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)

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.
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PMID:Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. 806 71

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon. Furthermore, a transforming growth factor beta (TGF-beta)-negative element is present in the promotor region of decorin gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 829 47

The original CA 125 serum tumor marker test is a homologous double-determinant (OC 125 monoclonal antibody based) assay for the quantification of tumor associated mucin-like CA 125 molecules present in the serum. Commercial kits, now supplied by various manufacturers (and in different versions, e.g. IRMA, EIA, etc.) are currently widely applied in the following clinical situations: (i) Monitoring of disease. Doubling or halving of CA 125 serum values correlated (in 87% of all cases) with tumor progression or regression, respectively. (ii) Early prediction of outcome. Deviation from the ideal CA 125 regression curve predicts poor outcome within 3 months of cytostatic treatment. (iii) Tumor status after completion of therapy. Patients with CA 125 > 35 U/ml have (in 95% of all cases) still tumor present (at second look surgery). However, patients with CA 125 < 35 U/ml have in 50% (mostly minimal) residual disease. (iv) Early detection of recurrence. After a complete remission, a rise in CA 125 precedes tumor recurrence in 75% of all patients, with lead times up to more then 1 year, surpassing the CT-scan in cheapness and accuracy. (v) Diagnosis and differential diagnosis. Only when used in combination with other markers, do CA 125 determinations have a value as a diagnostic adjunct in the discrimination of ovarian cancer patients from those with benign ovarian tumors and from those with advanced colon cancer. Today, optimal management of ovarian cancer patients can only be provided using the CA 125 serum test.
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PMID:CA 125 in gynecological pathology--a review. 836 5

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 850 May 99

The cytosine DNA methyltransferase (MT) enzyme, which catalyzes DNA methylation at CpG sites, is overexpressed at the mRNA level during the progressive stages of colon cancer. This paper describes the adaption of a sensitive microassay for determining MT enzyme activity during tumor progression in human colon and murine lung. MT activity was progressively elevated in mucosa from familial adenomatosis polyposis patients, mucosa adjacent to cancers, and in colonic adenocarcinomas when compared to colonic mucosa from control patients. In addition, the activity of this enzyme was increased in alveolar type II but not Clara cells isolated from A/J mice following carcinogen exposure and continued to increase during tumor progression. The use of a microassay for measuring MT activity indicates that changes in enzyme activity were in general agreement with previous findings of increased MT mRNA levels during colon cancer progression and also implicates the involvement of this pathway in lung cancer development.
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PMID:A microassay for measuring cytosine DNA methyltransferase activity during tumor progression. 859 74

Alterations of the N-linked carbohydrate core structure of cell surface glycoproteins (beta 1-6 branching) can be detected by phytohemagglutinin (PHA-L) lectin binding and has been linked to tumor progression and K-ras activation in colon cancer. The purpose of this study was to determine the prevalence of this carbohydrate alteration and its relationship to K-ras activation in pancreatic cancer. Nine human pancreatic cancer cell lines and 4 colon lines as controls were grown under standard tissue culture conditions. K-ras genome analysis was performed by polymerase chain reaction amplification and sequencing. The proportion of cellular p21-ras bound to GTP (ras-GTP level) was determined using immunoprecipitation of 32P-labeled cell lysates followed by thin layer chromatography and phosphoimaging analysis. Lectin blot analysis was performed on crude membrane preparations. Sensitivity to lectins was assessed with cell culture thymidine incorporation. Of 9 pancreatic cancer lines tested, 3 had wild type K-ras, 2 had heterozygous and 4 had homozygous mutations in codon 12 of K-ras. These genotypes correlated strongly with the level of ras-GTP measured. K-ras mutants had increased levels of ras-GTP compared to wild-type cell lines. PHA-L binding to cell membranes correlated positively with ras-GTP levels in 7 out of 9 cell lines. PHA-L toxicity was greatest in cells with positive PHA-L reactivity on Western blotting. A positive correlation between the presence of K-ras mutation, increased ras-GTP level, and increased cell surface beta 1-6 N-linked carbohydrate exists in pancreatic cancer cell lines.
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PMID:Phytohemagglutinin-L (PHA-L) lectin surface binding of N-linked beta 1-6 carbohydrate and its relationship to activated mutant ras in human pancreatic cancer cell lines. 894 26

During cancer progression, tumor cells interact with stromal cells. As a consequence, matrix metalloproteinases are produced that contribute to the degradation of the extracellular matrix. This study used coculture systems to investigate fibroblast interaction with three colon cancer cell lines isolated from a single patient. Cells from primary colorectal carcinoma, but not from corresponding liver or lymph node metastases, induced gelatinase B expression by fibroblasts of different tissue origin. Remarkably, direct cell-cell contact was required for this induction, which occurred at the pretranslational level (as revealed by Northern blot analysis) and was completely blocked by anti-beta1 integrin monoclonal antibody, but only partially blocked by anti-alpha5 or anti-alpha(v). Induction was also inhibited by cytochalasin D, staurosporine, or dexamethasone, suggesting the need, respectively, for an organized actin cytoskeleton, protein kinase C, and AP-1-driven gene transcription. Our data suggest that direct tumor-stromal cell contact is one inductive event involved in matrix metalloproteinase expression by stromal cells.
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PMID:Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. 896 8

Mismatch repair genes are the responsible genes for hereditary non-polyposis colon cancer, and mutation of these genes causes replication error (RER). In several RER-positive colon cancer cell lines, mutations of repetitive sequences of transforming growth factor beta (TGF-beta) type II receptor (RII) gene have been reported. Since TGF-beta inhibits cell proliferation, loss of response to TGF-beta is an important tumor progression step. In this study, the relationship between RER status and mutation of the RII gene was analyzed in 112 cases of various types of sporadic gastrointestinal and hepatobiliary cancer (41 with gastric, 49 with colorectal, 5 with gallbladder, and 17 with hepatic cancers). RER was found in 17 cases (4 with gastric, 12 with colorectal, and 1 with gallbladder cancer), and 10 of those (3 with gastric and 7 with colorectal cancer) showed mutations of the RII gene. Of interest was that in all seven cases with colorectal cancer, tumors were located at the cecum. These data indicate that mutation of the RII gene, presumably caused by abnormality of repair gene, play an important role in carcinogenesis of sporadic gastrointestinal cancer, especially at the cecum.
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PMID:A transforming growth factor beta type II receptor gene mutation common in sporadic cecum cancer with microsatellite instability. 897 Nov 66

The matrix-degrading metalloproteinases (MMPs) have been implicated in tumor invasion and metastasis. Recently it has become clear that the expression of MMPs in tumors is frequently localized to stromal cells surrounding malignant tumor cells. In the mouse skin model of multi-stage carcinogenesis, the MMP stromelysin is expressed in stromal fibroblast-like cells surrounding benign and malignant squamous cell carcinomas. Conversion of these tumors to highly invasive and metastatic spindle-cell tumors is however, associated with the expression of stromelysin-1 mRNA in the tumor cells themselves. The analysis of MMPs in human colon adenocarcinomas at different stages of tumor progression revealed that matrilysin was the only MMP expressed in the tumor cells, while stromelysin-1 and stromelysin-3 mRNA was detected in stromal cells surrounding malignant tumor cells. Matrilysin mRNA is detected in benign tumors as well as malignant tumor cells, and the relative level and percent of tumors expressing matrilysin correlates with the stage of tumor progression. These results suggest that both stromal and tumor cell metalloproteinases may contribute to tumor invasion and metastasis, and also suggests that MMPs may play a role in earlier events in the tumor progression pathway. A potential role for MMPs in tumor growth is illustrated by results which suggest that the expression of matrilysin in human colon cancer-derived cells increases tumorigenicity following injection into the cecum, and that transgenic mice expressing matrilysin mRNA show a marked proliferative response. MMPs may therefore play multiple roles in tumor progression.
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PMID:Matrix-degrading metalloproteinases in tumor progression. 898 72

Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in Hereditary Non-Polyposis Colorectal Cancer (HNPCC). To test that the targets of genetic instability could include critical transforming genes involved in colon tumor progression, we examined 23 colorectal carcinomas in patients with HNPCC in order to detect somatic mutations in K-ras and p53 genes. Using single strand conformation polymorphism followed by direct DNA sequencing, we detected 4 mutations in K-ras gene (17%) and 3 in p53 gene (13%) which change the amino acid sequence of the protein p53. This is significantly lower than in sporadic cancer. Our data suggest that colon cancer in HNPCC might partly involve a distinct pathogenetic mechanism that involves other genes than those altered in sporadic tumors.
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PMID:K-ras and p53 mutations in hereditary non-polyposis colorectal cancers. 903 76


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