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

Skin papillomas and squamous cell carcinomas (SCCs) are induced in mice by tumor initiation with a carcinogen followed by tumor promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). These usually arise from preneoplastic lesions characterized by epidermal proliferation and hyperplasia, dermal edema, and inflammation. To evaluate the role of polypeptide growth factors in chemically induced skin carcinogenesis, we used transgenic mice carrying the cDNA for a TGF-beta related molecule, bone morphogenetic protein-4 (BMP-4), under the control of the regulatory elements of the cytokeratin IV* gene in a skin carcinogenesis protocol. Control non-transgenic littermates and BMP-4 transgenic mice were treated with a single dose of a carcinogen, N-methyl-N'-nitrosoguanidine (MNNG), and biweekly with the tumor promoter TPA for 9 months. In control littermates TPA induced epidermal hyperproliferation, atypia with "dark" cells, and dermal inflammation, resulting in papillomas and SCCs in 13 of 26 animals tested. In BMP-4 transgenic mice, TPA treatment induced the expression of the BMP-4 transgene in interfollicular epidermis but only minimal epidermal thickening, hyperproliferation, and inflammation were noted after the initial dose of TPA. Furthermore, the mitotic indices in transgenic epidermis after 9 months of TPA treatment were significantly lower than the corresponding indices from untreated transgenic epidermis. Consequently, none of the 22 transgenic animals tested developed papillomas or SCCs. In conclusion, we have shown that the TPA induced expression of the BMP-4 transgene blocks proliferation and inflammation in skin, steps that are critical to the subsequent formation of papillomas and SCCs and we characterized an inducible promotersystem which expresses polypeptides in interfollicular epidermis after exogenous stimulation.
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PMID:Chemical skin carcinogenesis is prevented in mice by the induced expression of a TGF-beta related transgene. 760 88

Inositol hexaphosphate (InsP6 or phytic acid) has been shown to have antineoplastic action in in vivo models of colon carcinogenesis. We therefore investigated its effect on proliferation and differentiation of the human colon cancer cell line HT-29 in vitro. Proliferation was evaluated by neutral red incorporation assay, and differentiation was assessed by expression of the markers, cytokeratin, carcinoembryonic antigen (CEA) and beta-D-galactose-[1-->3]-N-acetyl-galactosamine (Gal-GalNAc). InsP6 in the culture media (0.66-10 mM) inhibited cell proliferation in a dose-dependent manner (P < 0.001), while inositol or inositol hexasulfate used as controls or media without InsP6 did not show any suppressive effect. The expression of the tumor marker, Gal-GalNac, was augmented (100.7% increase) by low dose (0.66 mM) of InsP6 but was subsequently suppressed with higher concentrations of InsP6. The expression of cytokeratin and CEA were both augmented by either InsP6 or inositol at all concentrations tested, although the degree of augmentation was milder with inositol than with InsP6. The combination of InsP6 and inositol (both 0.66 mm) resulted in augmentation (P < 0.001) of cytokeratin expression, while that of CEA remained unchanged. The inhibitory effect of InsP6 on cell proliferation was not altered by combination with additional inositol at any concentrations tested. Our results show that InsP6 inhibits cell proliferation and concomitantly increases differentiation and is therefore a candidate chemopreventive and chemotherapeutic agent for human large intestinal cancer.
Carcinogenesis 1993 Sep
PMID:Growth inhibition and differentiation of HT-29 cells in vitro by inositol hexaphosphate (phytic acid). 769 27

Immunohistochemical studies have been used to show the time course for the cell-specific methylation of DNA in the upper gastrointestinal tract of rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The doses used were 1, 5, 25 and 50 mg MNNG/kg (i.g.) and tissue samples were analysed at intervals of from 1 to 192 h after treatment. Relatively little reaction with nuclear DNA was observed in the forestomach and still less in the oesophagus. Reaction with DNA was most extensive in the corpus, pylorus and the duodenum, reaching a peak of staining intensity between 2 and 4 h and then declining progressively there-after. Staining for the presence of O6-methyldeoxyguanosine (O6-MedG) in DNA was highly selective and tended to occur in the nuclei of the basal cell of the oesophagus and forestomach and in the cells of the lumenal border of the glands and villi of the corpus, pylorus and duodenum. There were also areas, 5-15, glands apart where staining for O6-MedG in the corpus and pylorus extended as far down as the basal mucosa. From 12 h after MNNG treatment, in the corpus and pylorus, a band of strongly methylated cells became apparent about 3-6 cells deep from the lumen and remained identifiable up to 168 h after treatment with the higher doses. These cells, which apparently have a very low O6-MedG repair capacity, are stationary (i.e. not part of the escalator) and are located in the mesenchymal tissue elements as demonstrated by staining of serial sections with cytokeratin or vementin. The significance of this population of cells is unknown.
Carcinogenesis 1995 Mar
PMID:Identification in rat stomach mucosae of a cell population characterized by a deficiency for the repair of O6-methyldeoxyguanosine from DNA. 769 99

We compared morphological, biological and molecular biological patterns of a newly established, spontaneously immortalized pancreatic ductal cell line, TAKA-1, with a hamster pancreatic ductal adenocarcinoma cell line, PC-1. PC-1 cells grew in a monolayer on plastic tissue culture flasks, whereas TAKA-1 cells required type I collagen gel matrix to propagate. The growth rate and argyrophilic nuclear organizer region (Ag-NOR) counts were greater in PC-1 cells than in TAKA-1 cells. More TAKA-1 cells were in G0/G1 and less were in the S cell cycle phase than PC-1 cells. Karyotypically, the consistent change in TAKA-1 cells was an abnormal no. 3 chromosome, whereas additional chromosomal abnormalities were found in PC-1 cells. Ultrastructurally, TAKA-1 cells formed ductal structures and were composed of two types of cells, as in the normal hamster pancreatic ducts, whereas PC-1 cells were pleomorphic, showed evidence for loss of differentiation and contained intracytoplasmic lumens. Unlike the PC-1, TAKA-1 cells did not show a point mutation at codon 12 in the c-Ki-ras oncogene and did not grow in soft agar. Receptor binding assay showed specific epidermal growth factor binding to both cell lines, but secretin binding only to TAKA-1 cells. Both cells produced and released transforming growth factor-alpha in serum-free medium. Both cell lines expressed blood group A antigen, carbonic anhydrase, coexpressed cytokeratin and vimentin, and reacted with tomato and Phaseolus vulgaris leucoagglutinin (L-PHA) lectins. The results demonstrate that chromosomal abnormalities, cell cycle patterns, expression of cytokeratin 18, lectin bindings and the c-Ki-ras mutation are the features that distinguish the benign from the malignant pancreatic ductal cells in Syrian hamster.
Carcinogenesis 1995 Apr
PMID:Differences in molecular biological, biological and growth characteristics between the immortal and malignant hamster pancreatic cells. 772 76

Primary human ovarian surface epithelial (HOSE) cells were immortalized by a retroviral vector (LXSN-16E6E7) expressing HPV-E6E7 open reading frames (ORF). Immortalizations of primary ovarian epithelial cells were achieved in three of three attempts. Detailed analysis was carried out in one line, HOSE 6-3, selected on the basis of its epithelial morphology. The immortalized line (HOSE 6-3) was nontumorigenic in nude mice when examined at subculture number 20. Cytogenetic analysis confirmed its human origin and detailed karyotypic analysis revealed a mixed karyotype made up of about 60% of diploid and 40% of near-tetraploid cells. Clonal chromosomal aberration was observed in a subpopulation of cells involving a ring chromosome number 9. Immunofluorescence and two-dimensional gel electrophoresis revealed the presence of vimentin and several species of cytokeratin (K7, K8, K18, K19). The profile of the cytoskeletal filaments of HOSE 6-3 cells is largely identical with that of normal ovarian epithelial cells before immortalization. The immortalized ovarian epithelial cells have a lower sensitivity to TGF-beta 1 inhibition compared to normal ovarian epithelial cells. The immortalized line, HOSE 6-3, has altered growth properties including a higher proliferation rate, plating efficiency, and saturation density. The establishment of a continuous line of human ovarian epithelial cells may provide an in vitro model for study of carcinogenesis in human ovarian cancers.
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PMID:Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV-E6E7 ORFs). 779 85

As in most other tumor types, expression of mutated or phenotypically altered p53 is a common occurrence in head and neck carcinogenesis. Since the prognosis for many head and neck tumor patients is severely affected by the occurrence of multiple primary and secondary tumors, we have analyzed the phenotype and genotype of p53 in squamous and respiratory epithelia either adjacent to or at significant distance from the primary tumors. Many tumor patients showed multifocal overexpression of the p53 protein in a variety of these epithelia. Overexpression of p53 correlated with increased proliferation and dedifferentiation, as demonstrated by immunohistochemistry and in situ hybridization using histone H3 and cytokeratin-specific probes. Polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing of p53 DNA, amplified from these biopsies after immunostaining and microdissection, confirmed and extended these findings. We have identified different mutations in p53 in different tumor-distant epithelia from the same patients. The data indicate that mutation of p53 is an early event in head and neck carcinogenesis, preceding signs of overt neoplasia, and that different mutations in p53 in multiple foci may provide a molecular basis for the development of multiple tumors.
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PMID:Expression of mutated p53 occurs in tumor-distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors. 836 14

Changes in cell cytoskeleton are known to play an important role in differentiation and embryogenesis and also in carcinogenesis. Previous studies indicated that neonatal hepatocytes undergo an epithelial-mesenchymal transition when cultured in a serum-free medium for several days. Here we show by Western blotting of neonatal rat liver cells cultured for 3 days that vimentin and cytokeratin were expressed by these cells. Epidermal growth factor treatment induced high coexpression of vimentin and cytokeratin filaments in hepatocytes from neonatal livers, as detected by double immunofluorescence microscopy. Confocal scanning laser microscopy was used to determine the spatial and cell distribution of cytokeratin and vimentin intermediate filament networks. Vimentin-expressing hepatocytes were mainly located on the periphery of epithelial clusters and presented a migratory morphology, suggesting that vimentin expression was related to the loss of cell-cell contact. Short vimentin filaments were mainly located at the cytoplasmic sites behind the extending lamella. Horizontal and vertical dual imaging of double immunofluorescence with anti-vimentin and anti-cytokeratin antibodies indicated that both filaments colocalize strongly. Three-dimensional reconstruction of serial optical sections revealed that newly synthesized vimentin distributed following the preexisting cytokeratin network and, when present, both filament scaffolds codistributed inside cultured hepatocytes. Immunoelectron microscopy performed in whole-mount-extracted cultured cells revealed that both filaments are closely interrelated but independent. However, a high degree of immunogold colocalization was found in the knots of the filament network. Further experiments with colcemide and cytochalasin treatment indicated that vimentin filament distribution, but not cytokeratin, was dependent on an intact microtubule network. These results are consistent with a mechanism of vimentin assembly, whereby growth of vimentin intermediate filaments is dependent on microtubules in topographically restricted cytoplasmic sites, in close relation to the cytokeratin cytoskeleton and to changes in cell-cell contact and cell shape.
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PMID:Vimentin filaments follow the preexisting cytokeratin network during epithelial-mesenchymal transition of cultured neonatal rat hepatocytes. 859 22

A human cervical cancer cell line, CX, was established from a patient with squamous cell carcinoma of the uterine cervix. The CX cells were epithelial in morphology with relatively large vesicular nuclei, and prominent nucleoli. Cytoplasmic organelles were generally sparse but tonofilaments were relatively abundant. The cells grew as a compact sheet with close membrane approximation interconnected by desmosome-like junctions. CX cells contained cytokeratin, but not vimentin. Elevated levels of squamous cell carcinoma antigen and carcinoembryonic antigen were detected in the cell supernatants. Population doubling time was estimated to be about 20 h. CX cells were not able to grow in soft agar and not tumorigenic in nude mice. Chromosome analysis revealed that CX cells were heterogeneous and mainly had a female diploid karyotype. Unlike cervical cancer cell lines published previously, CX cells were demonstrated to be human papillomavirus-negative, p53 mutation-negative. Based on the distinct characteristics, CX cell line may prove to be a useful tool for the study of human cervical carcinogenesis.
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PMID:Establishment and characterization of a human-papillomavirus negative, p53-mutation negative human cervical cancer cell line. 860 67

Oval cell proliferation occurs during spontaneous hepatitis in Long-Evans cinnamon (LEC) rats. It has been reported that oval cells undergo differentiation into mature hepatocytes via small hepatocytes during carcinogenesis. This study was designed to demonstrate in vivo differentiation of oval cells into typical bile ductular cells in the liver lobule and the characteristic feature of intralobular bile ductule formation in LEC rats. We have examined kinetics, intralobular distribution, and morphology of oval cells, small hepatocytes, and bile ductular cells in LEC rat livers at prehepatitic, acute hepatitic, chronic hepatitic, and precancerous stages by conventional light and electron microscopy, immunostaining for cytokeratin, and 3-dimensional reconstruction analysis. Our results indicate that oval cells proliferated and extended into the periportal zone of the liver lobule during acute hepatitis at 20 to 23 weeks after birth. They exhibited tubular structures with a poorly defined lumen and incomplete basement membrane. After remission of the jaundice, small hepatocytes proliferated in association with oval cells and predominated in the periportal zone at 26 weeks. In a chronic hepatitic stage at 28 to 30 weeks, tubular structures were transformed into typical bile ductules, which had a well defined lumen and complete basement membrane, and small hepatocytes became a normal size. Intralobular bile ductules originated from the interlobular bile ducts, ran in the space of Disse, giving rise to several branches in the course, and were terminated at the hepatocytes. The present results indicate that oval cells that proliferate in the liver lobule of LEC rats after spontaneous hepatitis not only differentiate into small hepatocytes but also into typical bile ductular cells. This study suggests that intralobular bile ductules may play roles in maintaining the bile excretion during and after the disorganized proliferation of oval cells and small hepatocytes.
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PMID:Development of intralobular bile ductules after spontaneous hepatitis in Long-Evans mutant rats. 868 39

A food-derived mutagenic heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), is a potent hepatocarcinogen in cynomolgus monkeys. In an ongoing carcinogenesis study, 34 out of 40 monkeys dosed with IQ have developed malignant liver tumors. The histology and cytokeratin expression was examined in a total of 94 tumors and non-neoplastic lesions obtained from 34 cases. The majority of the tumors were classified as hepatocellular carcinoma. In some cases, a striking difference in the histological features between individual tumor nodules was suggestive of a multicentric origin. Intrahepatic vascular invasion was seen in 14 (41.2%) and metastases in 6 (17.6%) of the hepatocellular carcinoma cases. There was no evidence of regenerative hyperplasia or fibrosis in the parenchyma of the tumor-bearing livers. Clear-cell foci composed of glycogen-rich hepatocytes were the only macroscopic lesions detected prior to gross tumor development. Other liver lesions included dysplastic hepatocyte foci and areas of proliferating bile ductular like (oval) cells, located around the periportal areas and along the portal tracts. Expression of bile duct type cytokeratin 7 was observed in a few of the oval cells and non-malignant hepatocytes, as well as in some of the hepatocellular carcinoma nodules. This aberrant cytokeratin expression raises questions concerning the histogenesis of the IQ-induced hepatocellular carcinoma.
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PMID:Liver tumors and possible preneoplastic lesions, induced by a food-derived heterocyclic amine in cynomolgus monkeys; a study of histology and cytokeratin expression. 874 Aug 38


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