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

Using a combination of transplacental carcinogen exposure and retrovirus-mediated oncogene transfer into fetal brain transplants, we have studied complementary transformation by N-ethyl-N-nitrosourea (NEU) and the v-myc oncogene in the nervous system. Previous experiments had demonstrated that both agents will not induce tumors independently whereas simultaneous expression of v-H-ras and v-gag/myc exerted a powerful transforming potential in neural grafts. In order to identify other genetic alterations that co-operate with an activated myc gene, the neurotropic carcinogen NEU was used to generate mutations of cellular genes. On embryonic day 14 (ED14), pregnant donor animals (F344 rats) received a single i.v. dose of NEU (50 mg/kg). Twenty-four hours later (ED15), the fetal brains were removed, triturated and incubated with a retroviral vector carrying the v-gag/myc oncogene. Subsequently, these primary cell suspensions were transplanted stereotactically into the caudate-putamen of syngenic adult recipients. After latency periods of 3-6 months, 5 of 10 recipients harboring ED15 fetal brain transplants developed malignant, poorly differentiated neuroectodermal tumors in the grafts. No tumor development was observed in seven recipients harboring ED16 neural grafts. Cell lines were established from three tumors and the 110 kd gag/myc fusion protein encoded by the retroviral construct was identified in the tumors by Western blotting. Several candidate genes for mutational activation by NEU including the H-ras, K-ras and neu oncogenes were analyzed for specific point mutations by polymerase chain reaction (PCR) and direct DNA sequencing of the PCR products. However, no mutations were found in any of these genes. These findings lend further support to the multistep hypothesis of neoplastic transformation in the brain. The tumors induced in this model provide an interesting tool for the identification of genes that co-operate with an activated myc gene in neurocarcinogenesis.
Carcinogenesis 1993 Aug
PMID:Complementary tumor induction in neural grafts exposed to N-ethyl-N-nitrosourea and an activated myc gene. 835 58

To determine if the tumor suppressor gene active in BHK hamster cells acts to maintain the normal phenotype by influencing oncogene transformation, careful, quantitative transfections with a variety of oncogenes were performed on four closely related BHK subclones. Two of the clones had an active suppressor gene (sup+ clones) and two of them had lost the suppressor (sup- clones) yet remained anchorage dependent. Both sup+ and sup- clones could be transformed to anchorage independence by ras, src, mos, neu, polyoma mT and SV40 suggesting that neither the presence nor the absence of the suppressor gene in BHK limits the transforming ability of these common oncogenes. All lines were resistant to transformation by N-myc, E1A and c-sis, oncogenes that may perform redundant functions in the immortal, fast growing BHK cell. SV40 small t antigen which has previously been considered unable to transform cultured cells by itself, was nevertheless able to transform sup+ BHK lines to anchorage independence in the absence of the viral large T antigen. Clones of sup- cells expressing high levels of small t antigen protein could be isolated, but they remained anchorage dependent and in tumorigenicity assays retained the long latent period characteristic of normal BHK cells. Such lines should enable the identification of cellular targets vital to the transforming function of SV40 small t.
Carcinogenesis 1993 Jun
PMID:Influence of a hamster tumor suppressor gene on transformation by viral and cellular oncogenes. 838 73

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a mutagen found in cooked meat, has been shown to induce mammary gland tumors in rats. Our laboratory recently observed that a high fat diet enhances the incidence and severity of PhIP-induced mammary gland cancer in rats. In the current study, reverse transcription followed by polymerase chain reaction amplification was used to determine whether EGFR, TGF-alpha, neu and c-myc are differentially expressed in PhIP-induced mammary gland tumors classified histologically as benign or malignant and to evaluate whether dietary fat intake influences the expression of these genes. Of 23 total PhIP-induced mammary tumors examined, 43%, 57% and 74% had increased expression of EGFR, TGF-alpha and neu mRNA respectively. Increased expression of these genes appeared to be consistently present in tumors displaying papillomatosis. In contrast, to the other three genes, c-myc mRNA levels were infrequently elevated. The percentage of dietary fat did not appear to influence the expression of EGFR, TGF-alpha or neu in either tumors or mammary gland from control rats. However, the levels of c-myc mRNA were 1.8- and 2.9-fold higher in the control mammary gland and benign PhIP-induced tumors respectively in rats fed the high-fat diet than in rats fed the low-fat diet, suggesting a slight effect of dietary fat (P < 0.08) on c-myc expression. These results suggest that increased expression of EGFR, TGF-alpha and especially neu is associated with PhIP-induced mammary gland cancer in rats.
Carcinogenesis 1995 Dec
PMID:Analysis of EGFR, TGF-alpha, neu and c-myc in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mammary tumors using RT-PCR. 860 90

The occurrence of different components of the cell growth regulation pathway as expressed in experimental skin carcinogenesis in haired carcinogen-sensitive NMRI, in haired carcinogen resistant DBA/2 mice and in hairless SKH/1 mice was studied by morphological and immunohistochemical methods. The results were compared with respect to neoplastic response, number of tumors, tumor behaviour and to the inducing agent (UV irradiation or chemical carcinogen), in order to increase our understanding of specific alterations in neoplastic development caused by extraneous agents and to determine their possible usefulness as indicators of carcinogen exposure. The expression of growth factors (transforming growth factor alpha and epidermal growth factor), growth factor receptors (epidermal growth factor receptor/c-erbB-1 and c-erbB-2/neu), cell signalling component c-myc, the nuclear transcription factor Harvey-Ras and the tumor suppressor gene p53, were studied in carcinogen- and UV-induced tumor formation in mouse. The results showed increased oncogene expression as well as growth factor expression in the skin during tumor development appearing early in neoplastic and premalignant conditions and becoming more distinct during neoplastic progression. Efforts to delineate specifically initiated cells prior to the appearance of morphologically detectable alterations including dysplasia, papilloma formation and squamous cell carcinomas, were unsuccessful. Increased staining by antibodies to growth factors and oncogenes were also observed in DBA/2 animals resistant to tumor formation. It is concluded that oncogene expression and growth factor protein deposits are associated with carcinogenic effects, partly explaining the mechanism of action of these agents, but the applicability, as such, for the analysis of potential hazardous agents needs further studies.
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PMID:Oncogenes and growth factors as indicators of carcinogen exposure. 867 68

The breast cancer gene BRCA1 has previously been cloned from both human and mouse. We cloned a fragment of the rat Brca1 homologue in order to map it and explore its biological function. Partial cDNA fragments of the rat Brca1 homologue were isolated by RT-PCR. Sequence analysis revealed that the RING-finger domain is well conserved among rat, mouse and human. Rat Brca1 mRNA was expressed in most tissues studied with the highest level in testis, consistent with studies in human and mouse. Next, intron 6-containing DNA fragments were amplified by PCR from WKY and WF rat strains. The splicing sites between exon 6 and exon 7 are conserved between rat and human. Partial sequencing of the rat Brca1 intron 6 revealed a polymorphism of a pentanucleotide TTTTG repeat between the WKY and WF strains. With this intragenic microsatellite marker, we were able to map precisely the rat Brca1 gene to chromosome 10 using a genetic linkage study of (WKY x WF)F1 x WF backcross rats. Brca1 cosegregates with marker BAND3A, and is flanked by R5123 and R5842. Using this polymorphic marker, we also investigated the loss of heterozygosity (LOH) of the Brca1 microsatellite marker in carcinogen- or radiation-induced mammary carcinomas in (WF x F344)F1 female rats. No LOH or somatic microsatellite instability was detected in 18 DMBA-induced tumors studied. Only one LOH of the F344 allele was observed in 26 radiation-induced tumors tested. Ribonuclease protection assays demonstrated that Brca1 mRNA levels are similar in normal rat mammary glands and mammary carcinomas of various etiologies, including those induced by DMBA, NMU, activated-neu and activated-ras oncogenes.
Carcinogenesis 1996 Aug
PMID:Cloning, genetic mapping and expression studies of the rat Brca1 gene. 876 10

Von Recklinghausen's disease, or neurofibromatosis type 1 (NF-1), is an autosomal dominant syndrome with a highly variable tumorous (neurofibromas, gliomas, Wilms' tumors, leukemia, pheochromocytomas) and non-tumorous (cafe-au-lait skin spots, iris and ciliar hamartomas, osseous lesions) manifestations. NF-1 gene is mapped to chromosome 17. Central or bilateral acoustic neurofibromatosis (NF-2) has a gene mapped to chromosome 22. Hereditary and sporadic NF-1 are recognized. The most typical manifestation of NF-1-skin neurofibroma--has has a characteristic plexiform structure. Spectrum of tumors (schwannomas, gliomas, Wilms' tumors) produced by transplacental treatment with strong environmental mutagens-carcinogens-ethylnitroso- and methylnitrosourea (ENU and MNU, respectively) resembles on the whole that observed in human sporadic NF-1. Location of neurofibromas depends on the species: skin and subcutaneous tissue in humans, cattle and hamsters, trigeminal nerve, spinal roots in rats. Rat schwannomas differ from human neurofibromas by malignant structure, frequently with cystic component, but if induced by ENU treatment at day 15 of the pregnancy they resemble human plexiform neurofibromas with intraneural and extraneural growth of tumor cells. There were attempts to reproduce a transgenerational transmission of ENU carcinogenic effect, i.e. hereditary form of NF-1. In the experiments of this type the offsprings of rats prenatally treated with ENU remained untreated. The incidence of PNS, CNS and Wilms' tumors in these untreated offsprings in some experiments was significantly higher than in controls thus confirming the possibility, in principle, of hereditary NF-1 modelling. Only 10% of tumors developing in such untreated descendants of ENU treated parents contained a specific mutation of neu oncogene compared to 90-100% in tumors arising following direct treatment with ENU. The mechanisms of the transgenerational carcinogenesis are discussed. Lesions imitating NF-1 and in part NF-2 in transgenic mice with an HTLV-1-tax gene as well as in p-53 knockout mice are mentioned.
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PMID:[Von Recklinghausen's disease: experimental models and comparative aspects]. 900 21

Recently, constitutively active mutants of MEK (MAP/ERK kinase) were shown to be capable of transforming cells to tumorigenicity suggesting that MEK can function as a dominant oncogene and potentially play a role in human carcinogenesis. Human lung cancer cells exhibit mutations in other components of the MAP kinase signaling pathway such as the Her-2/neu and ras oncogenes. Thus, the coding sequences of both MEK-1 and MEK-2 cDNAs from human lung cancer cell lines were screened by single strand conformation polymorphism analysis and DNA sequencing for alterations in these two genes. In 37 lung cancer cell lines we found: an allelic variant in MEK-1 cDNA, nt 783 G-->A, (no amino acid change); a MEK-2 cDNA change (nt 977 C-->T mutation leading to 298 Pro-->Leu change); a MEK-2 cDNA change nt 537 C-->T (no amino acid change); and a frequent MEK-2 cDNA germline polymorphism nt 744, A-->C (no amino acid change) with an allele frequency of 0.5 for each form. These results suggest that mutations in the MEK-1 and MEK-2 gene occur at a very low frequency in human lung cancer.
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PMID:Mutation analysis of the coding sequences of MEK-1 and MEK-2 genes in human lung cancer cell lines. 912 73

Carcinogenesis is most often viewed as a multistage disease process. An exception to this was suggested for neu transformation of mammary cells in a transgenic model (Muller et al., 1988); however, this interpretation is controversial (Bouchard et al., 1989). In order to better define neu mammary transformation in vivo, we directly measured the genetic penetrance of the neu oncogene. Mammary cells in situ were infected with replication-defective retroviral vectors carrying the activated neu oncogene (pJRneu). A limiting dilution in vivo transplantation assay was used to measure the percentage of mammary clonogenic (stem-like) cells that stably and functionally integrated this vector. Based on this, the percentage of clonogens integrating and expressing neu that could progress to mammary carcinomas was quantified to estimate the penetrance of this gene in mammary carcinogenesis. The genetic penetrance of neu was 3.6% (95% confidence interval 2.2%-5.8%). This high degree of genetic penetrance is compatible with the observations that certain neu-transgenic mice develop a very great number of mammary carcinomas (Muller et al., 1988). However, whether these data are compatible with a single-step transformation model (100% penetrance) is uncertain and is discussed.
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PMID:The genetic penetrance of the activated neu oncogene for the induction of mammary cancer in vivo. 917 68

Overexpression of c-erbB-2/neu/HER-2 oncoprotein, a receptor tyrosine kinase, has been demonstrated in a variety of human cancers. To elucidate the involvement of c-erbB-2 in human skin carcinogenesis, we examined expression of the protein in skin samples from five cases of keratoacanthoma (KA), 10 of actinic keratosis (AK), 24 of squamous cell carcinoma (SCC) and 10 of basal cell carcinoma (BCC) and five samples of normal epidermis, using an immunohistochemical method on formalin-fixed, paraffin-embedded sections. Expression of c-erbB-2 was also examined in cultured SCC cell lines, a premalignant cell line and in cultured normal keratinocytes. Normal epidermal cells showed no or very little c-erbB-2 protein, but the covering epidermal layer of some tumours showed a few strongly positive cells. Samples of KA and AK showed barely detectable c-erbB-2 protein in only a few cases. Twenty of the 24 cases of SCC had elevated expression of c-erbB-2 protein, with a tendency to more positive cells in metastatic lesions. Five of the 10 cases of BCC stained for c-erbB-2 but more weakly than those of SCC. Reaction products of the positive cells were seen in the cytoplasm. All three cultured SCC cell lines stained for c-erbB-2 protein more strongly than the premalignant HaCaT or normal keratinocytes. Our results indicate the possible involvement of c-erbB-2 overexpression in the malignant conversion of keratinocytes.
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PMID:Increased level of c-erbB-2/neu/HER-2 protein in cutaneous squamous cell carcinoma. 921 24

Loss of heterozygosity (LOH) analysis has been used in many types of human cancer to localize putative tumor suppressor genes important in carcinogenesis. However, this approach has only recently been applied to transgenic mouse tumor models, which offer greater opportunity for detailed molecular genetic analysis of tumor initiation and progression. To explore the possible role of secondary genetic events in transgenic mouse mammary tumor development, we performed microsatellite-based allelotypes on primary mammary adenocarcinomas and lung metastases arising in mice transgenic for the polyomavirus middle T antigen under the control of the mouse mammary tumor virus promoter/enhancer (MMTV-MTAg mice) and on primary mammary adenocarcinomas arising in mice transgenic for the neu proto-oncogene (MMTV-neu mice). We examined a total of 80 microsatellite loci distributed throughout the mouse genome for LOH and observed high rates of specific chromosomal loss but very low rates of background allelic loss in these tumors. For the MMTV-MTAg mice, no individual chromosomes showed rates of LOH significantly above the background rates. For MMTV-neu mice, markers on chromosome 4 showed LOH in 82% of mammary tumors, whereas markers on chromosome 3 showed loss in 29% of tumors. These data suggest that the middle T antigen transgenic mice do not undergo whole chromosome loss or large genomic deletions as common mechanisms of tumor formation and that chromosomes 3 and 4 may contain tumor suppressor gene loci that play important roles in the development of neu-mediated mouse mammary tumors.
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PMID:Loss of heterozygosity analysis in primary mammary tumors and lung metastases of MMTV-MTAg and MMTV-neu transgenic mice. 927 23


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