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)

Adenocarcinoma of the prostate is the most common type of cancer, excluding skin cancer, and the second leading cause of cancer death in adult men in the United States. The lifetime risk for developing symptomatic prostate cancer is one in five for an American man. A pivotal step in carcinogenesis is a shift in the balance between proliferation, differentiation, and apoptosis that favors cell proliferation. Transforming growth factor-beta (TGF-beta) is a key negative growth regulator in the normal prostate. Although TGF-beta) inhibits the proliferation of normal prostate cells and functions as a tumor suppressor in early tumorigenesis, it acts as a tumor promoter in later stages of tumor progression. Elevated expression of TGF-beta in prostate cancer cells is associated with poor clinical outcome. Over-expression of TGF-beta aids tumorigenesis by not only stimulating angiogenesis and suppressing the immune system, but also by acting directly on the prostate tumor cells. While prostate cancer cells become resistant to TGF-beta-induced growth inhibition and apoptosis, they retain other TGF-beta-induced responses that enhance tumorgenicity. such as induction of extracellular matrix proteins, cell adhesion proteins and proteases. These direct tumor effects are mediated primarily through Smad signaling. This review addresses the mechanisms by which prostate cancer cells may acquire TGF-beta resistance and promote tumorgenicity. Understanding the mechanisms underlying TGF-beta resistance is important for the identification and development of better diagnostic markers and more effective strategies for treating prostate cancer.
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PMID:TGF-betal/Smad signaling in prostate cancer. 1264 70

Adenocarcinoma of the small intestine (ASI) is a rare disease of unknown aetiology. The glutathione S-transferase M1 (GSTM1) enzyme catalyses the detoxification of compounds involved in carcinogenesis of adenocarcinoma of the stomach, colon and lung, including constituents of tobacco smoke. We investigated a possible interaction between the lack of GSTM1 enzyme activity and the carcinogenic compounds of tobacco smoke. Based on the theory that certain carcinogens cause specific point mutations in the p53 gene we analysed by single strand conformation polymorphism (SSCP) and sequencing, p53 exon 5-8 of 52 samples of ASI collected in Sweden, Germany, France, Italy and Denmark between 1995 and 1997. The GSTM1 gene status was investigated by multiplex PCR. The prevalence of GSTM1 negative genotype among cases with ASI was 69% and higher than previous reports of 50% suggesting a higher risk of ASI among GSTM1 negative compared with GSTM1 positive subjects. A 'case-only' approach was used to address the combined association between the GSTM1 negative genotype and lifestyle exposures in patients with ASI. Using this method, heavy smokers (> 20 pack-years) with the GSTM1 negative genotype had an odds ratio of 4.8; 95% confidence interval (CI) (0.6-38.7) for ASI as compared to smokers who expressed GSTM1. No similar association between alcohol consumption and ASI was found. No p53 mutations in exon 5-8 were found in these samples, but the method may not be sensitive enough to identify smaller differences. Thus p53 does not seem to be the target of carcinogens acting in the small intestine.
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PMID:Glutathione S-transferase genotype and p53 mutations in adenocarcinoma of the small intestine. 1294 Apr 38

Adenocarcinoma of the stomach is the second most common cause of cancer mortality in the world. The purpose of this study was to evaluate the potential role in carcinogenesis of two secreted Helicobacter pylori's proteins, CagA and HspB, both shown to increase the risk of gastric carcinoma in patients infected with H. pylori-positive strain. The effects of these two proteins on cell kinetics and the ability to selectively affect the expression of cell cycle-related proteins by transfection of a human gastric epithelial cell line (AGS) were analyzed. Using a genomic library of H. pylori, we isolated and cloned CagA and HspB. The effects of the overexpression of these proteins on cell growth were analyzed in AGS cells by immunoblots, proliferation assay, and flow cytometry. Coexpression of CagA and HspB in AGS cells in the first 48 h caused an increase of the level of E2F transcription factor, cyclin D3, and phosphorylated retinoblastoma protein, all involved in the G(1)-S checkpoint of the cell cycle. Consistently, an increase of cell proliferation, corresponding to an augment of the fraction of the cells in the S-G(2)-M phase of the cell cycle, was also demonstrated. Moreover, an increase of c-jun protein levels, but not of c-fos, was also found after coexpression of CagA and HspB. All these data suggest that CagA and HspB, independently from the bacterial infection, have a direct effect on the cell growth of the gastric cells acting on the G(1)-S checkpoint of the cell cycle.
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PMID:Coexpression of Helicobacter pylori's proteins CagA and HspB induces cell proliferation in AGS gastric epithelial cells, independently from the bacterial infection. 1455 23

Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histological types. These paradigms suggest lung tumor cell ontogeny is determined by consequences of gene expression that recapitulate events important in embryonic lung development. Using oligonucleotide microarrays, we acquired gene profiles from 32 microdissected non-small-cell lung tumors. We determined the 100 top-ranked marker genes for adenocarcinoma, squamous cell, large cell, and carcinoid using nearest neighbor analysis. Results were validated by immunostaining for 11 selected proteins using a tissue microarray representing 80 tumors. Gene expression data of lung development were accessed from a publicly available dataset generated with the murine Mu11k genome microarray. Self-organized mapping identified two temporally distinct clusters of murine orthologues. Supervised clustering of lung development data showed large-cell carcinoma gene orthologues were in a cluster expressed in pseudoglandular and canalicular stages whereas adenocarcinoma homologues were predominantly in a cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large-cell genes (E2F3, MYBL2, HDAC2, CDK4, PCNA) are expressed in the nucleus and are associated with cell cycle and proliferation. In contrast, adenocarcinoma genes are associated with lung-specific transcription pathways (SFTPB, TTF-1), cell adhesion, and signal transduction. In sum, non-small-cell lung tumors histology gene profiles suggest mechanisms relevant to ontogeny and clinical course. Adenocarcinoma genes are associated with differentiation and glandular formation whereas large-cell genes are associated with proliferation and differentiation arrest. The identification of developmentally regulated pathways active in tumorigenesis provides insights into lung carcinogenesis and suggests early steps may differ according to the eventual tumor morphology.
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PMID:Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. 1457 94

Adenocarcinoma of the distal esophagus is rising more rapidly in incidence than any other visceral malignancy in the Western world. It is well established that most, if not all, of these tumors develop in Barrett's esophagus via the metaplasia-dysplasia-carcinoma sequence and could theoretically be detected at an early stage, but despite this, the majority of these tumors are still detected late in their course. This highlights the fact that the goal of effective surveillance for patients at risk for developing an adenocarcinoma of the distal esophagus is still far off. In addition, adenocarcinomas of the esophagogastric junction and gastric cardia are also rising in incidence, but their carcinogenesis and their relation to Barrett's esophagus are still being defined, as are the meaning and significance of the relatively new entities "short-segment Barrett's" and "ultra-short-segment Barrett's". This review attempts to clarify the main histopathologic issues concerned with the definition of Barrett's esophagus, its distinction from intestinal metaplasia of the gastric cardia, as well as the criteria for the histologic diagnosis of dysplasia and carcinoma in Barrett's esophagus.
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PMID:Barrett's esophagus: histopathologic definitions and diagnostic criteria. 1472 64

An excessive duodenal reflux induced by surgery has been widely accepted to cause gastric carcinogenesis in the remnant stomach. As one of causative factors for malignancy, N-nitroso compounds produced by enteric bacteria have been postulated. However, there is no concrete information to prove this hypothesis. This study was undertaken to elucidate the factors underlying the remnant stomach carcinogenesis, by giving thiazolidine-4-carboxylic acid (thioproline; TPRO) to the rats with duodenal reflux as a nitrite scavenger. Operated 39 animals were used, divided into 2 groups; one with a diet containing 0.5% TPRO (n=18), and the other with a diet without TPRO (n=21). Adenocarcinoma developed in 16 rats out of 21 (76.2%) of untreated rats, whereas adenocarcinoma was detected in 1 rat of the TPRO-treated rats (5.6%). TPRO thus prevented the development of gastric cancer in the remnant stomach, thereby suggesting a concern of nitroso compounds to the carcinogenesis.
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PMID:Thioproline prevents carcinogenesis in the remnant stomach induced by duodenal reflux. 1605 25

Barrett's esophagus is the result of chronic injury which is usually caused by gastroesophageal reflux. NF-kappaB is expressed in the reflux esophagitis. Specialized columnar epithelium (SCE) is characteristic of Barrett's esophagus and has a malignant predisposition. SCE expresses Cdx1 and Cdx2. Adenocarcinoma in Barrett's esophagus is believed to develop through the metaplasia-dysplasia-carcinoma sequence. P53, beta-catenin, PPARgamma, and estrogen receptor beta are closely related to the development of esophageal carcinogenesis.
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PMID:[Expression of transcription factor in Barrett's esophagus]. 1610 Dec 23

The entity of serrated adenoma of the colorectum was first proposed in 1990, and it was characterized as epithelial neoplasia combining the architectural features of a hyperplastic polyp with the cytological features of an adenoma. Over the past few years, various clinicopathological studies on serrated adenoma have been reported, but its histogenesis remains unclear. Recently the existence of a "serrated neoplasia pathway" leading to malignancy, which is different from the so-called adenoma-carcinoma sequence, has been discussed. Yao et al. reported that hyperplastic polyps and serrated adenomas share a common cell lineage with gastric differentiation. To clarify the existence of the serrated neoplasia pathway, we performed immunohistochemical staining of cytokeratin 7 (CK7) and cytokeratin 20 (CK20), which are commonly used to determine the primary site of a metastatic lesion, and we examined the pattern of CK7/CK20 expression in various colorectal lesions including 44 serrated adenomas, 25 hyperplastic polyps, 20 traditional adenomas, and 48 carcinomas. An obvious difference existed in the pattern of CK7/CK20 expression between the serrated lesions (hyperplastic polyps and serrated adenomas) and others. The majority of serrated adenomas and hyperplastic polyps presented a CK7+/CK20+ pattern, whereas most conventional adenomas and adenocarcinomas expressed CK7-/CK20+. Adenocarcinoma developing in serrated adenoma also presented a CK7+/CK20+ pattern. There are several reports that CK7 is a possible marker of transient dedifferentiation in the gastric carcinogenesis process. Taken together with the present results, a distinct pathway of colorectal carcinogenesis must exist, which is different from the adenoma-carcinoma sequence. CK7 is a possible marker for the serrated neoplasia pathway of colorectal carcinogenesis.
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PMID:Expression of cytokeratins 7 and 20 in serrated adenoma and related diseases. 1613 82

Maspin, a mammary homologue of Serine Protease Inhibitors, has been shown to inhibit tumor progression and metastasis. Recently, its biological functions have been linked to its subcellular localization. Specifically, a nuclear, opposed to a combined nuclear and cytoplasmic localization has been associated with increased survival in human malignancies, including non-small cell lung cancer (NSCLC). However, it is not known whether transformation affects maspin expression during lung carcinogenesis, and whether its subcellular localization correlates with the morphological features of NSCLC. To address these questions, we studied maspin expression in a model of transformation of bronchial epithelial cells and in resected NSCLC. We found that decreased maspin accompanied chemical transformation of normal immortalized bronchial epithelial cells BEAS 2B. Immunohistochemistry revealed maspin expression to be virtually universal in NSCLC, occurring in 72/77 Adenocarcinoma (ACa), and 46/46 squamous cell carcinoma (SqCCa). SqCCa showed almost exclusively a combined nuclear-cytosolic stain. In contrast, nuclear maspin, but not combined nuclear-cytoplasmic maspin significantly correlated with low histological grade, lower proliferative rate, absence of invasion, and negative p53 stain in ACa. These data support the hypothesis that nuclear localization of maspin may stratify subtypes of NSCLC with favorable clinical-pathological features.
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PMID:Maspin nuclear localization is linked to favorable morphological features in pulmonary adenocarcinoma. 1615 82

The incidence and mortality of prostate cancer (PCa) vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1), which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN), and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM) models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP)]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt), FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC), and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN) according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN). In summary, targeted overexpression of h15-LO-1 (a gene overexpressed in human PCa and HGPIN) to mouse prostate is sufficient to promote epithelial proliferation and mPIN development. These results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression.
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PMID:Conditional expression of human 15-lipoxygenase-1 in mouse prostate induces prostatic intraepithelial neoplasia: the FLiMP mouse model. 1682 97


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