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

Bladder tumors were induced in male F344/NCr rats by administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at 500 p.p.m. in their drinking water for 12 weeks. Twenty-one bladder tumors that developed between 25 and 50 weeks after BBN administration was begun were evaluated for immunoreactivity with polyclonal or monoclonal antibodies raised against ras p21, for amplification of ras genes by Southern blotting, and for activating point mutations in ras genes by selective oligonucleotide hybridization of products from polymerase chain reaction (PCR). Increased expression of ras p21 was detected by avidin-biotin immunohistochemistry in 18/21 (85%) of the neoplastic bladder lesions. By Southern analysis, there was no significant amplification of H-ras, K-ras or N-ras in any of the tumors except one that showed a 5-fold amplification of K-ras. Point mutations in ras genes were detected by selective oligonucleotide hybridization of the products of PCR. Of the 21 bladder tumors, three tumors were shown to have mutations in codon 12 (GGA----GAA), six tumors in codon 61 (two CAA----CTA, four CAA----CGA), and one in both codon 12 (GGA----GAA) and codon 61 (CAA----CGA), all in H-ras. Thus 10 of 21 tumors has ras gene mutations in a portion of the tumor cells. The variable pattern of point mutation in H-ras suggests that these mutations may not all be a direct consequence of interaction of BBN metabolites with H-ras. Enhanced expression of ras p21 was always focal and was not necessarily associated with transforming ras mutations. It is therefore suggested that tumorigenesis in BBN-initiated bladder cells might involve H-ras activation as part of a multistep pathway; however, H-ras involvement is not obligatory for tumor development.
Carcinogenesis 1990 Dec
PMID:H-ras activation and ras p21 expression in bladder tumors induced in F344/NCr rats by N-butyl-N-(4-hydroxybutyl)nitrosamine. 226 74

Human papillomaviruses (HPV) are known etiological agents of benign proliferation of the skin and mucosa (papillomas and warts). They have also been implicated in the development of cervical dysplasia and anogenital carcinoma. The close association of HPV type 16 DNA with the majority of cervical carcinomas suggests the involvement of the virus in this type of cancer. We have developed an in vitro multistep model for human epithelial cell carcinogenesis. Primary human epidermal keratinocytes acquired an indefinite lifespan in response to transfection with HPV 16 DNA but did not undergo malignant conversion. Addition of Kirsten murine sarcoma virus (Ki-MSV), which contains an activated K-ras oncogene, to these cells induced morphological alterations associated with the acquisition of neoplastic properties. The frequency of transformation by Ki-MSV was markedly enhanced by the inclusion of glucocorticoid. At optimal conditions, a 125-fold stimulation was observed. These findings demonstrate the malignant conversion of human primary epithelial cells in culture by the cooperation of HPV type 16 and an activated ras oncogene and support a multistep process for neoplastic conversion. The availability of a human epithelial cell transformation model should facilitate studies of the interaction between HPV and human epithelial cells.
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PMID:Glucocorticoid-enhanced neoplastic transformation of human keratinocytes by human papillomavirus type 16 and an activated ras oncogene. 255 55

Using an in vitro amplification step (polymerase chain reaction) followed by oligonucleotide dot blot analysis, DNA samples from 29 familial polyposis coli patients (75 polyp-derived and 26 'normal' colon samples with no epithelial atypia) were screened for the presence of K-, N-, and H-ras mutations. Only 5 polyps contained ras mutations (7%)--all in K-ras codon 12. In each case 'normal' colon DNA was available and found to be negative in this assay. We also report the detection of K-ras codon 12 mutations in a stably non-tumorigenic immortal adenoma-derived cell line, PC/AA, and in a tumorigenic colorectal carcinoma cell line, PC/JW. Both epithelial cell lines were derived from different FPC patients. An activated K-ras gene was also found in cell line S/AN, isolated from a sporadic villous adenoma. These results provide further evidence that there are common molecular events involved in sporadic and hereditary colorectal carcinogenesis and that K-ras mutations can precede the development of malignancy. To our knowledge PC/AA is the first reported example of a human cell line bearing a mutant ras gene that is not tumorigenic and shows that the presence of an activated ras gene even in an immortal human cell line is insufficient for malignancy.
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PMID:A study of ras gene mutations in colonic adenomas from familial polyposis coli patients. 257 69

Efforts to investigate the progression of events that lead human cells of epithelial origin to become neoplastic in response to carcinogenic agents have been aided by the development of tissue culture systems for propagation of epithelial cells. We have recently developed an in vitro multistep model suitable for the study of human epithelial cell carcinogenesis. Primary human epidermal keratinocytes acquired indefinite lifespan in culture but did not undergo malignant conversion in response to infection with Adl2-SV40 virus. Subsequent addition of Ki-MSV, which contains a K-ras oncogene, to these cells induced morphological alterations and the acquisition of neoplastic properties. Nontumorigenic human epidermal keratinocytes immortalized by Adl2-SV40 virus (RHEK-1) were also transformed by treatment with chemical carcinogens (MNNG or 4NQO) and by X-ray irradiation. Such transformants showed morphological alterations and induced carcinomas when transplanted into nude mice. This in vitro system may be useful in assessing environmental carcinogens for human epithelial cells and in detecting new human oncogenes since ras oncogenes were not activated in these chemical--or X-ray--transformed RHEK-1 lines. Subsequently, it was found that this line could be transformed neoplastically by a variety of retroviruses containing H-ras, bas, fes, fms, erbB and src oncogenes. In addition, our recent results indicate that nontumorigenic RHEK-1 cells can be transformed following transfection with an activated human oncogene. Thus, this in vitro system may be useful in studying the interaction of a variety of carcinogenic agents and human epithelial cells. These findings demonstrate the malignant transformation of human primary epithelial cells in culture by the combined action of tumor viruses and chemical carcinogens or X-ray irradiation and support a multistep process for neoplastic conversion. Further, evidence for the multistep nature of neoplastic transformation of human epithelial cells in vitro using other model systems is presented.
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PMID:Neoplastic transformation of human epithelial cells in vitro. 268 34

An animal model of carcinogenesis has been exploited to analyze the various events involved in carcinogen-induced T cell lymphomagenesis. Two carcinogenic agents, the alkylating agent N-methylnitrosourea (NMU) and ionizing gamma-radiation, induce tumors in C57BL/6J mice that are phenotypically and histologically identical. Are the genetic events similar or different in the T cell tumors produced by these two carcinogenic agents? NMU treatment produced a different spectrum of activated oncogenes from gamma-irradiation. The K-ras oncogene was preferentially activated in all of the NMU-induced tumors, most frequently by a GGT to GAT transition in codon 12. Ionizing gamma-radiation produced two different transforming activities. Approximately half of the radiation-induced tumors contained activated N-ras genes and half contained a novel non-ras transforming activity. Analysis of NMU- and gamma-irradiated treated animals for chromosomal abnormalities showed anomalies early in the disease. Although both agents produce tumors containing trisomy of chromosome 15, the timing of this event appears to be different occurring early in NMU-induced tumors and later in gamma-radiation induced tumors. In addition, a unique marker chromosome consisting of a translocation between chromosomes one and five appears to be involved in the early stages of radiation-induced disease and may be associated with the novel transforming activity detected in these same tumors. Expression of receptors for the T cell growth factor (IL-2R) is similar in both NMU- and gamma-irradiation induced tumors. Changes in the expression of IL-2R on different T cell populations with disease progression may account for thymus dependent and thymus independent phases of malignant T cell growth.
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PMID:Multistage carcinogenesis in murine thymocytes: involvement of oncogenes, chromosomal imbalances and T cell growth factor receptor. 268 36

Adult Atlantic tomcod collected from the Hudson River slightly north of New York City have an extremely high incidence (55-90%) of histologically defined hepatocellular carcinomas, whereas tomcod from control sites in Maine or Rhode Island exhibit little evidence of this condition. Genomic DNA was isolated from Hudson tomcod tumors and from normal Hudson and Saco River, Maine tomcod livers and tested for transforming activity in the NIH3T3 transfection assay. Six out of nine tumors (66%) tested proved positive. Southern blot analysis of all primary (6/6) transfectant and nude mouse tumor DNAs revealed evidence of an exogenous tomcod K-ras gene, while no activation of the H-ras gene was observed. These studies demonstrate that an outbred population of fishes and inbred mammals suffer genetic alternations at the same oncogene loci and suggest that similar pathways to neoplasia may be operative in both systems. Oncogene activation in naturally exposed feral populations may prove a particularly sensitive marker of environmental degradation in aquatic systems.
Carcinogenesis 1989 Dec
PMID:Activation of the K-ras oncogene in liver tumors of Hudson River tomcod. 268 54

Skin fibroblasts derived from three patients with familial polyposis coli (FPC) were treated in vitro with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) alone or in combination with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). None of the cultures treated four times with MNNG alone (1 microgram/ml) or in combination with TPA (eight applications, 0.1 microgram/ml each) showed either morphological transformation or anchorage-independent growth for 18 months after treatments. FPC cells treated with MNNG alone showed cell growth inhibition, breakage and loss of chromosomes, as well as the deletion of 5.7 kilobase (kb) EcoRI fragment in the c-K-ras locus as detected by Southern blot analysis with v-K-ras specific probe (clone KBE-2). The control cells contained two EcoRI fragments of 5.7 and 4.2 kb. On the other hand, cells treated with MNNG first and then followed by treatment with TPA not only showed an increase in the rate of cell growth but also exhibited two novel EcoRI fragments of 9.4 and 12 kb. Treatment with TPA alone appeared to stimulate cell division long after application and to induce chromosomal aberrations but had no effect on c-K-ras sequences. The most likely explanation for the appearance of chromosome pulverization and hyperploidy in FPC cells treated with TPA is the induction of premature chromosome condensation of the S phase cells due to fusion with the mitotic chromosomes.
Carcinogenesis 1988 Oct
PMID:Chromosomal and c-K-ras oncogene alterations induced by a chemical carcinogen and phorbol ester in skin fibroblasts of individuals with familial polyposis coli. 284 31

We have examined the mechanism of transformation of a line of immortalized hamster dermal fibroblasts (4DH2 cells) following treatment with the simple alkylating agents, N-methyl-N-nitrosourea (MNU), N-ethyl-N-nitrosourea (ENU) and dimethyl sulphate (DMS). Treatment of 4DH2 cells with the potent point mutagens MNU and ENU gave rise to a spectrum of foci of different sizes, including progressively growing large foci and compact small foci. In contrast, treatment with the weak point mutagen DMS produced mostly large foci. The ability of cell lines derived from morphologically transformed foci to grow in soft agar in general reflects their original size. Thus most cell lines derived from large foci grew in soft agar while most lines derived from small foci did not. Transfection of cellular DNAs into the parent 4DH2 cell line and into NIH3T3 mouse fibroblasts has revealed the presence of dominantly acting transforming genes in the chemically transformed cell lines. Thus DNA from five of six cell lines derived by culturing large foci and from one of three cell lines derived by culturing small foci induced efficient morphological transformation of the recipient cells. Southern analyses of DNA from primary and secondary transfectants showed that several of the transforming genes transferred in these experiments were not closely related to H-ras, K-ras or N-ras.
Carcinogenesis 1988 Sep
PMID:Morphological transformation of immortalized hamster dermal fibroblasts following treatment with simple alkylating carcinogens. 304 38

It has been well established that specific alterations in members of the ras gene family, H-ras, K-ras and N-ras, can convert them into active oncogenes. These alterations are either point mutations occurring in either codon 12, 13 or 61 or, alternatively, a 5- to 50-fold amplification of the wild-type gene. Activated ras oncogenes have been found in a significant proportion of all tumors but the incidence varies considerably with the tumor type: it is relatively frequent (20-40%) in colorectal cancer and acute myeloid leukemia, but absent or present only rarely in, for example, breast tumors and stomach cancer. No correlation has been found, yet, between the presence of absence of an activated ras gene and the clinical or biological features of the malignancy. The activation of ras oncogenes is only one step in the multistep process of tumor formation. The presence of mutated ras genes in benign polyps of the colon indicates that activation can be an early event, possibly even the initiating event. However, it can also occur later in the course of carcinogenesis to initiate for instance the transition of a benign polyp of the colon into a malignant carcinoma or to convert a primary melanoma into a metastatic tumor. Apparently, the activation of ras genes is not an obligatory event but when it occurs it can contribute to both early and advanced stages of human carcinogenesis.
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PMID:The ras gene family and human carcinogenesis. 328 42

Previously, it has been demonstrated that thyroid hormone is an important cofactor of the initiation of oncogenesis in vivo and in vitro. In order to determine the mechanism of thyroid hormone modulation of the initiation of carcinogenesis we have addressed the hypothesis that thyroid hormone regulates the expression of the critical protooncogene at the time of exposure to the carcinogen, and that the transcriptional activity of the protooncogene correlates with the ability of a carcinogen to "activate" the oncogene and thus modulate the subsequent transformation event. It has previously been shown that 3-methylcholanthrene transformation of C3H/10T1/2 mouse embryo cells in culture is the result of activation of the k-ras oncogene. We report here that thyroid hormone modulates 3-methylcholanthrene transformation of C3H/10T1/2 cells in a dose-dependent manner that is similar to a thyroid hormone dose-dependent modulation of k-ras-specific RNA levels in these cells. Further, nuclear transcriptional run-on experiments suggest that the thyroidal-induced changes in K-ras RNA levels are a result of a regulation of K-ras transcription. These data support the hypothesis that thyroid hormone modulation of transformation is through regulation of protooncogene expression. It was of further interest to find that 3-methylcholanthrene-transformed C3H/10T1/2 cells have lost the sensitivity to thyroid hormone regulation of "activated" K-ras oncogene transcription and subsequent K-ras-specific RNA levels.
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PMID:Correlation of thyroid hormone dose-dependent regulation of K-ras protooncogene expression with oncogene activation by 3-methylcholanthrene: loss of thyroidal regulation in the transformed mouse cell. 358 Oct 59


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