Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.
 ...
PMID:Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. 973 99

Human colon cancer is a multistage disease which has been shown to have a number of well-defined histological and genetic events. This knowledge has identified a series of stages in the development of colon cancer in which dietary components and chemicals may play either a beneficial or detrimental role. Azoxymethane-induced colon cancer in the rat represents a way of investigating such effects on the temporal development of the disease. To assess the stages involved in the long-term development of colon cancer in this animal model, Sprague-Dawley rats were treated with either one or two (given 24 hours apart) doses of azoxymethane (15 mg/kg). These low doses were chosen in an attempt to mimic the slow development of the human disease. At varying time intervals (5-84 weeks) after treatment, animals were killed and their colons were examined for lesions. Evidence was found in the distal region of the colon of a progression from early alterations (aberrant crypt foci) to microadenomas and polyps. This progression occurs in the region where carcinomas were found. The best correlation with tumorigenicity was the multiplicity of the crypts in each focus rather than simply the number of aberrant crypt foci. The aberrant crypts were microdissected from the colon and DNA was prepared. The following genes were screened for mutation using polymerase chain reaction with single-strand conformation polymorphism, oligonucleotide hybridisation, restriction site changes and sequencing: Ki-ras (exons 1 and 2), p53 (exons 5, 6, and 7 which correspond to exons 5-8 in humans), and APC (exon 15 corresponding to the mutation cluster region in humans). Extensive studies of the aberrant crypt foci formed revealed no mutations in these lesions. These results suggest that the aberrant crypt focus may be a useful short-term preneoplastic marker. However, it is clear from this and other studies that the genetic progression in the rat may vary according to the treatment regimen used and differs from that found in human. Key genes in the development of colon cancer in the rat remain to be elucidated.
 ...
PMID:Long-term analysis of colonic aberrant crypt formation after treatment of Sprague-Dawley rats with azoxymethane. 980 74

Recent biochemical studies have demonstrated that the adenomatous polyposis coli gene, initially identified via its link to colon cancer, is expressed at high levels in the brain. Furthermore, the ability of this tumor suppressor protein to bind to Discs-Large and beta-catenin, proteins implicated in organizing synaptic structure, point to a role for APC in neuronal signalling. However, anatomical studies have provided conflicting results regarding its localization in brain. In situ hybridization studies predict neuronal expression of APC, while immunostaining studies performed with a panel of N-terminal antibodies detected staining of glial cells, especially oligodendrocytes. In this study, we have examined the basis for this discrepancy and provide evidence that the glial staining pattern detected in previous studies reflects cross-reactivity with an unrelated antigen rather than the localization of APC. Furthermore, we have performed immunohistochemical studies with a C-terminal APC antibody which reveal a neuronal pattern of staining closely matching that predicted by the in situ studies. For example, in the hippocampus APC immunostaining is detected in the pyramidal neurons and dentate granule cells, which fits well with the localization of APC mRNA. Examination of APC immunostaining in other regions revealed that particularly intense staining was displayed by large neurons, including layer V cortical pyramidal neurons, cerebellar Purkinje cells, and olfactory bulb mitral cells. Within labeled neurons, APC staining was apparent in the cytoplasm, as well as in dendritic and axonal processes. To help clarify the localization of APC in brain, we have conducted additional in situ hybridization and immunohistochemical studies. These results provide compelling evidence that APC is expressed predominantly in neurons rather than in glial cells as reported previously.
 ...
PMID:Neuronal localization of the Adenomatous polyposis coli tumor suppressor protein. 1036 23

beta-Catenin mediates the interaction of E-cadherin with alpha-catenin and the actin cytoskeleton. Recent evidence indicates that when the tumor suppressor gene APC is inactivated, beta-catenin can translocate to the nucleus, where it acts as a transcriptional regulator. Because APC is inactivated in most colorectal cancers, beta-catenin nuclear localization would be expected in these tumors. In a study of adhesion molecule expression in frozen colorectal cancer tissues, we were surprised by failure to detect nuclear beta-catenin. Here we compared the reactivity of an anti-beta-catenin monoclonal antibody with 11 colorectal cancers using immunohistochemistry on sections of frozen or paraffin-embedded samples. beta-Catenin was never detected in the nuclei of normal or tumor cells in frozen tissue sections. By contrast, in 8/11 cases it was detected in the nuclei of tumor cells but not of normal cells in paraffin-embedded tissue sections. These results were confirmed with an independent rabbit polyclonal anti-beta-catenin serum. We also examined beta-catenin distribution in SW480 colon cancer cells, in which its nuclear accumulation has been reported. As in tissues, nuclear beta-catenin was detected in paraffin-embedded but not in frozen samples. These findings are relevant because of the increasing interest in the study of beta-catenin in tumors, based on its dual role in cell adhesion and transcriptional regulation.
 ...
PMID:Nuclear beta-catenin in colorectal tumors: to freeze or not to freeze? Colon Cancer Team at IMAS. 1042 93

In patients with chronic ulcerative colitis (CUC), polypoid dysplastic lesions (PDLs) are morphologically similar to sporadic adenomas (SAs), but may be biologically distinct from them and are managed differently. p53 mutations have been shown to occur at an earlier phase in the progression of CUC-associated neoplasia when compared with sporadic colon carcinogenesis. In contrast, APC gene mutations are common and occur at an earlier stage in the development of SA. beta catenin is a cell membrane protein that accumulates in the nucleus of colon cancer cells in response to APC gene mutations. This study was performed to test the hypothesis that CUC-associated PDLs have a different molecular profile than do CUC-associated SAs and therefore may be distinguished on this basis. Mucosal biopsy specimens of 38 benign polypoid epithelial neoplasms (17 CUC-associated PDLs and 21 CUC-associated SAs) from 33 patients with CUC and 13 SAs from patients without CUC (controls) were immunohistochemically stained for p53 and beta catenin and graded as follows: 0 = no staining, 1+ = <50% of cells positive, and 2+ = > or =50% of cells positive. The results were correlated with the clinical and histologic features and compared between the two CUC-associated polyp subgroups. Overall, six (16%) polyps were p53-positive, of which five were CUC-associated PDLs (one 1+ and four 2+) and one was a CUC-associated SA (1+) (p = 0.05). Strong (2+) p53 positivity was detected, however, in only CUC-associated PDLs (4 of 5; 80%). Nine of 32 polyps evaluated for beta catenin were positive and included 1 (8%) of 12 CUC-associated PDLs and 8 (40%) of 20 CUC-associated SAs (p = 0.06). Two of the nine beta catenin polyps were strongly positive, and both were CUC-associated SAs. Non-CUC-associated (control) SAs were positive for p53 and beta catenin in 2 (15%) of 13 and 6 (46%) of 13 cases, but none in a strong (2+) fashion. No differences were observed in p53 or beta catenin staining, between CUC-associated and non-CUC-associated SAs. Neither p53 nor beta catenin expression correlated with any clinical or pathologic features, including size and degree of dysplasia of the polyps. CUC-associated PDLs and CUC-associated SAs may have a different molecular genotype. In patients with CUC, the combination of strong p53 expression and absent or weak beta catenin expression is evidence in favor of a CUC-associated PDL in diagnostically difficult lesions. Furthermore, CUC-associated and non-CUC-associated SAs have a similar P53 and beta catenin immunophenotype and thus provide evidence that they are pathogenetically related neoplasms regardless of the presence or absence of colitis.
 ...
PMID:P53 and beta catenin expression in chronic ulcerative colitis--associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study. 1043 67

A germline sequence alteration at codon 1307 of the APC gene (I1307K) has been reported in 6-7% of the Ashkenazi Jewish population in the United States. This alteration is believed to predispose the APC gene to a secondary mutation at the same locus, resulting in an increased risk of colorectal carcinoma. There is an increased risk of colorectal carcinoma in patients with inflammatory bowel disease (IBD), a relatively large proportion of whom are Ashkenazi Jews. We therefore sought to determine whether the I1307K sequence variant occurred in the germline DNA of IBD patients. To our surprise, we found this sequence in only two of 267 patients with IBD (0.7%), occurring in only 1.5% of Jewish IBD patients. The I1307K sequence variant was not found in 67 patients with esophageal cancer, 53 patients with gastric carcinoma (13 MSI-H and 44 MSI-negative), or ten patients with sporadic MSI-H colon cancer. These findings suggest that the I1307K sequence is relatively rare in the germline of Jewish as well as non-Jewish IBD patients. It does not appear to contribute to the increased colorectal cancer risk present in these patients.
 ...
PMID:Low prevalence of the APC I1307K sequence in Jewish and non-Jewish patients with inflammatory bowel disease. 1044 54

Germ-line mutations in APC and mismatch repair genes explain only a small percentage of all colorectal cancer cases. We have used the recombinant congenic strain mouse model to find new loci that are involved in the control of susceptibility to colon cancer. Five different colon cancer susceptibility genes, Scc1-Scc5, have been described previously using the recombinant congenic strains. Two of these loci, Scc4 and Scc5, show a reciprocal, genetic interaction. Here we report the mapping of four new colon tumor susceptibility genes: (a) Scc6 on chromosome 11; (b) Scc7 on chromosome 3; (c) Scc8 on chromosome 8; and (d) Scc9 on chromosome 10. Scc7 and Scc8 show a genetic interaction; Scc7 is only detected by virtue of its interaction with Scc8.
 ...
PMID:Four new colon cancer susceptibility loci, Scc6 to Scc9 in the mouse. 1048 58

Familial adenomatous polyposis (FAP) is an inherited colon cancer syndrome caused by mutations in the APC gene on chromosome region 5q21. Patients typically present with several hundred to several thousand polyps throughout the colon. Benign and malignant extracolonic manifestations are often present. Attenuated FAP (AFAP) is a recognized variant of FAP in which patients present with fewer than 100 polyps and appear to have a delayed onset of the clinical manifestations of FAP. Mutations in specific regions of the APC gene are associated with AFAP. A full deletion of the APC gene region has previously been thought to be associated with typical FAP. We now report on a 39-year-old man with a cytogenetically visible interstitial 5q deletion. Fluorescent in situ hybridization analysis with two cosmid probes specific for the 5' and 3' ends of the gene indicated that the entire APC locus is deleted. The number of polyps (50-60) seen in this patient was consistent with AFAP, as was the absence of multiple congenital hypertrophy of the retinal pigment epithelium (CHRPE). This is the first reported case of AFAP associated with a germline deletion of the entire APC gene.
 ...
PMID:Attenuated familial adenomatous polyposis in a man with an interstitial deletion of chromosome arm 5q. 1086 22

Defects in the APC-beta-catenin pathway are common in colon cancer. We investigated whether aberrant regulation of upstream ligands stimulating this pathway occur in colon cancer. Using RNAase protection analysis, six out of eight wnt genes were expressed in 14 matched cases of normal, adenomatous and malignant colorectal tissues. Wnt 2 and wnt 5a were significantly up-regulated in the progression from normal through adenoma to carcinoma. Transcripts for wnts 4, 7b, 10b and 13, but not wnt 2 and wnt 5a were detected in several colorectal cell lines. In situ hybridization demonstrated that wnt 2 and wnt 5a transcripts were mainly in the lamina propria/stroma region with labelling predominantly in macrophages. Immunostaining with CD68 confirmed the wnt-expressing cells as macrophages. These results show a major difference in wnt expression in colon cancer compared to colon adenomas and suggest stromal wnt expression may play a role in tumour progression.
 ...
PMID:Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer. 1050 76

Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.
 ...
PMID:beta-catenin signaling and cancer. 1058 Sep 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>