Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wilms' tumor 1 gene (WT1) encodes a transcription factor involved in cell growth and development. As we previously reported, WT1 expression is hardly detectable in normal hepatic tissue but is induced in liver cirrhosis. Although WT1 has been found to be overexpressed in a number of malignancies, the role of WT1 in hepatocarcinogenesis has not been clarified. We found that WT1 is expressed in several human hepatocellular carcinoma (HCC) cell lines, including PLC/PRF/5 and HepG2, and in HCC tumor tissue in 42% of patients. WT1 small interfering RNAs did not affect proliferation rate of HCC cells but abrogated their resistance to anoikis. Transcriptome analysis of PLC/PRF/5 cells after WT1 knockdown showed up-regulation of 251 genes and down-regulation of 321. Ninety percent of the former corresponded to metabolic genes, mostly those characterizing the mature hepatocyte phenotype. On the contrary, genes that decreased upon WT1 inhibition were mainly related to defense against apoptosis, cell cycle, and tumor progression. In agreement with these findings, WT1 expression increased the resistance of liver tumor cells to doxorubicin, a compound used to treat HCC. Interestingly, doxorubicin strongly enhanced WT1 expression in both HCC cells and normal human hepatocytes. Among different chemotherapeutics, induction of WT1 transcription was restricted to topoisomerase 2 inhibitors. When WT1 expression was prohibited, doxorubicin caused a marked increase in caspase-3 activation. In conclusion, WT1 is expressed in a substantial proportion of HCC contributing to tumor progression and resistance to chemotherapy, suggesting that WT1 may be an important target for HCC treatment.
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PMID:Wilms' tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. 1919 Mar 40

The prevalence of hepatocellular carcinoma in Europe and the US is increasing and is currently the leading cause of death in patients with cirrhosis. Surveillance programs for patients with cirrhosis aim to detect tumors at an early stage, when the greatest therapeutic benefits can be achieved. Curative treatments for early-stage tumors include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib can improve survival for patients with intermediate and advanced tumors, respectively. In clinical practice, combination therapies are often used, despite limited evidence to support this approach from randomized controlled trials. Combination therapy with radiofrequency ablation (RFA) plus percutaneous ethanol injection can, however, improve survival for selected patients compared with RFA alone. Combined treatment with TACE and RFA also improves patients' survival compared with TACE or RFA monotherapy. TACE performed before or after surgical resection, however, is not beneficial. Prevention of tumor progression in patients awaiting liver transplantation requires nonsurgical treatments; however, the real advantages of the available treatment modalities are yet to be defined. The role of sorafenib administration in combination with TACE after the use of potentially curative treatments, for the treatment of intermediate hepatocellular carcinoma, or in selective settings after liver transplantation, requires further study.
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PMID:Multimodal approaches to the treatment of hepatocellular carcinoma. 1919 May 99

Under most circumstances, hepatitis B virus (HBV) is noncytopathic. However, hepatocellular regeneration that accompanies each bout of hepatitis appears to be associated with increased integration of HBV DNA fragments expressing the virus encoded hepatitis B x antigen (HBxAg). Intrahepatic HBxAg staining correlates with the intensity and progression of chronic liver disease (CLD), and additional work has shown that HBxAg blocks immune mediated killing by Fas and by tumor necrosis factor alpha (TNFalpha). This is not only associated with the blockage of caspase activities by HBxAg, but also by the constitutive stimulation of hepatoprotective pathways, such as nuclear factor kappa B (NF-kappaB), phosphoinositol 3-kinase (PI3K), and beta-catenin (beta-catenin). HBxAg also appears to promote fibrogenesis, by stimulating the production of fibronectin. HBxAg also stimulates the production and activity of transforming growth factor beta1 (TGFbeta1) by several mechanisms, thereby promoting the profibrogenic and tumorigenic properties of this important cytokine. In addition, HBxAg appears to remodel the extracellular matrix (ECM) by altering the expression of several matrix metalloproteinases (MMPs), which may promote tumor metastasis. Hence, HBxAg appears to promote chronic infection by preventing immune mediated apoptosis of infected hepatocytes, by promoting the establishment and persistence of fibrosis and cirrhosis preceding the development of HCC, and by promoting the remodeling of EMC during tumor progression.
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PMID:Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. 1920 Oct 80

Hepatocellular carcinoma (HCC) usually affects patients with chronic liver disease. While resection is the primary treatment of HCC in patients without cirrhosis, in the setting of moderate to severe cirrhosis, liver transplantation is the preferred therapy, as it simultaneously treats the tumor and the underlying liver condition. The optimal management of patients with HCC and early cirrhosis remains controversial. Although liver transplantation for HCC within the Milan criteria has been shown to have excellent long-term survival rates and low recurrence rates, its application is limited by organ availability. Due to the shortage of donors, a portion of patients drop out from the waiting list due to tumor progression. One alternative to transplantation is hepatic resection. In addition to the reported 50% 5-year survival rates, resection allows a better understanding of tumor biology through pathologic examination of the specimen, which may guide decision-making regarding salvage liver transplantation. Other nonsurgical locoregional therapies, such as transarterial chemoembolization and radiofrequency ablation, also serve as primary therapies and as a bridge to transplantation. The management of patients with early HCC is complex and multidimensional. The care of these patients is best served by a multidisciplinary approach, with consideration of the feasibility of transplantation weighed against the aggressiveness of the tumor biology and underlying hepatic dysfunction. All modalities of therapy should be viewed as complementary, not exclusive, therapeutic strategies.
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PMID:Management of early hepatocellular carcinoma in patients with well-compensated cirrhosis. 1926 61

Angiogenesis is an important therapeutic target in cancer, and to fully exploit its therapeutic potential, combination chemotherapeutic/antiangiogenic regimens should be optimized and delivered earlier to more patients. Ideally, this could be done by a single potent oral agent with established safety. Rifampicin, a semisynthetic antibiotic derived from the rifamycins, is one of the most commonly used pharmaceutical compounds worldwide in the treatment of tuberculosis. Here, we present the effects of oral rifampicin on human cancer progression and its antiangiogenic properties, which were comparable to the angiogenesis inhibitor endostatin. Clinically, low-dose p.o. administration of rifampicin to six high-risk patients with hepatitis C virus-related liver cirrhosis resulted in a single occurrence of hepatocellular carcinoma during the follow-up period of 97.3 +/- 29.1 (mean +/- SD) months. Experimentally, rifampicin rapidly and markedly down-regulated the expression of a wide spectrum of angiogenesis-associated genes in growing human microvascular endothelial cells, thereby suppressing endothelial cell proliferation and migration. Rifampicin, at higher concentrations, also directly inhibited the growth of a variety of human cancer cells. P.o. administration of rifampicin significantly inhibited in vivo growth and metastases of subcutaneous human cancer xenografts. Thus, the potent antiangiogenic properties of oral rifampicin therapy were effective in suppressing cancer progression. It provides a promising new addition to antiangiogenic strategies for designing human cancer therapies. Considering the clinical pharmacokinetics of rifampicin, which enters the enterohepatic circulation and undergoes subsequent hepatic accumulation, it may be especially beneficial as an antitumor agent targeting hepatobiliary tumors.
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PMID:Rifampicin as an oral angiogenesis inhibitor targeting hepatic cancers. 1945 74

Angiogenesis is essential to the survival, growth, invasion, and metastasis of various human solid tumors. We compared the microvessel density (MVD) and clinicopathologic features of two different groups of hepatocellular carcinoma (HCC), namely HCC with cirrhosis (HCC-C) and without cirrhosis (HCC-NC). A tissue microarray composed of 20 normal livers, 20 cirrhotic livers, tumor and adjacent background non-neoplastic liver tissues from 20 HCC-C and 20 HCC-NC were constructed and stained immunohistochemically with antibodies against the antigen CD34. The MVD was determined by the measurement of the area and density of CD34 positive sinusoidal endothelial cells using the Image Pro Plus software. There was a trend of increased MVD in cirrhotic liver compared to normal liver and in cirrhotic background non-neoplastic liver adjacent to the tumor compared to the non-cirrhotic background non-neoplastic liver. Tumor tissue of HCC-C and HCC-NC both showed significantly higher MVD than their adjacent background non-neoplastic liver tissue. There was no statistical difference in MVD between HCC-C and HCC-NC. A higher value of MVD was seen in tumors of intermediate size (5-10 cm), high histologic grade, the presence of lymphvascular space invasion, and the underlying etiology of hepatitis C and alcoholic steatohepatitis. This data indicates that MVD may play an important role in liver carcinogenesis and neoplastic progression. The difference in clinical behavior between HCC-C and HCC-NC does not seem to be associated with differences in tumor MVD. Objective measurement of MVD using standardized computer software could potentially be used as a clinical marker to predict patients' prognosis.
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PMID:Microvessel density and clinicopathologic characteristics in hepatocellular carcinoma with and without cirrhosis. 1966 92

Radiofrequency (RF) ablation has gained great popularity in the treatment of Hepatocellular Carcinoma (HCC) on cirrhosis and is replacing Percutaneous Ethanol Injection (PEI) in treating 3 cm or less HCC nodules. Its necrotic effect is more predictable than that of PEI and therefore RF can achieve a longer local tumor progression control and survival. In the last four years many data on its efficacy have been added in the Literature and long-term results on 3-5-year survival are available. In this Review article data of the last 4 years on percutaneous RF ablation of HCC on cirrhosis are discussed in order to give an answer to questions put forward on this matter at 2000 EASL Barcelona Consensus Conference. Moreover, new perspectives in the percutaneous treatment of some form of advanced HCC (the so-called percutaneous thrombectomy) are presented together with some patents in the treatment of HCC.
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PMID:Percutaneous radiofrequency ablation of hepatocellular carcinoma on cirrhosis: state of the art and future perspectives. 1966 3

A 58-year-old man with hepatocellular carcinoma (HCC) with liver cirrhosis type C was admitted to our division in April, 2004 to receive transarterial chemo-embolization (TACE) as a first-line chemotherapy for HCC. Thereafter, he had TACE twice for multicentric HCC. In December, 2005, TACE was thought to have become ineffective since his multicentric HCC progressed. So, we employed transarterial injection therapy (TAI) with fine powder cisplatinum (IAC) as a second-line chemotherapy. Stable disease was accomplished by the 22 sessions of TAI with IAC. After February 2008, IAC was given in combination with degradable starch microspheres (DSM) to reinforce the anti-cancer effect. The total therapeutic sessions using IAC became 26 in number. Total IAC amount used reached to more than 2,200 mg without any serious adverse reaction. In conclusion, TAI using IAC is thought to be effective in the chemotherapy of HCC, safely controlling the tumor progression.
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PMID:[A case of hepatocellular carcinoma with liver cirrhosis type C surviving over 2 years by repeated transarterial infusion therapy using cisplatinum]. 1969 76

Investigating aberrant DNA methylation in the cancer genome may identify genes that play an important role in tumor progression. In this study, we combined differential methylation hybridization and a CpG microarray platform to characterize methylation profiles and identify novel candidate genes associated with hepatocellular carcinoma (HCC). The genomic DNA of 21 paired adjacent normal and HCC samples was used, and results were analyzed by hierarchical clustering. Twenty-seven hypermethylated candidates and 38 hypomethylated candidates were obtained. Six candidate genes from the hypermethylated group were validated by combined bisulfite restriction analysis; two genes, human kallikrein 10 gene (KLK10) and oxoglutarate (alpha-ketoglutarate) receptor 1 gene (OXGR1), were further analyzed by bisulfite sequencing. The DNA hypermethylation status of KLK10 and OXGR1 were subsequently examined in HCC cell lines and clinical samples using methylation-specific PCR. In 49 HCC samples, 46 (94%) showed that at least one of these two genes was highly methylated. Moreover, KLK10 and OXGR1 mRNA levels were inversely correlated (r = -0.435 and -0.497, P < 0.05) with DNA methylation as examined in paired adjacent normal and tumor samples. Statistical analyses further indicated that KLK10 hypermethylation was significantly associated with cirrhosis (P = 0.042) and HCV infection (P = 0.017) as well as inversely associated with HBV infection (P = 0.023). Furthermore, restoration of KLK10 and OXGR1 expression reduced the ability of anchorage-independent growth, and sensitized HCC cells to doxorubicin- or 5-fluorouracil-induced cytotoxicity. Our results suggest that the hypermethylated KLK10 and OXGR1 are frequent in HCC and may be useful as markers for clinical application.
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PMID:Aberrant DNA methylation profile and frequent methylation of KLK10 and OXGR1 genes in hepatocellular carcinoma. 1976 Jun 8

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the most frequent types of cancer worldwide. It normally develops in patients with chronic liver disease, especially cirrhosis, although some cases without an apparent underlying liver disease have been reported. The pathogenesis of HCC is multi-factorial and complex. Hepatitis viruses are the main factors favoring the development of HCC. In fact, chronic inflammation associated with hepatitis C or B virus infection can lead to progressive liver fibrosis, cirrhosis and ultimately HCC. Chronic inflammation and liver fibrosis cause a continuous remodeling of the extracellular matrix (ECM), a dynamic process that involves several molecules including integrins and matrix processing enzymes. An increasing body of evidence indicates that ADAMs are involved in promoting tumor formation and progression of HCC. A Disintegrin And Metalloproteases (ADAMs) are a group of proteins belonging to the zinc protease superfamily. ADAMs are usually transmembrane proteins that contain disintegrin and metalloprotease domains and are, therefore, able to carry out both cell adhesion and protease activities. Soluble isoforms of ADAMs have also been discovered and characterized. In this review, we focus on the contribution of ADAM proteins to HCC tumorigenesis and cancer progression. The potential role of ADAMs as key modulators of tumor-stroma interactions during tumor progression, by means of the activities of their constituent domains, is also discussed.
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PMID:Involvement of ADAMs in tumorigenesis and progression of hepatocellular carcinoma: Is it merely fortuitous or a real pathogenic link? 2019 81


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