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)

Little is known about the the signalling pathways driving the adenoma-to-carcinoma sequence in human colonic epithelial cells. Accumulation and activation of the src tyrosine kinase in colon cancer suggest a potential role of this oncogene in this early progression. Therefore, we introduced either activated src (m-src), polyoma-MT alone or combined with normal c-src in the adenoma PC/AA/C1 cell line (PC) to define the function and phenotypic transformations induced by these oncogenes in familial adenomatous polyposis (FAP) colonic epithelial cells. Functional expression of these oncoproteins induced the adenoma-to-carcinoma conversion, overexpression of the hepatocyte growth factor (HGF) receptor Met, but failed to confer invasiveness in vivo and in vitro, or to produce alterations in cell proliferation and differentiation. In contrast, PC-msrc cells became susceptible to the HGF-induced invasion of collagen gels and exhibited sustained activation of the pp60src tyrosine kinase and Tyr phosphorylation of the 120-kDa E-cadherin, which was further increased by HGF Transcripts of HGF were clearly identified by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot in the parental and transformed PC cells, suggesting an autocrine mechanism. Taken together, the data indicate that: (1) experimental activation of src and PyMT pathways directly induces tumorigenicity and Met upregulation in a colon adenoma cell line; (2) HGF-activated Met and src cooperate in inducing invasion; (3) in view of the molecular associations between catenins and cadherin or the tumour-suppressor gene product APC, the cell adhesion molecule E-cadherin may constitute a downstream effector of src and Met.
 ...
PMID:Progression of familial adenomatous polyposis (FAP) colonic cells after transfer of the src or polyoma middle T oncogenes: cooperation between src and HGF/Met in invasion. 901 33

Colon cancer provides an attractive setting for chemoprevention trials because of the frequency and variation of familial predisposition that is observed in this malignancy. Additionally, the adenomatous polyp, the precursor of colon cancer, is a valuable intermediate marker for judging the effectiveness of candidate chemopreventive agents. Inherited colon cancer susceptibility varies from mild to severe. Conditions with extreme susceptibility include the autosomal dominantly inherited syndromes of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). These are highly penetrant syndromes with extreme cancer risk. FAP arises from mutations of the APC gene and HNPCC from mutations of the mismatch repair genes. Specific and individual genetic diagnosis is now possible in both syndromes, thus allowing identification of genetically affected individuals for chemoprevention trials. FAP accounts for less than 1% of colon cancers, while HNPCC may be present in up to 5% of cases. Familial clustering is common in the remainder of cases, which are often referred to as sporadic, but probably arise in part from inherited susceptibility. Epidemiologic studies have shown that first-degree relatives have a two- to four-fold increased risk of acquiring colon cancer compared to the general population. Ten percent of individuals in the U.S. have a first-degree with colon cancer. This clinically identifiable higher risk group thus constitutes a large potential cohort for chemoprevention trials. The common familial cases of colon cancer can be further stratified by severity. A relative diagnosed under the age of 50 or two first-degree relatives affected with colon cancer confers an even greater risk for this malignancy, estimated to be four to six times that of the general population. Adenomatous polyps also precede the development of colon cancer in these categories, thereby providing a readily identifiable clinical endpoint to judge the effectiveness of chemoprevention. It is expected that genetic markers will soon be available for more precise identification of common colon cancer susceptibility. Candidate markers include mild mutations of the APC and mismatch repair genes, glutathione transferase isoenzymes, acetylator status, and phospholipase A2 expression. Bile acid concentrations of the bowel may be genetically and/or environmentally determined and likely have a role in colon cancer susceptibility. We recently identified a large kindred with polyp and cancer susceptibility arising from a mild mutation of the APC gene. There are over 4,000 kindred members and mutational testing has demonstrated 140 gene carriers to date. We expect to institute chemoprevention trials in this kindred using adenomatous polyp number as an endpoint of effectiveness.
 ...
PMID:Cohorts with familial disposition for colon cancers in chemoprevention trials. 902 9

Colorectal cancer remains a major health problem. Few therapies are effective apart from surgery, and survival has increased little in recent years. This is despite the fact that screening by colonoscopy can potentially remove nearly all colorectal tumours before they become malignant. Molecular genetics has identified some inherited mutations (such as at APC and the mismatch repair loci) that predispose to colon cancer and some somatic mutations (such as at APC and p53) that cause sporadic colon tumours. We review the likely role of these and other genes in colorectal tumorigenesis. We also highlight areas of relative ignorance in colon cancer and emphasise that many important genes, especially those that cause invasion and metastasis, remain to be identified. Colorectal cancer is, however, a well characterised tumour, as regards both its natural history and its histopathology; there are consequently good prospects for advances in colon cancer genetics, with probable benefits for its treatment. We anticipate: (a) that new genes predisposing to colon tumours, including those conferring relatively minor risks, will be characterised; (b) genes and proteins important in invasion and metastasis will be identified; (c) the network of protein interactions in which molecules such as APC are involved will be elucidated; (d) large-scale studies of somatic mutations in tumours will provide accurate predictions of prognosis and suggest optimal therapeutic regimens; and (e) new potential targets for therapy will be identified. Whilst molecular genetics is by no means sufficient for progress in preventing and treating colon cancer, it is a necessary and central part of such advances.
 ...
PMID:Molecular genetics of colon cancer. 915 80

The APC/MCC gene (Familial Adenomatous Polyposis) at 5q21 plays a role in colon cancer carcinogenesis. LOH at this locus has also been described in gastric cancer and preneoplastic lesions. The APC locus has been recently related to a cell surface adhesion molecule and its alteration may favour metastatic dissemination. LOH at 5q21 has been associated with poor prognosis in other tumors such as lung cancer. Thirty-six gastric cancers were evaluated for LOH at 5q21 with 2 polymorphic markers from microdissected paraffin-embedded material. All tumors were classified by stage, histologic type, degree of differentiation and survival rates. In 4 cases, intestinal metaplasia cells in the adjacent mucosae were also microdissected. Six cases of moderate-severe gastric dysplasia were also added to the study. LOH was determined in 84% of the informative cases of GC, affecting both early and advanced stages of disease. Genomic instability was assessed in 5 cases, 3 of them associated with LOH. The only case of gastric cancer that did not show LOH or instability at 5q21 was a stage II, poorly differentiated intestinal carcinoma without evidence of recurrence after a 36 month follow-up period (the mean survival rate in our series was 28.3% at 36 months). We also found LOH in 2/6 dysplastic lesions and 1/4 intestinal metaplasias. Our data show that LOH at 5q21 is frequent in gastric cancer and is also present in intestinal metaplasia and dysplastic lesions. LOH at this locus is not a prognostic factor in GC in our study, due to the high incidence of LOH that we found.
 ...
PMID:LOH at the APC/MCC gene (5Q21) in gastric cancer and preneoplastic lesions. Prognostic implications. 918 90

Familial adenomatous polyposis (FAP), an autosomal dominant inherited disease, confers a high risk of colon cancer. For presymptomatic diagnosis of FAP, we performed linkage studies in three unrelated Israeli families with FAP, using seven polymorphic systems around or at the APC locus on chromosome 5q. These systems are constituted of three DNA probes, recognizing four restriction fragment length polymorphism: C11p11, YN5.48 and pi227; three cytosine-adenine repeat markers: D5S318, D5S346 and MBC; and one intragenic polymorphism: APC-SspI. A meiotic recombination event was detected, apparently between the FAP gene and probe pi227. Based on the different analysis systems, we determined the haplotype at the APC locus in 11 at-risk individuals of the three families, six of whom were found to carry the disease-linked allele. Additionally, we identified a new FAP patient, in whom sigmoidoscopy showed the presence of adenomatous polyps throughout the colon.
 ...
PMID:The use of DNA markers in the pre-clinical diagnosis of familial adenomatous polyposis. 920 21

We report a male Japanese with corticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH) associated with multiple colon adenomas/carcinomas. The plasma cortisol level was elevated with no diurnal rhythm and was not suppressed with dexamethasone. Basal plasma ACTH was unmeasurable but subnormally increased after administration of metyrapone or corticotropin releasing hormone. Both adrenals were resected and weighed 90g; the histopathologic findings were similar to those of AIMAH as previously reported. At least 21 colon lesions which were adenomas or carcinomas, were resected endoscopically or surgically. This is the second reported case of the association of AIMAH with multiple colon polyps. An APC gene point mutation was detected in the colon cancer tissue by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP)/direct sequencing analysis at the putative splice acceptor site consensus sequence. However, no abnormality of APC gene was detected in the adrenocortical hyperplastic tissue. The possible etiological coexistence of these two diseases is discussed.
 ...
PMID:Adrenocorticotropin-independent macronodular adrenocortical hyperplasia associated with multiple colon adenomas/carcinomas which showed a point mutation in the APC gene. 926 Jul 67

The discovery of a tumor suppressor gene opens a new pathway to discovery of the fundamental mechanisms that underlie tumor initiation and progression. An inherited tumor suppressor gene is of special interest in that it defines a step in the tumorigenesis pathway that can be rate limiting in development of that tumor type. In the case of colon cancer, we were fortunate in identifying an inherited tumor suppressor gene, the APC gene, that plays a major etiologic role in both the inherited disease, familial adenomatous polyposis (FAP), and in sporadic colon polyps. Characterization of the molecular biology of that gene, and the underlying mechanisms that result in the development of colon tumors, could provide new approaches to both colon cancer diagnostics, therapeutics and chemopreventives. We have embarked, therefore, on a series of exploratory studies designed to provides clues to possible functional roles for the APC protein. We have found through immunocytochemistry that APC protein is distributed throughout the cell, in both the cytoplasm and nucleus. Furthermore, within the nucleus much of the APC protein seems associated with the nucleoli. The cytoplasmic label is distributed in a punctate pattern, with concentrations at the leading edge of migrating cells at the ends of microtubules. Furthermore, following an extraction of the cells that leaves behind primarily cytoskeletal and nuclear scaffold structures, we see strong APC staining of these structures. The yeast two-hybrid system has offered a number of potentially interacting partners for APC, including a new binding site for alpha-tubulin. These results, and others recent discoveries concerning APC, suggest a rather global role for APC protein, modulating cellular activity and signal transduction pathway from the cell periphery to the nucleus.
 ...
PMID:Colon cancer. Molecular biology of the APC protein. 929 69

Most epidemiological and animal studies show a positive correlation of the dietary intake of fat with the incidence of colon cancer, whereas an inverse correlation of the dietary intake of fiber. In rats fed a diet low in fat and high in wheat bran fiber and calcium, a significant decrease was reported in the number of azoxymethane-induced aberrant crypt foci compared with those fed a high-fat, low-fiber and low-calcium diet. Mutations in the human APC gene play a key role, not only in familial adenomatous polyposis, but also in many sporadic cancers of the entire digestive tract. We previously constructed a mouse strain Apc(delta716), carrying a truncation mutation at codon 716 of the Apc gene, the homolog of human APC (10). The heterozygous mice developed numerous intestinal polyps, and all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating the loss of heterozygosity. Using these Apc(delta716) knockout mice, we have investigated the effect of a low-fat and high-fiber diet (LRD for 'low-risk' diet) on intestinal polyposis, and compared it with that of a high-fat and low-fiber diet (HRD for 'high-risk' diet). The mice were fed either diet for 7 weeks, and the number and size of intestinal polyps were scored. The LRD-fed mice had fewer polyps than the HRD-fed mice, by 36% in the small intestine and by 64% in the colon. As for the polyp size distribution, there was no significant difference between the HRD- and LRD-fed mice. These results indicate that LRD can suppress intestinal polyposis compared with HRD which does not, and suggest that its suppression is at the initiation of polyp formation. This is likely to be due to a decreased frequency of loss of heterozygosity, rather than a retarded growth of the polyp adenomas.
 ...
PMID:Suppression of intestinal polyp development by low-fat and high-fiber diet in Apc(delta716) knockout mice. 936 91

Development of colon cancer is a multistep process frequently involving mutations in both the APC and p53 tumor suppressor genes. In this study we treated the HCT-116 colon cancer cell line with alkylating agents including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG),which is known to cause colon cancer in animals, and examined the expression of both APC and p53 genes. Exposure of cells with MNNG caused an 8-12-fold increase in the level of APC mRNA and protein. APC induction was shown to result from increased nuclear transcription of the APC gene and correlated with a concomitant increase in the p53 protein level after MNNG treatment. A necessary role for p53 in APC gene regulation is supported by the failure of MNNG to induce APC expression in cell lines either expressing very low levels of p53 (HeLa cells) or no p53 (K562 erythroleukemia cells). The overexpression of wild-type p53 gene into HCT-116 cells mimicked the effect of MNNG-induced expression of APC mRNA. A direct causal role for p53 in APC gene regulation was further evaluated by transfecting the wild-type p53 gene into K562 cells and observing a 5-fold increase in the APC gene expression. These results support a model featuring a direct link between p53 and APC in response to alkylation-induced DNA damage and suggest a novel role for p53 in a stress-response pathway involving APC.
 ...
PMID:Activation of adenomatous polyposis coli (APC) gene expression by the DNA-alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine requires p53. 938 95

A previously uncharacterized yeast gene (YER016w) that we have named BIM1 (binding to microtubules) was obtained from a two-hybrid screen of a yeast cDNA library using as bait the entire coding sequence of TUB1 (encoding alpha-tubulin). Deletion of BIM1 results in a strong bilateral karyogamy defect, hypersensitivity to benomyl, and aberrant spindle behavior, all phenotypes associated with mutations affecting microtubules in yeast, and inviability at extreme temperatures (i.e., >/=37 degrees C or </=14 degrees C). Overexpression of BIM1 in wild-type cells is lethal. A fusion of Bim1p with green fluorescent protein that complements the bim1Delta phenotypes allows visualization in vivo of both intranuclear spindles and extranuclear microtubules in otherwise wild-type cells. A bim1 deletion displays synthetic lethality with deletion alleles of bik1, num1, and bub3 as well as a limited subset of tub1 conditional-lethal alleles. A systematic study of 51 tub1 alleles suggests a correlation between specific failure to interact with Bim1p in the two-hybrid assay and synthetic lethality with the bim1Delta allele. The sequence of BIM1 shows substantial similarity to sequences from organisms across the evolutionary spectrum. One of the human homologues, EB1, has been reported previously as binding APC, itself a microtubule-binding protein and the product of a gene implicated in the etiology of human colon cancer.
 ...
PMID:BIM1 encodes a microtubule-binding protein in yeast. 939 84


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