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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogenic role of estradiol on the growth of colon cancer was examined in mice. Sham-operated or ovariectomized mice were injected with cancer cells and received estradiol treatment. Tumor growth was noted: tumor weights were higher in female than male mice. The growth of the tumors was least in ovariectomized mice and highest in estradiol-treated ovariectomized mice. Tumor messenger RNA (mRNA) levels for ornithine decarboxylase (ODC) and proto-oncogenes c-myc, c-fos, and H-ras were examined. Two transcripts (2.2 and 2.7 kilobase pairs) of ODC were observed. The steady-state mRNA levels for ODC paralleled the changes observed in the weight of the tumors in all groups of animals. Less dramatic changes were observed in c-myc mRNA levels. No significant differences were observed in the mRNA levels for H-ras and c-fos. It thus appears likely that an increase in the ODC mRNA levels and, to a lesser extent, an increase in c-myc mRNA levels may be some of the important mechanisms by which estradiol mediates its growth effects on colon cancer cells in vivo.
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PMID:Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA. 145 76

We have been studying a rat model of colon cancer in which tumors are induced by direct application of N-methyl-N-nitrosourea (MNU) to discrete areas of the colonic mucosa for a limited period of time. Activation of the ras genes by point mutation has been observed in many experimental tumors, including tumors induced by MNU. To detect potential activating point mutations in the H-ras and K-ras oncogenes in MNU-induced rat colon tumors, DNA samples from 40 adenomas, nine carcinomas, and 14 histologically normal tissue samples from 14 rats--as well as from 16 foci induced on NIH3T3 cells by tumor DNAs--were amplified by the polymerase chain reaction and hybridized with allele-specific oligonucleotide probes. No H-ras point mutations were observed in any of these samples. We did detect K-ras point mutations, however, in four primary tumours--one adenoma (2.5%) and three carcinomas (33%); these mutations were all G----A transitions at the second nucleotide of codons 12 and 13. The absence of detectable ras mutations from the majority of tumors suggests that, in contrast to other animal models utilizing MNU, tumorigenesis in MNU-induced rat colon tumors may predominantly involve activation of genes other than ras.
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PMID:K-ras oncogene mutations in rat colon tumors induced by N-methyl-N-nitrosourea. 173 72

We have studied the expression of oncogene-encoded mRNAs in a rat model of colon cancer. In this model, rats are intrarectally administered several low doses of the direct-acting carcinogen, N-methyl-N-nitrosourea (MNU). Tumors, predominantly adenomas, develop 5-7 months following administration of the carcinogen, and many of these progress to carcinomas. Upon assaying the steady-state levels of oncogene-encoded transcripts in normal rat colon, we found that fos and N-myc are highly expressed; H-ras, K-ras, myc, myb, and neu messages are present at lower levels; and N-ras, abl, and raf mRNAs are absent. When we compared transcript levels in rat tumors to those in normal colons from the same animal, we observed a 2-4 fold increase in both myc- and H-ras-encoded mRNAs and a 2-7 fold increase in myb message, but no change in expression of any of the 7 other genes. To test whether this increased expression is related to tumor production or is simply a result of the more rapid cellular turnover observed in tumor tissue, the level of oncogene-encoded transcripts was assayed in colonic mucosae of rats given two treatments known to enhance cell turnover and DNA synthesis in the colon. Neither acute application of MNU nor a diet containing 1% cholic acid caused any change in the level of oncogene-encoded mRNAs in rat colons, thus suggesting that the increased abundance of myc, myb, and H-ras messages in tumors is associated with tumor formation. The enhancement of expression of these genes in adenomas, as well as in carcinomas, further suggests that these alterations occur relatively early during the tumorigenic process.
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PMID:Enhanced expression of oncogene-encoded mRNA in a rat model of colon cancer. 201 8

An increase in dietary lipid has been associated with an increase in the development of certain forms of cancer, notably breast and colon cancer, both in experimental animal studies and in human epidemiology studies. The underlying mechanisms are not, however, known with certainty. In the present studies we have examined whether certain specific fatty acids (FA) might act by enhancing the role of an activated oncogene in a model cell culture system. We found that when the rat fibroblast cell line Rat 6 was transfected with an activated human c-H-ras oncogene and the cells subsequently grown in medium supplemented with myristic acid, palmitic acid or stearic acid (20-80 microM) there was a marked enhancement of the number of transformed foci obtained. On the other hand arachidonic acid had a marked inhibitory effect in this transformation assay. However, this inhibitory effect can be partially reversed by indomethacin, an inhibitor of cyclo-oxygenase, at dose response manner. Control studies indicated that these results were not simply due to the effects of the FAs on growth of the Rat 6 cells or the process of transfection per se. Lipid analyses of cells grown in the presence of stearic acid indicated that the added FA was extensively incorporated into the major lipid classes of the cell and produced transient changes in lipid composition. This simple cell culture system may be useful for elucidating the mechanisms by which various dietary lipids and nutritional factors influence the carcinogenic process.
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PMID:Effects of specific fatty acids on cell transformation induced by an activated c-H-ras oncogene. 210 93

In the present study we used monoclonal antibodies to investigate the expression of phosphotyrosine, c-myc and c-Ha-ras proteins along the crypt continuum of normal and transformed rat colon tissue. Colon cancer was induced by administration of dimethylhydrazine. Particular attention was focused on the immunohistochemical pattern of murine colon mucosa during preneoplastic stages so as to permit the identification of putative changes in the expression/location of the oncoproteins prior to frank neoplasia. The immunohistochemical analysis of tyrosinephosphorylated proteins in the normal rat indicated that positive staining was mostly restricted to the lower colonic crypt zones. The carcinogenetic insult altered the magnitude and positional profile of phosphotyrosine along the colon crypt axis during the preneoplastic period. An intense positive reaction was observed in the upper crypt regions. Four weeks following the last DHM administration, viz. before tumor appearance, positive staining was evident in invasive adenocarcinoma tissue. In contrast to phosphotyrosine, the feeble c-myc immunohistochemical staining of normal rat colonic did not exhibit a focal topology. However, following DMH administration and prior to frank neoplasia, a substantial increase in the staining intensity for c-myc was noted, confined mostly to the supranuclear region of luminal cells. Invasive adenocarcinomas displayed intense cytoplasmic c-myc immunoreactivity. p21 c-Ha-ras expression and location along the colon crypt axis showed a different pattern when compared to p62 c-myc and phosphotyrosine. The p21 c-Ha-ras protein was prominently expressed in surface epithelium of normal and DMH-treated rats. Midcrypt colonocytes exhibited moderate p21 ras staining; in contrast, proliferating colonic cells resident in the lower crypt regions were consistently negative. These results suggest that c-Ha-ras gene product plays an important contributory role in determining the differentiated phenotype of the colonic cell.
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PMID:Phosphotyrosine, p62 c-myc and p21 c-Ha-ras proteins in colonic epithelium of normal and dimethylhydrazine-treated rats: an immunohistochemical analysis. 753 85

Knowledge about transcription factors is crucial for understanding the molecular basis of neoplasia. Homeobox-containing genes are a family of transcription factors mostly involved in normal development. Class I human homeobox-containing genes (HOX genes) are organized in four clusters on different chromosomes. The order of the genes within each cluster is highly conserved throughout evolution suggesting that the physical organization of HOX genes may be (1) essential for their expression and (2) responsible for major biological functions. We have studied HOX gene expression in several human tissues and organs as well as in their neoplastic counterparts. We have observed (a) characteristic patterns of HOX gene expression for each normal solid organ analyzed, (b) altered HOX gene expression in kidney and colon cancer, (c) a correlation between HOX gene expression and different histological types of primary small cell lung cancer (SCLC) and (d) marked alterations of HOX gene expression among primary and metastatic SCLC variant types. Furthermore, we have shown that differential patterns of HOX gene expression correlate with the adhesion profile (VLA-2, VLA-5, VLA-6 and ICAM-1) and N-RAS mutation in clonal melanoma populations isolated from a single human melanoma metastasis. This suggests that HOX genes act as a network of transcriptional regulators involved in the process of cell to cell communication during normal morphogenesis, the alteration of which may contribute to the evolution of cancer.
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PMID:HOX genes in human cancers. 765 31

Ras regulates novel patterns of gene expression and the differentiation of various eukaryotic cell types. Stable transfection of Ha-ras into the human colon cancer line CaCo2 results in the morphologic differentiation to a small bowel phenotype. The purpose of our study was to determine whether the Ras regulatory pathway plays a role in the expression of the neurotensin gene (NT/N), a terminally differentiated endocrine product specifically localized in the gastrointestinal tract to the adult small bowel. We found that CaCo2-ras cells, but not parental CaCo2, express high levels of the human NT/N gene and, moreover, that this increase in gene expression is regulated at the level of transcription. Transfection experiments using NT/N-CAT mutation constructs identify the proximal 200 bp of NT/N flanking sequence as sufficient for maximal Ras-mediated NT/N reporter gene induction. Furthermore, a proximal AP-1/CRE motif is crucial for this Ras-mediated NT/N activation. Wild-type Ha-ras induces NT/N gene expression, albeit at lower levels than activated Ras; a dominant-negative Raf blocks this NT/N induction, suggesting that Raf lies down-stream of Ras in this pathway. In addition, postconfluent cultures of CaCo2 cells, which are differentiated to a small bowel phenotype, express the NT/N gene by 6 d after reaching confluency; this increase of NT/N expression is associated with concomitant increases of cellular p21ras protein. We conclude that Ras (both wild-type and activated) enhances expression of the NT/N gene in the gut-derived CaCo2 cell line, suggesting an important role for the Ras signaling pathway in NT/N gene transcription. Our results underscore the possibility that tissue-specific genes (such as NT/N) expressed in distinct subpopulations of the gut may be subject to Ras regulation. Finally, we speculate that the NT/N gene and the CaCo2 and CaCo2-ras cell systems will provide unique models to further define the cellular mechanisms leading to mammalian intestinal differentiation.
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PMID:The neurotensin gene is a downstream target for Ras activation. 776 22

In our previous study, we demonstrated that azoxymethane (AOM) treatment significantly enhanced the expression of ras p21, the protein product of ras genes, and that the dietary administration of chemopreventive agents such as D,L-alpha-difluoromethylornithine (DFMO), a irreversible inhibitor of ornithine decarboxylase, and piroxicam, a non-steroidal anti-inflammatory drug (NSAID), exerted a significant inhibitory effect on AOM-induced ras p21 expression. In the present study, which is an extension of our earlier investigation, we have determined the effect of DFMO and piroxicam on mutational activation of ras protooncogenes during AOM-induced colon carcinogenesis. Groups of male F344 rats were fed the modified AIN-76A diet containing 0 or 150 p.p.m. piroxicam, or 4000 p.p.m. DFMO and administered s.c. AOM dissolved in normal saline at a dose rate of 15 mg/kg body wt, once weekly, for 4 weeks. Vehicle control groups received s.c. equal volumes of normal saline. Groups of animals were then killed at 0, 4, 16, 24 or 32 weeks after last AOM or saline injection. AOM-induced colon tumors and colonic mucosa from AOM treated as well as saline treated animals were analyzed for point mutations in K- and H-ras protooncogenes by a combination of polymerase chain reaction mediated restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Our results demonstrate that of the total 65 AOM-induced colon tumors analyzed, 45/50 (90%) obtained from AOM-treated animals fed the control diet, 4/11 (36%) from AOM-treated animals fed piroxicam diet, and 1/4 (25%) from AOM-treated animals fed the DFMO diet, contained single-point mutations occurring specifically at the second nucleotide of codon 12 which were identified exclusively as G to A transitions in case of K-ras, and G to A transitions and also G to T transversions in H-ras. Similar point mutations were identified in colonic mucosa of 21/30 (70%) of AOM-treated animals fed the control diet, 10/30 (33%) of AOM-treated animals fed piroxicam diet, and none of 30 (0%) of AOM-treated animals fed DFMO diet. These results indicate that the administration of piroxicam and DFMO may inhibit the selective amplification of AOM-induced initiated cells carrying mutated ras genes. Dietary DFMO exerted more pronounced inhibition of selective amplification of initiated cells containing AOM-induced mutant ras. Data suggest that determination of ras activation may be a useful marker for chemoprevention of colon cancer.
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PMID:Modulation of azoxymethane-induced mutational activation of ras protooncogenes by chemopreventive agents in colon carcinogenesis. 803 6

The process of malignant transformation can be ascribed to a series of characteristics and definable mutations of genes which encode proteins that control cell growth and differentiation. During the course of malignant transformation the cancer-related genes are altered by a variety of mechanisms including translocations, deletions, and point mutations which commonly result in the expression of aberrant proteins. Our laboratory has focused on determining the extent to which cancer-specific proteins expressed by aberrant cancer-related genes can function as tumor-specific antigens. The current paper reviews our studies with two prototype cancer-specific proteins, mutated p21ras protein and chimeric p210bcr-abl protein. Ras protooncogenes are activated by point mutation in approximately 20% of human malignancies. The mutations occur primarily at codons 12 or 61 and result in the expression of p21ras proteins with single substituted amino acids. Only a limited number of amino acid substitutions occur. Murine studies demonstrate that immunization with synthetic peptides corresponding to the mutated segment can elicit both class II restricted CD4+ helper/inducer T-cell responses and class I restricted CD8+ cytotoxic T-cell responses specific for mutated p21ras protein. In addition, the existence in vivo of tumors expressing mutated ras proteins can be detected by assaying for T-cell immunity to the mutated segment of ras protein. Preliminary human studies show that some patients with colon cancer have existent antibody responses to p21ras protein, implying the possible existence of autochthonous T-cell immunity to mutated ras proteins in those patients. In chronic myelogenous leukemia the human c-abl protooncogene from chromosome 9 is translocated to the specific breakpoint cluster (bcr) region on chromosome 22. The translocation results in the formation of a bcr-abl fusion gene that encodes at 210-kD chimeric protein. The joining region segment of chimeric bcr-abl protein is composed of a unique combination of c-abl and bcr amino acids and is expressed only by malignant cells. Studies demonstrate that immunization of mice with synthetic peptides corresponding to the joining region segment can elicit class II restricted CD4+ T-cell responses to p210bcr-abl proteins. Preliminary studies show that bcr-abl peptides can bind in the groove of both murine and human class I MHC molecules and can elicit bcr-abl peptide-specific cytotoxic T lymphocytes (CTL). Whether bcr-abl peptide-specific CTL can lyse cells expressing bcr-abl protein is a yet unknown. In summary, the results of the studies reviewed confirm that cancer-specific oncogenic proteins can serve as tumor-specific antigens.
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PMID:T-cell immunity to oncogenic proteins including mutated ras and chimeric bcr-abl. 810 58

In our attempts to evaluate the influence of chemopreventive agents on intermediate biomarkers of colon cancer, we have investigated the effect of D,L-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase and piroxicam, a non-steroidal anti-inflammatory drug (NSAID) on the expression levels of biochemically active p21ras, the protein product of cellular ras protooncogenes during the development of azoxymethane (AOM) induced colon carcinogenesis in male F344 rats in order to explore the plausibility of using p21ras as an intermediate biochemical marker of colon cancer. Groups of male F344 rats were fed the modified AIN-76A diets containing 0 or 150 p.p.m. piroxicam or 4000 p.p.m. DFMO and administered s.c. AOM dissolved in normal saline at a dose of 15 mg/kg body wt/week, once weekly, for 4 weeks. Vehicle control groups received s.c. equal vol of normal saline. Groups of animals were then killed at 0, 4, 16, 24 and 32 weeks after the last injection of AOM or saline and their colonic mucosa and tumors analyzed for biochemically active p21ras levels. AOM treatment significantly increased the expression of biochemically active p21ras. The AOM-induced expression of biochemically active p21ras was significantly suppressed by dietary DFMO and piroxicam. DFMO exerted a more pronounced inhibitory effect on AOM-induced colon tumor development as well as the expression of biochemically active p21ras. These results indicate that the determination of biochemically active p21ras may be effectively used in clinical chemoprevention trials as an intermediate end-point to monitor the colon carcinogenesis.
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PMID:Intermediate biomarkers of colon cancer: modulation of expression of ras oncogene by chemopreventive agents during azoxymethane induced colon carcinogenesis. 847 34


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