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

Carcinogenesis in human large intestine is a result of multiple, heterogeneous and random genetic changes. Deletion of tumor suppressor genes and activation of oncogenes appear to be important molecular events. These compromise the loss of chromosomes 5, 17, 18 or functional inactivation of FAP, p53 and DCC genes. Activation of Ki-ras and c-myc oncogenes seems to be crucial for both cell immortalization and morphology modification. Identification of genes involved in this process enables both a screening and a new classification. Also it is an important step towards a gene therapy.
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PMID:Colorectal carcinoma as a genetic phenomenon. 129 35

In this study, structural changes of the p53 gene in primary specimens of human colorectal carcinomas were analyzed by polymerase chain reaction mediated-DNA sequencing method. Point mutations of p53 gene, including an intronic mutation case, were detected in 8 of 14 carcinomas (57%). Point mutations of the gene were also observed in 2 of 2 adenomas, suggesting that mutations occur prior to the carcinoma stage. These results support that p53 gene plays an important role in the development of colorectal cancer. The frequency of Ki-ras oncogene mutations was also studied by polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP). This resulted in the rate of 42% (10/24), a quite similar value obtained by other methods. As PCR-SSCP analysis is a convenient method to detect point mutation, we have now examined 24 colorectal cancers for the p53 gene by this method, and detected the mutations. Furthermore, expression of the DCC gene, a candidate of tumor suppressor gene involved in colorectal carcinogenesis, was examined by reverse transcriptase-mediated PCR (RT-PCR) assay, resulting in significant reduction on the DCC expression in 8 of 14 carcinoma cases (57%).
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PMID:Mutations of the p53 gene and other genes involving in human colorectal carcinogenesis. 130 99

Primary rat hepatocytes were transfected with simian virus 40 DNA and cultured in a chemically defined medium. Proliferating colonies developed after 2-3 weeks. Three cell lines were established by cloning albumin-secreting colonies, as identified by an immunooverlay assay. Two of the cell lines, ALB-6 and ALB-8, expressed all five liver-specific mRNAs studied, albumin, alpha-1-antitrypsin, fibrinogen, alpha-1-acid glycoprotein, and histidase. ALB-6 cells were nontumorigenic in nude mice while ALB-8 cells were weakly tumorigenic with only one of four injected nude mice developing a slowly growing tumor. Further transfection of ALB-6 and ALB-8 cells with an activated c-Ha-ras or N-ras oncogene resulted in strongly tumorigenic cells. The tumors induced by ras-transformed ALB-6 cells were moderately differentiated hepatocellular carcinomas. The tumors derived from ras-transformed ALB-8 cells were poorly differentiated, while the slowly growing tumors induced by untransfected or control DNA-transfected ALB-8 cells were well-differentiated trabecular hepatocellular carcinomas, suggesting histological dedifferentiation of cells following ras transformation. However, the synthetic capabilities of the cells were not lost in that the ras-transfected cultures and the tumors induced by ras-transformed cells retained the ability to synthesize the five liver-specific mRNAs. Thus we have developed an in vitro model of carcinogenesis in which, by sequential exposure to SV40 DNA and a ras oncogene, primary rat hepatocytes are transformed.
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PMID:ras transformation of simian virus 40-immortalized rat hepatocytes: an in vitro model of hepatocarcinogenesis. 130 23

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

Retinoblastoma (RB) and the familial adenomatous polyposis/colorectal cancer (FAP/CRC) complex provide well-characterised examples of multistage carcinogenesis and inheritance of a predisposition to cancer. Retinoblastoma appears to conform to the simple two-step model first proposed by Knudson. The gene responsible for RB, now called Rb1, has been located in chromosome region 13q14. The Rb1 gene has been cloned and subjected to extensive analysis. It is probable that the Rb1 gene product has a role in the regulation of transcription. The familial form of RB occurs as the result of a germline mutation of one of the copies of the Rb1 gene. Colorectal cancer, in contrast, appears to be the result of four or five steps involving both activation of oncogenes and inactivation of antioncogenes. The FAP gene has been located in chromosome region 5q21 by genetic linkage, and a candidate gene, MCC (mutated in colon cancer), has been cloned. Other mutations in previously-identified genes that have been identified as important in the genesis of CRC include the activation of p53 and of Ki-ras. A gene lying in chromosome region 18q which is deleted in colorectal cancer, and hence named DCC has been cloned. Its protein product has sequence homology to neural cell adhesion molecules and other related cell-surface glycoproteins. Delineation of the genes involved in the development of tumours such as RB and CRC provides insight into the mechanisms by which sequential mutations result in carcinogenesis.
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PMID:Multistage carcinogenesis in paediatric and adult cancers. 131 30

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

8-Bromo-cAMP and substances elevating cAMP levels within cells, such as forskolin, cholera toxin, and Bordetella pertussis-invasive adenylate cyclase (BPAC), suppress the growth of cultured granulosa cells cotransfected by simian virus-40 (SV40) DNA and Ha-ras oncogene concomitantly with the induction of steroidogenesis and without affecting oncogene expression. We, therefore, tested the hypothesis that cAMP can modulate tumorigenesis and metastatic spread of these cells in vivo. The cotransfected cells induced rapid development of tumors when injected sc in nude mice. Tumor development was faster in less differentiated cotransfected cells originating from preantral ovarian follicles than in those obtained from highly differentiated transformed cells originating from preovulatory follicles. Cells transfected by SV40 DNA alone produced only slow-growing small tumors. Metastatic lesions of cotransfected cells were most abundant in lung and less frequent in ovaries, kidney, and spleen. No metastatic lesions were found in the liver. However, metastatic spread was dramatically suppressed when cotransfected cells injected into nude mice were pretreated with the invasive BPAC. In contrast, no suppression of metastases was observed when the cells were pretreated with 8-bromo-cAMP, forskolin, or cholera toxin. Removal of forskolin in cultured cotransfected cells yielded a rapid decrease in cAMP levels. In contrast, high levels of cAMP persist in cell cultures even several hours after 1-h pretreatment and subsequent removal of BPAC from the medium of culture cotransfected cells. It is suggested that the inhibitory effect of BPAC on the metastatic spread of these cells is due to prolonged elevation of cAMP in vivo. The newly established granulosa cell lines transformed by SV40 and the Ha-ras oncogene can serve as a model for further studies of cAMP modulation of carcinogenesis in ovarian malignancies.
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PMID:Adenosine 3',5'-monophosphate suppresses metastatic spread in nude mice of steroidogenic rat granulosa cells transformed by simian virus-40 and Ha-ras oncogene. 131 28

To determine if asbestos exposure could contribute to mesothelial cell carcinogenesis by selection and/or expansion of an initiated cell population, we compared normal human pleural mesothelial cells to either human mesothelioma cell lines or mesothelial cells transfected with cancer-related genes for sensitivity to amosite fibers in vitro. Neither normal nor mesothelioma cells were directly stimulated to replicate or increase DNA synthesis by any of the asbestos exposure conditions tested. The potential selective effect of asbestos exposure was demonstrated by a differential sensitivity of normal mesothelial cells and mesothelioma cells to amosite: for example, up to 20-fold higher concentrations of amosite fibers were required to inhibit replication of mesothelioma cell lines than normal mesothelial cells. In addition, a significant resistance (4-fold) to amosite toxicity was observed for SV40 immortalized mesothelial cell lines that had previously been selected in vitro for resistance to asbestos. SV40 immortalized cells that have become tumorigenic after transfection with either Ha-ras or PDGF A-chain genes were not significantly more resistant to the cytotoxic effects of amosite than primary normal cells, and the primary cells were equally sensitive to amosite as mesothelial cells that were only immortalized by SV40. The sensitivity of normal mesothelial cells to asbestos does not appear to be simply a result of general fragility of the mesothelial cells, since similar levels of hydrogen peroxide and silica were cytotoxic for normal mesothelial cells and mesothelioma cell lines. Because mesothelioma cells have a greater resistance to asbestos cytotoxicity than normal mesothelial cells, we hypothesize that a differential resistance to cell killing by asbestos fibers in vivo may result in a selective expansion of an initiated or transformed cell population and thus contribute to the carcinogenesis process. Since tumorigenicity and asbestos resistance occur independently of one another in genetically altered mesothelial cell lines, genotypic and phenotypic alterations that lead to tumorigenic conversion may not be the same changes that provide resistance to cell killing by asbestos.
Carcinogenesis 1992 Aug
PMID:Human mesothelioma cells and asbestos-exposed mesothelial cells are selectively resistant to amosite toxicity: a possible mechanism for tumor promotion by asbestos. 132 25

Bovine papillomavirus type 4 (BPV-4) morphologically transforms primary bovine cells in vitro only in the presence of an activated ras gene. The transformed cells are capable of anchorage-independent growth, but are not immortal and are incapable of inducing tumors in nude mice, suggesting that other events are needed to convert the cells to the fully transformed phenotype. We show here that treatment of the cells with a single dose of the flavonoid quercetin leads to full oncogenic transformation of cells transfected with BPV-4 and ras. Quercetin is one of the most potent mutagens found in bracken fern, the environmental cofactor in BPV-4-associated carcinogenesis of the upper alimentary canal of cattle. Our results point to quercetin as the probable in vivo cocarcinogen synergizing with BPV-4 in malignant progression.
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PMID:Synergism between bovine papillomavirus type 4 and the flavonoid quercetin in cell transformation in vitro. 132 10

This study examines proto-oncogene hypomethylation in rat livers during the early stages of hepatocarcinogenesis by dietary methyl deprivation in the presence and absence of initiation by diethylnitrosamine (DEN). Male weanling F344 rats were fed a complete diet, or a diet deficient in methionine and choline (MDD). Half the animals in each dietary group were given a single initiating dose of DEN (20 mg/kg). Animals from each of the treatment groups were killed at 1, 3, 8, 16 and 32 weeks, and hepatic DNA was isolated. This DNA was digested with the restriction enzymes MspI and HpaII to determine the extent of methylation of the CCGG sequences in c-Ha-ras, c-Ki-ras and c-fos proto-oncogenes. The results indicate that the administration of the MDD produced hypomethylation of these proto-oncogenes at all times investigated, independent of DEN initiation. The methylation changes in the c-Ha-ras gene increased in intensity throughout the experiment until at 32 weeks they were similar to the patterns seen in both neoplastic and preneoplastic livers of rats fed the deficient diet for 18 months. These results demonstrate that early, selective hypomethylation of some, but not all, CCGG sites occurs in rats undergoing hepatocarcinogenesis by dietary methyl deprivation.
Carcinogenesis 1992 Oct
PMID:The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. 133 Mar 45


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