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)

Genetic instability is closely correlated to the pathogenesis of hereditary non-polyposis colon cancer (HNPCC), which is clinically characterized by a family history and early onset. To investigate the role of genetic instability in young patients with colorectal cancer (CRC), 22 CRC patients, who were aged younger than 30 at the time of diagnosis, were studied. Patients with familial adenomatous polyposis were excluded. Among the 22 cases, seven were identified as microsatellite instability positive (MI+), and more than five microsatellite markers among the 15 tested markers showed an additional band pattern in the tumor tissue. None of the remaining 15 cases showed instability in any microsatellite marker. Two of seven MI+ cases were classic HNPCC. While all MI+ cases had one or no metastatic lymph node, 53.3% of MI- cases showed metastasis in two or more regional lymph nodes. Allelic deletion of the 17p12-13 chromosome around the p53 locus occurred in 16.7% of MI+ cases, and 80.0% of MI- cases showed loss of heterozygosity at that locus. hMSH2 Protein expression, assessed by immunohistochemistry, was absent in two cases, both of which were MI+. When we tested two to four sites of MI+ tumors, transforming growth factor beta receptor type II was mutated in a homogeneous pattern in five MI+ cases. In addition, frame-shift mutations of BAX, insulin-like growth factor II receptor, hMSH3 and hMSH6 were found in three cases, five cases, five cases and one case, respectively. In contrast to the consistent mutation of the transforming growth factor-beta receptor type II gene, mutations of other genes varied in different portions of the tumors.
 ...
PMID:Microsatellite instability in young patients with colorectal cancer. 973 5

We investigated the action of a protein-bound polysaccharide, PSK, on transforming growth factor-beta (TGF-beta). (1) In in vitro-mixed culture of peripheral blood mononuclear cells (PBMC) from healthy human and mitomycin C-treated human colon cancer cells, PSK or polyclonal antibody to TGF-beta significantly enhanced incorporation of 3H-thymidine into PBMC, and apparently decreased TGF-beta1 levels of acid-treated culture supernatant. (2) PSK or the antibody interfered with the quantitation by enzyme immunoassay of TGF-beta1 in acid-treated supernatant of the mixed culture. (3) PSK was suggested to form a complex with 125I-human recombinant TGF-beta1 standard, when changes in molecular weight of radioactivities were assessed by gel filtration. Recombinant human TGF-beta1 inhibited growth of mink lung epithelial cell line Mv1Lu and promoted collagen synthesis in rat kidney fibroblast cell line NRK49F, but the complex did not have such activities. (4) In addition to TGF-beta1, PSK bound with TGF-beta2 and platelet-derived growth factor; however, PSK did not bind with 22 other species of cytokines and growth factors. (5) Protein moiety of PSK is suggested to play an important role in the expression of the activity. These results suggest that PSK modulates the biological activity of TGF-beta1 by binding to its active form.
 ...
PMID:Direct action of a protein-bound polysaccharide, PSK, on transforming growth factor-beta. 985 65

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
 ...
PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

Many colorectal cancer cells are resistant to the anti-proliferative effects of transforming growth factor-beta (TGF-beta). TGF-beta also acts as paracrine factor from cancer cells on their mesenchymal cells. The aim of this study was to examine the expression of TGF-beta and its receptors in human colorectal cancer tissue and determine any relationship with cancer growth. In situ hybridization and Northern blot hybridization detection of TGF-beta1, type I and type II receptor mRNA and immunohistochemical staining of TGF-beta1 were performed using 11 human colorectal adenomas, 22 colorectal cancers and ten normal colorectal mucosas as control. TGF-beta receptor mRNAs were expressed mainly by normal colorectal epithelial cells and adenoma. However, mRNAs for TGF-beta receptors were only faintly, if at all, expressed in eight of 22 human colorectal cancers. In addition, intense signals of TGF-beta1 mRNA and the protein were detected in all colorectal cancers. TGF-beta receptor mRNAs and TGF-beta1 protein were also distributed in fibroblasts and endothelial cells in the interstitium. Moreover, Smad 4 protein was translocated to nucleus in primarily cultured adenoma cells, but not in cancer cells after TGF-beta stimulation. The escape of human colon cancer from TGF-beta-mediated growth inhibition by down-regulation of TGF-beta receptors as well as the effects of TGF-beta on stroma formation and angiogenesis indicate a possible role for TGF-beta in the progression of colon cancer in an intact host.
 ...
PMID:Down-regulation of TGF-beta receptors in human colorectal cancer: implications for cancer development. 1038 96

Smad4/DPC4 is a tumor suppressor gene frequently mutated or deleted in pancreatic and metastatic colon cancers. Smad4 acts as a cofactor that binds transforming growth factor-beta (TGF-beta) receptor-activated Smad2 and Smad3 generating transcriptional complexes. Using SW480.7 colon carcinoma cells, defective in Smad4 function, we have investigated whether this loss plays a role in the resistance of colon cancer cells to the antiproliferative effects of TGF-beta. SW480.7 cells contain only one Smad4 allele, which we found encodes a wild type protein that is not expressed. We generated SW480.7 cells conditionally expressing Smad4 via an ecdysone-inducible system. Smad4 expression in these cells failed to rescue TGF-beta antiproliferative and gene responses (c-myc down-regulation and induction of p21/Cip1 and plasminogen activator inhibitor-1). SW480.7 cells contain an activated Ki-ras oncogene. Hyperactivation of Ras can inhibit Smad nuclear accumulation by their phosphorylation at mitogen-activated protein kinase sites. Co-transfection into SW480.7 cells of Smad4 together with a Ras phosphorylation-resistant Smad3 (but not with wild type Smad2, Smad3, adenomatous polyposis coli (APC), or TGF-beta type II receptor) restored the TGF-beta antiproliferative response. These results suggest that loss of Smad4 function by both deletion and silencing and inhibition of Smad2/3 function by a hyperactive Ras pathway jointly prevent TGF-beta antiproliferative responses in SW480.7 colon cancer cells.
 ...
PMID:Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factor-beta antiproliferative responses in colon cancer cells. 1055 52

IL-10 modulation of human intestinal T lymphocyte functions was studied for the first time. Lymphocyte proliferation was determined by 3H-thymidine incorporation; cytokine production, by ELISA; expression of surface markers, by immunofluorescence and flow cytometric analysis; and cytotoxicity, by lysis of 51Cr-labelled target cells. IL-10 blocked phytohaemagglutinin (PHA)-induced activation and proliferation of CD8+ T cells from the epithelium and lamina propria. It was a greater inhibitor of IL-2, interferon-gamma, and tumour necrosis factor-alpha production than were IL-4 or transforming growth factor-beta. In contrast, IL-10 enhanced IL-2-stimulated proliferation of both CD4+ and CD8+ T cells by increasing cell division after activation. It also augmented IL-2- but not IL-15-induced cytotoxicity of intestinal lymphocytes against colon cancer by a mechanism independent of natural killer cells. In conclusion, IL-10 blocking of proinflammatory cytokine secretion probably reduces intestinal inflammation. IL-10 augmentation of IL-2-induced cytotoxicity may help to maintain host defence.
 ...
PMID:IL-10 enhances IL-2-induced proliferation and cytotoxicity by human intestinal lymphocytes. 1069 13

We investigated facilitation of invasion by growth factors and chemotactic factors in tumor cell lines, particularly hepatocellular carcinoma. Hepatoma cells (PLC/PRF/5 and Hep G2) showed strong chemotaxis toward their respective conditioned media while metastatic pancreatic cancer cells (SU.86.86) and colon cancer cells (LS 174T) did not migrate toward their respective conditioned media. Based on immunoblotting, PLC/PRF/5 cells secrete fibronectin (an extracellular matrix constituent), transforming growth factor-beta (TGFbeta; a growth factor), and cathepsin D (a protease). Fibronectin induced a migratory response in PLC/PRF/5 cells, and anti-fibronectin antibody abolished the migratory response of these cells to their conditioned medium. Anti-integrin-beta(1) antibody also impeded migration of these cells toward conditioned medium. Polyclonal anti-TGFbeta antibody and protease inhibitors (alpha(2)-macroglobulin and leupeptin) added to culture media-modulated secretion of fibronectin by PLC/PRF/5 cells. Although exogenous TGFbeta suppressed SU.86.86 cells, it enhanced PLC/PRF/5 cell adhesion to substrate, increasing viable cell numbers. These actions indicate that hepatocellular carcinoma may possess a forceful autocrine mechanism enabling cells to survive and proliferate under cirrhotic conditions.
 ...
PMID:Secretion of extracellular matrix (fibronectin), growth factor (transforming growth factor beta) and protease (cathepsin D) by hepatoma cells. 1076 30

MCF-7E breast cancer cells express transforming growth factor-beta (TGF-beta) receptors RI and RII in comparison to MCF-7L cells. We present data showing that Sp3 acts as a transcriptional repressor of RI and RII in MCF-7L cells and GEO colon cancer cells. MCF-7L and GEO cells express high levels of Sp3 protein. Gel shift analysis indicated enhanced binding of Sp3 from MCF-7L cells to a consensus Sp1 oligonucleotide. Southwestern data indicated increased binding of Sp3 to RI and RII promoters in MCF-7L cells, suggesting a correlation between Sp3 binding and reduced expression of TGF-beta receptors in MCF-7L cells. Cotransfection of CMV-Sp3 cDNA with RI and RII promoter-luciferase reporter constructs decreased RI and RII promoter activities by 70% in MCF-7E and GEO cells. Southwestern analysis detected the binding of transiently expressed Sp3 to RI and RII promoters in MCF-7E cells. Significantly, ectopic Sp3 expression led to repression of RI and RII transcripts in MCF-7E cells. This report demonstrates that inappropriate overexpression of Sp3 is a mechanism that contributes to repression of TGF-beta receptors.
 ...
PMID:Sp3 is a transcriptional repressor of transforming growth factor-beta receptors. 1102 77

Previous studies by our laboratory have shown that a noncalcemic fluorinated analog of 1alpha,25-dihydroxyvitamin D3, 1alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholcal ciferol (F6-D3), significantly reduced the frequency of colonic adenomas and completely abolished the development of colonic adenocarcinomas in rats treated with azoxymethane. The mechanisms involved in this analog's chemopreventive actions, however, remain unclear. In the present study, we now show that although both 1alpha,25-dihydroxyvitamin D3 and F6-D3 inhibited the proliferation of CaCo-2 cells, a human colonic adenocarcinoma cell line, by increasing their doubling times, only F6-D3 caused an arrest of these cells in the G1 phase of their cell cycle. This arrest was accompanied by an increase in the expression of the cyclin-dependent kinase (cdk) inhibitor proteins, p2Waf1 and p27Kip1, which served to decrease the activity of cyclin-dependent kinase 2 and cyclin-dependent kinase 6, whereas the expression and phosphorylation of pRB were unchanged. In contrast to the increased expression of these cdk inhibitors, the expression of cyclin E was decreased, which further inhibited the activity of cyclin-dependent kinase 2. Collectively, the inhibition of these cyclin-dependent kinases served to arrest the CaCo-2 cells, independent of changes in pRB. Furthermore, antibody neutralization studies suggest that transforming growth factor-beta may mediate the coassociations between cdk2 and p27Kip1 and cyclin E induced by F6-D3. These data indicate that cell cycle arrest may, at least in part, underlie the chemopreventive actions of F6-D3 observed in the azoxymethane model of colon cancer. Furthermore, if the antiproliferative action observed in CaCo-2 cells also occurs in human colonic epithelium, F6-D3 may have chemopreventive potential against human colon cancer, as well.
 ...
PMID:A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: roles of cyclin E, p21Waf1, and p27Kip1. 1108 22

Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8% versus 36.9%, P: < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P: < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P: < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats.
 ...
PMID:Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer. 1129 May 69


<< Previous 1 2 3 4 5 Next >>