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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The detection of activated protooncogenes in mouse lung tumors has led to a major advance in our understanding of carcinogenesis of the lung at the molecular level. A high frequency of activated K-ras protooncogenes has been detected in tetranitromethane (TNM)- and 1,3-butadiene-induced lung tumors in B6C3F1 mice. In the past several years, we have pursued protooncogene activation in spontaneous and chemically induced tumors of strain A mice. The strain A mouse has a high incidence of spontaneous lung tumors and is susceptible to tumor induction by chemical carcinogens. We have detected and characterized the activated protooncogenes in the DNA of both spontaneously occurring and chemically induced lung tumors of strain A mice. Activated K-ras genes were detected using the NIH/3T3 transfection assay, and the activating mutations were identified by utilizing the polymerase chain reaction (PCR) and direct sequence analysis. A strong selectivity of mutations in the K-ras genes were observed in chemically induced lung tumors, as compared to spontaneous tumors, indicating that the carcinogens directly induced point mutations in the K-ras protooncogene. These findings suggest that the strain A mouse lung tumor model appears to be a very sensitive system to identify the mechanism by which chemical carcinogens activate the K-ras gene in lung tissue in vivo.
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PMID:Activation of protooncogenes in mouse lung tumors. 205 38

Kirsten-ras-revertant 1 (Krev-1) cDNA encodes a ras-related protein and exhibits an activity of inducing flat revertants at certain frequencies (2-5% of total transfectants) when introduced into a v-K-ras-transformed mouse NIH 3T3 cell line, DT. Toward understanding the mechanism of action of Krev-1 protein, we constructed a series of point mutants of Krev-1 cDNA and tested their biological activities in DT cells and HT1080 human fibrosarcoma cells harboring the activated N-ras gene. Substitutions of the amino acid residues in the putative guanine nucleotide-binding regions (Asp17 and Asn116), in the putative effector-binding domain (residue 38), at the putative acylation site (Cys181), and at the unique Thr61 all decreased the transformation suppressor activity. On the other hand, substitutions such as Gly12 to Val12 and Gln63 to Glu63 were found to significantly increase the transformation suppressor/tumor suppressor activity of Krev-1. These findings are consistent with the idea that Krev-1 protein is regulated like many other G proteins by the guanine triphosphate/guanine diphosphate-exchange mechanism probably in response to certain negative growth-regulatory signals.
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PMID:Genetic analysis of the Kirsten-ras-revertant 1 gene: potentiation of its tumor suppressor activity by specific point mutations. 211 51

High mol. wt genomic DNA was prepared from normal hamster pancreas and the solid and ascites variants of two different hamster transplantable carcinomas, one induced by N-nitrosobis(2-oxopropyl)amine and the other spontaneously occurring. This DNA was transfected into NIH/3T3 cells and resulted in cells that were capable of forming tumors when injected into nude mice. Analysis of the nude mouse tumors by Southern blotting revealed the presence of a band specific for hamster K-ras. Polymerase chain reaction (PCR)-mediated amplification of the K-ras codon 12-13 region of genomic DNA prepared from the transplantable tumors produced a 117 bp fragment which was analyzed by both allele-specific oligonucleotide hybridization and direct DNA sequencing. Oligonucleotide hybridization with probes specific for changes in the first or second position of codons 12 or 13 detected a G to A transversion in the second position of codon 12 in the chemically induced transplantable tumor, and a G to A change in the second position of codon 13 in the spontaneously occurring transplantable carcinomas. The result obtained for the chemically induced tumor was confirmed by direct dideoxy sequencing of the PCR-amplified product. These findings are the first to show a specific oncogene activation in an experimental pancreatic tumor model and also parallel the results recently reported for K-ras mutations in human pancreatic carcinoma.
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PMID:Activation of K-ras in transplantable pancreatic ductal adenocarcinomas of Syrian golden hamsters. 217 98

The identification of ras oncogenes in human and animal cancers including precancerous lesions indicates that these genes participate in the early stages of neoplastic development. Yet, these observations do not define the timing of ras oncogene activation in the multistep process of carcinogenesis. To ascertain the timing of ras oncogene activation, an animal model system was devised that involves the induction of mammary carcinomas in rats exposed at birth to the carcinogen nitrosomethylurea. High-resolution restriction fragment length polymorphism analysis of polymerase chain reaction-amplified ras sequences revealed the presence of both H-ras and K-ras oncogenes in normal mammary glands 2 weeks after carcinogen treatment and at least 2 months before the onset of neoplasia. These ras oncogenes can remain latent within the mammary gland until exposure to estrogens, demonstrating that activation of ras oncogenes can precede the onset of neoplasia and suggesting that normal physiological proliferative processes such as estrogen-induced mammary gland development may lead to neoplasia if the targeted cells harbor latent ras oncogenes.
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PMID:Activation of ras oncogenes preceding the onset of neoplasia. 218 64

Head and neck squamous cell carcinomas (SCC) from 21 patients were analyzed for structurally rearranged or amplified proto-oncogenes by Southern blot hybridization. The int-2 proto-oncogene was amplified 3-5 fold in 5 (50%) of 10 laryngeal SCC and 2-3 fold in 5 (45%) of 11 nonlaryngeal SCC of the head and neck. Adjacent histologically normal tissue from the same patients had single int-2 gene copy number. Coamplification of int-2 and the epidermal growth factor receptor (c-erbB-1) gene was found in one laryngeal SCC and one SCC metastatic to the neck. No amplification or structural alterations of proto-oncogenes c-erbB-2/HER2, c-myc, H-ras-1, or K-ras-2 was detected in any of the head and neck tumors. In a survey of head and neck tumor-derived cell lines, int-2 was amplified 9 fold in a hypopharyngeal tumor cell line (FaDu), but not amplified in 3 laryngeal tumor cell lines. int-2 has been localized to the q13 band of chromosome 11. We used chromosome 11 specific probes to demonstrate that int-2 amplification was not due to complete or partial chromosome 11 duplication. int-2 amplification was localized to 11q13, but did not extend to the ets-1 locus 11q23. The results indicate that int-2 is frequently amplified in SCC of the head and neck and suggest that int-2 amplification may correlate with clinical disease progression.
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PMID:Amplification of the int-2 gene in human head and neck squamous cell carcinomas. 219 94

1,3-Butadiene has been detected in urban air, gasoline vapors, and cigarette smoke. It has been estimated that 65,000 workers are exposed to this chemical in occupational settings in the United States. Lymphomas, lung, and liver tumors were induced in female and male C57BL/6 X C3H F1 (hereafter called B6C3F1) mice by inhalation of 6.25 to 625 ppm 1,3-butadiene for 1 to 2 years. The objective of this study was to examine these tumors for the presence of activated protooncogenes by the NIH 3T3 transfection and nude mouse tumorigenicity assays. Transfection of DNA isolated from 7 of 9 lung tumors and 7 of 12 liver tumors induced morphological transformation of NIH 3T3 cells. Southern blot analysis indicated that the transformation induced by 6 lung and 3 liver tumor DNA samples was due to transfer of a K-ras oncogene. Four of the 7 liver tumors that were positive upon transfection contained an activated H-ras gene. The identity of the transforming gene in one of the lung tumors has not been determined but was not a member of the ras family or a met or raf gene. Eleven 1,3-butadiene-induced lymphomas were examined for transforming genes using the nude mouse tumorigenicity assay. Activated K-ras genes were detected in 2 of the 11 lymphomas assayed. DNA sequencing of polymerase chain reaction-amplified ras gene exons revealed that 9 of 11 of the activating K-ras mutations were G to C transversions in codon 13. One liver tumor contained an activated K-ras gene with mutations in both codons 60 and 61. The activating mutation in one of the K-ras genes from a lymphoma was not identified but DNA sequence analysis of amplified regions in proximity to codons 12, 13, and 61 demonstrated that the mutation was not located in or near these codons. Activation of K-ras genes by codon 13 mutations has not been found in any lung or liver tumors or lymphomas from untreated B6C3F1 mice. Thus, the K-ras activation found in 1,3-butadiene-induced B6C3F1 mouse tumors probably occurred as a result of genotoxic effects of this chemical. The oncogenes most frequently detected in human pulmonary adenocarcinomas are K-ras genes. Activated K-ras genes have also been found in some human lymphomas. This suggest that activation of K-ras may be important in the induction of human pulmonary adenocarcinomas and lymphomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activation of K-ras by codon 13 mutations in C57BL/6 X C3H F1 mouse tumors induced by exposure to 1,3-butadiene. 219 19

Fifty-eight colorectal carcinomas were studied for HLA class-I antigen expression and for the presence of point mutations in codons 12 and 61 of the K-ras gene. Eight carcinomas were completely negative for class I by the APAAP technique. Analyses using the polymerase chain reaction (PCR) method, together with selective hybridization using mutation-specific synthetic oligonucleotides, demonstrated K-ras mutations in 14 cases (24.1%), all of them in codon 12. None of the mutations corresponded to the negative cases for class-I HLA antigen expression. We did not observe any correlation between K-ras mutations and the extent of tumor differentiation.
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PMID:K-ras mutations (codon 12) are not involved in down-regulation of MHC class-I genes in colon carcinomas. 220 88

To determine if human fibroblasts can be transformed into malignant cells by transfection of a K-ras oncogene, we transfected the provirus of Kirsten murine sarcoma virus (v-Ki-ras) into an infinite life span human cell strain, MSU-1.1, which has a normal morphology, is not anchorage independent, and has a stable, near-diploid karyotype. The transfected populations gave rise to distinct foci composed of morphologically-altered cells. The cells from several independent foci were isolated, propagated, and assayed for anchorage independence and/or tumorigenicity. They formed large-sized colonies in soft agar at a high frequency. Cell strains derived from colonies isolated from agar as well as focus-derived cell strains were injected subcutaneously into athymic mice to test for tumorigenicity. One cell strain yielded myxoid fibromas, the rest produced well-differentiated, progressively-growing, invasive, myxoid or spindle cell sarcomas. The karyotype of each of the cell strains tested, including cell strains derived from tumors, was identical to that of non-transfected MSU-1.1 cells. Two focus-derived strains, and two cell strains derived from sarcomas produced from them, were tested and shown by DNA and RNA hybridization to contain and express the v-Ki-ras oncogene. Radioimmunoprecipitation analysis showed that these strains expressed ras-specific p21 products not found in non-transfected MSU.1.1 cells. When injected intraperitoneally, a cell strain derived from a myxoid tumor gave rise to invasive myxoid tumors at various sites in the body. The same cell strain gave rise to invasive spindle cell sarcomas when injected into the tail vein of the animals.
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PMID:Malignant transformation of an infinite life span human fibroblast cell strain by transfection with v-Ki-ras. 221 65

This investigation has employed the NIH 3T3 cell transfection assay in an effort to detect transforming genes in DNA from squamous carcinomas of the head and neck. Of 11 tumor DNAs tested, 1 DNA sample from a gingival squamous carcinoma was able to produce primary and secondary transformants containing the human K-ras oncogene. This is the first report of an activated ras oncogene derived from a carcinoma of the head and neck. Head and neck cancers may possess activated ras oncogenes more often than is indicated by this study because of the relative inefficiency of transfection assays in detecting large transforming genes such as K-ras.
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PMID:A transforming Kirsten ras oncogene in an oral squamous carcinoma. 223 35

The relationships between DNA methylation and repair induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the activation of proto-oncogenes and the induction of pulmonary neoplasia by this carcinogen is described. The formation of the O6-methylguanine (O6MG) adduct following metabolic activation of NNK appears to be a major factor in the induction of lung tumors in both rats and mice and in the activation of the K-ras oncogene in lung tumors from A/J mouse. The potent carcinogenicity of NNK in the rat lung correlated strongly with cell specificity for formation and persistence of the O6MG adduct in the Clara cells. This conclusion was supported by studies with nitrosodimethylamine (NDMA), a weak carcinogen in the rodent lung. Treatment with NDMA was not associated with any pulmonary cell specificity for DNA methylation. The high affinity for activation of NNK compared to NDMA was ascribed to a difference in cytochrome P-450 isozymes involved in the activation of these two nitrosamines. In the A/J mouse, the induction of pulmonary tumorigenesis involved direct genotoxic activation of the K-ras proto-oncogene as a result of the base mispairing produced by formation of the O6MG adduct. In contrast, the induction of pulmonary tumors in the rat by NNK does not appear to involve the ras pathway. It is apparent that different molecular mechanisms are involved in the development of pulmonary tumors by NNK in the mouse and rat. The studies described in this paper illustrate the utility of performing dose-response experiments and the quantitation of DNA methylation and repair in not only target tissues but also target cell types. The fundamental knowledge gained from unraveling the mechanism of carcinogenesis by NNK could lead ultimately to the identification of factors important in the development of human lung cancer.
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PMID:Role of DNA methylation in the activation of proto-oncogenes and the induction of pulmonary neoplasia by nitrosamines. 223 92


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