Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:Q86TM3 (cage)
29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE, De Marzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American Journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase IIalpha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.
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PMID:Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. 1241 2

Decreased E-cadherin expression permits dissociation and widespread dissemination of gastric adenocarcinoma cells. We studied the relationship between paranuclear E-cadherin distribution and the histopathologic characteristics of gastric adenocarcinomas. E-cadherin immunostains of 173 gastric adenocarcinoma sections revealed paranuclear; punctate to vesicular staining in 18% (16/87) of the intestinal-type adenocarcinomas, 30% (17/56) of the diffuse-type adenocarcinomas, and 30% (9/30) of the mired adenocarcinomas. These data suggest that in some gastric adenocarcinomas, there is a defect in transport of E-cadherin to the cell surface, which may prevent intercellular adhesion and encourage dissemination. Of 34 cancers with paranuclear E-cadherin staining, 20 (59%) had paranuclear staining within the nonneoplastic epithelium, but only 22.0% of 100 carcinomas with absent or membranous E-cadherin staining were accompanied by morphologically benign epithelium with paranuclear E-cadherin. In surface epithelium, paranuclear E-cadherin staining colocalized with Griffonia simplicifolia lectin II in the Golgi apparatus. The presence of paranuclear E-cadherin in cancer-associated benign epithelium suggests that the alteration in the E-cadherin molecule responsible for the paranuclear distribution may be an early change in gastric adenocarcinoma progression.
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PMID:Paranuaclear E-cadherin in gastric adenocarcinoma. 1247 82

Effective eradication of established tumors and generation of a lasting systemic immune response is an important goal for cancer gene immunotherapy. The method of gene delivery may also be critical for the generation of an effective antitumor response. We compared the level of transgene expression and antitumor activity of two different interleukin (IL)-12 DNA preparations (naked DNA versus DNA lipid complex). Established murine adenocarcinoma (CT26) and renal cell carcinoma (Renca) tumors in BALB/c mice were treated by direct intratumoral injection of a nonviral plasmid DNA vector encoding the murine IL-12 (mIL-12) gene, either alone (naked) or in complexes with cationic lipid. Both treatments resulted in the same percentage (87%) of mice undergoing a complete tumor regression of the CT26 tumor. For the Renca tumor model, complete tumor regression was observed in 67 and 75% of animals treated with naked mIL-12 DNA and mIL-12 DNA plus lipid, respectively. Mice that were rendered tumor free for > 50 days by mIL-12 gene therapy rejected a subsequent challenge of parental tumor cells but not of an unrelated, syngeneic tumor. The marked reduction of tumor growth in tumor-bearing mice treated with mIL-12 cDNA was associated with the augmentation of tumor-specific cytotoxic T cells, enhanced production of IFN-gamma in spleen and lymph node cells, and increased splenomegaly and lymphadenopathy. The CD8+: CD4+ ratio in tumor-infiltrating lymphocytes was significantly increased in the tumor-bearing mice treated with mIL-12 DNA alone and mIL-12 cDNA plus lipid as compared with a control vector-treated group. These results indicate that direct intratumoral gene transfer with naked nonviral IL-12 DNA provides an effective and simple method for the treatment of murine tumors, suggesting an approach for clinical application.
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PMID:Intratumoral injection of interleukin-12 plasmid DNA, either naked or in complex with cationic lipid, results in similar tumor regression in a murine model. 1248 17

Cancer cachexia has been suggested to be mediated by various cytokines derived either from tumor or host tissue. In the murine colon-26 (C-26) adenocarcinoma model IL-1, secreted by tumor-infiltrating mononuclear phagocytes, has an important role in induction of cancer cachexia. In order to suppress production of IL-1 in peritoneal macrophages we have used liposome-mediated gene transfer of the anti-inflammatory cytokine mIL-4, known as a potent inhibitor of IL-1 production. Balb/c mice were transfected by intraperitoneal inoculation of C-26 tumor cells. The mIL-4 transfected animals showed increased survival rate, delayed symptoms of cachexia and reduced anorexia in comparison with tumor-bearing control groups. However, tumor growth inhibition was not seen in mIL-4-transfected animals. Peritoneal macrophages from surviving mIL-4-transfected mice, when stimulated with LPS ex vivo, showed decreased IL-1 alpha production, 1672 +/- 202 pg/2 x 10(6) cells in contrast to tumor-bearing control animals, 3975 +/- 89 pg/2 x 10(6) cells, mock-transfected tumor-bearing animals 4004 +/- 174 pg/2 x 10(6) cells and tumor-free animals, 3142 +/- 60 pg/2 x 10(6) cells (p < 0.004). The present study demonstrates that in vivo gene transfer of an anti-inflammatory cytokine reduces cancer-associated cachexia by inhibition of IL-1 alpha production of tumor surrounding peritoneal macrophages, without a significant effect on tumor growth.
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PMID:In vivo gene transfer of murine interleukin-4 inhibits colon-26-mediated cancer cachexia in mice. 1252 62

Helicobacter pylori may protect against the development of dysplasia in Barrett's epithelium of patients with gastroesophageal reflux disease. The aim of this study was to determine whether H. pylori preferentially induces apoptosis in Barrett's-derived cancer cells compared to normal cells. A Barrett's-derived adenocarcinoma cell line (OE33) was grown. H. pylori wild-type, isogenic vacA-, cagA(-), and picB-/cagE- mutant strains were grown on agar plates. Intact or sonicated bacteria were used to treat normal and OE33 cells for 24 hours, and Hoechst dye binding was performed to measure apoptosis. FAS protein expression was determined by Western immunoblotting. OE33 cells treated with intact H. pylori wild-type strains produced significant (P < 0.05) dose-dependent increases in apoptosis compared to normal esophageal cells. H. pylori wild-type and vacA- isogenic strains were more effective than cagA- and picB-/cage- isogenic strains in inducing apoptosis in OE33 cells. In OE33 cells, H. pylori sonicates produced lower levels of apoptosis than intact bacteria. Wild-type H. pylori strains increased Fas protein expression in OE33 cells at 18 hours. H. pylori induced apoptosis at a higher rate in the Barrett's-derived human esophageal adenocarcinoma cells than in normal esophageal cells. The H. pylori-induced apoptosis was primarily dependent on intact bacteria and the presence of the cagA and picB/cagE gene products. H. pylori-induced apoptosis may involve the Fas-caspase cascade.
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PMID:Helicobacter pylori induces apoptosis in Barrett's-derived esophageal adenocarcinoma cells. 1255 87

The molecular events associated with the development of adenocarcinoma of the oesophagus are not well understood. Gene expression associated with oesophageal adenocarcinoma was investigated using a cDNA array containing 1,176 human cancer-associated genes. Approximately 59% of the genes were expressed at detectable levels with 15 genes (1.3%) exhibiting differential (> 2.5-fold) expression in either normal oesophagus or adenocarcinoma tissue. Nine genes were up-regulated in oesophageal adenocarcinoma tissue (matrix metalloproteinase 11 (MMP11), ornithine decarboxylase (ODC), cytokeratins 8 and 18, integrin alpha 3 (ITGA3), integrin alpha 6 (ITGA6), BIGH3 (transforming growth factor beta-induced), beta-catenin and CDC25B (M-phase inducer phosphatase 2)). Six genes were down-regulated in adenocarcinoma tissue (cytokeratin 4, plasminogen activator inhibitor 2 (PAI-2), interleukin 1 receptor antagonist (IRAP), cytokeratin 13/15/17, MAD and retinoic acid receptor gamma 1 (RARG)). Many of these differentially expressed genes influence cell-cell adhesion, cell-extracellular matrix and composition, transcriptional activation and cell cycle progression and are likely to contribute to development of oesophageal adenocarcinoma.
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PMID:Transcriptional gene expression profiles of oesophageal adenocarcinoma and normal oesophageal tissues. 1268 Feb 8

The structure and T cell stimulatory effects of the recently discovered cytokine IL-23 are similar to, but distinct from, those of IL-12. Although the antitumor activities of IL-12 are well characterized, the effect of IL-23 on tumor growth is not known. In this study, murine CT26 colon adenocarcinoma and B16F1 melanoma cells were engineered using retroviral vectors to release single-chain IL-23 (scIL-23) to evaluate its antitumor activity. In BALB/c mice, scIL-23-transduced CT26 cells grew progressively until day 26 to an average size of 521 +/- 333 mm(3), then the tumors started to regress in most animals, resulting in a final 70% rate of complete tumor rejection. scIL-23 transduction also significantly suppressed lung metastases of CT26 and B16F1 tumor cells. In addition, mice that rejected scIL-23-transduced tumors developed a memory response against subsequent wild-type tumor challenge. Compared with scIL-12-expressing CT26 cells, scIL-23-transduced tumors lacked the early response, but achieved comparable antitumor and antimetastatic activity. These results demonstrated that IL-23, like IL-12, provided effective protection against malignant diseases, but it probably acted by different antitumor mechanisms. As a first step in identifying these antitumor mechanisms, tumor challenge studies were performed in immunocompromised hosts and in animals selectively depleted of various lymphocyte populations. The results showed that CD8(+) T cells, but not CD4(+) T cells or NK cells, were crucial for the antitumor activity of IL-23.
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PMID:Antitumor and antimetastatic activity of IL-23. 1284 24

We investigated the role of beta 3 Gal-T5, a member of the beta 1,3galactosyltransferase (beta 1,3Gal-T) family, in cancer-associated glycosylation, focusing on the expression of sialyl-Lewis a (sLea, the epitope of CA19.9 antigen), poly N-acetyllactosamines, and sialyl-Lewis x (sLex) antigen. A clone permanently expressing an antisense fragment of beta 3Gal-T5 was obtained from the human pancreas adenocarcinoma cell line BxPC3 and characterized. Both beta 1,3Gal-T activity and sLea expression are dramatically impaired in the clone. Analysis of the oligosaccharides synthesized in cells metabolically labelled with tritiated galactose shows that a relevant amount of radioactivity is associated to large O-glycans. Endo-beta-galactosidase mostly releases NeuAc alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNAc beta 1-3Gal and NeuAc alpha 2-3Gal beta 1-3GlcNAc beta 1-3Gal from such O-glycans of BxPC3 membranes, but GlcNAc beta 1-3Gal and type 2 chain oligosaccharides, including NeuAc alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc beta 1-3Gal, from those of the antisense clone. Furthermore, BxPC3 cells secrete sLea in the culture media but not sLex, while antisense clone secretes mostly sLex, and accumulation of both antigens is prevented by benzyl-alpha-GalNAc. These data indicate that beta 3Gal-T5 suppression turns synthesis of type 1 chain O-glycans to poly N-acetyllactosamine elongation and termination by sLex. In other cell lines and clones, beta 3Gal-T5 transcript, beta 1,3Gal-T activity, and sLea antigen are also correlated, but quantitatively the relative expression ratios are very different from cell type to cell type. We suggest that beta 3Gal-T5 plays a relevant role in gastrointestinal and pancreatic tissues counteracting the glycosylation pattern associated to malignancy, and is necessary for the synthesis and secretion of CA19.9 antigen, whose expression still depends on multiple interacting factors.
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PMID:Suppression of beta 1,3galactosyltransferase beta 3Gal-T5 in cancer cells reduces sialyl-Lewis a and enhances poly N-acetyllactosamines and sialyl-Lewis x on O-glycans. 1468 31

Caffeic acid phenethyl ester (CAPE) derived from honeybee propolis has been used as a folk medicine and has several proven biological activities. The present study investigated the effect of CAPE on angiogenesis, tumor invasion, and metastasis. A cytotoxicity assay of CAPE in CT26 colon adenocarcinoma cells showed a dose-dependent decrease in cell viability but no significant influence on the growth of human umbilical vein epithelial cells (HUVEC). A low concentration of CAPE (1.5 microg/mL) inhibited 52.7% of capillary-like tube formation in HUVEC culture on Matrigel. CAPE (6 microg/mL)-treated CT26 cells showed not only inhibited cell invasion by 47.8% but also decreased expression of matrix metalloproteinase (MMP)-2 and -9. Vascular endothelial growth factor (VEGF) production from CT26 cells was also inhibited by treatment with CAPE (6 microg/mL). Intraperitoneal injection of CAPE (10 mg/kg/day) in BALB/c mice reduced the pulmonary metastatic capacity of CT26 cells accompanied with a decreased plasma VEGF level. CAPE treatment also prolonged the survival of mice implanted with CT26 cells. These results indicate that CAPE has potential as an antimetastatic agent.
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PMID:Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis. 1469 Mar 72

The association of chronic inflammation with a variety of epithelial malignancies has been recognised for centuries. Well established examples include, among many others, oesophageal adenocarcinoma associated with chronic oesophagitis and bowel cancer associated with chronic inflammatory bowel diseases. By now no data, other than clinical observation, have been available in understanding the pathogenesis of these inflammation-related tumours. However, recent molecular studies on the relationship between solid malignancies and the surrounding stroma have given new insights. There is now enough evidence to accept that the chronic inflammatory process per se is able to provide a cytokine-based microenvironment which is able to influence cell survival, growth, proliferation, differentiation and movement, hence contributing to cancer initiation, progression, invasion and metastasis. Here it is discussed whether also oral lichen planus (OLP), being a chronic inflammatory autoimmune disease which has been clinically associated with development of oral squamous cell carcinoma, might be categorised among these disorders. With this aim, we critically reviewed and detailed the presence, in OLP subepithelial infiltrate, of inflammatory cells and cytokine networks that might act to promote squamous tumorigenesis.
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PMID:Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence ? 1469 34


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