Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor p53 exerts important protective functions towards DNA-damaging agents. Its inactivation by allelic deletions or point mutations within the P53 gene as well as complex formation of wildtype p53 with cellular or viral proteins is a common and crucial event in carcinogenesis. Mutations increase the half-life of the p53 protein allowing the immunohistochemical detection and anti-p53 antibody formation. Distinct G to T point mutations in codon 249 leading to a substitution of the basic amino acid arginine by the neutral amino acid serine are responsible for the altered functionality of the mutant gene product and were originally identified in 8 of 16 Chinese and 5 of 10 African HCC patients. Both groups are frequently exposed to mycotoxin contaminations of their food. Today an average P53 gene mutation rate of 25% is assumed for high-aflatoxin B1-exposure regions. This is double the rate observed in low-aflatoxin B1-exposure countries. Although many HCC patients displaying P53 mutations also suffer from HBV infection, which itself can lead to rearrangements of P53 coding regions or induce the synthesis of viral proteins possibly interacting with p53, the specific G to T transversion within codon 249 of the P53 gene seems to directly reflect the extent of aflatoxin B1 exposure.
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PMID:Point mutations of the P53 gene, human hepatocellular carcinoma and aflatoxins. 830 Oct 66

The extracellular matrix (ECM) located in and around tumors is different from normal organ stroma, and there is evidence that it is critically involved in carcinogenesis and malignant growth. Whereas an abnormal composition of ECM in hepatocellular carcinomas (HCC's) has previously been demonstrated, not much is known so far with respect to putative HCC precursor lesions. We have, therefore, systematically analyzed the immunohistochemical reactivity for two major ECM components, tenascin and type IV collagen, in three types of liver cell dysplasia (LCD), and compared the findings with patterns observed in HCC's of different types and grades. Tenascin reactivity was generally stronger in HCC's than in cirrhosis. In cirrhotic nodules harboring areas of LCD, tenascin expression was significantly lower in small cell LCD than in large cell LCD. Type IV collagen reactivity in and around HCC's decreased as a function of a lower differentiation grade. In both groups of cirrhosis, i.e. with or without HCC, cirrhotic nodules occupied by the small cell variant of LCD exhibited a significantly lower type IV collagen reactivity than those with large cell LCD or simple regenerative cells. Taken together these findings suggest that, similar to adenomatous hyperplasia, small cell LCD is characterized by an abnormal tenascin and type IV collagen expression, thus reflecting the defective ECM pattern observed in HCC's.
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PMID:Tenascin and type IV collagen expression in liver cell dysplasia and in hepatocellular carcinoma. 886 54

Tigroid cell foci (TCF) are a well-defined entity induced in rat liver by chemical carcinogens, their significance for hepatocarcinogenesis being controversial. Using cytomorphological, cytochemical and morphometric approaches, we studied the evolution and fate of TCF sequentially from 7 to 110 weeks in groups of 50 male Sprague-Dawley rats, which remained untreated or received N-nitrosomorpholine (NNM) orally at concentrations of 3 and 1 mg/kg body wt/day for 7 and up to 75 weeks, respectively. An increased incidence of hepatocellular neoplasms developed in exposed animals compared with controls, which was significant for adenomas at both dose levels, and for carcinomas (HCC) after the longer exposure to the lower dose level (P < 0.0001). TCF appeared frequently in addition to other types of proliferative foci of altered hepatocytes (FAH) including clear/acidophilic and mixed cell foci (MCF) in NNM-treated and rarely in untreated rats. Striking similarities in the cellular phenotypes of TCF and many hepatocellular neoplasms indicated the potential of TCF for progression to both adenomas and carcinomas. TCF emerged from xenomorphic cell foci (XCF), which consisted of hypertrophied hepatocytes typically presenting an enlarged nucleus, abundant glycogen, smooth and rough endoplasmic reticulum, altered activities of several enzymes of carbohydrate metabolism and an increased cell proliferation (P < 0.001) compared with the extrafocal parenchyma. TCF shared many features with XCF, but their basophilia and proliferative activity was higher. The number of FAH appearing at the two dose levels of NNM was similar but the average size of TCF and MCF was frequently higher at late time points in the group developing a significantly higher incidence of HCC, which suggests a pronounced acceleration of neoplastic conversion in established preneoplastic cell populations rather than the induction of additional FAH by sustained effects of low doses of carcinogens.
Carcinogenesis 1998 Dec
PMID:Xenomorphic hepatocellular precursors and neoplastic progression of tigroid cell foci induced in rats with low doses of N-nitrosomorpholine. 988 59

A close relationship and possible interaction has been noted between alcohol intake and hepatitis C virus infection, since the discovery of HCV markers. It is not understood whether these are additive or synergistic effects in causing liver injury. Interactions between alcohol and HCV may be studied at several levels, including epidemiology, virology (including viral load), histology (effect on the severity of liver lesions), carcinogenesis (the role of alcohol in the occurrence of hepatocellular carcinoma), and the effect on the extrahepatic manifestations or severity of HCV infection. At the epidemiological level, a high prevalence of HCV infection was noted in patients with alcoholic liver diseases (14-37%), also characterized by a high rate of viral replication as detected by PCR, which was present in over 90% of patients tested. Moreover, the prevalence of anti-HCV antibodies increased proportionally with the severity of liver lesions. Virological analysis based on the determination of HCV RNA levels in the serum showed variations of HCV RNA levels with diet, and a clear relationship between self reported alcohol consumption and the levels of serum HCV RNA (r = .26, p = .001). At the histologic level the role of alcohol may be evaluated either through the development of fibrosis or by determination of the incidence of cirrhosis. A study on the effect of alcohol intake below or over 40 g per day on the histologic progression of liver lesions has confirmed a more rapid increase in fibrosis and a doubling in the incidence of cirrhosis in patients admitting to alcohol consumption >40 g per day. The role of alcohol in the occurrence of hepatocellular carcinoma in patients with cirrhosis due to HCV infection has been extensively studied with controversial results. A recent case control study performed in Italy showed that the relative risk of HCC in patients with HCV infection and heavy alcohol consumption doubled. Finally, alcohol consumption potentially worsens the evolution of dermatological diseases associated with HCV infection such as porphyria cutanea tarda. All of the above are strong arguments which should be used to advise HCV patients against alcohol consumption, regardless of the degree of liver injury. However, the deleterious effect of the occasional intake of small amounts of alcohol has not been demonstrated and therefore an occasional drink may be allowed in some cases.
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PMID:Hepatitis C and alcohol. 1062 72

Currently, one of the most popular applications of proteomics is in the area of cancer research. In Africa, Southeast Asia, and China, hepatocellular carcinoma is one of the most common cancers, occurring as one of the top five cancers in frequency. This project was initiated with the purpose of separating and identifying the proteins of a human hepatocellular carcinoma cell line, HCC-M. After two-dimensional gel electrophoresis separation, silver staining, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses, tryptic peptide masses were searched for matches in the SWISS-PROT and NCBI nonredundant databases. Approximately 400 spots were analyzed using this approach. Among the proteins identified were housekeeping proteins such as alcohol dehydrogenase, alpha-enolase, asparagine synthetase, isocitrate dehydrogenase, and glucose-6-phosphate 1-dehydrogenase. In addition, we also identified proteins with expression patterns that have been postulated to be related to the process of carcinogenesis. These include 14-3-3 protein, annexin, prohibitin, and thioredoxin peroxidase. This study of the HCC-M proteome, coupled with similar proteome analyses of normal liver tissues, tumors, and other hepatocellular carcinoma cell lines, represents the first step towards the establishment of protein databases, which are valuable resources in studies on the differential protein expressions of human hepatocellular carcinoma.
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PMID:Two-dimensional electrophoresis map of the human hepatocellular carcinoma cell line, HCC-M, and identification of the separated proteins by mass spectrometry. 1087 Sep 66

Relationship between p53 protein overexpression and clinicopathological findings and the proliferative activity was studied in 50 cases of hepatocellular carcinoma (34 biopsy and 16 surgically resected cases) using immunohistochemistry. Overexpression of p53 was observed in 26.5% of biopsy cases and 31. 3% of surgically resected cases. Investigation of the relationship between the p53-positive rate and the clinical stage of HCC showed that it was significantly higher in Stage IV (the most advanced cancer; 54.5%) than in Stage I/II/III (13.0%) (p<0.05). Examination of the relationship between the p53-positive rate and tumor differentiation in the biopsy cases showed that p53 was positive in 9.1% of well differentiated carcinomas, 21.4% of moderately differentiated carcinomas, and 55.6% of poorly differentiated carcinomas, indicating that p53 positivity increased as tumors became less differentiated. The p53-positive rate of poorly differentiated carcinoma (55.6%) was significantly higher than that of well and moderately differentiated carcinoma (16.0%) (p<0.05). In the surgically resected cases, p53 overexpression tended to be more frequent in the less differentiated parts of each tumor nodule. In cases with nodule in nodule pattern of HCC, the p53-positive rate was different among nodules with the same level of differentiation. Examination of tumor cell proliferative activity using the proliferating cell nuclear antigen L.I. showed that this indicator was significantly higher in the p53-positive tumors than in the p53-negative tumors (52.7+/-32.4% vs. 32.4+/-15.3%: p<0.05). These results suggest that p53 overexpression may be involved in determining the dedifferentiation and the proliferative activity of HCC. Examination of the surgically resected cases confirmed that p53 overexpression became heterogeneous during the multistep carcinogenesis and growth process of HCC, which is considered to develop from a single cell. This finding suggests that p53 overexpression may be involved in tumor progression.
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PMID:Relationship between p53 overexpression and the proliferative activity in hepatocellular carcinoma. 1089 56

Nickel(II) is a human carcinogen causing respiratory cancers. The purpose of this study was to determine whether Ni(II) may induce microsatellite mutations in human cells. We transfected the three human lung tumor cell lines A427, HCC15 and NCI-H2009 with a mammalian expression vector containing a (CA)(13) repeat in the coding sequences of the reporter hygromycin gene (hyg). A total of 33 clones carrying the integrated vector derived from the three cell lines was investigated for spontaneous and Ni(II)-induced hygromycin-resistant (hyg(r)) reversion mutants. Significantly higher frequencies of hyg(r) reversion mutations were observed in Ni(II)-treated cells (NCI-H2009 and HCC-15) than control cells. In the majority of the colonies hyg(r) phenotype was due to mutations within the integrated (CA) repeat sequence. The type of mutations consisted of both contraction and expansion of the (CA) repeat unit. The finding that Ni(II) promotes microsatellite mutations raises the possibility that genetic instability may be a mechanism involved in nickel carcinogenesis.
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PMID:Nickel(II) induces microsatellite mutations in human lung cancer cell lines. 1089 95

HCC is the most severe complication of liver cirrhosis. For the majority of patients the chances of cure are still limited. The recent experience in liver transplantation for HCC in the authors unit and in other centers allows the definition of a subgroup of patients, with small tumors (up to 3.0 cm, or 5 cm if solitary), no more than 3 nodules, and the absence of portal vein tumor thrombus. In these patients, liver transplantation offers a disease-free survival that is better than after liver resection, and similar to the survival of liver transplantation for benign liver disease. Patients with contraindications to transplantation, patients in whom a long waiting-time before transplantation is anticipated, and patients in countries with limited access to transplantation can be treated with a palliative intent (because of de novo tumors) by liver resection. Depending on liver function and local expertise, percutaneous ethanol injection (PEI) can be equally effective for small HCC. Other forms of treatment currently being evaluated, such as radio-frequency, thermal destruction or cyro-therapy, offer advantages similar to PEI without the need for multiple sessions. Further progress will probably come from a wider use of screening to detect a larger proportion of treatable lesions, and from strategies to prevent carcinogenesis in the cirrhotic liver, and possibly from innovative treatments such as gene therapy to alter the tumor biology.
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PMID:[Multimodal therapy concepts in hepatocellular carcinoma]. 1096 Sep 77

The pathogenesis of HCC is poorly understood at present. There is insufficient understanding to propose a robust general model of hepatic carcinogenesis, partly because pathogenic host and environmental factors show significant regional variation, making such generalization difficult. Figure 4 is a model based on data presented in this article. Multiple risk factors for HCC have been identified, including cirrhosis, male gender, increasing patient age, toxins, chronic viral hepatitis, and other specific liver diseases. The understanding of how the individual risk factors result in genetic changes is rudimentary, and there is even less understanding about interactions between risk factors. Future studies should acknowledge the geographic origin of the HCCs studied and consider the effects of cirrhosis, gender, and age. A more rigorous approach to these factors may help explicate the interaction with specific liver diseases so that a comprehensive model of hepatic carcinogenesis can be developed.
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PMID:Pathogenesis of hepatocellular carcinoma. 1121 20

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.
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PMID:A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas. 1124 31


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