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

Inbred rodent strains with differing sensitivity to experimental tumor induction provide model systems for the detection of genes that either are responsible for cancer predisposition or modify the process of carcinogenesis. Rats of the inbred BD strains differ in their susceptibility to the induction of neural tumors by N-ethyl-N-nitrosourea (EtNU). Newborn BDIX rats that are exposed to EtNU (80 microg/g body weight; injected s.c.) develop malignant schwannomas predominantly of the trigeminal nerves with an incidence >85%, whereas BDIV rats are entirely resistant. A T:A-->A:T transversion mutation at nucleotide 2012 of the neu (erbB-2) gene on chromosome 10, presumably the initial event in EtNU-induced schwannoma development, is later followed by loss of the wild-type neu allele. Genetic crosses between BDIX and BDIV rats served: (a) to investigate the inheritance of susceptibility; (b) to obtain animals informative for the mapping of losses of heterozygosity (LOH) in tumors with polymorphic simple sequence length polymorphisms (SSLPs); and (c) to localize genes associated with schwannoma susceptibility by linkage analysis with SSLPs. Schwannoma development was strongly suppressed in F1 animals (20% incidence). All of the F1 schwannomas displayed LOH on chromosome 10, with a consensus region on the telomeric tip encompassing D10Rat3, D10Mgh16 and D10Rat2 but excluding neu. A strong bias toward losing the BDIV alleles suggests the involvement of a BDIV-specific tumor suppressor gene(s). Targeted linkage analysis with chromosome 10 SSLPs in F2 intercross and backcross animals localized schwannoma susceptibility to a region around D10Wox23, 30 cM centromeric to the tip. Ninety-four % of F1 tumors exhibited additional LOH at this region. Two distinct loci on chromosome 10 may thus be connected with susceptibility to the induction and development of schwannomas in rats exposed to EtNU.
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PMID:Ethylnitrosourea-induced development of malignant schwannomas in the rat: two distinct loci on chromosome of 10 involved in tumor susceptibility and oncogenesis. 1007 Sep 70

In order to understand the origin of bladder cancer, very early urothelial lesions must be investigated in addition to more advanced tumors. Tissue from 31 biopsies of 12 patients with urothelial hyperplasias and simultaneous or consecutive superficial papillary tumors were used to microdissect urothelium from 15- microm sections of biopsies. The biopsies were obtained with the recently developed highly sensitive diagnostic method of 5-aminolevulinic acid-induced fluorescence endoscopy (AFE). Besides flat and papillary urothelial neoplasms, the method of photodynamic diagnostics also detects simple urothelial hyperplasias as fluorescent positive lesions. In addition, 12 fluorescence-positive biopsies showing histologically normal urothelium were investigated. Fluorescence in situ hybridization was done using a dual color staining technique of biotinylated centromeric probes of chromosomes 9 and 17 and digoxigenin-labeled gene-specific P1 probes for chromosomes 9q22 (FACC), 9p21(p16/CDKI2), and 17p13(p53). Ten of 14 hyperplasias (70%) showed deletions of chromosome 9. In 7 out of 8 patients with genetic alterations in the hyperplasias the genetic change was also present in the papillary tumor. Six out of 12 samples of microdissected normal urothelium also showed genetic alterations on chromosome 9. Microdissection of urothelial lesions, obtained during AFE, has led to the first unequivocal documentation of genetic changes in urothelial lesions diagnosed as normal in histopathology. Thus, this technical approach is important to provide insight into the earliest molecular alterations in bladder carcinogenesis.
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PMID:Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. 1007 49

The activation of telomerase, a ribonucleoprotein maintaining telomeric length, might represent an additional required event in the multigenetic process of tumorigenesis in human cancer. To investigate whether telomerase activity is a prerequisite or a useful indicator of malignant potential, we assayed the enzyme in squamous cell carcinomas and tried to observe any correlation with clinical staging and histopathological grading. We have studied telomerase activity in 23 samples of squamous cell carcinomas of the aerodigestive tract and in 22 corresponding samples of adjoining tissues using the telomerase repeat amplification assay. Telomerase activity was detected in 100% of the tumor samples studied. The telomerase activity increased with tumor grading, but was not statistically significant. Low levels of enzyme activity were also detected in 60.86% of the adjoining normal tissue samples. Reactivation of telomerase may play an important role in the carcinogenesis of aerodigestive tract tumors. Detection of enzyme activity in the adjoining normal tissue is suggestive of microinvasion of tumor cells and/or early activation of telomerase in the progression towards cancer, before possible pathological identification.
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PMID:Telomerase activity in Indian patients with carcinomas of the aerodigestive tract. 1039 33

Background: Allelic losses from the short arm of chromosome 8 (8p) are frequent in a variety of epithelial malignancies. In colorectal cancer, there are two discrete regions of 8p loss of hterozygosity (LOH), suggesting the existence of two putative tumor suppressor genes. Previous studies have shown an association of 8p LOH with tumor invasiveness. To better define the deletion extent and the clinical significance of these losses, a series of 41 colorectal cancers were examined for 8p LOH and correlated with clinical features. Methods and Results: Paired normal and enriched tumor DNA from the same individual was typed by polymerase chain reaction for 11 microsatellite polymorphisms and scored as positive or negative for 8p LOH. Loss of 8p markers was observed in 44% of the cases. Most cases had large deletions, but several had localized interstitial losses, enabling specification of two nonoverlapping regions of LOH. The telomeric region of loss is defined by the markers D8S262 and D8S133 at 8p22, and the centromeric region is proximal to NEFL. Clinical, histopathologic, and molecular data were obtained and a significant correlation of 8p LOH with microinvasion (invasion of lymphatics, vessels, or perineurium, ascertained by light microscopy) (P=.01) and also with loss of chromosome arm 18q (P=.001) was found. Conclusions: An association of 8p allelic loss with poor outcome was demonstrated. The correlation between 8p loss and 18q loss suggests that 8p LOH is a late event in the multistep model of colorectal carcinogenesis. 8p LOH may provide a clinically useful prognostic marker in colorectal cancer, thereby warranting further testing. The involvement of two independent loci on 8p is confirmed, and the refined localization of these sites will contribute to the eventual identification of these genes, which appear to play an important role in the progression of epithelial malignancies.
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PMID:Chromosome 8 Losses in Colorectal Carcinoma: Localization and Correlation With Invasive Disease. 1046 85

Telomerase activities in endoscopically resected colorectal adenomas, surgically resected colorectal cancers and adjacent normal colonic mucosa were examined semiquantitatively by a polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) assay. All normal mucosa (n = 15) presented weak telomerase activity (mean +/- SE: 0.99 +/- 0.00). When the value of 1.00 was arbitrary given to the mean activity of normal mucosa, the telomerase activity in the adenomas (n = 14) was up-regulated (2.01 +/- 0.22) relative to the normal mucosa. The telomerase activity in the high-grade atypia (severe atypia and carcinoma in situ) (2.58 +/- 0.34) was significantly higher than that in the low-grade (mild and moderate) atypia (1.59 +/- 0.18) (P < 0.05), and the adenomas 10 mm or more in diameter presented significantly higher telomerase activity (2.56 +/- 0.09) than compared to the smaller ones (1.44 +/- 0.17) (p < 0.05). Carcinomas (n = 20), showed a telomerase activity that varied from 0.97 to 16.93, which was than the greater mean telomerase activity (6.96 +/- 1.25) noted in the adenomas. The telomerase activity in the carcinomas tended to be higher in the larger (> or = 4 cm), histologically less-differentiated (moderately differentiated), late-stage (Dukes C + D), and nodal metastatic tumors, suggestive of unfavorable prognosis. These results suggests that the weak telomerase activity in normal colonic mucosa is gradually activated during the course of colorectal carcinogenesis.
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PMID:Change in telomerase activity during human colorectal carcinogenesis. 1047 26

Telomerase is a ribonucleoprotein complex which, by de novo synthesized telomeric TTAGGG repeats, prevents telomere erosion. While telomerase is active in most cancers, conflicting results exist for normal tissues and premalignant lesions. To establish the telomerase status of normal gastrointestinal mucosa and to elucidate whether telomerase up-regulation is an early or late event in carcinogenesis, we determined the telomerase activity of 88 biopsies of normal mucosa from esophagus, stomach, and intestine and compared it with that of 21 samples of premalignant lesions and 6 adenocarcinomas using the telomere-repeat amplification protocol assay. Telomerase was found in all normal tissues, revealing most activity in esophagus (11 samples), followed by intestine (45 samples), and stomach (32 samples). In 53% of the stomach samples, enzyme activity could only be demonstrated when telomerase inhibitors were eliminated by a modified telomerase assay. In the 21 precancerous lesions (5 Barrett's esophagus, 3 stomach intestinal metaplasias, and 13 colorectal adenomas of type I/II dysplasia) a similar or even reduced telomerase activity was seen, while the adenocarcinomas showed high activity. These data demonstrate that telomerase activity is expressed in all epithelia along the gastrointestinal tract, thus confirming our previous hypothesis that telomerase is constitutively expressed in permanently renewing epithelia. Furthermore, activity was not increased in preneoplastic lesions, suggesting that telomerase up-regulation is a late event during carcinogenesis of the esophagus, stomach, and intestine.
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PMID:Telomerase is active in normal gastrointestinal mucosa and not up-regulated in precancerous lesions. 1048 Mar 37

To investigate the role of telomerase in oral carcinogenesis, we assayed telomerase activity in various oral tissues by a modified telomeric repeat amplification protocol (TRAP) analysis. Also, using digoxigenin-labeled probes, we measured the in situ expression of human telomerase RNA component (hTR) in paired oral squamous cell carcinomas (OSCC) and adjacent non-cancerous matched tissue (NCMT). We detected telomerase activity in three OSCC cell lines, but not in primary oral keratinocytes. In patient samples, most OSCC (36/42, 86%) and oral premalignant lesions (8/12, 67%) possessed telomerase activity. In addition, 6 of 27 (22%) NCMT contained weak telomerase activity. In situ hybridization showed that hTR was expressed in almost all OSCC (23/27, 85%) as well as in the majority of NCMT (20/25, 80%). In most cases, accumulation of hTR was observed both in the nucleus and cytoplasm of epithelial cells. A correlation between hTR expression and more advanced tumor grade was observed. The appearance of telomerase activation and hTR expression during oral carcinogenesis was different. This study indicates that the activation of telomerase is an early and frequent event in OSCC.
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PMID:Telomerase activity and in situ telomerase RNA expression in oral carcinogenesis. 1053 61

Telomerase activity has been detected in germ cells as well as in the developing embryo. Activity is no longer detectable in most somatic cells of the neonate, although low levels of activity persist in regenerative tissues. Telomerase has been found to be reactivated or up-regulated in the majority of cancers. The colorectal adenoma-carcinoma sequence is one of the best-characterized models of multistep tumourigenesis and is thus suitable for determining at which stage telomerase is activated. Telomerase activity was examined by telomeric repeat amplification protocol (TRAP) assay in 96 cases of colorectal tissues, including 50 carcinomas, 31 adenomas, and 15 normal colonic tissues. For each case, histological diagnosis and telomerase activity were determined on consecutive frozen sections. In order to reduce the chance of a false-negative TRAP assay due to RNA degradation, the integrity of rRNA in the tissues was verified in each case. Twenty-five carcinomas, 30 adenomas, and all of the 15 normal colorectal mucosal samples showed no or only partial rRNA degradation and only in these cases was the TRAP assay interpreted. None of the normal tissues exhibited telomerase activity. In contrast, all of the 25 cancers and 47 per cent (14/30) of the adenomas were positive. In adenomas, telomerase activation was highly significantly related to the grade of dysplasia (p< 0.0001). All adenomas which contained high-grade dysplasia revealed telomerase activity, whereas telomerase activity was detectable in only 20 per cent (4/20) of cases with exclusively low-grade dysplasia. These results indicate that telomerase activation, which may be an obligatory step in colorectal carcinogenesis, occurs in the progression from low-grade to high-grade dysplasia in adenomas. Furthermore, in the adenoma-carcinoma sequence, telomerase activation seems to occur later than K- ras mutation but earlier than p53 mutation.
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PMID:Telomerase activation in colorectal carcinogenesis. 1054 76

Telomerase is a ribonucleoprotein that synthesizes telomeric DNA on chromosomal ends. While telomerase is undetectable in most normal somatic tissues, telomerase activation has been detected by a polymerase chain reaction (PCR)-based assay (TRAP) in many immortal cell lines and various cancers, including prostate cancers. To investigate the role of telomerase in prostate cancer at the cellular level, the expression of one of the ribonucleoprotein complexes, the RNA component of human telomerase (hTR), was studied in normal, preneoplastic, and cancerous prostate tissues using a non-radioactive in situ hybridization procedure. Nine human prostates resected at the time of radical prostatectomy were studied. In each case, archival paraffin-embedded samples from normal tissue, prostatic intraepithelial neoplasia (PIN) lesions, the putative precancerous lesion, and prostate carcinomas were selected for in situ hybridization. hTR mRNA expression was detected in carcinomatous glands of seven out of the nine cancers (75 per cent). Furthermore, in seven out of the eight cases showing PIN lesions, the epithelial cells of PIN foci also expressed hTR mRNA. By contrast, in normal tissue, epithelial cells were negative, whereas hTR mRNA expression was detected in the basal cells. The detection of hTR mRNA in PIN lesions clearly strengthens the link between PIN and carcinomatous glands and suggests that telomerase expression occurs early in prostate carcinogenesis. Furthermore, this study confirms previous experimental data suggesting that the basal cell layer is the stem cell compartment in prostate.
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PMID:Expression of the RNA component of human telomerase (hTR) in prostate cancer, prostatic intraepithelial neoplasia, and normal prostate tissue. 1054 77

We have recently characterized two types of normal human breast epithelial cells (HBECs) from reduction mammoplasty. Type I cells express estrogen receptor, luminal epithelial cell markers, and stem cell characteristics (i.e., the ability to differentiate into other cell types and to form budding/ductal structures on Matrigel), whereas Type II cells show basal epithelial cell phenotypes. In this study, we have examined whether Type I HBECs are more susceptible to telomerase activation and immortalization after transfection with SV40 large T-antigen. The results show that both types of cells acquire extended life span [(EL); i.e., bypassing senescence] at a comparable frequency. However, they differ significantly in the ability to become immortal in continuous culture, ie., 11 of 11 Type I EL clones became immortal compared with 1 of 10 Type II EL clones. Both parental Type I and Type II cells as well as their transformed EL clones at early passages [approximately 30 cumulative population doubling level (cpdl)] showed a low level of telomerase activity as measured by the telomeric repeat amplification protocol assay. For all 11 of the Type I EL clones and the single Type II EL clone that became immortal, telomerase activities were invariably activated at middle passages (approximately 60 cpdl) or late passages (approximately 100 cpdl). For the four Type II EL clones randomly selected from the nine Type II clones that did not become immortal, the telomerase activities were found to be further diminished at mid-passage, before the end of the life span. Thus, normal HBECs do have a low level of telomerase activity, and Type I HBECs with stem cell characteristics are more susceptible to telomerase activation and immortalization, a basis on which they may be major target cells for breast carcinogenesis.
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PMID:High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization. 1062 1


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