Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic instability, alterations of tumor suppressor genes as well as activation of oncogenes and aberrant expression of growth factor/receptor system found in human stomach carcinogenesis are overviewed. Aberrant expression and amplification of the c-met gene, inactivation of the p53 gene and amplification of the cyclin E gene are common events of both well differentiated and poorly differentiated gastric carcinomas. K-ras mutations, c-erbB2 gene amplification, loss of heterozygosity (LOH) and mutations of the APC, LOH of the bcl-2 gene and LOH at DCC locus are preferentially associated with well differentiated gastric cancer. On the other hand, microsatellite instability, reduction or loss of cadherin and catenins, K-sam and c-met gene amplification confer the development and progression of poorly differentiated or scirrhous gastric carcinomas. Interaction between cell-adhesion molecules in the c-met expressed cancer cells and hepatocyte growth factor from stromal cells is involved in morphogenesis of gastric cancer.
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PMID:[Multistep stomach carcinogenesis]. 892 Jun 75

The development of colorectal carcinoma from adenomas is recognized as the dominant mechanism of colon carcinogenesis. However, early colon carcinomas are being increasingly detected which have no adenomatous elements in their vicinity, and which, despite their small size, already show submucosal invasion. Such tumours (so-called 'de novo' carcinomas) have renewed consideration of the de novo colorectal carcinogenesis pathway. The goal of this study was to evaluate the expression of tumour suppressor gene p53 and apoptosis control gene bcl-2 in de novo carcinomas, compared with early carcinomas developing in the background of an adenoma (ex-adenoma). Fifty cases each of de novo and ex-adenoma carcinomas (pT1) were studied. p53 expression was significantly higher in the de novo carcinomas than in the ex-adenoma carcinomas (62 per cent vs. 42 per cent), while bcl-2 tended to be weaker in the de novo than in the ex-adenoma carcinomas. These differences' support the concept that de novo carcinomas are a unique pathological entity, with a phenotype reflecting their more aggressive behaviour.
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PMID:Expression of bcl-2 and p53 in de novo and ex-adenoma colon carcinoma: a comparative immunohistochemical study. 895 2

The present study was designed to clarify whether bcl-xL is involved in the development of carcinoma in the stomach. Levels of bcl-xL and bcl-2 mRNA were determined by a reverse-transcription/polymerase-chain reaction in endoscopic gastric biopsy specimens from 10 control subjects, 11 patients with adenomas and 14 patients with carcinomas. In 6 of 11 adenomas, 5 of 8 early carcinomas and 3 of 6 advanced carcinomas, the bcl-xL gene was over-expressed. In carcinomas, over-expression of the bcl-xL gene was observed in 6 of 9 intestinal-type carcinomas and 2 of 5 diffuse-type carcinomas. No correlation was observed between bcl-xL and bcl-2 gene expression. In cases in which the bcl-xL gene was over-expressed, an apparent increase in the protein level of Bcl-xL was observed by immunoblot analysis and intense Bcl-x immunoreactivity was detected immunohistochemically within the tumor cells. In conclusion, we showed that bcl-xL is over-expressed in gastric carcinomas at both the RNA and protein levels, suggesting that over-expression of bcl-xL may play a role in gastric carcinogenesis.
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PMID:Over-expression of bcl-xL gene in human gastric adenomas and carcinomas. 898 Jan 74

The response to ionising radiation, in terms of level of cell killing, depends on a number of factors that may be grouped into those that are genetically controlled, radiation quality and dosage, and environmental factors. There is a range of genetically controlled cellular properties such as stage of differentiation, mutations in specific genes (such as p53 and bcl-2) and stage of transformation that will determine the ability of the target cell to enter apoptosis. The so-called normal cells, are usually more radiosensitive and the majority of the cell population will enter into an apoptotic death. However, in response to high doses of ionising radiation and complex DNA damage as produced by high-LET radiation, an increased fraction of these cells will die by necrosis. There are several examples of environmental factors with relevance for the combined action of radiation and xenobiotics on carcinogenesis and in tumour therapy. In the case of normal cells, agents such as growth factors and tumour promoters, may decrease radiosensitivity. For certain type of tumour cells, radiation sensitivity can be increased in the presence of agents such as hormones, and the cells may die an apoptotic death. Removal of heavily compromised cells is essential to prevent a potential spreading of mutated clones. However, if apoptosis is inhibited (e.g., by tumour promoter), an increased fraction of damaged cells carrying genotoxic lesions may survive. This would significantly increase the risk of proliferation of precancerous cells. As discussed above, it is probably incorrect to make predictions about relative radiosensitivity based solely on mode of death. Intrinsic characteristics deriving from the cell type of origin of a line may be more important in determining radiosensitivity. The rapidly increasing knowledge about the process of radiation induced apoptosis has opened new frontiers in radiation biology, genetic toxicology, and cancer therapy and strongly motivates further research in this field.
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PMID:Radiation induced apoptosis. 900 84

Several oncogenes involved in prostate carcinogenesis activate mitogen-activated protein (MAP) kinases, which can relay both proliferative (via extracellular regulated kinases (ERK)) and apoptotic signals (via jun N-terminal protein kinases (JNK)) to the nucleus. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is induced by several oncogenes in the ras-dependent pathway and can inactivate both MAP kinase pathways. The role of MKP-1 in proliferation and apoptosis is, however, still controversial. A series of 51 prostate cancers, including a subset (n = 13) that had been previously treated by androgen ablation, was used to examine whether MKP-1 mRNA and protein expression correlated with that of ERK-1, JNK-1, bcl-2, which confers resistance to apoptosis, and apoptotic index measured by in situ end-labeling of fragmented DNA. In a subset of tumors, MKP-1 expression was assessed by semiquantitative RT-PCR and was compared with both ERK-1 and JNK-1 enzymatic activity. In cases not treated by androgen ablation, MKP-1 was overexpressed in the preinvasive stage of prostate cancer, but its expression decreased with higher histologic grade and advanced disease stage. There was coexpression of MKP-1, ERK-1, and JNK-1 proteins. In addition, MKP-1 expression was inversely correlated to JNK-1 but not to ERK-1 enzymatic activity. Finally, MKP-1 and bcl-2 were inversely related to apoptotic indices. In cases treated by total androgen ablation, MKP-1 and bcl-2 were both down-regulated, whereas JNK-1 was up-regulated. Subpopulations of cells that did not undergo apoptosis maintained expression of both MKP-1 and bcl-2. These results suggest that MKP-1 overexpression is associated with the early phases of neoplastic transformation in prostate tissue. The enzymatic data on MKP-1 kinase substrates and the inverse correlation between MKP-1 and parameters of programmed cell death support the hypothesis that MKP-1 inhibits apoptosis in human prostate tumors, perhaps through the JNK pathway.
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PMID:Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. 901 Apr 48

The bcl-2 oncogene is a member of a family of genes encoding for proteins which regulate apoptosis (programmed cell death). Recent evidence suggests that the bcl-2 protein is regulated by a homologous protein bax which counteracts its effects and promotes apoptosis. Overexpression of bcl-2 has been reported in a number of human cancers, although correlations with tumour differentiation and clinical outcome are conflicting and depend on tumour type and site. We studied bcl-2 and bax protein expression in adjacent serial sections of 30 squamous cell carcinomas of the oral cavity and correlated this with tumour differentiation. Examination of normal epithelium showed bcl-2 expression confined to basal keratinocytes and dendritic cells. The bax immunostaining was seen throughout the thickness of the epithelium but was most intense in the suprabasal cells. Overall, moderate or marked immunostaining for bcl-2 was identified in 18/30 (60%) carcinomas and for bax in 19/30 (63%) tumours. The bcl-2 immunoreactivity was strongest in the poorly differentiated carcinomas where 6/7 (86%) showed strong staining. By contrast, bax immunoreactivity was strongest in the well-differentiated carcinomas with 8/11 (72%) staining strongly. In the well-differentiated tumour islands, there was inverse topographic distribution of bcl-2 and bax, with both proteins showing a pattern that recapitulated normal epithelium. Upregulation of bcl-2 protein was identified in dysplastic epithelium adjacent to invasive tumour and in many cases there was reduced bax immunostaining. These results suggest that alterations of bcl-2 and bax may play a role in the development of squamous cell carcinoma. Furthermore, disturbances of protein expression in dysplastic epithelium suggest a role in the early stages of epithelial carcinogenesis.
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PMID:Differential expression of bcl-2 and bax in squamous cell carcinomas of the oral cavity. 903 23

Expression of bcl-2 oncoprotein (Bcl-2) in carcinomas and their precursor lesions in the colon, stomach, uterine cervix (squamous and glandular epithelium), and endometrium was examined immunohistochemically using clone 124 monoclonal antibody. Most cases of premalignant lesions in the colon (adenoma, 80.6%), stomach (metaplastic gastritis, 77.1%, mainly positive in the proliferative zone), endocervix (glandular dysplasia, 87.5%) and endometrium (endometrial hyperplasia, 65.4%) showed intense immunoreactivity for Bcl-2, whereas fewer than 30% of adenocarcinomas in these tissues had no or weak Bcl-2 expression. In the stomach, adenomas with definite Bcl-2 expression were 37.5% of the cases examined. Conversely, most of both squamous intraepithelial neoplasia and squamous cell carcinoma of the uterine cervix showed weak or no Bcl-2 expression. These results suggest that upregulation of Bcl-2 in premalignant lesions and downregulation after malignant change is, to some extent, a common event in the glandular system, but not in the squamous epithelium of the uterine cervix. Bcl-2 may play an important role in keeping the transformed cells alive at the early stage of multistep carcinogenesis in the glandular tissue by an escape from a regulatory mechanism of apoptosis for further accumulation of gene abnormalities.
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PMID:Expression of bcl-2 oncoprotein in gastrointestinal and uterine carcinomas and their premalignant lesions. 904 95

Basaloid proliferations overlying dermatofibromas resembling superficial basal cell carcinomas have been interpreted both as reactive/regressive and frankly malignant. Basal cell carcinoma is a slow-growing tumour, which so far has been regarded as an actively proliferating lesion with a high apoptotic activity. We examined immunohistochemically 6,dermatofibromas with overlying simple hyperplasia, 12 dermatofibromas with overlying basaloid proliferations, and 24 basal cell carcinomas for expression of Ki-67 protein, and bcl-2 protein. The Ki-67 labelling index represents an estimate of proliferative activity. Bcl-2 protein suppresses apoptosis. The Ki-67 labelling indexes of basaloid proliferations, basal cell carcinomas, and normal epidermis were similar (11-15%, p < 0.05, Mann-Whitney test). Bcl-2 protein was expressed in all cells of basaloid proliferations, similar to the expression pattern in basal cell carcinomas. We suggest that basaloid proliferations overlying dermatofibromas might have achieved a phenotype that equals an early stage of BCC carcinogenesis.
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PMID:Bcl-2 overexpression in basaloid proliferations overlying dermatofibromas and basal cell carcinomas. 906 99

To further characterize bcl-2 expression in nasopharyngeal carcinoma (NPC), the authors analyzed bcl-2 expression immunohistochemically in biopsy specimens from 101 cases of NPC, of which 65 had the component of normal nasopharyngeal epithelium (NPE), 24 with dysplastic lesions adjacent to carcinoma, and 14 with both primary and metastatic lesions. An additional 25 nasopharyngeal biopsies of NPE from patients with chronic inflammation of nasopharynx were also included. The percentage of detectable bcl-2 expression shown in NPC (80%) and adjacent dysplastic lesions (71%) was significantly higher than in adjacent NPE (37%) and NPE from patients with chronic inflammation of the nasopharynx (30%) (P < .05). In both normal and inflamed NPE, the detectable bcl-2 expression was restricted to the basal cells; however, in dysplastic lesions, the bcl-2 staining distribution was increased with the dysplastic cell layers, and in entire layers of epithelium in severe dysplasia or carcinoma in situ. In addition, the staining intensity of bcl-2 in carcinomas and adjacent dysplastic lesions was generally stronger than that of adjacent NPE. These observations suggest that the expression of bcl-2 in dysplasia and carcinoma is enhanced relative to that of adjacent NPE. Enhanced bcl-2 expression to prevent apoptosis seems to occur from the early stages and may play an important role in the carcinogenesis of NPC. Furthermore, up to 77% of NPC with the coexpression of bcl-2 and p53 was observed and suggested that the association of bcl-2 and p53 expression seems to occur from the early stages of the development of NPC. The overexpression of p53 protein in NPC suggests that the mutation of p53 gene or altered function of wild-type p53 protein may contribute to the pathogenesis. It is conceivable that the presence of both enhanced bcl-2 expression and altered p53 functions may play a crucial synergistic effect in the carcinogenesis of NPC.
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PMID:Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: association with p53 expression. 915 4

The effects of two types of selenium compounds on the expression levels of growth arrest and DNA damage-inducible (gadd) genes and on selected cell death genes were examined in mouse mammary MOD cells to test the hypothesis that the diversity of selenium-induced cellular responses to these compounds could be distinguished by unique gene expression patterns. Whereas the expression patterns of known cell death-related genes (bcl-2 and bax) were not informative with respect to the cellular response patterns upon exposure to selenium compounds, time-dependent and selenium species-specific induction patterns were observed for gadd34, gadd45 and gadd153 genes. It was also observed that the MOD cells expressed a truncated p53 transcript but no detectable immunoreactive P53 protein, indicating a null p53 phenotype. The fact that selenium compounds induced growth arrest and death of these cells and that these compounds induced specific patterns of expression of gadd genes indicates that these genes may mediate some selenium-induced cellular responses. The findings further imply that selenium compounds may be effective chemopreventive agents for human breast carcinogenesis, in which p53 mutations are frequent.
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PMID:Differential induction of growth arrest inducible genes by selenium compounds. 917 4


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