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

Decreased dietary intakes of calcium, vitamin D and folic acid have been suggested as risk factors for human colon cancer. We previously fed a Western-style diet (WD) containing reduced calcium, vitamin D and increased fat content to normal C57/Bl6 mice: hyperproliferation, hyperplasia and whole crypt dysplasias developed in the colon following WD administration. Utilizing the same diet, we now also decreased the levels of several nutrients that are required for biochemical reactions involving methyl group inadequacy, i.e. folic acid, methionine, choline and vitamin B(12). Dietary levels of these nutrients were reduced to nutrient-density levels approximating those consumed by large segments of human Western populations. This further modification of the WD resulted in adenoma and carcinoma development in normal mouse colon (P < 0.04 compared with AIN-76A diet). The results indicate, for the first time, that a semi-purified rodent diet designed to mimic the human Western diet can induce colonic tumors in normal mice without carcinogen exposure.
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PMID:A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. 1169 51

Low intake of folate and methionine and heavy alcohol consumption have been associated with an increased overall risk of colon cancer, possibly related to their role in methylation pathways. We estimated the relative risk (RR) of colon cancer according to a history of colorectal cancer in a first-degree relative and categories of folate, methionine, and alcohol intake in a prospective cohort study of 88,758 women who completed family history and detailed food frequency questionnaires. During 16 years of follow-up, colon cancer was diagnosed in 535 women. The inverse association of folic acid with colon cancer risk was greater in women with a family history. Compared with women who consumed 200 microg or less of folic acid/day, the age-adjusted RR of colon cancer for those who consumed >400 microg/day was 0.81 (95% confidence interval, 0.62-1.07) in women without a family history of colorectal cancer and 0.48 (95% confidence interval, 0.28-0.83) in women with a family history (P for interaction = 0.02). The influence of family history was markedly diminished by use of multivitamins containing folic acid (P for interaction = 0.04). High levels of dietary methionine also reduced the effect of family history (P for interaction = 0.05), whereas moderate to heavy alcohol consumption increased the risk associated with family history (P for interaction = 0.004). Other risk factors for colorectal cancer did not significantly modify the influence of family history. Our results suggest that higher intake of folate and methionine, regular use of multivitamins containing folate, and avoidance of moderate to heavy alcohol consumption may diminish the excess risk of colon cancer associated with a family history of the disease.
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PMID:The influence of folate and multivitamin use on the familial risk of colon cancer in women. 1189 70

Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy.
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PMID:Oncolytic reovirus against ovarian and colon cancer. 1191 42

A low intake of vegetables (but not fruit) is established as a risk factor for colon cancer. Although there are a multitude of active agents that may explain this, one important candidate is folate. Among studies specifically examining intake of folate derived from food and supplements, higher intake is generally associated with lower risk of both adenomas and cancer. Other nutrients associated with the folate pathway-methionine, vitamin B-6, vitamin B-12-or that impact the pathway-alcohol-have also been shown to influence risk in predictable ways. Polymorphisms in enzymes involved in the metabolism of folate also are associated with modification in risk, but essentially only in the presence of low intakes of folate and related nutrients. The consistency of the above evidence suggests that folate is an active agent, not just a marker for the intake of other effectors found in vegetables and multivitamin preparations. There are at least two mechanisms that may explain these findings: folate is central both to the provision of S-adenosylmethionine, the universal methyl donor, and to the provision of nucleotides for DNA synthesis and repair. Fortification of food with folate, as well as intake from multivitamin and pharmacological sources, may increasingly contribute to the primary prevention of colorectal neoplasia although it is possible that there is such a condition as having too much folate.
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PMID:Methyl supply, methyl metabolizing enzymes and colorectal neoplasia. 1216 2

Currently, selenium (in the form of high selenium containing yeast or selenomethionine) is being evaluated for anticancer effects against both human colon polyp recurrence and human prostate cancer, respectively. Chemical speciation analysis of the high selenium containing yeast indicates that selenomethionine (SeMet) is a major constituent of selenized yeast. We tested the hypothesis that SeMet might affect colon cancer cell growth by mechanisms involving cyclooxygenases (COX). The growth of all four-colon cancer cell lines tested was inhibited by selenomethionine. Furthermore, selenomethionine decreased COX-2 protein and PGE2 levels in HCA-7 cells. Selenomethionine suppressed COX-2 RNA levels in HCA-7 cells which could account for decreased COX-2 protein levels. Finally, the addition of PGE2 protected cells from the antiproliferative effects of selenomethionine in a concentration dependent manner. Selenomethionine might regulate COX-2 at the transcriptional level. These data suggests that Se-Met-induced cell growth inhibition may be, in part, mediated by COX-2 dependent mechanisms. The results of this study support the use of selenium agents in colon cancer chemoprevention trials.
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PMID:Selenomethionine inhibits growth and suppresses cyclooxygenase-2 (COX-2) protein expression in human colon cancer cell lines. 1243 49

Although many mechanisms remain unclear, a large body of evidence indicates that several dietary and lifestyle factors are likely to have a major influence on the risk of colon cancer. Physical inactivity, excess body weight, and a central deposition of adiposity are consistent risk factors. Overconsumption of energy is likely to be one of the major contributors to the high rates of colon cancer in Western countries. Beyond their influence on energy balance, the independent role of specific macronutrients remain controversial. Red meat, processed meats, and perhaps refined carbohydrates contribute to risk. Recent evidence indicate that chronic hyperinsulinemia may increase risk of colon cancer. As insulin resistance and subsequent hyperinsulinemia is induced by excess energy intake and some aspects of the Western diet (e.g., saturated fats and refined carbohydrates), insulin may be a focus of factors influencing colon cancer risk. Recent evidence also points to a role of IGF-1, but our understanding of modifiable factors that influence levels of these is poor at present. Of note is that hyperinsulinemia increases free IGF-1 exposure [25]. High alcohol consumption, probably in combination with a diet low in some micronutrients such as folate and methionine, and smoking early in life are likely to increase risk of colon cancer. Recent epidemiologic studies have tended not to support a strong influence of fiber; instead, some micronutrients or phytochemicals in fiber-rich foods may be important. Folate is one such nutrient that has received attention lately and is being studied in randomized intervention trials. Agents with chemopreventive properties, such as aspirin and postmenopausal estrogens, have potential adverse effects so a careful consideration of the risk-benefit ratio is required before general recommendations can be made. Other NSAIDs with a potential for reduced toxicity, such as celecoxib, are currently being evaluated for efficacy and toxicity. The overwhelming evidence indicates that primary prevention of colon cancer is feasible. At least 70% of colon cancers may be preventable by moderate changes in diet and lifestyle [197]. Secondary prevention, through screening by sigmoidoscopy and colonoscopy, is also critically important to prevent mortality from colon cancer; however, many of the diet and lifestyle risk factors for colon cancers are the same for cardiovascular disease and for some other cancers, so focusing on the modifiable risk factors for colon cancer is likely to have many additional benefits beyond this cancer.
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PMID:Modifiable risk factors for colon cancer. 1248 70

The RON receptor tyrosine kinase is a member of the MET proto-oncogene family that has been implicated in regulating motile-invasive phenotypes in certain types of epithelial cancers. The purpose of this study was to determine if RON expression is altered in primary human colorectal adenocarcinomas. Results from immunohistochemical staining showed that RON is highly expressed in the majority of colorectal adenocarcinomas (29/49 cases). Accumulated RON is also constitutively active with autophosphorylation in tyrosine residues. Moreover, three splicing variants of RON, namely RONdelta165, RONdelta160, and RONdelta155 were detected and cloned from two primary colon cancer samples. These RON variants were generated by deletions in different regions in extracellular domains of the RON beta chain. Functional studies showed that expression of RONdelta160 or RONdelta155 in Martin-Darby canine kidney cells resulted in increased cell dissociation (scatter-like activity). RON variants, RONdelta160 and RONdelta155, also exerted the ability to induce multiple focus formation and sustain anchorage-independent growth of transfected NIH3T3 cells. Moreover, NIH3T3 cells expressing RONdelta160 or RONdelta155 formed tumors in athymic nude mice and colonized in the lungs. These data suggest that RON expression is altered in certain primary colon cancers. Abnormal accumulation of RON variants may play a role in the progression of certain colorectal cancers in vivo.
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PMID:Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. 1252 88

It is hypothesized that diets deficient in folate, methionine, and vitamins B-6 and B-12 cause DNA hypomethylation and, as a result, increase risk of colorectal cancers. Furthermore, it is proposed that alcohol, a methyl group antagonist, increases risk of colorectal cancers among those with low intake of folate. Data from the Iowa Women's Health Study, a population-based cohort of incident cancer, were used to examine the relationship of folate, methionine, and vitamins B-6 and B-12 to occurrence of cancers of the colon (n = 598) and rectum (n = 123) over 13 yr of follow-up. There were no independent associations of folate, methionine, or vitamins B-6 and B-12 derived from a food frequency questionnaire with incidence of colon cancer. Adjusted relative risks (RRs) of rectal cancer were similar across categories of folate, vitamin B-12, and methionine intake, but RRs increased progressively with increasing intake of vitamin B-6 [P (for trend) = 0.03]. RRs suggested that incidence of cancer of the proximal colon was lower among those with 1) high folate and high vitamin B-12 intake [RR = 0.59, 95% confidence interval (CI) = 0.39-0.89] and 2) high folate and high vitamin B-6 intake (RR = 0.65, 95% CI = 0.50-0.84) than among those with the lowest intake of these nutrients. Incidence of cancer of the proximal colon was also somewhat lower among those with high folate and low alcohol intake (RR = 0.44, 95% CI = 0.22-0.89). Findings provide limited support for an association between dietary factors involved in DNA methylation and risk of cancers of the colon and rectum.
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PMID:Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. 1258 95

We have investigated the influence of Ki-ras oncogene on Met/hepatocyte growth factor (HGF) receptor signaling in human carcinoma cells. The model system used in these studies included the DLD-1 colon cancer cell line with a mutated Ki-ras allele, and the DKO-4 cell line generated from DLD-1, with its mutant Ki-ras allele inactivated by targeted disruption. These cell lines were transduced with cDNAs of either active Met receptor or dominant negative Met receptor. As compared to the DLD-1 cells, constitutive overexpression of Met receptor in this cell line (DLD-1-Met) resulted in increased tumorigenicity in SCID mice. In contrast, overexpression of Met in DKO-4 cells (DKO-4-Met) that have lost oncogenic Ras activity demonstrated suppressed tumorigenicity with respect to the parent DKO-4 cell line. Tumors formed by the DLD-1-Met cells showed increased levels of mitogen-activated protein kinase (MAPK) and lower levels of apoptosis compared to the DKO-4-Met tumors. Overexpression of the dominant negative Met receptor cDNA decreased the Met phosphorylation levels in both DLD-1 and DKO-4 cells, but only suppressed tumorigenicity in the DKO-4 cell line. In vitro, HGF stimulation of DLD-1 cells resulted in a prolonged duration of MAPK activation, while DKO-4 cells exhibited a rapid attenuation of MAPK phosphorylation. The results suggest that Ki-ras mutations and HGF signaling cooperate to enhance tumor growth by increased duration of MAPK activation and decreased apoptosis in human carcinoma cells.
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PMID:Met receptor overexpression and oncogenic Ki-ras mutation cooperate to enhance tumorigenicity of colon cancer cells in vivo. 1265 12

We report the first mutational study of thymidine kinase 1 (TK1) performed in human solid tumors. We sequenced cDNAs representing the complete coding region of TK1 in human breast (n=22) and colorectal (n=26) cancer. Codon 106 near the ATP binding site constantly differed (ATG --> GTG; Met --> Val) from the one deposited by Bradshaw and Deininger in the Genbank database (Accession number NM_003258). Silent polymorphisms at codon 11 (CCC --> CCT; Pro --> Pro) and codon 75 (GCG --> GCA; Ala --> Ala) were frequently detected in tumors as well as in normal tissues. In breast cancer the two polymorphisms were observed in 63.6% of the samples analyzed. No significant association could be found between polymorphisms and TK activity. In colorectal cancer the incidence of the two changes was 73.1% and 69.2%, respectively. Interestingly, one colon cancer with high cytosolic TK activity displayed two missense mutations located in and near the putative phosphorylation site by tyrosine kinase (s) (TAT --> CAT; Tyr --> His) and by cAMP-, cGMP-dependent protein kinase (TAC --> TGC; Tyr --> Cys), respectively; adjacent normal mucosa showed no mutation. This may open new avenues that imply TK1 activity in tumor cell proliferation.
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PMID:Mutation analysis in the coding sequence of thymidine kinase 1 in breast and colorectal cancer. 1269 56


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