a regeneration obtained in the rat after partial hepatectomy associated with an acetylaminofluorene treatment, we observed a periportal accumulation of oval cells, which also expressed Gas6. In vitro, we also showed the anti-apoptotic effect of Gas6 on WB-F344 cells used as an oval cell model. Thus, Gas6 plays a role in liver regeneration by favouring inflammatory cell recruitment, and the accumulation of HSC/MFB and oval cells by protecting them against apoptosis.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Novel insights into the impact of liver inflammatory responses on primary liver cancer development

Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development

Signal Transducer and Activator of Transcription 3 in Liver Diseases: A Novel Therapeutic Target

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by many cytokines and growth factors and plays a key role in cell survival, proliferation, and differentiation. STAT3 activation is detected virtually in all rodent models of liver injury and in human liver diseases. In this review, we highlight recent advances of STAT3 signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis. The cytokines and small molecules that activate STAT3 in hepatocytes may have therapeutic benefits to treat acute liver injury, fatty liver disease, and alcoholic hepatitis, while blockage of STAT3 may have a therapeutic potential to prevent and treat liver cancer.</p

Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: involvement of hepatocyte STAT3 in TIMP-1 production

BACKGROUND: Tissue inhibitor of metalloproteinase 1 (TIMP-1), which is thought to be produced mainly by activated hepatic stellate cells and Kupffer cells in the liver, plays a pivotal role in matrix remodeling during liver injury and repair; while the effect of TIMP-1 on hepatocellular damage remains obscure. RESULTS: Hepatic expression of TIMP-1 mRNA and protein was up-regulated both in acute and chronic liver injury induced by carbon tetrachloride (CCl(4)). Compared with wild-type mice, TIMP-1 knockout mice were more susceptible to CCl(4)-induced acute and chronic liver injury, as shown by higher levels of serum alanine aminotransferase (ALT), greater number of apoptotic hepatocytes, and more extended necroinflammatory foci. TIMP-1 knockout mice also displayed greater degree of liver fibrosis after chronic CCl(4 )injection when compared with wild-type mice. In vitro treatment with TIMP-1 inhibited cycloheximide-induced cell death of primary mouse hepatocytes. Finally, up-regulation of TIMP-1 in the liver and serum after chronic CCl(4 )treatment was markedly diminished in hepatocyte-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. In vitro treatment with interleukin-6 stimulated TIMP-1 production in primary mouse hepatocytes, but to a lesser extent in STAT3-deficient hepatocytes. CONCLUSIONS: TIMP-1 plays an important role in protecting against acute and chronic liver injury and subsequently inhibiting liver fibrosis induced by CCl(4). In addition to activated stellate cells and Kupffer cells, hepatocytes are also responsible for TIMP-1 production during liver injury via a STAT3-dependent manner

Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury

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Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice.: Gas6 deficiency impairs hepatic wound healing

International audienceBACKGROUND/AIMS: Resident macrophages and myofibroblasts derived from hepatic stellate cells play a key role in liver wound healing. We previously reported that these sinusoidal cells secrete the growth arrest-specific protein 6 (Gas6) and express Axl, one of its receptors. Here we address the role of Gas6 in the healing process during acute liver injury. METHODS: Toxic hepatitis was induced by a single carbon tetrachloride injection in Gas6 deficient (Gas6(-/-)) mice and liver recovery was compared with wild-type animals. RESULTS: Gas6 deficiency did not cause any change in CCl(4)-induced liver damage. At 72 h, an efficient tissue repair was observed in wild-type animals whereas in Gas6(-/-) mice, we noticed a defective wound healing accounted by reduced Kupffer cell activation revealed by a decrease in the induction of CD14, TNF-alpha, IL6 and MCP-1. Gas6-deficiency, by limiting cytokine/chemokine release, prevents hepatocyte proliferation, recruitment of circulating monocytes and accumulation of myofibroblasts in healing areas. We also report a direct chemotactic effect of Gas6 on circulating monocytes which might explain defective macrophage infiltration in liver necrotic areas of Gas6(-/-) mice. Interestingly in Gas6(-/-) mice, we observed a high and constitutive expression of Axl and an induction of the suppressor of cytokine signaling SOCS1 after CCl(4) treatment. CONCLUSIONS: The lower level of cytokines/chemokines in Gas6(-/-) mice after CCl(4) injury, is the consequence of an inhibitory signal arising from Axl receptor overexpression, leading to delayed liver repair in deficient mice

Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury

International audienceBackground & Aims: Hepatic ischemia-reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia/reperfusion injuryMethods: We measured the activity of 9 small-molecule inhibitors of cyclophilins in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif–/– (CypD knockout) mice and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemia/reperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion and collected samples of blood and liver for histologic analysis.Results: The compounds inhibited peptidyl-prolyl isomerase activity (half maximal inhibitory concentration values, 0.2–16.2 μmol/L) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration values, 1.4–132 μmol/L) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif–/– mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia/reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle.Conclusions:Recently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria from mouse and human liver tissues. Administration of these compounds to mice during ischemia/reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage. These compounds might be developed to protect patients from ischemia/reperfusion injury after liver surgery or for other hepatic or nonhepatic disorders related to abnormal mPTP opening