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

Oncogene activation induced by chromosomal changes is now regarded as one of the most important phenomena during carcinogenesis. We have reported c-abl activation in a rat leukemia cell line K3D, caused by a secondary chromosomal translocation. Another erythroblastic leukemia cell line D5A1, originally derived from a leukemia induced by 7,12-dimethylbenz(a)anthracene (DMBA) in a Long-Evans rat, is characterized by a marker chromosome 1q+, which also probably occurred as a secondary change. In this cell line, the transcription level of Ha-ras related mRNA increased compared with other cell lines. By the in situ hybridization technique, the c-Ha-ras locus was assigned to 1q43 and the breakpoint 1q+. Because the breakpoint was so near the c-Ha-ras locus on the chromosome, the present system may provide a model of activation of the c-Ha-ras gene brought about by chromosomal translocation.
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PMID:Chromosome marker and enhanced expression of c-Ha-ras in a DMBA-induced erythroleukemia cell line (D5A1). 311 19

Previous results in a number of laboratories have demonstrated that epidermal papillomas and carcinomas induced by the two-stage protocol of initiation and promotion contain a point mutation in the 61st codon of the c-Ha-ras oncogene when the initiating agent used is 7,12-dimethylbenz[a]anthracene (DMBA). In the present report, we have analyzed DNA purified from 'spontaneously initiated' papillomas and carcinomas induced in SENCAR mouse epidermis after repetitive treatments with a tumor-promoting agent. Southern blot hybridization studies of tumor DNA digested with diagnostic restriction endonucleases demonstrated that seven of nine papillomas and carcinomas contained a point mutation in the 61st codon of one allele of the c-Ha-ras oncogene. The implications of our findings with respect to the role which a point-mutated Ha-ras proto-oncogene plays in initiation of skin tumorigenesis are discussed.
Carcinogenesis 1988 Apr
PMID:Epidermal papillomas and carcinomas induced in uninitiated mouse skin by tumor promoters alone contain a point mutation in the 61st codon of the Ha-ras oncogene. 312 10

Two normal mortal human fibroblast cell strains were transformed into immortal cell lines, SUSM-1 and KMST-6, by treatment with 4-nitroquinoline 1-oxide (4NQO) and Co-60 gamma rays, respectively. These immortalized cell lines showed morphological changes of cells and remarkable chromosome aberrations, but neither of them grew in soft agar or formed tumors in nude mice. The immortal cell line, KMST-6, was then converted into neoplastic cells by treatment with Harvey murine sarcoma virus (Ha-MSV) or the c-Ha-ras oncogene derived from a human lung carcinoma. These neoplastically transformed cells acquired anchorage-independent growth potential and developed tumors when transplanted into nude mice. All the tumors grew progressively without regression until the animals died of tumors. In addition, the tumors were transplantable into other nude mice. Normal human fibroblasts, on the other hand, were not transformed into either immortal or tumorigenic cells by treatment with Ha-MSV or c-Ha-ras alone. Our present data indicate that (1) the chemical carcinogen, 4NQO, or gamma rays worked as an initiator of carcinogenesis in normal human cells, giving rise to immortality, and (2) the ras gene played a role in the progression of the immortally transformed cells to more malignant cells showing anchorage-independent growth and tumorigenicity. In other words, the immortalization process of human cells seems to be a pivotal or rate-limiting step in the carcinogenesis of human cells.
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PMID:Multistep carcinogenesis of normal human fibroblasts. Human fibroblasts immortalized by repeated treatment with Co-60 gamma rays were transformed into tumorigenic cells with Ha-ras oncogenes. 314 Jul 12

Gene transfer experiments have shown that ras effector functions are sufficient to transform cells from a variety of established lines (e. g., mouse NIH3T3 cells). In contrast, primary cells and early passage rodent cells can be transformed by ras oncogenes only at low frequencies, unless cotransfected with collaborating genes such as adenovirus early region IA (EIA) or myc retroviral oncogene homologue. Primary rat embryo fibroblasts (REF) were chosen as a model for the analysis of multistep cellular transformation. Transfection of REF, immortalized by early region of simian adenovirus SA7 with c-Ha-ras oncogene cannot induce their morphological transformation. This phenomenon is observed only after second transfection with the same oncogene. These different cell lines can be used for further analysis of the mechanisms of carcinogenesis.
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PMID:[Model systems of carcinogenesis in vitro: the interaction of the ras oncogene with immortalized cells]. 328 50

The expression of three cellular oncogenes (c-myc, c-Ha-ras, and c-delta-raf), the epidermal growth factor receptor gene, and two endogenous retrovirus-like sequences [rat leukemia virus (RaLV) and 30S] was examined in control rat livers and in 16 liver tumors. The tumors were induced in Sprague-Dawley male and female rats by a single i.p. injection of diethylnitrosamine at 1 or 2 days after birth, followed by dietary exposure to phenobarbital beginning at weaning. Increased expression of c-myc was seen in most of the tumors, but there was no consistent increase or decrease in expression of c-Ha-ras or c-delta-raf. It is of interest that a number of the tumor samples showed a decrease in epidermal growth factor receptor RNA. In all of the tumors, including both hepatocellular adenomas and carcinomas, there was a marked increase in expression of the endogenous RaLV sequence, and over 90% of the tumors displayed increased expression of the 30S endogenous retroviral-like sequence. No or a very low level of expression of the RaLV and 30S sequences was found in the control livers. The extent of expression of the RaLV and 30S sequences in individual tumors did not correlate with the extent of expression of c-myc or c-Ha-ras. Although increased expression of certain endogenous retrovirus-related sequences appears to be a common finding during rat liver carcinogenesis, the significance of this finding remains to be determined.
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PMID:Expression of retroviral sequences and oncogenes in rat liver tumors induced by diethylnitrosamine. 355 72

C3H/10T1/2-CL8 mouse cells were shown to take up and express a plasmid-cloned drug resistance gene (Ecogpt) after DNA transfection at a frequency (2-6 X 10(-4) which is acceptable for routine recovery of gene-transformed populations. Transfection of 10T1/2 cells with a mutant c-Ha-ras oncogene (pEJ6.6 plasmid) results in neoplastically transformed 10T1/2 cell populations as judged by colony morphology and tumorigenic growth in nude mice. The levels of mutant c-Ha-ras gene integration and expression in the tumorigenic cell populations and 10T1/2 cell controls were determined, and the highest level of mutant ras transcript was seen in the most tumorigenic cell population. A preliminary comparison of 10T1/2 and NIH/3T3 cells showed similar frequencies for pEJ 6.6-induced transformed foci and a similar lack of sensitivity to the transforming effects of a cloned B-lym oncogene. The results identify a genetic event, which has previously been shown to be carcinogen-inducible, that is permissive for neoplastic transformation of the widely used carcinogen-transformable 10T1/2 mouse cell line.
Carcinogenesis 1985 Sep
PMID:Integration of a mutant c-Ha-ras oncogene into C3H/10T1/2 cells and its relationship to tumorigenic transformation. 402 28

A point mutation alters the 12th amino acid of the c-Ha-ras oncogene product p21 in a human bladder cancer cell line. This is, at present, the only mutation known to result in a human transforming gene. This mutation may therefore represent a possible target for mutagenesis leading to carcinogenesis in humans. By means of restriction enzyme analysis, 29 human cancers, including 20 primary tumor tissues, derived from organs commonly exposed to environmental carcinogens, were tested for the presence of this mutation. None of ten primary bladder carcinomas exhibited the mutation; nor did nine colon carcinomas or ten carcinomas of the lung. Thus the point mutation affecting the 12th amino acid of the c-Ha-ras gene product, while a valuable model for carcinogenesis, does not appear to play a role in the development of most human epithelial cancers of the bladder, colon, or lung.
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PMID:Mutation affecting the 12th amino acid of the c-Ha-ras oncogene product occurs infrequently in human cancer. 630 75

Chemical carcinogenesis generally proceeds via the formation of strongly electrophilic reactants, termed ultimate carcinogens. The observation that many ultimate carcinogens are potent mutagens and the results of studies on the covalent binding of carcinogens to cellular macromolecules suggest that tumour initiation results from mutations arising from the binding of ultimate carcinogens to DNA. Recently, gene transfer experiments have shown that some tumours contain activated oncogenes which are members of the ras gene family (reviewed in refs 6. 7) and which differ by single base pair substitutions from their non-transforming counterparts, the proto-oncogenes (see, for example, refs 8-11). Here we have used clones of the c-Ha-ras-1 proto-oncogene to show that reaction in vitro with an ultimate carcinogen generates a transforming oncogene when the modified DNA is introduced into NIH 3T3 cells. As DNA is the only cellular macromolecule present in the reactions, our experiments also show that reaction of an ultimate carcinogen with DNA alone can lead to the induction of mutations in mammalian cells.
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PMID:Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo(a)pyrene diol-epoxide. 643 Dec 99

The established mouse cell line NIH 3T3 has been used with considerable success over the past three years as the basis of an in vitro transformation assay for demonstrating the presence of transfectable transforming genes in the DNA of certain human and rodent tumour cells (for review see ref. 1). In the case of the human bladder carcinoma cell lines EJ and T24, this approach has led to the molecular cloning of a transforming gene which is closely related to the rat-derived Harvey sarcoma virus oncogene, v-Ha-ras. A single point mutation, which distinguishes these genes from their normal human homologue (c-Ha-ras1), is thought to be solely responsible for their transforming potential. However, carcinogenesis in both humans and laboratory rodents is a multi-stage process (reviewed in ref. 11) of which the NIH 3T3 cell, already partly transformed, may represent only the penultimate stage. We therefore chose to examine the transforming effects of the EJ oncogene in a hamster fibroblast system originally developed in our laboratory to study stages in carcinogen-induced malignant transformation of normal diploid cells. We show here that EJ c-Ha-ras-1 lacks complete transforming activity when transfected into normal fibroblasts which have a limited lifespan, but can fully transform fibroblasts that have been newly 'immortalized' by carcinogens.
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PMID:Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. 687 85

While the life-extending and disease-modulating effects of caloric restriction (CR) are well documented in whole animal studies and in correlative experiments using cells taken from CR animals, very few studies have used cells in culture after their removal from the CR-fed animal. In using this in vivo-->in vitro approach we have attempted to examine the proposition that the effects of CR can be transferred to individual cells by analyzing the cellular functions of proliferation and transformation, the activation of oncogenes, and the methylation of DNA as a function only of diet. Pancreatic acinar cells excised from CR-fed Brown-Norway rats and placed in rich medium showed different responses compared to cells from ad libitum (AL)-fed controls. CR had the effect of slowing growth rate and protecting against spontaneous and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced transformation over 14 passages of cells in culture. At the molecular level, cells from the CR animals showed reduced c-Ha-ras oncogene expression and mutation as well as reduced mutation of the p53 suppressor gene. CR also increased genomic methylation of ras DNA. We conclude that the effects of CR treatment of the animal are transferred to individual cells and note that these responses (decreased proliferation and transformation; depressed oncogene expression and mutation and decreased suppressor gene mutation; and increased oncogene methylation) are cellular and molecular analogs of in vivo weight loss, life extension, and carcinogenesis modulation, which are hallmarks of CR in the whole animal. The fact that these responses are seen generations after the cells are removed from the CR-treated animal indicates that CR causes a permanent predisposition of pancreatic acinar cells to these modulated responses and shows the value of the in vivo-->in vitro protocol in studies that relate diet to cellular and molecular function.
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PMID:Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro. 750 63


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