Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

Iredale, John P.; Bataller, Ramón

doi:10.1053/j.gastro.2014.03.019

Cited by 21 publications

(16 citation statements)

References 19 publications

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“…The stroma and the tumor cells always create a complex system with reciprocal signaling [24].Uncontrolled or sustained damage of liver tissue with the activation and infiltration HSC is now recognized as a hallmark feature of HCC development and metastasis [25]. Accumulating evidence supports the concept that activated HSCs are the main matrix-producing cells in the process of liver fibrosis, resulting in ECM accumulation and HCC progression [26,27]. The functions of CCN family proteins are involved in the regulations of HCC microenvironment [28].…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

Wei¹,

Wang²,

Zhang³

et al. 2018

Oncotarget

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Background: Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. While, the precise mechanism associated with HSCs trending, infiltration and remodeling is still vague in HCC, especially in Oxaliplatin-resistant HCC.Materials and Methods: The chemoresistant cell and mouse model, and the HCC clinical samples were collected and were established. We explored the relationship between secretory CCN3 from Oxaliplatin-resistant HCC and the infiltration of HSCs in Oxaliplatin-resistant HCC microenvironment. We also evaluated the associated mechanism of HSCs infiltration and HSCs remodeling in HCC with high expression of CCN3.Results: We constructed oxaliplatin-resistant HCC models and found the increased infiltration of HSCs into the microenvironment. We reanalyzed the cDNA profiles of the oxaliplatin-resistant HCC and found CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then we proved that CCN3 could enhance the migration and proliferation of HSC, and induce the remodeling of HSC with elevation of cytokines relating to HCC malignancy, which was related to ERK signaling pathway activation. Finally, we confirmed that the role of CCN3 enhanced the transmigration of HSCs using the xenograft tumor model. Conclusions: HSCs transmigration and remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

Wei¹,

Wang²,

Zhang³

et al. 2018

Oncotarget

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“…68,87 This apparent dual role of VEGF in fibrogenesis and fibrosis resolution resembles that seen with macrophages overall and highlights an important point when considering translational strategies: namely that caution needs to be exercised when identifying antifibrotic targets as these molecules may also have a key role in fibrosis resolution. 88 What remains to be seen is how closely this murine macrophage heterogeneity relates to human disease. Similar to murine Kupffer cells, a population of "resident" macrophages can be identified in human cirrhotic liver as CD14 l°C D16 À , while human hepatic monocyte-derived macrophages could be defined as CD14 hi CD16 À and CD14 þ CD16 þ subsets.…”

Section: The Role Of the Macrophagementioning

confidence: 99%

Resolution of Liver Fibrosis: Basic Mechanisms and Clinical Relevance

2015

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With evidence from a large number of animal models and clinical trials, it is now beyond debate that liver fibrosis and even cirrhosis are potentially reversible if the underlying cause can be successfully eliminated. However, in a significant proportion of patients cure of the underlying disease may not result in fibrosis regression or a significant reduction of the risk for hepatocellular carcinoma development. Understanding of the mechanistic pathways and regulatory factors that characterize matrix remodeling and architectural repair during fibrosis regression may provide therapeutic approaches to induce or accelerate regression as well as novel diagnostic tools. Recent seminal observations have determined that in resolving liver fibrosis a significant proportion of hepatic stellate cell-myofibroblasts (HSC-MFs) can revert to a near quiescent phenotype. Hepatic macrophages derived from inflammatory monocytes may contribute to fibrosis resolution through an in situ phenotypic switch mediated by phagocytosis. Emerging therapeutic approaches include deletion or inactivation of HSC-MFs, modulation of macrophage activity and autologous cell infusion therapies. Novel noninvasive diagnostic tests such as serum and imaging markers responsive to extracellular matrix degradation are being developed to evaluate the clinical efficacy of antifibrotic interventions.

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“…Liver fibrosis is considered as the first common step of different liver diseases toward cirrhosis and its complications, such as liver failure, hepatocellular carcinoma and death [2, 3]. It is preventable and at least partially reversible if the underlying etiology is removed [1–3]. For instance, in the general Dutch population the prevalence of clinically relevant liver fibrosis is 5.6% and it is strongly associated with higher age, steatosis and diabetes [4].…”

Section: Introductionmentioning

confidence: 99%

Presence of atrial fibrillation is associated with liver stiffness in an elderly Finnish population

et al. 2017

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BackgroundChronic liver injury from different etiologies drives liver fibrosis. However, little is known about the associated factors, systemic factors in particular. Recently, non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation have been shown to be associated with each other. Thereby, we aimed to study the association between atrial fibrillation and liver stiffness.StudyExtensive clinical measurements including echocardiography of the heart, transient elastography (TE) of the liver and the presence of atrial fibrillation were determined in elderly Finnish study subjects (n = 76, mean age 73 years) from OPERA (Oulu Project Elucidating the Risk of Atherosclerosis) study cohort. Half of the study subjects had non-alcoholic fatty liver disease, whereas others did not have any known hepatic morbidity. The present study was cross-sectional by nature.ResultsThe subjects with atrial fibrillation had higher TE values (with atrial fibrillation TE = 9.3kPa, without atrial fibrillation TE = 6.3kPa, p = 0.018). When the cohort was divided to four subgroups (those without NAFLD or atrial fibrillation, with NAFLD but without atrial fibrillation, with both conditions, and with atrial fibrillation but without NAFLD), the TE value was the highest in the subjects with both conditions (5.3kPa, 7.4kPa, 10.8kPa and 7.8kPa, respectively, p = 0.019). Moreover, the higher the TE value, the more prevalent atrial fibrillation was (the atrial fibrillation prevalence by tertiles of TE 27% / 36% / 77%, p = 0.001). Likewise, the greater the TE value, the greater the left atrial diameter, a collateral of atrial fibrillation (left atrial diameters by tertiles of TE 39mm / 45mm / 48mm, p<0.001) was. All these p-values for continuous variables remained statistically significant even after adjustment for common clinically relevant risk factors.ConclusionsThere is an association between atrial fibrillation and liver stiffness. This novel association may have multiple explanations and mechanistic links, which are discussed here and need further studies, prospective studies in particular.

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Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

Cited by 21 publications

References 19 publications

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

Resolution of Liver Fibrosis: Basic Mechanisms and Clinical Relevance

Presence of atrial fibrillation is associated with liver stiffness in an elderly Finnish population

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