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

Dichloroacetic acid (DCA) has recently been shown to increase significantly the incidence of hepatic adenomas (HAs) and hepatocarcinomas (HCs) in male B6C3F1 mice. Although little is known about the mechanism of DCA carcinogenesis, chronic ingestion of the compound in drinking water induces primarily hyperplastic nodules (HNs) prior to the appearance of HAs and HCs. Given the putative preneoplastic potential of the HNs, we undertook this study to determine the role of the HNs in the progression of DCA-induced hepatocarcinogenesis. This role was assessed by detecting the expression of five different tumor markers: p21 ras, p39 c-jun, phosphotyrosine, tumor-associated aldehyde dehydrogenase and alpha-fetoprotein, all known from previous studies to be expressed more often in neoplastic liver lesions than in normal liver. Tumor marker expression was detected by immunohistochemical methods using formalin-fixed, paraffin-embedded sections of normal B6C3F1 mouse liver, and DCA-induced HNs, HAs and HCs. The results demonstrated that, except for the c-jun marker, HNs expressed the markers significantly less often than either HAs or HCs. Equal expression of c-jun occurred in any of the three lesion types. Although these results could be used to argue that no relationship existed between HNs and later-appearing HAs and HCs, those HNs that were marker positive contained small nests of marker-positive hepatocytes among a field of normally appearing unstained hepatocytes. No similar nests of marker-positive cells were detected in any area of normal liver outside the HNs. Also very few altered hepatic foci (AF) were detected with these markers or with hematoxylin and eosin, or with histochemical stains for ATPase or glucose-6-phosphatase deficiencies. These results suggested that these nests within some HNs were areas of transformed, or neoplastic hepatocytes. Phenotypic heterogeneity analysis, in which the number of tumor markers co-expressed by any given lesion was examined, confirmed a significantly greater percentage of HAs and HCs expressing multiple markers than HNs. Those HNs that expressed multiple markers, however, expressed at the same frequency as HAs and HCs and the expression was confined to the same nests of cells. Taken together, these data suggest that these nests of marker-positive cells within the HNs were neoplastic and could develop into later-appearing HAs and/or HCs. The absence of marker expression in normal liver and limited expression in the few AF indicates that the HNs may be the only significant preneoplastic lesion in DCA-induced hepatocarcinogenesis.
Carcinogenesis 1991 Aug
PMID:The role of hyperplastic nodules in dichloroacetic acid-induced hepatocarcinogenesis in B6C3F1 male mice. 186 Jan 58

Mouse epidermal cells have frequently been used to study the role of ras oncogenes in transformation in vivo and in vitro. After initiation with dimethylbenzanthracene (DMBA) in vivo, greater than 90% of the papillomas arising show the same A:T----T:A transversion at codon 61 of the H-ras gene, presumed to be the initiating event. On the other hand, initiation of epidermal cells in culture with carcinogens, followed by selection of initiated cells by resistance to calcium-induced differentiation, does not in general lead to the isolation of clones carrying mutant ras genes. Some other aspects of tumour progression in vivo can be reproduced using epidermal cells in culture: a rare DMBA transformant carrying the codon 61 mutation and expressing a 2:1 ratio of normal to mutant ras alleles gave rise upon transplantation to a more aggressive line in which the ratio of normal to mutant H-ras genes (and p21 products) was reversed. Similar alterations in ras gene dosage have been seen during progression of papillomas to carcinomas in vivo. We conclude that the mechanisms of initiation in vitro may differ substantially from in vivo, and depend on the particular culture conditions used. Moreover, the effects of mutant H-ras expression in mouse epidermal cells are variable depending on the genetic background of the cell.
Carcinogenesis 1991 Oct
PMID:Comparison of ras activation during epidermal carcinogenesis in vitro and in vivo. 193 68

To determine whether the c-Ha-ras oncogene plays a role in the initiation of mammary carcinogenesis, an immortalized human breast epithelial cell line, MCF-10A, was transfected with the plasmid vector pHo6T1 containing the T24 Ha-ras oncogene and the aminoglycoside phosphotransferase gene, which confers resistance to geneticin. Transfected cells exhibited an altered pattern of growth and tridimensional morphology in collagen gel. They also exhibited anchorage-independent growth and loss of requirement for hormones and epidermal growth factor; in addition, they expressed invasiveness and increased collagenolytic activity in an in vitro system and became tumorigenic in irradiated nude mice, all properties indicative of malignant transformation. Transformed cells contained the mutated c-Ha-ras oncogene and expressed the p21 mutated protein. These data indicate that the c-Ha-ras oncogene is capable of inducing malignant phenotypes in immortalized human breast epithelial cells.
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PMID:Transformation of human breast epithelial cells by c-Ha-ras oncogene. 200 32

Flow cytometry (FCM) is a useful method for clinical research of oncogene products since it can analyze proteins quantitatively which are located at cell surfaces or inside of cells. Oncogene products are now under study by FCM not only as tumor markers but also as functioning proteins in carcinogenesis. The examples of oncogene products analyzed by FCM are ras, myc, p53, myb and fos; those of cell-proliferation-related proteins are Ki-67, PCNA and DNA polymerase alpha. In some diseases the relationship between these proteins and disease classification, stage, pathophysiology, or prognosis have been clarified. Using dual color FCM of H-ras p21 and DNA, we analyzed the expression of H-ras p21 in human multiple myeloma and leukemias and found that H-ras p21 levels in multiple myeloma strongly correlated to the prognosis of patients (p = 0.03). When AML cells were stimulated by adding G-CSF, it was found that many cells proliferated but some were dying. The percentage of dying cells was small in one AML case whose myeloblasts showed increased expression of H-ras p21 by G-CSF stimulation. Together with other papers reviewed, it is conceivable that H-ras p21 expression is related to cell proliferation and inhibition of cell autolysis. Thus FCM is useful in the classification of the role of oncogene products in carcinogenesis in clinical cases.
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PMID:[Application of flow cytometry to the study of hematologic disorders: analysis of oncogene products]. 214 49

Oncogenic potential of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) which are both associated with occurrence of cervical cancer and the mechanism of oncogenesis by these viruses were investigated by transformation experiments in vitro. The results were obtained as follows. 1) HSV-2 induced neoplastic transformation of normal diploid cells is a multistep process. Cervical cancer associated antigen AG-4 is encoded within the specific region of HSV-2 DNA which converts immortalized cells to tumorigenic lines. 2) Tumor cells express cellular oncogene at a final stage of neoplastic transformation induced by HSV-2 and "hit and run" theory is applicable to oncogenesis of this virus. 3) Complete carcinogenesis can be mediated by HPV-16 or HPV-18 DNA under collaboration with other cofactors such as HSV-2. 4) It is suggested that neoplastic transformation induced by HPV-18 DNA is based on "hit and run" oncogenesis. 5) HPV-16 or HPV-18 DNA can immortalize primary diploid cells and convert them to fully tumorigenic phenotype by repeating cell passage. 6) It has been experimentally proved that the difference in transforming potential exists between HPV 6/11 and HPV 16/18. 7) Amplification and overexpression of c-myc oncogene was detected in transformed cells obtained by HPV-16 transfection. While overexpression of c-myc was detected in transformed cells induced by HPV-18 DNA, but no amplification was observed. On the other hand, detection of HPV, DNA and amplification or overexpression of protooncogenes was performed in cervical intraepithelial neoplasias (CIN) and invasive cervical carcinomas. The results were summarized as follows. 1) HPV DNA was detected in approximately 70% of a population with CIN by in situ hybridization. CIN II showed the highest incidence of positive HPV DNA (91%), and the positive ratio decreased in CIN III (56%). 2) Immunohistochemical study of paraffin-embedded specimens with monoclonal antibodies to oncogene products revealed that only some of cervical invasive carcinomas expressed c-myc protein, ras p21 or EGFR. 3) HPV DNA was detected in 46% of invasive cervical carcinomas by Southern blot hybridization. The percentage of patients with positive results for HPV 16/18 was 29%. However, it increased up to 58% by use of polymerase chain reaction (PCR), suggesting that there are many cervical cancer tissues in which a number of cells lack viral DNA. 4) Northern blot hybridization analysis revealed overexpression of c-myc mRNA in 30% of cervical invasive carcinomas although amplification of c-myc oncogene was detected in only one of invasive carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[The possibility of viral etiology in cervical carcinogenesis]. 217 17

A mouse mRNA, provisionally designated 5B10, has been cloned based on its inducibility by serum in quiescent murine fibroblasts. Here we report the full-length complementary DNA sequence and a partial characterization. There are about five copies of the gene in the mouse genome. Sequence analysis of the 5B10 coding region reveals 94 and 97% amino acid identity to human and rat calcyclin, respectively. Although the coding region has been highly conserved during evolution of the rodent and human genomes, the untranslated flanking sequences differ significantly. A protein of Mr about 8000 was produced by in vitro translation of the mRNA transcribed in vitro from 5B10 complementary DNA in a riboprobe vector. An antiserum raised against a portion of the predicted human calcyclin protein cross-reacted with this mouse protein. 5B10 mRNA was found in greatest amount in organs containing proliferating cells, e.g., epidermis, skin, stomach, uterus of pregnant mouse, placenta, and decidua. Brain, liver, mature thymus, and skeletal muscle had little or no detectable 5B10 mRNA. 5B10 mRNA levels were higher in cells treated with 7,12-dimethylbenzanthracene and 12-O-tetradecanoylphorbol-13-acetate than in their normal counterparts, suggesting a role in tumorigenesis. In addition, high 5B10 mRNA levels were associated with metastatic ability in a series of ras-transformed cells, in proportion to levels of ras p21 expressed by the cells, implicating 5B10 even more deeply in carcinogenesis.
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PMID:Identification of a serum-inducible messenger RNA (5B10) as the mouse homologue of calcyclin: tissue distribution and expression in metastatic, ras-transformed NIH 3T3 cells. 217 33

To examine the correlations between ras oncogene expression and the development of cervical cancer, the authors studied the reactivity of cervical intraepithelial neoplasia (CIN) and microinvasive lesions of the human uterine cervix by using anti-ras p21 mouse monoclonal antibody rp35. The frequency of positive p21 staining increased with increased grades of malignancy from 17.9% in CIN 1 to 28.9% in CIN 2 and 53.9% in CIN 3, whereas in microinvasive carcinoma it was 50.0%. Furthermore, ten cases of lesions that regressed during a 1-year follow-up period were positive for ras p21 in 20% of cases, but 14 cases of lesions that progressed and developed into higher graded lesions during the 2- to 5-year follow-up period had a 50.0% rate of positive p21 staining. It was concluded that ras oncogene product p21 correlates with the early phase of carcinogenesis of squamous cells of the uterine cervix.
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PMID:Ras oncogene expression and progression in intraepithelial neoplasia of the uterine cervix. 219 11

Male F344 rats were fed N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for up to 4 wk, then were given the basal diets (Prolab 3200 or AIN-76A) with or without 5% sodium saccharin for up to 100 wk. Eleven transitional cell carcinomas (TCCs), one undifferentiated carcinoma, and two sarcomas of the urinary bladder were examined for the expression of ras gene product, p21, by immunohistochemical staining and western blot analysis. Point mutation in codons 12 or 61 of the Ha-ras genes amplified by polymerase chain reaction was examined by a slot-blot screening procedure using allele-specific oligonucleotide probes. Immunohistochemical staining showed enhanced immunoreactivity with the antibody to ras p21 in seven TCCs and one undifferentiated carcinoma. Western blot analysis showed faster migration of the p21 band in 6 of 11 TCCs. Oligonucleotide hybridization revealed the point mutation in codon 12 of Ha-ras gene (GGA----GTA in 1 TCC) and in codon 61 (CAA----CGA in 5 TCCs and CAA----CTA in 1 TCC). Two mutations in codons 12 and 61 coexisted in one tumor, which were found to be present in different Ha-ras alleles. The incidence of Ha-ras gene mutations were similar in groups treated with (3 of 6) or without (3 of 8) sodium saccharin. These results suggest the involvement of activated Ha-ras gene in rat urinary bladder carcinogenesis induced by FANFT.
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PMID:Point mutation in codons 12 and 61 of the Ha-ras gene in rat urinary bladder carcinomas induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. 220 84

Proto-oncogene expression by cultured urothelial cells prepared from the bladders of male F344 rats that had been treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Although all of the cultured cells showed varying degrees of anchorage-independent growth, only 9 of them were transplantable into nude mice. A Northern blot technique was employed for the detection of proto-oncogene transcripts. The c-Ha-ras transcripts were detected in all the cultured urothelial cells prepared from the carcinogen-treated rats and in normal urothelial cells. However, the transcript levels were several-fold higher in the former than in normal cells. Increased expression of p21, as determined by immunohistochemical techniques, was also observed in all the original bladder tissues from which the cultures were derived. c-myc transcripts were detected in the cells from carcinogen-treated rats but not in the normal cells. The presence of myc product in hyperplastic urothelial lesions and carcinomas of original bladder tissues was confirmed by immunohistochemical methods. Transcripts of mos, erb B, Ki-ras, abl and src were not detected. Since increased expression of c-myc and c-Ha-ras were present in both transplantable and non-transplantable cell lines, and the expression of p21 occurs in preneoplastic cells, this suggests that elevated expression of these 2 genes may be an early genetic event during bladder carcinogenesis in the rat and further alteration of these 2 genes or mutation of additional genes may be required for the completion of malignant transformation.
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PMID:Oncogene expression of FANFT- or BBN-induced rat urothelial cells. 222 19

Ten of amino acid sequences of ras p21 which come from human, fruit fly, yeast, Dictyostelium and virus were collected and analyzed. Data analysis indicates that: 1. the mean duplicate rate of ras p21 is approximately 2.78 x 10(-9) per gene per year for concerted evolution; 2. the mean amino acid replacement of p21 is about 2.23 x 10(-10) per year. It also shows that v-Has and v-Kis were derived from c-H-ras1 and c-K-ras2, respectively, and that c-H-ras1, c-K-ras2 and c-N-ras come from the same ancestor. These result are in accordance with the experimental results reported by other authors. According to the view of Fitch et al., we present here a speculative view for carcinogenesis mechanism the hypothesis for covarions and invarions, by which, the codon 12 or 61 mutated in p21 may be responsible for last one or more steps in carcinogenesis.
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PMID:[Molecular evolution and a speculative carcinogenesis mechanism for ras p21]. 224 80


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