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

Tumour formation may involve interactions between genetic factors and environmental carcinogens. Adenoma formation in APCMin/+ mice is associated homozygous adenomatous polyposis coli (APC) gene mutation, but the effects on carcinogen susceptibility are unknown. This study tests the hypothesis that APCMin/+ adenoma formation is accompanied by changes in metabolic proficiency and carcinogen susceptibility. Cytochrome P450 (CYP)1A1/1A2, glutathione S-transferase (GST)alpha, mu and pi classes and DNA adduct formation were assayed in adenomas and uninvolved mucosa from APCMin/+ mice, before and after benzo[a]pyrene (B[a]P) treatment. In untreated adenomas and mucosa, CYP1A1/1A2 and B[a]P-DNA adducts were undetected but GSTalpha, mu and pi class enzymes were constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level while GSTalpha and pi class enzymes were unaffected. A GST mu band which was absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2 and GSTalpha and pi, to high levels. B[a]P-DNA adduct levels were 56 +/- 15/10(8) nucleotides (median +/- SE) in adenomas versus 89 +/- 19/10(8) nucleotides in mucosa (P < 0.0001). APCMin adenomas show reduced bioactivation capacity and sustain less DNA damage from B[a]P exposure, than APCMin uninvolved mucosa. These properties could influence mutagenesis and subsequent neoplastic transformation of adenomas.
Carcinogenesis 1999 Jun
PMID:Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa. 1035 94

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

We examined whether the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) could increase intestinal tumorigenesis in neonatal C57BL/6J-Min/+ mice, a murine model for familial adenomatous polyposis. Min/+ mice are heterozygous for a nonsense mutation in the adenomatous polyposis coli gene and spontaneously develop multiple intestinal adenomas, primarily in the small intestine. Neonatal Min/+ mice (3-6 days old) were exposed to PhIP via breast milk from lactating dams given 8 s.c. injections of 50 mg/kg PhIP three times a week or to 8 s.c. injections of 25 or 50 mg/kg PhIP directly, over the same period. At the age of 11 weeks, the number, diameter and location of the intestinal tumors were scored. Remarkably, a 2- to 4-fold increase in the number of small intestinal tumors was seen in Min/+ mice exposed to PhIP via breast milk (P < 0.001). To our knowledge, this is the first time PhIP has been reported to induce tumors following exposure via breast milk from PhIP-exposed dams. Upon direct exposure to 50 mg/kg PhIP, a 6- to 9-fold increase in the number of small intestinal tumors was observed (P < 0.001). The diameter of the PhIP-induced small intestinal tumors was slightly increased (P < 0.001). In the colon, a 3- to 4-fold increase in the number of tumors was seen in Min/+ mice exposed to PhIP via breast milk (P = 0. 004). Direct exposure to 50 mg/kg PhIP caused a 2- to 6-fold increase in the number of colonic tumors (P = 0.014). The PhIP-induced colonic tumors were located more distally and displayed a smaller diameter than the tumors from the controls (P < 0.05). In contrast to a previous study, where PhIP showed only a moderate tumorigenic effect in adult Min/+ mice, the present study demonstrates a strong tumorigenic effect of PhIP in neonatally exposed Min/+ mice, even after exposure via breast milk from PhIP-exposed dams.
Carcinogenesis 1999 Jul
PMID:Neonatal exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine via breast milk or directly induces intestinal tumors in multiple intestinal neoplasia mice. 1038 1

An albumin-simian virus 40 (SV40) large T-antigen (T-Ag) transgenic model and a chemically induced model of multistage hepatocarcinogenesis were created in our laboratory to study the molecular mechanisms involved in the genesis and progression of neoplasia in the rat liver. In the study presented here, these two models of rat hepatocarcinogenesis were used to perform a comparative mutational analysis of three tumor suppressor genes involved in hepatic neoplastic growth. By using polymerase chain reaction-single strand conformation polymorphism analysis and sequencing, exons 5-8 of the p53 tumor suppressor gene and a region between nt 4325 and 4479 of the rat mannose 6-phosphate/insulin-like growth factor 2 receptor (M6p/Igf2r) coding sequence were screened. The latter is homologous to the human M6P/IGF2r coding sequence which is mutated in human hepatocellular carcinoma. A complete single strand conformation polymorphism analysis of the entire coding region of the rat adenomatous polyposis coli (Apc) gene was also performed for the first time in rat tumorigenic samples. Twenty-six chemically induced rat hepatocellular carcinomas, 21 neoplasms from the livers of SV40 T-Ag animals, and five immortalized hepatic cell lines from the transgenic rats were evaluated. None of the hepatic tumors exhibited mutations in the regions analyzed. The albumin-SV40 T-Ag transgenic cell line L-60, derived from normal hepatic tissue, had two mutations in contiguous codons of exon 5 of the p53 gene: a GGT --> GTT missense transversion in codon 183 and a silent mutation in codon 184. The transversion, which may affect the DNA binding domain of the p53 protein, probably originated during cell culture and may have been positively selected because it gave a growth advantage to the mutated cells. The studied region of the M6p/Igf2r gene was not found to be mutated in these two models of rat hepatocarcinogenesis. Although M6p/Igf2r, Apc, and p53 have been shown to be mutated in a variety of human hepatic proliferative diseases, our results indicate that aberrations in these genes may not be necessary for liver carcinogenesis in the rat.
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PMID:Mutational analysis of three tumor suppressor genes in two models of rat hepatocarcinogenesis. 1041 Nov 41

We have previously shown that the connexin (Cx) 26 and 32 genes are expressed during the secretory phase of the human endometrium and that their expression is downregulated during the proliferative phase, suggesting a role for intercellular transduction in cell growth control in human endometrium. To further study the possible role of cell-to-cell interaction in growth regulation, we immunohistochemically analyzed 80 endometrial samples (30 of normal endometrium, 20 of endometrial hyperplasia, and 30 of endometrial cancer) for the expression of E-cadherin; alpha-, beta-, and gamma-catenin; adenomatous polyposis coli (APC) protein, and sex-steroid hormone receptors at three points in the cells: the cell-to-cell border, the cytoplasm, and the nucleus. In this study, moderate or strong staining of beta-catenin in the nuclei was observed in 60.0% of endometrial hyperplasia samples and 30.0% of endometrial cancer samples, although the beta-catenin gene was mutated in only two of the nine samples that showed the intensive nuclear staining. Western blotting analysis showed that the samples that had intense nuclear staining of beta-catenin had much higher expression of beta-catenin than the samples that did not have nuclear staining. Furthermore, normal endometrium showed nuclear localization, especially in the mid- and late-proliferative and early-secreting phases of the menstrual cycle. The results suggest that the nuclear localization of beta-catenin observed in endometrial hyperplasia and endometrial cancer, as in other tumors, implies that beta-catenin/Wnt-1 signal transduction is highly activated in carcinogenesis of the endometrium as well as in normal physiological conditions.
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PMID:Nuclear localization of beta-catenin in normal and carcinogenic endometrium. 1041 Nov 47

Mutations in the adenomatous polyposis coli gene or activating mutations in the beta-catenin gene itself are thought to be responsible for the excessive beta-catenin signaling involved in intestinal carcinogenesis. We generated transgenic mice that expressed large amounts of a NH2-terminally truncated mutant beta-catenin (deltaN131beta-catenin) in the intestine. These mice had multifocal dysplastic lesions in the small intestine, reminiscent of the early lesions observed in the mouse models of familial adenomatous polyposis. The number of apoptotic cells in the villi of these transgenic mice was 3-4-fold higher than in nontransgenic mice. Expression of the truncated beta-catenin mutant in the kidney led to the development of severe polycystic kidney disease. Our findings support the concept that deregulation of the beta-catenin signaling pathway is the major oncogenic consequence of adenomatous polyposis coli mutations in intestinal neoplasia.
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PMID:Intestinal dysplasia and adenoma in transgenic mice after overexpression of an activated beta-catenin. 1046 73

Although the cyclooxygenase pathway of the arachidonic acid cascade has been suggested to play an important role in colon carcinogenesis, the molecular species of prostanoids and receptors involved have not been fully elucidated yet. We examined the development of aberrant crypt foci (ACFs), putative preneoplastic lesions of the colon, in two lines of knockout mice, each deficient in prostaglandin E receptors, EP1 and EP3, by treatment with the colon carcinogen, azoxymethane. Formation of ACFs was decreased only in the EP1-knockout mice to approximately 60% of the level in wild-type mice. Administration of 250, 500, or 1000 ppm of a novel selective EP1 antagonist, ONO-8711, in the diet to azoxymethane-treated C57BL/6J mice also resulted in a dose-dependent reduction of ACF formation. Moreover, when Min mice, having a nonsense mutation in the adenomatous polyposis coli gene, were given 500 ppm ONO-8711 in the diet, the number of intestinal polyps was significantly reduced to 57% of that in the basal diet group. These results strongly suggest that prostaglandin E2 contributes to colon carcinogenesis to some extent through its action at the EP1 receptor. Thus, EP1 antagonists may be good candidates as chemopreventive agents for colon cancer.
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PMID:Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. 1053 80

Mutation of the adenomatous polyposis coli (APC) gene is associated with the earliest stages of colorectal tumorigenesis and appears to be responsible for the hereditary condition familial adenomatous polyposis (FAP). Evidence indicates that cyclooxygenase-2 (COX-2) is induced and at elevated levels in human colorectal cancers and in the polyps of mouse FAP models. We have used HT-29 cells, a human colorectal carcinoma cell line with a mutant carboxy-truncated APC gene, in which intact APC gene has been introduced under the control of an inducible promoter. These HT-29-APC cells provide a suitable model system to examine how COX-2 expression becomes dysregulated after loss of APC function. Induction of full-length APC causes the HT-29-APC cells to undergo apoptosis. However, differentiation, as measured by alkaline phosphatase activity, is not induced upon expression of full-length APC. Full-length APC protein has been shown to bind the intracellular protein beta-catenin and, as a result, the Lef/Tcf transcription factors are down-regulated. Analysis of APC immunoprecipitates demonstrate a time-dependent increase of beta-catenin interacting with full-length APC. Thus, the Lef/Tcf signaling pathway is intact at this point in these cells. Furthermore, upon expression of full-length APC, COX-2 protein expression is down-regulated while COX-2 mRNA levels remain the same. These data indicate that APC plays a role, either directly or indirectly, in the translational regulation of COX-2. Treatment of the HT-29-APC cells with sodium butyrate, an inducer of apoptosis, does not alter COX-2 protein expression. Thus, COX-2 down-regulation appears to be APC specific and not just due to apoptotic induction. APC appears to uniquely regulate COX-2 expression. The mechanism by which COX-2 protein expression is down-regulated in the HT-29-APC cells is under investigation.
Carcinogenesis 1999 Nov
PMID:Introduction of full-length APC modulates cyclooxygenase-2 expression in HT-29 human colorectal carcinoma cells at the translational level. 1054 4

Wingless/Wnt signaling directs cell-fate choices during embryonic development. In Drosophila, Wingless signaling mediates endoderm induction and the establishment of segment polarity in the developing embryo. The fly Wingless cascade is strikingly similar to the vertebrate Wnt signaling pathway, which controls a number of key developmental decisions such as dorsal-ventral patterning in Xenopus. Factors of the TCF/LEF HMG domain family (Tcfs) have recently been established as the downstream effectors of the Wingless/Wnt signal transduction pathways. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic beta-catenin (or its fly homolog, Armadillo). There is also a concomitant translocation of beta-catenin/Armadillo to the nucleus, where it interacts with a specific sequence motif at the N terminus of Tcfs to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes including Siamois and Nodal related gene-3 in Xenopus, engrailed and Ultrabithorax in Drosophila via the sequence-specific HMG box, and mediates their transcriptional activation by virtue of transactivation domains contributed by beta-catenin/Armadillo. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3 beta, is activated, which mediates the downregulation of cytoplasmic beta-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear beta-catenin, the Tcfs recruit the corepressor protein Groucho to the target gene enhancers and actively repress their transcription. An additional corepressor protein, CREB-binding protein (CBP), may also be involved in this repression of Tcf target gene activity. Several other proteins, including adenomatous polyposis coli (APC), GSK3 beta, and Axin/Conductin, are instrumental in the regulation of beta-catenin/Armadillo. In APC-deficient colon carcinoma cell lines, beta-catenin accumulates and is constitutively complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/beta-catenin complexes as a result of dominant mutations in the N terminus of beta-catenin that render it insensitive to downregulation by APC, GSK3 beta, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc. Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression as a result of constitutive Tcf-4/beta-catenin activity promotes uncontrolled intestinal cell proliferation. This would readily explain the formation of intestinal polyps during colon carcinogenesis. Similar mechanisms leading to deregulation of Tcf target gene activity are likely to be involved in melanoma and other forms of cancer.
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PMID:The Yin-Yang of TCF/beta-catenin signaling. 1054 54

Several lines of evidence indicate that beta-catenin acquires oncogenic activity when its intracellular concentration increases as a result of either mutation in the beta-catenin gene itself or inactivation of the adenomatous polyposis coli (APC) gene. In an attempt to elucidate the molecular mechanisms underlying hepatocellular carcinogenesis, we have studied the frequency of beta-catenin gene alterations in exon 3, a region known to represent a mutation hot spot, and its inappropriate protein expression by immunohistochemistry in 73 hepatocellular carcinomas (HCCs). The results were correlated with different clinical and pathological data, particularly with the presence or not of an associated cirrhosis. Fourteen (19%) HCCs showed beta-catenin gene alterations with missense mutations in nine cases and interstitial deletions in five cases. These genetic alterations were present in both cirrhotic and non-cirrhotic groups. By contrast, we did not find any beta-catenin gene alterations in the nine fibromellar carcinomas we examined. Nuclear accumulation of the protein was observed in 18 of them (25%). Remarkably, these included ten of the 14 tumors harboring somatic mutations in the beta-catenin gene (P < 0.001). Our results indicate that accumulation of beta-catenin resulting from genetic mutations is a frequent event in non-fibrolamellar type hepatocellular carcinoma. The close association between increased beta-catenin protein stability and mutation indicates that immunohistochemistry may be a powerful method for the detection of the mutated protein in future clinical practice.
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PMID:Close correlation between beta-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. 1059 62


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