c‐Met Signaling Protects from Nonalcoholic Steatohepatitis‐ (NASH‐) Induced Fibrosis in Different Liver Cell Types

Drescher, Hannah K.; Schumacher, F.; Schenker, Teresa; Baues, Maike; Lammers, Twan; Hieronymus, Thomas; Streetz, Konrad L.; Kroy, Daniela C.

doi:10.1155/2018/6957497

Cited by 10 publications

(6 citation statements)

References 56 publications

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“…Although the mechanism by which CARCs develop remains unknown, studies have speculated the involvement of abnormal lipid metabolism with inflammation in certain cells or tissues based on the pathological findings in our case. A previous study revealed that mice lacking MET proto-oncogene (MET) exhibited severe fatty liver degeneration with increased inflammation of immune cells, causing nonalcoholic steatohepatitis [18]. Evidence suggests that MET inhibition by crizotinib might generate CARCs, although it is difficult to rule out the ability of other MET inhibitors to cause CARC-like complications in clinical studies.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Multiple Brain Metastases in a Patient with ROS1 Fusion-Positive Lung Adenocarcinoma as a Disease Flare due to Crizotinib Cessation Caused by Disseminated Aseptic Inflammation from Crizotinib-Associated Renal Cysts: A Case Report

et al. 2022

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Rapid tumor growth after cessation of molecularly targeted drugs, called “disease flare,” may occur and affect the prognosis of lung cancer. However, this phenomenon has never been reported in ROS proto-oncogene 1 (ROS1) fusion-positive lung adenocarcinoma. Herein, we report a disease flare in a patient with ROS1 fusion-positive lung adenocarcinoma. A 60-year-old female was diagnosed with stage IVA ROS1 fusion-positive lung adenocarcinoma via bronchoscopy. Although crizotinib, an ROS1 tyrosine kinase inhibitor, achieved a partial response, a mass lesion appeared in the patient’s right kidney 12 months after starting crizotinib, which was diagnosed pathologically as crizotinib-associated renal cysts (CARCs). Given that readministration of crizotinib repeatedly induced CARC-like aseptic inflammation that appeared to be disseminated around surgical site, crizotinib treatment had to be abandoned. Around 25 days after crizotinib cessation, she was referred to the emergency department with a convulsive seizure and hemiparesis due to new, rapidly growing brain metastases. Whole-brain irradiation and administration of another ROS1 tyrosine kinase inhibitor, entrectinib, markedly ameliorated the metastases and improved hemiparesis. This has been the first report of a disease flare after crizotinib cessation due to CARCs in a patient with ROS1 fusion-positive lung adenocarcinoma. Attention should be paid to disease flare, especially in the brain, when molecularly targeted medication is stopped due to adverse events in ROS1 fusion-positive lung adenocarcinoma. Switching to drugs that penetrate the blood-brain barrier could overcome disease flare in the brain.

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Section: Discussion/conclusionmentioning

confidence: 99%

Multiple Brain Metastases in a Patient with ROS1 Fusion-Positive Lung Adenocarcinoma as a Disease Flare due to Crizotinib Cessation Caused by Disseminated Aseptic Inflammation from Crizotinib-Associated Renal Cysts: A Case Report

et al. 2022

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“…MSP/HGFL and HGF both function to promote liver differentiation, regeneration, and tissue repair. Both Ron and the closely-related Met receptor are protective in hepatic fibrosis [ 36 , 103 , 104 , 105 , 106 ]. Recombinant HGF, the ligand for Met, suppressed the progression in a mouse model of NASH, and MSP negatively regulated inflammation and lipogenesis in ex vivo models of NASH [ 54 , 106 , 107 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both Ron and the closely-related Met receptor are protective in hepatic fibrosis [ 36 , 103 , 104 , 105 , 106 ]. Recombinant HGF, the ligand for Met, suppressed the progression in a mouse model of NASH, and MSP negatively regulated inflammation and lipogenesis in ex vivo models of NASH [ 54 , 106 , 107 ]. Ron and Met primarily signal through the large adaptor protein, Gab1 and loss of Gab1 has been shown to aggravate experimental liver fibrosis in mice [ 108 , 109 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profiling Reveals Aggravated Non-Alcoholic Steatohepatitis in High-Fat High-Cholesterol Diet-Fed Apolipoprotein E-Deficient Mice Lacking Ron Receptor Signaling

et al. 2020

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Non-alcoholic steatohepatitis (NASH) represents the progressive sub-disease of non-alcoholic fatty liver disease that causes chronic liver injury initiated and sustained by steatosis and necroinflammation. The Ron receptor is a tyrosine kinase of the Met proto-oncogene family that potentially has a beneficial role in adipose and liver-specific inflammatory responses, as well as glucose and lipid metabolism. Since its discovery two decades ago, the Ron receptor has been extensively investigated for its differential roles on inflammation and cancer. Previously, we showed that Ron expression on tissue-resident macrophages limits inflammatory macrophage activation and promotes a repair phenotype, which can retard the progression of NASH in a diet-induced mouse model. However, the metabolic consequences of Ron activation have not previously been investigated. Here, we explored the effects of Ron receptor activation on major metabolic pathways that underlie the development and progression of NASH. Mice lacking apolipoprotein E (ApoE KO) and double knockout (DKO) mice that lack ApoE and Ron were maintained on a high-fat high-cholesterol diet for 18 weeks. We observed that, in DKO mice, the loss of ligand-dependent Ron signaling aggravated key pathological features in steatohepatitis, including steatosis, inflammation, oxidation stress, and hepatocyte damage. Transcriptional programs positively regulating fatty acid (FA) synthesis and uptake were upregulated in the absence of Ron receptor signaling, whereas lipid disposal pathways were downregulated. Consistent with the deregulation of lipid metabolism pathways, the DKO animals exhibited increased accumulation of FAs in the liver and decreased level of bile acids. Altogether, ligand-dependent Ron receptor activation provides protection from the deregulation of major metabolic pathways that initiate and aggravate non-alcoholic steatohepatitis.

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“…Therefore, it is of great significance to identify new and effective strategies for the treatment of liver fibrosis. There is increasing evidence indicates that several cell types are involved in the development of liver fibrosis (29,30). However, activation of HSCs is a central process in the pathogenesis of liver fibrosis (4), and the activation of HSCs is mediated by a variety of inflammatory factors and growth factors (5).…”

Section: Discussionmentioning

confidence: 99%

Plantamajoside exerts antifibrosis effects in the liver by inhibiting hepatic stellate cell activation

Wang

Yan

2019

Exp Ther Med

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The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs) into muscle fiber cells and fibroblasts. The aim of the current study was to investigate whether plantamajoside (PMS) exerted antifibrosis effects by affecting HSCs activation and survival during liver fibrosis, and to investigate the underlying mechanism. HSC-T6 cells were activated by exposure to platelet-derived growth factor BB (PDGF-BB), and were subsequently treated with increasing concentrations of PMS (0, 20, 40, 80 and 160 µg/ml). Cell viability, apoptosis, migration and invasion were determined using the Cell Counting Kit-8 (CCK-8) assay, flow cytometry and the Transwell assay, respectively. Results indicated that PDGF-BB significantly activated HSC-T6 cells, demonstrated by increased cell proliferation, enhanced cell migration and invasion as well as increased expression of α-smooth muscle actin (α-SMA) and collagen type 1 α 1 (Col1α1). PMS inhibited proliferation, induced cell apoptosis and prevented cell migration and invasion in PDGF-BB-treated HSC-T6 cells in what appeared to be a dose-dependent manner. PMS appeared to dose-dependently reduce the protein and mRNA levels of α-SMA and Col1α1 in PDGF-BB-treated HSC-T6 cells. Furthermore, the results of the present study suggested that PMS administration inhibited the protein expression of phosphorylated-protein kinase B in what appeared to be a dose-dependent manner. In conclusion, the data indicated that PMS exhibited an antifibrotic effect in the liver by inhibiting hepatic stellate cell activation and survival.

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c‐Met Signaling Protects from Nonalcoholic Steatohepatitis‐ (NASH‐) Induced Fibrosis in Different Liver Cell Types

Cited by 10 publications

References 56 publications

Multiple Brain Metastases in a Patient with ROS1 Fusion-Positive Lung Adenocarcinoma as a Disease Flare due to Crizotinib Cessation Caused by Disseminated Aseptic Inflammation from Crizotinib-Associated Renal Cysts: A Case Report

Multiple Brain Metastases in a Patient with ROS1 Fusion-Positive Lung Adenocarcinoma as a Disease Flare due to Crizotinib Cessation Caused by Disseminated Aseptic Inflammation from Crizotinib-Associated Renal Cysts: A Case Report

Metabolic Profiling Reveals Aggravated Non-Alcoholic Steatohepatitis in High-Fat High-Cholesterol Diet-Fed Apolipoprotein E-Deficient Mice Lacking Ron Receptor Signaling

Plantamajoside exerts antifibrosis effects in the liver by inhibiting hepatic stellate cell activation

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