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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study the establishment and characterization of a nontumorigenic liver epithelial cell line (HACL-1) derived from a human hepatocellular adenoma is described. The HACL-1 cells have a finite life span (i.e., they proliferate for a period of 2 months and then senesce), show cell-cell contact inhibition, do not grow in soft agar, are not tumorigenic when injected in nude mice, and possess a normal diploid karyotype. The cultured cells resemble hepatocytes, but exhibit some features of dedifferentiation. At the ultrastructural level the cells are endowed with round or oval nuclei, abundant cytoplasmic organelles, and varying amounts of glycogen. The rough endoplasmic reticulum is disorganized, while peroxisomes and matrix granules within mitochondria are lacking. HACL-1 cells are cytokeratin 18-positive as well as (transiently) albumin- and alpha-fetoprotein-positive, but do not express cytokeratin 19. Furthermore, no mutations were observed in exons 5-8 of the tumor suppressor gene p53. Taken together these results show that HACL-1 cells are nontumorigenic proliferating liver epithelial cells, which might prove to be of great value in future studies on diverse aspects of human liver cell biology and carcinogenesis.
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PMID:Establishment and characterization of a nontumorigenic cell line derived from a human hepatocellular adenoma expressing hepatocyte-specific markers. 936 26

It is said that stable strontium (Sr), which exists naturally in living cells as a microelement, has cytoprotective effects on liver cells in mammals. We attempted to examine the cytoprotective and anticancer effects of Sr using the rat carcinogenetic model induced by DMH (1,2-dimethylhydrazine). In a comparison of animals given UFT, PSK and Sr or UFT and PSK, carcinogenes in the colon and also increases in immunosuppressive acidic protein (IAP) levels were suppressed. Electron microscopic observation in the Sr group revealed a tendency toward stabilization of the mitochondrial membrane and highly developed rough endoplasmic reticulum in both the right and left lobe. This tendency became more obvious as the duration of oral intake of Sr was prolonged. Our study suggest that the cytoprotective effect of Sr on mitochondria in the liver may suppress carcinogenesis.
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PMID:The efficacy of immunochemotherapy with strontium (Sr) in the 1,2-dimethylhydrazine (DMH) induced rat carcinogenetic model: ultrastructural characteristics of the mitochondria in the liver. 956 71

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

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are proteins implicated in tumor-associated microvascular angiogenesis. Expressions of VEGF and bFGF in various stages of chemical-induced rat bladder carcinogenesis were immunohistochemically investigated. Thirty-two male 6-week-old Wistar rats were given drinking water containing 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 20 weeks. VEGF and bFGF were not detected in the normal bladder epithelium. In simple hyperplasia, intensive expression of VEGF was observed in a few epithelial cells, and the expression of epithelial VEGF became more pronounced in papillary or nodular (PN) hyperplasia and papilloma. In carcinoma, heterogeneous expression of VEGF was observed in focal tumor cells, intensely expressed in the invading tumor cells. Ultrastructurally, carcinoma cells showed VEGF immunoreactivity in the cytoplasmic matrix and some rough endoplasmic reticulum, and VEGF-positive and -negative carcinoma cells were also clearly defined. High levels of VEGF mRNA were observed in the carcinoma. However, bFGF was not detected in the epithelium throughout the carcinogenesis. Increased microvessel counts appeared at simple hyperplasia and became more pronounced in PN hyperplasia, papilloma, and carcinoma (F-test; P < 0.05). In the carcinoma, the microvessel counts of the VEGF-expressing tumor areas were significantly higher than that of the non-VEGF-expressing tumor areas (U-test; P < 0.05). The present study suggests that upregulation of epithelial VEGF may begin at a quite early stage in BBN-induced rat bladder carcinogenesis, but bFGF may not be involved.
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PMID:Expression of vascular endothelial growth factor in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis. 1009 38

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance and a number of associated disorders that develop in the alcoholic. These were elucidated by the discovery of the microsomal metabolism of ethanol. The physiologic role of this system comprises gluconeogenesis from ketones, fatty acid metabolism, and detoxification of xenobiotics, including ethanol. After chronic ethanol consumption, the activity of the microsomal ethanol-oxidizing system (MEOS) increases, with an associated rise in cytochromes P-450, especially CYP2E1. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans. The role of MEOS in vivo and its increase after chronic ethanol consumption was shown most conclusively in alcohol dehydrogenase-negative deer mice. Enhanced ethanol oxidation is associated with cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, there is increased conversion of known hepatotoxic agents (such as CCl4) to toxic metabolites, which may explain the enhanced susceptibility of alcoholics to the adverse effects of industrial solvents. CYP2E1 also has a high capacity to activate some commonly used drugs, such as acetaminophen, to their toxic metabolites, and to promote carcinogenesis (e.g., from dimethylnitrosamine). Moreover, catabolism of retinol is accelerated and there also is induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs through competition for the at least partially shared microsomal pathway. In addition, metabolism by CYP2E1 results in a significant free radical release and acetaldehyde production which, in turn, diminish reduced glutathione (GSH) and other defense systems against oxidative stress. Acetaldehyde also forms adducts with proteins, thereby altering the functions of mitochondria and of repair enzymes. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP1A2 and CYP3A4, two other perivenular P-450s, can also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. By contrast, CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds were too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated lecithins extracted from soybeans, was discovered to decrease CYP2E1 activity. PPC (and its active component dilinoleoylphosphatidylcholine) also oppose hepatic oxidative stress and fibrosis. PPC is now being tested clinically for the prevention and treatment of liver disease in the alcoholic.
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PMID:Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)--a review. 1039 83

Machine learning techniques have improved predictions of secretory proteins from protein, genomic and expressed sequence tag (EST) sequences. Artificial neural networks, physical sequence analysis using high-performance optimization, and hidden Markov models identify extremely variable signal peptides (the vehicles of protein transport across the endoplasmic reticulum membrane), transmembrane segments, and specific extracellular and intracellular domains as indicators of possible roles in the intercellular and intracellular chemical signaling pathways. The major role of peptide hormones, blood coagulation factors, carcinogenesis agents, and other secretory proteins in orchestrating multicellular life indicates pharmacological potential in the cure of major diseases and numerous biotechnological applications.
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PMID:Large-scale predictions of secretory proteins from mammalian genomic and EST sequences. 1067 37

The effects of defatted soybean and/or iodine-deficient diet feeding were investigated in female F344 rats. Rats were divided into four groups, each consisting of 10 animals, and fed basal AIN-93G diet in which the protein was exchanged for 20% gluten (Group 1), iodine-deficient gluten (Group 2), 20% defatted soybean (Group 3) and iodine-deficient defatted soybean (Group 4). At week 10, relative thyroid gland weights (mg/100 g body wt) were significantly (P < 0.01) higher in Groups 2 (15.5 +/- 1.3) and 4 (81.7 +/- 8.6) than in Group 1 (8.4 +/- 2.0) and pituitary gland weights (mg/100 g body wt) were significantly (P < 0.01) higher in Groups 3 (9.1 +/- 0. 6) and 4 (9.7 +/- 1.5) than in Group 1 (6.5 +/- 1.5). Serum biochemical assays revealed thyroxine to be significantly (P < 0.05) lower in Groups 2 and 4 than in Group 1. On the other hand, serum thyroid-stimulating hormone (TSH) was significantly (P < 0.01) higher in Groups 3 and 4 than in Group 1. This was particularly striking for TSH (ng/ml) at week 10 in Group 4 (126 +/- 11) as compared with Groups 1 (4.36 +/- 0.30), 2 (4.84 +/- 0.80) and 3 (5. 78 +/- 0.80). Histologically, marked diffuse follicular hyperplasia of the thyroid was evident in Group 4 rats. Proliferating cell nuclear antigen labeling indices (%) were significantly higher (P < 0.05) in Groups 2 (4.8 +/- 2.5) and 4 (13.2 +/- 1.1) than in Group 1 (0.4 +/- 0.5). Ultrastructurally, severe disorganization and disarrangement of mitochondria were apparent in thyroid follicular cells of Group 4. In the anterior pituitary, dilated rough surfaced endoplasmic reticulum and increased secretory granules were remarkable in this group. Our results thus strongly suggest that dietary defatted soybean synergistically stimulates the growth of rat thyroid with iodine deficiency, partly through a pituitary-dependent pathway.
Carcinogenesis 2000 Apr
PMID:Dramatic synergism between excess soybean intake and iodine deficiency on the development of rat thyroid hyperplasia. 1075 7

RTP, also called Drg1/Cap43/rit42/TDD5/Ndr1, was originally identified as a homocysteine-responsive gene product, and is now considered to be involved in stress responses, atherosclerosis, carcinogenesis, differentiation, androgen responses, hypoxia, and N-myc pathways. We raised an antiserum against a recombinant human RTP. Western blot analysis showed that RTP expression was induced in human umbilical vein endothelial cells under conditions causing endoplasmic reticulum stress. RTP was partially phosphorylated at seven or more sites. The phosphorylation was reversible, and was enhanced by an increased level of intracellular cAMP and inhibited by both a protein kinase A inhibitor and a calmodulin kinase inhibitor. Protein kinase A directly phosphorylated recombinant RTP in vitro. The phosphorylated forms were abundant in cells at the early log phase, and then decreased with increasing cell density. These data demonstrated that RTP is a phosphorylated stress-responsive protein, and its phosphorylation may be related to cell growth.
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PMID:Phosphorylation of RTP, an ER stress-responsive cytoplasmic protein. 1086 Aug 7

Although there is evidence for specific subcellular morphological alterations in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), it is not clear whether these morphological changes are stereotypical or if they depend on the specific misfolded protein retained. This issue may be particularly important for mutant secretory protein alpha(1)-antitrypsin (alpha(1)AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with alpha(1)AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression and ER retention of mutant alpha(1)ATZ and in human liver from three alpha(1)AT-deficient patients. In addition to marked expansion and dilatation of ER, there was an intense autophagic response. Mutant alpha(1)ATZ molecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of alpha(1)ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTRDeltaF508, expression of mutant alpha(1)ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant alpha(1)ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of alpha(1)AT-deficient patients attempts to protect itself from injury and carcinogenesis.
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PMID:Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. 1105 93

Tumors of the exocrine pancreas of the inbred strain 13 guinea pigs, induced by N-methyl-N-nitrosourea, reveal duct-like glandular differentiation and marked desmoplastic reaction of the stroma, characteristic of adenocarcinoma of human pancreas. During the course of induction of these tumors in the guinea pigs by N-methyl-N-nitrosourea, atypical pseudo-ductular proliferations were encountered in the pancreas which appeared to be precursor lesions for pancreatic carcinoma. The histogenesis of these pseudo-ductular lesions was studied by light and electron microscopy. The earliest changes consisted of dilatation of acinar lumina with decrease of apical cytoplasm and increased mitotic activity of the acinar cells. The actively proliferating, well-formed pseudo-ductules were lined by cuboidal or flattened epithelium containing a prominent nucleus and scant cytoplasm with few or no discernible zymogen granules by light microscopy. By electron microscopy, the cells lining the pseudo-ductules displayed features of immature or embryonic pancreatic acinar cells characterized by prominent nucleoli, marked decrease in rough endoplasmic reticulum with increase of free ribosomes, atypical zymogen granules and abundant microfilaments and microtubules. In two guinea pigs, transition from pseudo-ductular changes to adenocarcinoma was clearly evident. On the basis of these findings, it is proposed that the pseudo-ductular lesions of the guinea pig pancreas, and possibly those occuring in other species, are derived from acinar cells as a consequence of carcinogen induced cell proliferation leading to immature or dedifferentiated phenotypes. This hypothesis can, in part, be confirmed by immunocytochemical localization of pancreatic acinar cell specific secretory proteins and lectins in these pseudo-ductules.
Carcinogenesis 1980
PMID:Histogenesis of pseudo-ductular changes induced in the pancreas of guinea pigs treated with N-methyl-N-nitrosourea. 1127 7


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