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

The expression of Ha-ras and fes oncogenes was investigated with the immunohistochemical method in formalin-fixed, paraffin-embedded tissue specimens of 147 lung carcinomas. Positive immunoperoxidase reactions for Ha-ras p21 were found in 80.5% of the adenocarcinomas, 39.5% of the squamous cell carcinomas, 21.4% of the large cell carcinomas, and 15.4% of the small cell carcinomas; those for fes P85 were found in 51.2% of the adenocarcinomas, 26.3% of the squamous cell carcinomas, 35.7% of the large cell carcinomas, and 15.4% of the small cell carcinomas. Both Ha-ras p21 and fes P85 were expressed most frequently and most strongly in adenocarcinoma. In addition, adenocarcinoma showed significantly higher incidence of concomitant expression of Ha-ras p21 and fes P85 as compared with other histologic types of lung cancer. Thus, the authors suggest that the cooperative effects of Ha-ras and fes oncogenes are especially important in the carcinogenesis of adenocarcinoma. In adenocarcinoma, the incidence and grade of Ha-ras p21 expression increased with the degree of histologic differentiation, suggesting that Ha-ras oncogene might be related to cellular differentiation. Papillary adenocarcinoma showed more frequent Ha-ras p21 expression in comparison with acinar adenocarcinoma. In well- or moderately differentiated adenocarcinoma, the incidence and grade of Ha-ras p21 immunoreactivity in the cases with poor prognosis were significantly higher than in those with good prognosis if other major prognostic factors were equivalent in the two groups. The authors propose that the expression of Ha-ras p21 may be one of the useful prognostic factors in such carcinomas.
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PMID:Clinical and histopathologic evaluation of the expression of Ha-ras and fes oncogene products in lung cancer. 131 Aug 87

To analyze the role of human papillomavirus (HPV) infection and c-myc and c-Ha-ras oncogene activation in cutaneous and mucosal lesions, serial frozen sections of 47 lesions from grafted recipients and 10 biopsies from non-immunosuppressed patients were examined. HeLa, CaSki, MCF7, Colo 320 and 3T3 cells, which contain various copy numbers of HPV DNA and/or c-myc gene, were used as controls. HPV, myc and ras oncogene DNAs were not detected in normal epithelia by in situ hybridization with biotinylated DNA probes. The amplification of ras oncogene was detected in 20/57 lesions. The amplification of myc oncogene was found in 14/57 lesions, 13 of which showed both myc and ras gene amplification. c-myc and/or c-Ha-ras DNA was more frequently amplified in cutaneous squamous cell carcinomas (8/14 cases) and anogenital papillomas (4/6 cases), than in common and plantar warts (3/14 cases) or actinic keratoses (2/10 cases). HPV DNA was detected in 26/57 biopsies. Oncogene amplification was codetected with HPV DNA in 10/26 lesions, each of them containing at least one potentially oncogenic HPV type (5,16 and/or 18). The amplification was also found in 11/31 cases in the absence of HPV DNA. No significant difference was observed in the detection of HPV or oncogene DNA between the lesions of transplant recipients and those of the non-immunosuppressed population. Viral antigen was detected in 17/55 lesions by indirect immunofluorescence; 5 of the positive biopsies showed ras oncogene amplification. Myc and ras p21 oncoproteins were respectively localized in the nuclei and on the membrane of epithelial cells by indirect immunofluorescence. A good correlation was observed between the amplification of oncogenes and the expression of oncoproteins. Our results favor the hypothesis of a cooperation between HPV infection and myc and ras oncogene activation in skin carcinogenesis.
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PMID:c-myc and c-Ha-ras cellular oncogenes and human papillomaviruses in benign and malignant cutaneous lesions. 131 8

N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) administration to rats followed by sodium saccharin results in transitional cell carcinomas of the bladder, of which 24% harbor an activated H-ras gene. Since 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) is the mutagenic and carcinogenic metabolite of FANFT in vivo, we wished to examine ras activation in in vitro ANFT-transformed rat bladder epithelial cells as well as four cell lines established in culture from in vivo FANFT-induced rat bladder tumors. Screening by Western blotting revealed no enhanced levels of p21ras in ANFT-transformed cells nor in cells established in culture from FANFT-induced rat bladder carcinomas. Further investigations using immunohistochemical staining with a different pan-reactive p21 monoclonal antibody (Cetus Corporation) specific for this method, however, showed two groups of cells from FANFT-induced rat bladder tumors had enhanced immunoreactivity. Apart from this, p21ras expression of most of the cells groups varied little from the controls. We examined the reported hot spots (exons 1 and 2) of each of the ras genes (H-, K- and N-ras) by direct sequencing of amplified DNA. No mutations were present. We conclude, therefore, that ANFT transformation of primary rat bladder epithelial cells in vitro may not in this case be mediated by ras activation, although this is difficult to determine since others have observed that optimal culture conditions can select for certain populations of cells without ras activation.
Carcinogenesis 1992 Sep
PMID:Ras involvement in cells transformed with 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in vitro and with N-[4-(5-nitro-2-furyl)-2-thiazoyl]formamide in vivo. 139 51

The expression of the ras oncogene in aberrant crypt foci was studied by both in situ hybridization and immunohistochemical approaches. Aberrant crypt foci are hypothesized to represent the earliest identifiable microscopic lesions of colon cancer in rodent colons. Sprague-Dawley male rats were injected with azoxymethane (20 mg/kg s.c.) once. Twelve weeks later, aberrant crypt foci were identified topographically, microdissected and processed for histology. In situ hybridization with an antisense oligomer of c-ras demonstrated increased expression of ras-specific RNA in aberrant crypts compared to normal crypts. A low amount of non-specific hybridization was obtained with the corresponding sense oligomer. The percentage of cells with grains (labeling index) was calculated in early and advanced aberrant crypt foci. This index was also calculated in normal appearing crypts. The labeling indices for the early and advanced aberrant crypt foci were significantly greater than that of normal crypts (18.0 and 25.0 versus 11.9). In the same tissue specimens, immunohistochemical staining for ras p21 with the monoclonal antibody (Y13-259) revealed strong staining intensity in early aberrant crypts (15/22) and advanced aberrant crypts (22/30) compared to normal crypts (3/50). The immunohistochemical results demonstrate the presence of elevated levels of ras p21 in the same tissue as increased levels of ras-specific message. This investigation provides the earliest demonstration of increased expression of the ras oncogene in precursor lesions of colon cancer possessing dysplastic features.
Carcinogenesis 1992 Oct
PMID:Expression of ras oncogene mRNA and protein in aberrant crypt foci. 142 46

The GTPase activating proteins (GAP) stimulate the intrinsic GTPase activity of ras-p21 thus converting the protein into its inactive form. We have now analyzed carcinogen-induced mouse liver tumors for the possible occurrence of mutational changes in one of the two known GAP genes, namely p120-GAP. RNA from a total of 21 tumors was reverse transcribed by use of GAP-specific primers, amplified by PCR and sequenced. All known functional domains of p120-GAP were included into the analysis. None of the liver tumors analyzed was found to be mutated within these regions of the gene. Moreover, Southern blot analysis of the gene did not reveal any structural changes. However, at five positions we discovered deviations from the published mouse fibroblast sequence, including two mouse strain-specific sequence polymorphisms.
Carcinogenesis 1992 Oct
PMID:Absence of mutations in the functional parts of the p120-GAP gene in carcinogen-induced mouse liver tumors. 142 50

Previously, we demonstrated point mutations of the H-ras gene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced rat urinary bladder carcinomas. In this study, ras oncogene activation was examined in urinary bladder carcinomas induced by N-(4-hydroxybutyl)nitrosamine (BBN) or N-methyl-N-nitrosourea (MNU) administration followed by uracil treatment. In the first experiment, MNU (20 mg/kg body wt) was i.p. injected into 11 male F344 rats twice a week for 4 weeks, followed by feeding 3% uracil for 20 weeks (MNU/uracil group). Ten rats were given only 3% uracil without MNU pretreatment. In the second experiment, 20 male F344 rats were given 0.05% BBN in the drinking water for 4 weeks, then fed 3% uracil for 20 weeks (BBN/uracil group). Another 20 rats were fed 3% uracil without the BBN pretreatment. Transitional cell carcinomas were induced in the urinary bladder of all rats in the MNU/uracil and BBN/uracil groups. Papillomas and hyperplasias were present in the rats given uracil without prior BBN or MNU. DNA and protein were extracted from the tumors (MNU/uracil or BBN/uracil groups) or from the scraped bladder epithelium (uracil alone groups). Sequences around codons 12, 13 and 61 of H-, K- and N-ras genes were examined by direct sequencing after polymerase chain reaction, and p21 was examined by Western blotting. No mutation was found within the examined sequences and p21 showed no changes in mobility. There was no difference in the level of p21 expression between rats treated with MNU/uracil or BBN/uracil compared to corresponding uracil alone groups. These results indicate that the ras oncogene was not activated in urinary bladder carcinomas induced by BBN or MNU in combination with uracil treatment, in contrast to previous findings with FANFT.
Carcinogenesis 1992 Dec
PMID:Absence of ras oncogene activation in rat urinary bladder carcinomas induced by N-methyl-N-nitrosourea or N-butyl-N-(4-hydroxybutyl)nitrosamine. 147 35

Although regeneration-competent newts like Notophthalmus viridescens have been reported to be resistant to carcinogenesis, we have been able to induce transplantable epidermal squamous cell carcinomas with 10-20% incidence by implanting 20-methylcholanthrene s.c. into the scapular region, a tissue that cannot regenerate. As soon as 1 week after exposure to this carcinogen, malignant cells were present in the treated skin, and after 4 weeks, macroscopic tumors of infiltrating squamous carcinoma cells positive for Type IV collagenase and/or rasHa p21 had dissolved areas of the epidermal basement membrane and colonized the dermis. Analysis of Ki-67 expression revealed that these tumors grow via a high growth fraction rather than a short cell cycle time. Morphological and immunohistochemical analyses showed that these tumors caricature the biology of the renewing epidermis: the presence of basal-like cells; differentiating cells; apoptotic cells; and keratinized horn pearls with an exaggerated or overabundant stem cell compartment as compared to the differentiated cell compartment. Immunochemical analyses indicated that the squamous carcinomas arose from the epidermis rather than the mucous glands. Thus, the principle that malignant tumors caricature the process of tissue renewal originally established in rodent tumors appears to be valid down the phylogenetic tree at least to regeneration-competent amphibia. Such a broad conservation indicates that the caricature principle also holds in human tumors.
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PMID:Newt squamous carcinoma proves phylogenetic conservation of tumors as caricatures of tissue renewal. 151 43

In northeast Thailand, the traditional habit of eating ground, raw freshwater and salt-fermented fish on a daily basis results in a local population repeatedly exposed to both liver fluke (Opisthorchis viverrini) infection and consuming nitrosamine-contaminated food from early in life. Epidemiological studies have revealed a coincident high prevalence of cholangiocarcinoma in this region and we have demonstrated in animal models that dietary contamination with nitrosamines and Opisthorchiasis are strong predisposing factors for cholangiocarcinogenesis. Thus all Syrian golden hamsters receiving a combination of subcarcinogenic doses of dimethylnitrosamine (DMN) and infection with flukes developed cholangiocarcinomas, while chemical administration or fluke infection alone did not cause cancer. Synergistic induction by chemical carcinogens and liver fluke infection was found to be related to levels of exposure to both. In this two-stage carcinogenesis model, nitrosamines are considered to act as genotoxicants exerting carcinogenic effects, while the liver flukes are assumed to play epigenetic roles. In our studies of biliary pathology related to worm burden in humans we found that while most of the subjects had worms, only a minority (25%) demonstrated a pathology of adenomatous hyperplasia, which is believed to predispose bile ducts to subsequent development of carcinomas, indicating the possible role of flukes as promoters. Biliary changes in nontumorous areas of hepatectomy specimens, including fibrosis (with or without adenomatous hyperplasia) which is found in most cases, and dysplasia in the fibrotic ducts indicate a conversion event in carcinogenesis: other factors may be required to aggravate the simple proliferation lesion so that they subsequently change to carcinomas. Furthermore, commonality in tumor phenotypes and expressions of ras p21 in both fluke related and non-fluke-related cholangiocarcinomas suggest that some similar mechanisms might be operating, at least in the relatively late stages of this multistage carcinogenesis involving the bile ducts.
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PMID:Multistage carcinogenesis of liver-fluke-associated cholangiocarcinoma in Thailand. 166 94

Pulmonary carcinogenesis due to occupational and environmental exposures to chemical carcinogens such as polycyclic aromatic hydrocarbons presents an interesting model for study of possible oncogene-related cancer biomarkers. Polycyclic aromatic hydrocarbons are important respiratory carcinogens and have been shown to cause specific mutational lesions that can lead to the activation of the ras oncogene and expression of its p21 protein product; ras oncogene activation and p21 expression frequently are detected in human lung cancers. In addition, the p21 protein is detectable via immunoblotting techniques in the serum of lung cancer patients and in selected persons in exposed worker cohorts at risk for the development of lung cancer. Thus, the ras oncogene and p21 protein may be useful biomarkers for monitoring pulmonary carcinogenesis in exposed populations.
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PMID:Advances in cancer biomarkers as applied to chemical exposures: the ras oncogene and p21 protein and pulmonary carcinogenesis. 174 43

The use of oncogene proteins as biomarkers offers a new approach to the molecular epidemiologic evaluation of occupational carcinogenesis. The ras oncogene-encoded p21 protein represents a prototype for this type of study, since it is known to be activated by common occupational carcinogens, is frequently found in human tumors of occupational concern, and, at least in certain instances, appears to be expressed relatively early in the disease process, allowing the possibility of early detection and intervention. Herein, we review our experience with the use of immunologic detection of p21 in cohorts with cancer or at risk for the development of cancer due to their occupational exposures. The results suggest that p21 (particularly when used with other oncoproteins and biomarkers such as PAH-DNA adducts) will indeed be a useful addition to the growing armamentarium of molecular epidemiologic biomarkers in the study of occupational carcinogenic mechanisms and in the detection and prevention of occupational cancers.
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PMID:Oncogene proteins as biomarkers in the molecular epidemiology of occupational carcinogenesis. The example of the ras oncogene-encoded p21 protein. 185 18


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