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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined tissue extracted from 19 gastric, 7 pancreatic, and 23 colorectal carcinoma specimens to determine the comparative incidence of allele loss on chromosomes 5, 17, and 18 and that of KRAS2 point mutations. Chromosome 5 allele loss occurred at the same frequency in all three gastrointestinal tumors (approximately 30%), whereas chromosome 17 and 18 allele losses were seen at a significantly lower frequency in gastric (20%) and pancreatic (0%) malignancies than in colorectal cancer (57%). Point mutations in KRAS2 were seen in 83% of pancreatic and 52% of colon cancers, but not in gastric cancer specimens. In pancreatic tumors, these mutations were always found in the second nucleotide of codon 12. In colorectal cancer, the distribution was more variable, involving the second nucleotide of codon 13 and both the first and second nucleotides of codon 12. These results suggest that inactivation of the adenomatous polyposis coli gene on chromosome 5 may be an initiating step for carcinomas of the stomach and pancreas as well as of the colon, but that the genes involved in tumor progression events may be tissue- or tumor-specific.
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PMID:Evidence for a common molecular pathogenesis in colorectal, gastric, and pancreatic cancer. 166 81

Orthotopic transplantation of human tumors in nude mice reproduces the pattern of local growth and distal dissemination. The aim of our study was to determine the pattern of genetic alterations in human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice. Eight of the sixteen orthoimplanted human pancreatic carcinomas were perpetuated through several passages. Four perpetuated tumors followed distinct patterns of distal dissemination. Point mutations in the K-ras gene, genetic aberrations in the p53 and p16 genes, and allelic losses at retinoblastoma, adenomatous polyposis coli, and deleted in colorectal cancer loci were analyzed. Perpetuated tumors maintained the pattern of genetic alterations present in primary tumors. Five perpetuated tumors contained K-ras mutations, and all tumors contained p53 and/or p16 genetic aberrations. Allelic losses were present in four of the perpetuated tumors. Additional genetic alterations were detected in 6 of 35 metastases analyzed. Five of 9 peritoneal metastases or malignant ascitic cells acquired either K-ras or second p53 mutations. In contrast, only 1 of 25 liver metastases and none of the lymph node metastases acquired additional mutations. No additional p16 gene aberrations or other allelic losses were evidenced during tumor dissemination. We conclude that orthotopically implanted pancreatic carcinomas xenografted in nude mice show a high degree of genetic stability. Mutations in K-ras and p53 genes can occur in this model system in the more advanced stages of pancreatic tumor progression, mainly during peritoneal dissemination.
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PMID:Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. 897 Nov 80

It has long been known that cell-cell adhesiveness is generally reduced in human cancers. Tumor cells are dissociated throughout the entire tumor masses of diffuse-type cancers, whereas those of solid tumors with high metastatic potentials are often focally dissociated or dedifferentiated at the invading fronts. Thus, both irreversible and reversible mechanisms for inactivating the cell adhesion system appear to exist. This paper focuses on the cadherin system, which mediates Ca2+-dependent homophilic cell-cell adhesion. The E (epithelial)-cadherin-mediated cell adhesion system in cancer cells is inactivated by multiple mechanisms corresponding to the pathological features described above. Mutations have been found in the genes for E-cadherin and its undercoat proteins, alpha- and beta-catenins, which connect cadherins to actin filaments and establish firm cell-cell adhesion. Transcriptional inactivation of E-cadherin expression was shown to occur frequently in tumor progression. E-cadherin expression in human cancer cells is regulated by CpG methylation around the promoter region. The cadherin system interacts directly with products of oncogenes, eg, cerbB-2 protein and the epidermal growth factor receptor, and of the tumor suppressor gene, adenomatous polyposis coli (APC) protein, through beta-catenin, which may be important in signal transduction pathways contributing to the determination of the biological properties of human cancers. In conclusion, inactivation of the E-cadherin system by multiple mechanisms, including both genetic and epigenetic events, plays a significant role in multistage carcinogenesis.
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PMID:Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. 970 92

The activation of beta-catenin to an oncogenic state can result from the inactivation of the tumor suppressor adenomatous polyposis coli (APC), by direct mutation in the beta-catenin gene, or by the activation of wnt receptors. Once activated, beta-catenin most likely promotes tumor progression through its persistent interaction with one or more of its numerous downstream targets.
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PMID:The oncogenic activation of beta-catenin. 1007 52

beta-catenin is a multifunctional protein, acting both as a structural component of the cell adhesion machinery and as a transducer of extracellular signals. Deregulated beta-catenin protein expression, due to mutations in the beta-catenin gene itself or in its upstream regulator, the adenomatous polyposis coli (APC) gene, is prevalent in colorectal cancer and in several other tumor types, and attests to the potential oncogenic activity of this protein. Increased expression of beta-catenin is an early event in colorectal carcinogenesis, and is usually followed by a later mutational inactivation of the p53 tumor suppressor. To examine whether these two key steps in carcinogenesis are interrelated, we studied the effect of excess beta-catenin on p53. We report here that overexpression of beta-catenin results in accumulation of p53, apparently through interference with its proteolytic degradation. This effect involves both Mdm2-dependent and -independent p53 degradation pathways, and is accompanied by augmented transcriptional activity of p53 in the affected cells. Increased p53 activity may provide a safeguard against oncogenic deregulation of beta-catenin, and thus impose a pressure for mutational inactivation of p53 during the later stages of tumor progression.
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PMID:Excess beta-catenin promotes accumulation of transcriptionally active p53. 1035 17

The interaction of the adenomatous polyposis coli (APC) tumor-suppressor protein and the intracellular cell-adhesion protein beta-catenin is crucial for the development of colorectal tumors. Since functional nuclear complexes of beta-catenin with transcription factors have been identified recently, the knowledge of level and distribution of beta-catenin in sporadic colorectal tumors will give important insights into the intracellular mechanism of sporadic colorectal tumor initiation and progression. In contrast to the familiar adenomatous polyposis syndrome and to the majority of sporadic colorectal tumors, Peutz-Jeghers (PJ) syndrome is not caused by mutations in the APC gene. Since PJ syndrome is an inherited disease with an increased risk for gastrointestinal adenocarcinoma, whether beta-catenin plays a similarly important role for the development of PJ polyps should be further investigated. For these reasons we analyzed the distribution of beta-catenin in a total of 60 sporadic colorectal tumors at different stages of progression and in 6 PJ polyps. In addition to the localization at the cell-to-cell border membranes, fluorescence immunohistochemistry revealed a nuclear accumulation of beta-catenin in single tumor cells of 10/14 small adenomas with mild dysplasia and in 14/16 adenomas with moderate dysplasia. Further tumor progression is accompanied by an expansion of cells with increased level of nuclear and cytoplasmic beta-catenin. These cells were observed in 5/16 adenomas with moderate dysplasia and in 15/15 adenomas with severe dysplasia. In all adenocarcinomas investigated, as well as in the corresponding lymph node metastases, a sub-population of tumor cells exhibited a remarkably increased level of beta-catenin within the entire cytoplasm and the nucleus. In contrast to the situation in sporadic colorectal tumors, nuclear and cytoplasmic beta-catenin was not increased in PJ polyps. These results point to an extensive redistribution of beta-catenin, which starts early in colorectal tumorigenesis. The nuclear accumulation in single cells of small adenomas can be considered as the first visible sign of the loss of APC function. Thus the immunohistochemical detection of beta-catenin distribution could serve as a criterion for estimating the malignant potential in the clinico-pathological evaluation of colon tumors during their early progression.
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PMID:Intracellular distribution of beta-catenin in colorectal adenomas, carcinomas and Peutz-Jeghers polyps. 1035 35

The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
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PMID:Colorectal cancer: molecules and populations. 1130 47

Inactivation of the adenomatous polyposis coli (APC) gene is an early event in sporadic colorectal cancer. Somatic mutations have also been detected in cancers of the stomach, pancreas, thyroid, ovary and breast. Over 95% of the mutations reported in the APC gene are frameshift and nonsense mutations. The large exon 15 accounts for 77% of the coding sequence. The APC gene product interacts with cytoplasmic beta-catenin, mediates its degradation and thereby downregulates transcription exerted by the beta-catenin-Tcf complex. In the absence of a functional APC protein, beta-catenin is stabilized and accumulates in the cytoplasm. This results in uncontrolled transcriptional activation of Tcf responsive genes which may contribute to cancer progression. In order to investigate whether this pathway is disrupted by APC mutations in breast carcinoma cells, we screened 227 breast tumors for truncating mutations in exon 15 using the protein truncation test (PTT). Only one mutation, 4678delA, which was shown to be somatic, was detected by this approach. The mutation resided just outside the mutation cluster region (MCR) and resulted in a premature stop in codon 1564. Our findings do not indicate that the suppressive function of APC is commonly abrogated by truncating mutations in human breast carcinomas.
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PMID:Truncating somatic mutation in exon 15 of the APC gene is a rare event in human breast carcinomas. Mutations in brief no. 179. Online. 1066 Mar 30

Barrett's esophagus carries a 30- to 100-fold increased risk of adenocarcinoma, which is thought to develop via a metaplasia-dysplasia-carcinoma progression. A common genetic abnormality detected in Barrett's adenocarcinoma is loss of heterozygosity (LOH) at the sites of known or putative tumor suppressor genes, of which there are at least 9 associated with esophageal adenocarcinoma. The aim of this study was to identify at which histological stage of carcinogenesis LOH at these sites occur. Microdissection of multiple paraffin-embedded tissue blocks from 17 esophagogastrectomy specimens of adenocarcinoma arising in Barrett's esophagus yielded areas of metaplasia, low-, intermediate- and high-grade dysplasia, and carcinoma. LOH analysis of microdissected tissues was performed using a double polymerase chain reaction technique with 11 microsatellite primers shown previously to have LOH in at least 30% of esophageal adenocarcinomas. Identical LOH was detected in premalignant and malignant tissues in 4 of 17 patients, and was located at 5q21-q22 (D5S346 primer), 17p11.1-p12 (TCF2 primer), 17p13.1 (TP53 primer), 18q21.1 (detected in colon cancer tumor suppressor gene [DCC] primer), and 18q23-qter (D18S70 primer). These results suggest that LOH at the sites of the DCC, adenomatous polyposis coli (APC), and TP53 tumor suppressor genes occur before the development of adenocarcinoma in Barrett's esophagus, and so merit further study as potential biomarkers of neoplastic progression in patients with Barrett's esophagus undergoing endoscopic and histological surveillance.
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PMID:LOH at the sites of the DCC, APC, and TP53 tumor suppressor genes occurs in Barrett's metaplasia and dysplasia adjacent to adenocarcinoma of the esophagus. 1066 31

Min (multiple intestinal neoplasia) mice carry a mutant allele of the murine Apc (adenomatous polyposis coli) locus and are predisposed to intestinal adenoma formation in the intestinal tract. Early studies have shown complete loss of function of Apc by whole chromosome loss on the tumor-sensitive C57BL/6J genetic background and in AKR x B6 F1 hybrids. Gamma-radiation-induced chromosomal losses focus the critical region on wt Apc, but because of the limited number of polymorphic markers used, no other critical regions of loss on chromosome 18 were identified. Using intestinal tumors arising spontaneously and induced by X-rays in CBA/H x C57BL/6J F1 hybrid mice and high-resolution microsatellite loss of heterozygosity (LOH) techniques, we provide mapping data for wt Apc loss, which confirms and extends earlier observations. In addition, high-frequency loss events at the Dpc4 locus were found in both spontaneous and radiation-induced tumors. These data identified LOH of Dpc4 as a critical secondary event following complete functional loss of Apc. LOH across the Trp53 genomic region of chromosome 11 was not observed. No LOH was recorded for the Mom1 candidate gene Pla2g2a or for 9 out of 10 polymorphic markers from the Mom1 genomic region on murine chromosome 4. One marker mapping distal to Pla2g2a showed LOH in a small minority of spontaneous tumors. These data support the contention that Mom1 does not act as a classical tumor suppressor. Overall, our data indicates a significant role for Dpc4 mutation in intestinal tumor progression in the mouse and provides further evidence for the importance of interstitial chromosome losses in radiation tumorigenesis.
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PMID:Loss of heterozygosity in spontaneous and X-ray-induced intestinal tumors arising in F1 hybrid min mice: evidence for sequential loss of APC(+) and Dpc4 in tumor development. 1086 47


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