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

High fat consumption has been implicated as a risk factor for breast cancer. Experimental mammary carcinogenesis studies have demonstrated that the effect of high fat consumption is mainly exerted on the postinitiation stage of the disease process. We report data that have recalled in the formulation of a new hypothesis about the effect of dietary fat on mammary carcinogenesis, namely, that it promotes the development of a subpopulation of cells lacking a specific pathogenetic characteristic. In comparison with animals fed a low-fat diet, female Sprague-Dawley rats fed high-fat diets during the promotional stage developed significantly more (number and proportion) 1-methyl-1-nitrosourea-induced mammary adenocarcinomas that did not contain a codon 12 GGA-->GAA mutation in the c-Ha-ras protooncogene. The effect was independent of the types of fat fed, i.e., corn oil vs. fish oil. A model is presented to account for the preferential promotional effect of high fat consumption on 1-methyl-1-nitrosourea-initiated mammary epithelial cells. The hypothesis that the level of dietary fat consumed affects the proportion of mammary carcinomas that occur with a particular pathogenetic characteristic, in this case, the presence or absence of a Ha-ras point mutation, has important implications on the direction of future investigations concerning fat and cancer risk.
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PMID:ras may mediate mammary cancer promotion by high fat. 760 88

Non-tumorigenic SV40-immortalized human cells may be transformed to tumorigenicity by activated oncogenes, but the molecular genetics of this process are still poorly understood. We describe here 4SV40-transformed bronchial epithelial (BE) cell lines that became immortalized after a period of crisis, and then transfection of 6 BE lines or sub-lines with an activated c-Ha-ras (EJ-ras) oncogene. pSV2neo-transfected cells did not form any tumors in athymic nude mice. Even though each of the EJ-ras-transfected lines was shown to be expressing the mutant ras gene, only one cell line, BEAS-2B, and 2 of its sub-lines were tumorigenic after transfection. We conclude that immortalization is not sufficient for BE cells to be transformed by the EJ-ras oncogene. Thus there are at least 2 unknown genetic events in this in vitro model of carcinogenesis: escape from crisis (immortalization), and development of ability to cooperate with activated ras in tumorigenic transformation. We found no evidence that either immortalization or ability to complement ras is related to abnormalities of the SV40 T antigens, of p110RB or of p53.
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PMID:SV40-induced immortalization and ras-transformation of human bronchial epithelial cells. 770 48

We previously reported that 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) at the second position of codon 12 of the c-Ha-ras gene induces many types of mutations in NIH3T3 cells. In this study we incorporated the modified base into the first and second positions of codon 12 in the coding strand and into the first position of codon 61 in the non-coding strand of the gene using a new 8-hydroxyguanine phosphoramidite as a building block during oligonucleotide synthesis. The ras genes with 8-hydroxyguanine were transfected into NIH3T3 cells and the mutations induced were analyzed. 8-Hydroxyguanine residues at the first positions of codons 12 and 61 induced mutations to T at the modified sites almost exclusively. On the other hand, the DNA lesion at the second position of codon 12 induced a G-->A transition in addition to a G-->T transversion, confirming our previous results. Mutations in 5'-flanking sites were observed with 8-hydroxyguanine at the second position of codon 12 or the first position of codon 61. These results indicate that 8-hydroxyguanine in mammalian cells mainly induces a G-->T transversion at the modified site, but that other types of mutations are also elicited.
Carcinogenesis 1995 Apr
PMID:8-Hydroxyguanine (7,8-dihydro-8-oxoguanine) in hot spots of the c-Ha-ras gene: effects of sequence contexts on mutation spectra. 772 70

Aspartyl and cysteine proteinases at distinct stages of carcinogenesis were analyzed in rat embryo fibroblasts, sequentially immortalized and transformed by 2 different genes: the early region of simian adenovirus SA7 and c-Ha-ras oncogene. The dynamics of expression and distribution of proteinases throughout the transformation process were examined. It was shown that in immortalized and transformed cells the activities of the aspartyl and cysteine proteinases were expressed to a variable degree and that the expression was dependent on cell-propagation time in vitro. The increase in activity both of cathepsin-D-like aspartyl proteinase and of cathepsin-L- and -B-like cysteine proteinases in cell lysates was correlated with the stages of fibroblast transformation (immortalization and tumorigenic transformation). In all cell types the major part of cysteine proteinases was localized inside the cell, while the cathepsin-D-like proteinase was apparently predominant among secreted proteinases. The cathepsin-L-like proteinase accounts for the major part of the cysteine-proteinase activity as measured by Z-Phe-Arg-MCA hydrolysis. We suggest that considerable portions of the cathepsin-D- and -L-like proteinases in all cell lines studied are secreted as a complex with inhibitor(s) and that inhibitor expression plays an important role in regulating the activity of cathepsin-D-like proteinase at different stages of transformation. Cathepsin-L-like proteinase is probably secreted in the precursor form.
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PMID:Proteolytic enzymes at various stages of oncogenic transformation of rat fibroblasts. I. Aspartyl and cysteine proteinases. 782 63

Runs of G residues on the G-rich strands of 30mers from the region spanning codon 12 of c-Ha-ras appear to be protected against chemical modification by dimethylsulfate. This suggests that the G-rich strand might spontaneously form a Hoogsteen-paired quadruplex, which is characteristic of telomere-like DNA sequences. In this report we show that the predominant species in 1:1 mixtures of complementary 30mers from this region are duplex DNA and a smaller amount of unimolecular foldback formed by the C-rich strand. Foldbacks of this type resemble structures first observed in the C-rich strand of telomeric DNA and also occur at the CCG triplet repeat present in the FMR-1 gene of human fragile X syndrome. Foldbacks from the C-rich strand of c-Ha-ras and the FMR-1 triplet repeat are exceptional substrates for the human methyltransferase in isolation. Substituting inosine for guanosine alters the secondary structure of the folded oligomers and dramatically reduces their ability to serve as substrates for the human methyltransferase, suggesting that secondary structure is required for recognition by the enzyme. These findings suggest that one mechanism by which methyl groups accumulate in the c-Ha-ras region of chromosome 11 during carcinogenesis and at the FMR-1 locus during repeat expansion at fragile X may be structurally induced de novo methylation at sites undergoing local conformational change. Such methylation might serve to mark unusual structures for repair. In the absence of repair, asymmetrically methylated duplexes produced by resolution of the unusual structures would be rapidly converted to symmetrically methylated duplexes through the methyl-directed activity also carried by the human methyltransferase.
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PMID:Hypermethylation of telomere-like foldbacks at codon 12 of the human c-Ha-ras gene and the trinucleotide repeat of the FMR-1 gene of fragile X. 793 45

The mutagenicity of oxygen free radicals was studied in a forward mutation system. pEC plasmid containing the human c-Ha-ras-1 proto-oncogene was reacted with oxygen free radicals generated by Cu2+ and H2O2 and was then transfected into NIH/3T3 cells. Transformed foci were observed with oxygen free radical-modified DNA but not with unmodified DNA. The mutations responsible for the Ha-ras-1 gene activation in 11 transformed foci were characterized. G-->T mutations at the second base of codon 12 were found in two transformed foci, A-->T transversions at the second base of codon 61 in five foci, and G-->T mutations at the third position of codon 61 in four transformed foci. These observed mutations are identical to those commonly found in human skin carcinomas, suggesting that reactive oxygen species may play an important role in the carcinogenesis of these tumors. Interestingly, a significant proportion of mutations was found at the second and third base of codon 61 (CAG). In a previous study, the same oxygen free radical-generating system was found to cause an intrastrand cross-link between adjacent purine nucleotides at AG sites in DNA (Carmichael et al., Carcinogenesis 13:1127-1135, 1992). These data demonstrate that oxygen radicals can induce DNA damage that can result in a specific activation of a human proto-oncogene.
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PMID:Induction of activating mutations in the human c-Ha-ras-1 proto-oncogene by oxygen free radicals. 794 6

The spectrum of human papillomavirus (HPV) subtypes in laryngeal carcinomas was investigated by combined polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. HPV DNA was detected in 11 (24%) of 45 cases, including HPV 16 in 9 cases and HPV 18 in 2 cases. Other HPV subtypes commonly found in the female genital organs were not detected. In addition, the point mutation of codons 12 and 13 in c-Ki-ras-2, c-Ha-ras-1, and N-ras genes was studied by the PCR-single-strand conformational polymorphism (SSCP) method. Of 45 cases tested, only 1 had a point mutation of c-Ki-ras-2 gene at codon 12. These results indicate that the incidence of ras gene point mutation is uncommon and that the synergistic effect of HPV infection and ras gene activation in laryngeal carcinogenesis is probably rare.
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PMID:Lack of synergistic association between human papillomavirus and ras gene point mutation in laryngeal carcinomas. 805 64

We have shown previously that overexpression of c-Ha-ras, v-mos or c-fos increases the spontaneous level of chromosomal aberrations and gene mutations in NIH 3T3 cells, and that reduction of the Fos protein level inhibits aberration induction by c-Ha-ras and v-mos and also by irradiation with ultraviolet light (van den Berg et al., Mol. Carcinogenesis, 4, 460-466). In order to examine whether fos is also involved in DNA recombination, thymidine kinase (tk) deficient human osteosarcoma cells containing two versions of the herpes simplex virus tk gene inactivated by base insertion were either transiently or stably transfected with various fos expression plasmids. The frequency of tk+ revertants was significantly enhanced both upon transient transfection with RSV-promoter-fos gene constructs and by stimulation of Fos synthesis in stably transfected cells harbouring an inducible metallothionein promoter-fos construct. No such increases were observed in cells transfected with plasmids containing a truncated version of c-fos. The data indicate that c-fos is involved in generating various types of genetic changes including homologous recombination; a role of c-fos in genetic instability may contribute to its action in tumor promotion and progression.
Carcinogenesis 1993 May
PMID:Overexpression of c-fos increases recombination frequency in human osteosarcoma cells. 809 16

Human fibroblasts (KMST-6) immortalized by treatment with 60Co gamma rays were further neoplastically transformed by transfection of the c-Ha-ras oncogene from human lung cancer. The ras-transfected cells formed undifferentiated fibrosarcoma in nude mice. One of the tumors was recultured and a neoplastic human fibroblast line, KMST-6/RAS, was established. To analyze multistep carcinogenesis of human cells, the cellular characteristics of these genetically matched immortalized (KMST-6) and neoplastic (KMST-6/RAS) cell lines were studied in detail. KMST-6/RAS cells showed an increased saturation density, colony formation on confluent monolayers of normal human fibroblasts, proliferation in neomycin-containing medium, anchorage-independent growth, and enhanced expression of the transfected c-Ha-ras oncogene, whereas the immortalized cells did not demonstrate these characteristics. Unexpectedly, growth of KMST-6/RAS cells was serum-dependent, although they were neoplastic. Interestingly, the neoplastic cells did not show the criss-crossing or piling up growth pattern characteristic of transformed rodent fibroblasts.
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PMID:Neoplastic transformation and characterization of human fibroblasts by treatment with 60Co gamma rays and the human c-Ha-ras oncogene. 811 10

Transplant recipients successively develop benign, premalignant and malignant skin lesions on sun-exposed areas. It has been suggested that UV radiations might induce mutations in ras oncogenes and p53 tumour-suppressor gene, responsible for skin cancers. With PCR and oligoprobe hybridization, we investigated c-Ha-ras gene mutations at codons 12 and 61 in 120 cutaneous lesions from grafted patients, since they could represent a marker of the evolution of benign skin lesions towards malignancy in this population; 29 similar skin biopsies from non-immunosuppressed patients were also analyzed. In transplant recipients, we detected mutations at codon 12 only in 1/42 non-melanoma skin cancers and 2/29 pre-cancerous keratoses. No mutation was detected in 11 cases of cutaneous Bowen's disease from grafted patients and in pre-malignant and malignant skin samples from control patients. Benign warts exhibited an overall incidence of 18% and 15% of mutations at codon 12 of c-Ha-ras gene in grafted and control patients respectively. We detected only one mutation at codon 61 in a plantar wart. Human papillomaviruses (HPV) are thought to be involved in the malignant evolution of cutaneous disorders in transplant recipients and cooperate with a ras oncogene to induce malignancy in vitro. The presence of HPV DNA in our series of skin samples from grafted patients showed no correlation with the occurrence of c-Ha-ras mutations. Our findings indicate that c-Ha-ras-gene activation by mutations is rare in cutaneous lesions from transplant recipients, and is unlikely to play a crucial role in transformation towards malignancy in skin carcinogenesis among grafted patients.
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PMID:Low incidence of c-Ha-ras gene mutations in benign and malignant cutaneous lesions from transplant recipients. 825 28


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