Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas/Fas ligand (FasL) interaction has been suggested to play a role in the pathogenesis of Hashimoto's thyroiditis. This manuscript addressed a role for Fas/FasL interaction in the pathogenesis of Graves' disease (GD). Apoptosis was detected in 0.5-5.0% of GD thyrocytes, but not in normal thyrocytes from patients with adenoma (N). Fas was constitutively expressed on the basement membrane of both GD and N thyrocytes. Thyrocytes expressed Bcl-2 constitutively in both GD and N thyrocytes. FasL was detected at the messenger ribonucleic acid level in thyroid tissue and cultured thyroid cells by Northern blotting and RT-PCR. FasL protein was detected in the cytoplasm and basolateral surface of thyrocytes from GD, but not in N. Cell surface expression of FasL on cultured thyrocytes disappeared within 48 h after their isolation. However, it was retained by culturing the cells with a matrix metalloproteinase inhibitor. Coculture with thyrocytes induced apoptosis of Fas transfectants, which was blocked by an anti-FasL antibody. Although cultured thyrocytes expressed Fas on the surface, they were not killed by an agonistic anti-Fas antibody. Interferon-gamma-induced Fas up-regulation was suppressed by TSH. These results suggest that the increased expression of FasL in GD thyrocytes, the down-regulation of Fas expression by TSH or possibly by TSH receptor autoantibody, and the overexpression of Bcl-2, which could render thyrocytes resistant to FasL-mediated elimination, may thus be involved in the pathogenesis of GD.
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PMID:Functional Fas ligand expression in thyrocytes from patients with Graves' disease. 1044 44

Expression of the apoptosis-promoting Fas gene is frequently reduced or lost during the development of colorectal carcinoma. However, loss of heterozygosity at the Fas locus or Fas gene rearrangements do not account for the loss of expression of Fas, raising the possibility that methylation of the Fas promoter may inhibit gene expression in colorectal carcinomas. We have examined the Fas promoter region CpG island for evidence of hypermethylation in colorectal tumours. Forty-seven specimens of colorectal adenoma and carcinoma, as well as six samples of normal colonic mucosa, were examined by Southern blotting for methylation at HpaII and Cfol sites in this region. No methylation was detected in any of the specimens, suggesting that hypermethylation is not primarily responsible for the loss of expression of the Fas gene during colorectal tumorigenesis.
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PMID:Promoter region methylation does not account for the frequent loss of expression of the Fas gene in colorectal carcinoma. 1063 79

Expression of apoptosis-related proteins, bcl-2, Bax, Fas and Fas ligand (L), in ovarian epithelial neoplasms together with its clinical relevance was examined by immunohistochemistry. They included 36 cases with adenoma, 33 with low potential malignancy (LPM) and 63 with carcinomas. bcl-2 expression was observed in 14 of 36 cases (39%) with adenoma, five of 33 (15%) with LPM (P< 0.05) and 12 of 63 (19%) with carcinoma (P < 0.05). Cases with bcl-2 expression showed more favourable prognosis than those without, but the difference was not statistically significant. There was no difference in frequency of Bax and Fas expression between each histologic category. Fas L expression was observed in one of 36 cases (3%) with adenoma, but in 12 of 33 (36%) with LPM (P < 0.001) and 42 of 63 (67%) with carcinoma (P < 0.0001). In carcinomas, cases expressing Fas L showed a less favourable prognosis than those without (P = 0.02). Density of CD8+ lymphocytes, possibly cytotoxic T-cells, was higher in serous carcinoma with negative Fas L expression than those with positive Fas L expression. These findings suggest that Fas L expressing carcinomas induce apoptosis in infiltrating CTL with Fas expression, and escape from immune surveillance.
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PMID:Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms. 1078 May 25

The Fas-FasL system seems to mediate thyrocyte death in Hashimoto's thyroiditis. In thyroid cancer, down-regulation of bcl-2 seems to alter apoptosis control. We compared the expression of immunoreactive Fas and FasL in normal thyroid with that of tumors ranging from benign to highly aggressive. Fas is essentially not expressed in normal thyrocytes, whereas FasL is expressed in approximately one-third of cases. Expression of both markers is significantly up-regulated in adenoma and in well-differentiated papillary and follicular carcinoma. In contrast, Fas is suppressed and FasL is strongly reduced in the most aggressive histological variants (poorly differentiated and undifferentiated carcinoma). Immunohistochemistry findings have been confirmed by analysis of Fas-FasL mRNA transcripts. In vitro studies showed that the Fas receptor of thyroid tumor cells was functional, because apoptosis was induced by an agonistic Fas antibody. Fas-expressing and Fas-resistant mammary cell lines were used as specificity controls. Together with our previous data inversely relating bcl-2 expression and thyroid tumor grade, the present findings further indicate that apoptotic pathways are altered in thyroid neoplasia. Thus, the Fas-FasL system may represent a marker of tumor aggressiveness.
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PMID:Suppression of Fas expression and down-regulation of Fas ligand in highly aggressive human thyroid carcinoma. 1100 9

Serrated adenoma of the colorectum is a recently proposed entity characterized by a saw-toothed structure of hyperplastic polyp and cytologic atypia of tubular adenoma. To clarify the role of apoptosis in morphogenesis of serrated adenoma, we investigated apoptotic indices and expression of apoptosis-related antigens in the tumor cells. Thirty-eight serrated adenomas were examined by the nick-end DNA labeling method and immunostained for CD95 (Fas), bcl-2, bax, and p53. Thirty-seven hyperplastic polyps, 48 tubular adenomas, and 16 sections containing normal colonic mucosa were similarly examined for comparison. The apoptotic indices in the upper and middle zones of the crypts of serrated adenomas and hyperplastic polyps were lower than those of normal colon mucosa and tubular adenomas with statistically significant differences. The CD95 expression was diffusely observed throughout the epithelium of normal crypts and tubular adenomas, whereas it was reduced in serrated adenomas and hyperplastic polyps. The bcl-2 expression was confined to the basal crypts in the latter two lesions but was diffuse throughout the neoplastic epithelium in tubular adenomas. The bax expression was increased in serrated adenomas and tubular adenomas but was decreased in hyperplastic polyps. Overexpression of p53 protein was observed in 50% of serrated adenomas, none of hyperplastic polyps, and 14% of tubular adenomas. These findings suggest that inhibition of apoptosis is caused by reduced CD95 expression in serrated adenomas and hyperplastic polyps, which may induce the characteristic saw-toothed structure in these lesions. Based on the similarities and differences between serrated adenoma and hyperplastic polyp observed in the present study, a progression from the latter to the former lesion may be postulated.
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PMID:Apoptosis index and apoptosis-related antigen expression in serrated adenoma of the colorectum: the saw-toothed structure may be related to inhibition of apoptosis. 1181 48

A distinctive feature of malignant adrenocortical neoplasms is decreased major histocompatibility complex (MHC) class II molecule expression. However, it is unknown whether there exists a restriction to certain MHC genotypes and whether this involves alterations of the Fas/Fas ligand system and thereby affects tissue homeostasis. Therefore, MHC class II phenotype and genotype and expression patterns of the Fas/Fas ligand system were investigated in 24 adrenocortical tumors (n(Adenomas) = 14, n(Carcinomas) = 10) and an adrenal cancer cell line (NCI-H295). No MHC class II antigen expression was detected in carcinomas. The DRB1*01 genotype was found in 54.5% of patients with carcinoma (P = 0.046). No prevalence of any genotype could be detected in patients with adenomas, which exhibited varying levels of antigen expression. Fas receptor expression was 75.0% in adenomas compared with 20.0% in carcinomas (P = 0.0196), whereas ligand expression was 37.7% in adenomas and reached almost 100% in the carcinomas investigated in this study (P = 0.0033). In summary, the DRB1*01 genotype may be correlated to a higher risk for malignancy. Additional studies on MHC class II genotype and phenotype and the altered Fas/Fas ligand system in adrenal neoplasms may help to identify mechanisms of immune escape and suggest new diagnostic approaches.
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PMID:Prevalence of HLA-DRB1 genotype and altered Fas/Fas ligand expression in adrenocortical carcinoma. 1558 55

A thorough understanding of the naturally occurring events in the immune system in response to carcinogenesis will facilitate the development of strategies for the immunoprevention of cancer. The adenoma-carcinoma sequence in the human colon is a well-established clinical example of multi-step carcinogenesis and can be used for immunological studies. Based on previous observations that both apoptosis and the expression of Fas (Apo-1, CD95) are altered during carcinogenesis in the human colon, we asked the question whether serum titers of autoantibodies against Fas show any modification during the adenoma-carcinoma sequence. Healthy controls (38), patients with colorectal adenomas (38) and patients with colorectal adenocarcinomas (21) were investigated. Anti-Fas antibody titers were found to be significantly higher in patients with colorectal adenomas than in healthy controls and higher still in patients with colorectal adenocarcinomas. This increase in anti-Fas autoantibody titers during carcinogenesis might reflect the activation of natural defense mechanisms by the immune system.
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PMID:Increase in autoantibodies against Fas (CD95) during carcinogenesis in the human colon: a hope for the immunoprevention of cancer? 1586 86

PRIMA-1 (p53 reactivation and induction of massive apoptosis) is a chemical compound that was originally identified as a selective mutant p53-dependent growth suppressor by screening a library of low-molecular-weight compounds. However, its mechanism of action is unknown. In this study, we examined toxicity of PRIMA-1 to three premalignant human colorectal adenoma cell lines (RG/C2, BR/C1, and AA/C1) and four colorectal carcinoma cell lines (DLD-1, SW480, LOVO, and HCT116) and its mechanism of action. It selectively induced apoptosis only in the mutant p53 premalignant and malignant colon cell lines, but was not toxic to the wild-type p53 premalignant and malignant colon cell lines. Using stable transfectants of temperature-sensitive p53 mutant Ala(143) in null p53 H1299 lung cancer cells, we found that PRIMA-1 induced significantly more apoptosis in cells with mutant p53 conformation (37 degrees C) than the wild-type p53 conformation (32.5 degrees C). Cell cycle analysis indicated that its inhibition of cell growth was correlated with induction of G(2) arrest. Western blot analysis showed PRIMA-1 increased p21 and GADD45 expression selectively in the mutant p53 cells. However, Fas, Bcl-2 family proteins, and caspases were not involved in PRIMA-1-induced cell death. The c-Jun-NH(2)-kinase (JNK) inhibitor SP 600125, but not p38 mitogen-activated protein kinase inhibitor SB 203580 or extracellular signal-regulated kinase inhibitor PD 98059, blocked PRIMA-1-induced apoptosis. Transfection with a dominant-negative phosphorylation mutant JNK, but not a dominant-negative p38 or wild-type JNK, inhibited PRIMA-1-induced cell death, suggesting that the JNK pathway plays an important role in PRIMA-1-induced apoptosis. PRIMA-1 is a highly selective small molecule toxic to p53 mutant cells and may serve as a prototype for the development of new p53-targeting agents for therapy of premalignant and malignant cells.
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PMID:Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. 1595 47

The nuclear factor kappaB signaling pathway has gained attention for its role in the carcinogenic process. We have measured the protein levels of the p65 subunit during a growth of adenomas in the Min mouse model for colon cancer. To study how an accelerated growth of adenomas affect cell signalling, adenoma growth was increased by an inulin diet (10%) that we have shown previously to be a promotor of adenoma formation. In our study, the association between NF-kappaB, p53, beta-catenin, Fas and COX-2 were evaluated by measuring their protein levels in 9- and 15-week old Min mouse adenomas and surrounding mucosa. The amount of p65 rouse between 9- and 15-weeks in the mucosa of the control-fed mice (p = 0.032). The inulin-fed mice had less p65 in the nucleus of the mucosa at 15 weeks of age compared to the control (p = 0.064), although the adenomas were significantly larger (1.46 mm +/- 0.12 for inulin, 0.97 mm +/- 0.12 for control, p < 0.001). Nuclear p65 correlated positively with nuclear p53 in the mucosa (p < 0.001) and adenoma (p < 0.001) tissues. Also, p65 correlated positively with nuclear beta-catenin in the mucosa (p = 0.012) and the adenoma (p = 0.001). Fas expression increased in the inulin group between 9-15 weeks (p = 0.034) and correlated negatively with p65 (p = 0.03). The amount of COX-2 in the adenoma tissue increased between 9-15 weeks and did not correlate with p65. The results suggest that p65 is involved in a p53-dependent apoptotic response in the Min mouse.
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PMID:Nuclear factor kappaB is downregulated and correlates with p53 in the Min mouse mucosa during an accelerated tumor growth. 1604 62

To investigate the expression of apoptosis-related protein (Fas, FasL, and Bcl-2) in the pathogenesis of autoimmune thyroid disorders (ATDs), immunohistochemical staining was performed on 20 Hashimoto's thyroiditis (HT), 20 Graves' disease (GD), and 20 thyroid follicular adenoma (TFA, as control). All the cases expressed Fas, mainly on the cell surface and cytoplasm. FasL was found in 17 cases of the TFA. Bcl-2 was detected in 15 cases of HT, 19 of GD and 17 of TFA. In TFA, a moderate Fas expression and a minimal or no FasL expression was detected on follicular cells. In HT, the follicles adjacent to infiltrating lymphocytes showed increased levels of Fas and FasL expression. A weaker staining of Fas and FasL was exhibited on infiltrating lymphocytes than on thyrocytes. In a comparison of GD with HT, thyrocytes and lymphocytes showed similar Fas staining, but for FasL the staining was rather weaker in HT. The expression of Bcl-2 was nearly identical in GD and TFA, but much weaker on the follicular cells in vicinity of lymphocytes and on the lymphocytes located in germinal centers of HT tissues. The expression of Fas, FasL, Bcl-2 in Hashimoto's thyroiditis and Graves' disease were almost same. FasL strong expression and Bcl-2 weak expression on the follicles in HT may induce apoptosis. These results provided evidence for expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disease. The lymphocytes seem not to be directly engaged in the process via their own FasL, but they may provide some cytokines that, in turn, upregulate Fas and/or FasL expression to induce apoptosis.
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PMID:Analysis of the expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disorders. 1621 72


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